Pei-Ling Chen

T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. We show that loss of PTEN in tumor cells in preclinical models of melanoma inhibits T cell-mediated tumor killing and decreases T-cell trafficking into tumors. In patients, PTEN loss correlates with decreased T-cell infiltration at tumor sites, reduced likelihood of successful T-cell expansion from resected tumors, and inferior outcomes with PD-1 inhibitor therapy. PTEN loss in tumor cells increased the expression of immunosuppressive cytokines, resulting in decreased T-cell infiltration in tumors, and inhibited autophagy, which decreased T cell-mediated cell death. Treatment with a selective PI3Kβ inhibitor improved the efficacy of both anti-PD-1 and anti-CTLA-4 antibodies in murine models. Together, these findings demonstrate that PTEN loss promotes immune resistance and support the rationale to explore combinations of immunotherapies and PI3K-AKT pathway inhibitors.This study adds to the growing evidence that oncogenic pathways in tumors can promote resistance to the antitumor immune response. As PTEN loss and PI3K-AKT pathway activation occur in multiple tumor types, the results support the rationale to further evaluate combinatorial strategies targeting the PI3K-AKT pathway to increase the efficacy of immunotherapy.

Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

Immune checkpoint blockade represents a major breakthrough in cancer therapy; however, responses are not universal. Genomic and immune features in pretreatment tumor biopsies have been reported to correlate with response in patients with melanoma and other cancers, but robust biomarkers have not been identified. We studied a cohort of patients with metastatic melanoma initially treated with cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) blockade (n = 53) followed by programmed death-1 (PD-1) blockade at progression (n = 46), and analyzed immune signatures in longitudinal tissue samples collected at multiple time points during therapy. In this study, we demonstrate that adaptive immune signatures in tumor biopsy samples obtained early during the course of treatment are highly predictive of response to immune checkpoint blockade and also demonstrate differential effects on the tumor microenvironment induced by CTLA4 and PD-1 blockade. Importantly, potential mechanisms of therapeutic resistance to immune checkpoint blockade were also identified.These studies demonstrate that adaptive immune signatures in early on-treatment tumor biopsies are predictive of response to checkpoint blockade and yield insight into mechanisms of therapeutic resistance. These concepts have far-reaching implications in this age of precision medicine and should be explored in immune checkpoint blockade treatment across cancer types. Cancer Discov; 6(8); 827-37. ©2016 AACR.See related commentary by Teng et al., p. 818This article is highlighted in the In This Issue feature, p. 803.

Immune checkpoint blockade produces clinical benefit in many patients. However, better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1) and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T cell receptor sequencing and whole-exome sequencing within the same cohort and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of CNAs identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.

Anaplastic lymphoma kinase (Alk) has been proposed to regulate neuronal development based on its expression pattern in vertebrates and invertebrates; however, its function in vivo is unknown. We demonstrate that Alk and its ligand Jelly belly (Jeb) play a central role as an anterograde signaling pathway mediating neuronal circuit assembly in the Drosophila visual system. Alk is expressed and required in target neurons in the optic lobe, whereas Jeb is primarily generated by photoreceptor axons and functions in the eye to control target selection of R1-R6 axons in the lamina and R8 axons in the medulla. Impaired Jeb/Alk function affects layer-specific expression of three cell-adhesion molecules, Dumbfounded/Kirre, Roughest/IrreC, and Flamingo, in the medulla. Moreover, loss of flamingo in target neurons causes some R8-axon targeting errors observed in Jeb and Alk mosaic animals. Together, these findings suggest that Jeb/Alk signaling helps R-cell axons to shape their environment for target recognition.

Appreciation for genomic and immune heterogeneity in cancer has grown though the relationship of these factors to treatment response has not been thoroughly elucidated. To better understand this, we studied a large cohort of melanoma patients treated with targeted therapy or immune checkpoint blockade (n = 60). Heterogeneity in therapeutic responses via radiologic assessment was observed in the majority of patients. Synchronous melanoma metastases were analyzed via deep genomic and immune profiling, and revealed substantial genomic and immune heterogeneity in all patients studied, with considerable diversity in T cell frequency, and few shared T cell clones (<8% on average) across the cohort. Variables related to treatment response were identified via these approaches and through novel radiomic assessment. These data yield insight into differential therapeutic responses to targeted therapy and immune checkpoint blockade in melanoma, and have key translational implications in the age of precision medicine.

Abstract Purpose: Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes. Experimental Design: IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm2) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs. Results: No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3+ (P = 0.004) and CD8+ (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8+ T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3+ (P = 0.026) and CD8+ (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV+ but not MCPyV− MCC. TCRseq revealed clonal overlap among MCPyV+ samples, suggesting an antigen-specific response against a unifying antigen. Conclusions: These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 22(22); 5553–63. ©2016 AACR.

Abstract Nowadays, cell membrane‐targeted therapy, which owns high antitumor efficacy by avoiding cell barriers, has received great attention. Here, a cell membrane‐targeted self‐delivery theranostic chimeric peptide CMP‐PpIX is designed for simultaneously targeted photodynamic therapy (PDT) of tumor and real‐time therapeutic feedback. Self‐assembled CMP‐PpIX nanoparticles can effectively accumulate in tumor by enhanced permeability and retention effect without additional vector. And this chimeric peptide CMP‐PpIX has low background fluorescence, which is due to its relatively high intramolecular Förster resonance energy transfer (FRET) quenching efficiency between 5(6)‐carboxyfluorescein (FAM) and 4‐(dimethylaminoazo)‐benzene‐4‐carboxylic acid (Dabcyl). More importantly, CMP‐PpIX can be anchored on the tumor cell membrane for more than 8 h. Under irradiation, reactive oxygen species produced by CMP‐PpIX directly damage cell membrane and rapidly induce apoptosis, which significantly improve the efficacy of PDT in vitro and in vivo. Then, peptide sequence Asp‐Glu‐Val‐Asp (DEVD) is subsequently cleaved by activated caspase‐3 and activated caspase‐7, which separates the FAM and Dabcyl and terminates the FRET process. Therefore, fluorescence of FAM is recovered to monitor the expression of activated caspase‐3 in vitro and in vivo to feedback real‐time PDT therapeutic efficacy. In general, a novel cell membrane‐targeted self‐delivery theranostic chimeric peptide offers new promise for effective imaging‐guided PDT.

The NCCN Guidelines for Squamous Cell Skin Cancer provide recommendations for diagnostic workup, clinical stage, and treatment options for patients with cutaneous squamous cell carcinoma. The NCCN panel meets annually to discuss updates to the guidelines based on comments from panel members and the Institutional Review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new surgical recommendation terminology (peripheral and deep en face margin assessment), as well as recent updates on topical prophylaxis, immunotherapy for regional and metastatic disease, and radiation therapy.

Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs); thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the major histocompatibility complex (MHC)-II protein HLA-DRB1 in melanoma cells, triggering CD4+ T cell-mediated increases in itICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-programmed cell death protein 1 (PD1) responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity and, importantly, suggest that L-fucose is a powerful agent for safely increasing itICs and immunotherapy efficacy in melanoma.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS-mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CAE545K mutation as conferring drug resistance. We demonstrate that PIK3CAE545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CAE545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CAE545K-induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways.Significance: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CAE545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CAE545K-expressing NRAS-mutant melanoma cells to MEKi + CDK4i. Cancer Discov; 8(5); 556-67. ©2018 AACR.See related commentary by Sullivan, p. 532See related article by Teh et al., p. 568This article is highlighted in the In This Issue feature, p. 517.

Cellular barriers such as the cell membranes, lysosomes or nuclear pores of tumor cells hinder the drugs delivery and weaken the efficiency of traditional tumor therapies. Targeted destructing tumor cell membranes can quickly destroy cell homeostasis and kill cells without facing intracellular delivery barriers. Herein, we designed a self-delivery phototherapeutic chimeric peptide (CCP) for high efficient cell membrane-targeting combinational low-temperature photothermal therapy (LTPTT) and photodynamic therapy (PDT). The self-assembled CCP nanoparticles display remarkable tumor accumulation after systemic administration without additional carriers, avoiding the carriers related side toxicities. The CCPs are able to generate reactive oxygen species (ROS) and mild heat (<45 °C) locally at cell membrane and quickly induce immunogenic cell death to achieve efficient combinational LTPTT/PDT. The damage-associated molecular patterns released after cell membrane rupture effectively elicit antitumor immunity to eradicate residual tumor cells. With a single dosage and short-term near-infrared (NIR) light irradiation, CCPs significantly inhibit growth and metastasis of tumor, and prolong survival time of tumor-bearing mice. This work presents a unique cell membrane-targeting phototherapy strategy to kill tumor and suppress metastasis in an effective, safe and minimally invasive manner.

Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided in situ evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74.Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma. This article is highlighted in the In This Issue feature, p. 1171.

<h2>Summary</h2> Quantitative differences in cadherin activity have been proposed to play important roles in patterning connections between pre- and postsynaptic neurons. However, no examples of such a function have yet been described, and the mechanisms that would allow such differences to direct growth cones to specific synaptic targets are unknown. In the <i>Drosophila</i> visual system, photoreceptors are genetically programmed to make a complex, stereotypic set of synaptic connections. Here we show that the atypical cadherin Flamingo functions as a short-range, homophilic signal, passing between specific R cell growth cones to influence their choice of postsynaptic partners. We find that individual growth cones are sensitive to differences in Flamingo activity through opposing interactions between neighboring cells and require these interactions to be balanced in order to extend along the appropriate trajectory.

k-truss, a type of cohesive subgraphs of a network, is an important measure for a social network graph. However, with the emergence of large online social networks, the running time of the traditional batch algorithms for k-truss decomposition is usually prohibitively long on such a graph with billions of edges and millions of vertices. Moreover, the size of a graph becomes too large to load into the main memory of a single machine. Currently, cloud computing has become an imperative way to process the big data. Thus, our aim is to design a scalable algorithm of k-truss decomposition in the scenario of cloud computing. In this paper, we first improve the existing distributed k-truss decomposition in the MapReduce framework. We then propose a theoretical basis for k-truss and use it to design an algorithm based on graph-parallel abstractions. Our experiment results show that our method in the graph-parallel abstraction significantly outperforms the methods based on MapReduce in terms of running time and disk usage.

Sentinel lymph node evaluation is a critical component of melanoma staging, and lymph node status provides one of the most powerful predictors of melanoma recurrence and survival. One of the well-known diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi, which has been demonstrated in up to 26% of lymphadenectomy specimens and specifically in melanoma patients. Melanocytic markers enhance the sensitivity of melanoma detection in sentinel lymph nodes. However, established markers such as anti-melan-A/MART1, S100 protein and SOX10 antibodies cannot discriminate melanoma metastasis from nodal nevi. Recent studies have demonstrated strong expression of neural stem/progenitor cell markers nestin and SOX2 in melanoma. In this study, we tested the diagnostic utility of nestin and SOX2 in differentiating metastatic melanomas from nodal nevi. Twenty-three lymph nodes with metastatic melanomas and 17 with nodal nevi were examined. Of the 23 metastatic melanomas, 18 showed diffuse and strong (3+) nestin, 4 showed rare cells with strong (3+) nestin, and one showed diffuse but faint (1+) nestin staining. Nuclear SOX2 was positive in 13 metastatic melanomas. In contrast, 15 nodal nevi showed no nestin, and 2 showed rare cells with very faint (<1+) nestin staining. SOX2 was negative in 13 nodal nevi. Overall, nestin was strongly expressed in metastatic melanomas (n=22/23; 96%), but not in nodal melanocytic nevi (n=15/17; 88%; P<0.0001). SOX2 was also expressed in metastatic melanomas (n=13/23; 57%) but not in the majority of nodal melanocytic nevi (n=13/16; 81%; P=0.02). In one lymph node harboring metastatic melan-A-negative desmoplastic melanoma, nestin and SOX2 strongly highlighted the infiltrating tumor cells, suggesting the potential clinical value of these two markers in desmoplastic melanoma lymph node biopsies. This study provides evidence that nestin and SOX2 can effectively differentiate nodal melanocytic nevi from metastatic melanomas and serve as powerful diagnostic adjuncts in melanoma staging.

A palladium-catalyzed C–H bond activation reaction, via a redox-neutral pathway, for the preparation of dihydrophenanthridine, phenanthridine, and carbazole derivatives from biaryl 2-iminoquinones is developed. The preinstalled iminoquinone was designed to act as a directing group for ortho C–H activation and an internal oxidant or a co-oxidant. This catalysis proceeded through the following sequence: C–H bond activation, coordination and insertion of activated olefins, β-hydride elimination, H-shift, insertion, and protonation or β-hydride elimination. In addition, carbazoles can be prepared efficiently by using this method without the addition of external oxidants.

The impact of intrinsic amorphous silicon bilayers in amorphous silicon/crystalline silicon (a‐Si:H/c‐Si) heterojunction solar cells is investigated. Intrinsic a‐Si:H films with a wide range of film densities and hydrogen contents are prepared via a plasma‐enhanced chemical vapor deposition (PECVD) technique by modifying various process parameters. For silicon heterojunction (SHJ) solar cells with a‐Si:H films applied as single i‐layers, the resulting surface passivation at the a‐Si:H/c‐Si interface is poor. However, surface passivation is significantly improved by applying intrinsic bilayers, which are composed of a porous interfacial layer (≈2 nm) and an overlying dense layer (≈8 nm). The microstructure factor R * of the interfacial a‐Si:H layer, which is related to the SiH bond microstructure and determined by infrared absorption spectroscopy, closely correlates to the surface passivation capability of the bilayers. A variety of PECVD process parameters (temperature, pressure, or precursor gas species) can be utilized to grow an interfacial layer for good surface passivation, provided that its R * is controlled within a suitable range. This indicates that R * is a key universal parameter for optimizing i‐bilayers and realizing high‐efficiency SHJ solar cells.

Primary cutaneous lymphomas are a rare group of diseases, with an estimated incidence of 0.5–1 case per 100,000 people per year. Primary cutaneous B-cell lymphomas (pCBCLs) represent 25–30% of all primary cutaneous lymphomas. There are three main subtypes of pCBCL: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type. Cutaneous B-cell lymphomas have a broad spectrum of clinical presentations, which makes diagnostic and therapeutic strategies challenging. To date, treatment recommendations for cutaneous B-cell lymphomas have been largely based on small retrospective studies and institutional experience. Recently, the pharmacotherapeutic landscape has expanded to include drugs that may modify the underlying disease pathology of pCBCLs, representing new therapeutic modalities for this rare group of diseases. Novel therapies used for other systemic B-cell lymphomas show promise for the treatment of pCBCLs and are being increasingly considered. These new therapies are divided into five main groups: monoclonal antibodies, immune checkpoint inhibitors, small-molecule inhibitors, bispecific T-cell engaging, and chimeric antigen receptor T cell. In this review, we discuss the clinical, histopathological, molecular, and cytogenetic features of the most common pCBCL subtypes with a focus on current and innovative therapeutic developments in their management. These emerging treatment strategies for B-cell lymphomas and cutaneous B-cell lymphomas may represent novel first-line options for the management of these rare diseases.

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Most patients with advanced cancer experience pain. However, many cancer patients do not find satisfaction with conventional treatment of pain relief. This study examined the effect of electromyography (EMG) biofeedback-assisted relaxation on cancer-related pain in advanced cancer patients. We hypothesized that changes in EMG activity in frontal muscles underlie the efficacy of EMG biofeedback-assisted relaxation. This was a randomized control study. The experimental group (n = 12) received 6 EMG biofeedback-assisted relaxation sessions over a 4-week period, whereas the control group (n = 12) received conventional care. The primary efficacy measure was the level of pain, measured by the Brief Pain Inventory. Findings from this study show that relaxation training supplemented with visual and auditory EMG biofeedback signals is effective in reducing cancer-related pain in advanced cancer patients, possibly through a mechanism of attenuation of physiological arousal. Electromyography biofeedback-assisted relaxation training may be used along with medications for effective pain management in patients with advanced cancer.

The response to glucocorticoids (GCs) for patients with systemic lupus erythematosus (SLE) is characterized by wide interindividual variability, with a significant number of patients who have no response. We analyzed whether genetic polymorphisms within glucocorticoid receptor (GR) gene are related to variability in the efficacy of GCs in Chinese population with SLE. A cohort of 220 patients with SLE was studied. These patients were treated with GCs (prednisone) for 12 weeks. The efficacy of GCs was measured with the scores on SLE disease activity index (SLEDAI). Patients were classified into two groups (sensitive and insensitive) according to their response to GCs. Polymorphisms of GR gene were genotyped by using multiplex SNaPshot method. A total of 212 patients (96.4%) were included in the final data analyses. Of these patients, 110 patients were considered sensitive to GCs, and 102 patients were considered insensitive to GCs. Eighteen tag single nucleotide polymorphisms (SNPs) of GR gene were selected. Significant associations were seen for rs4912905 (dominant model: crude OR = 0.410, 95%CI = 0.233–0.722, p = 0.002; adjusted OR = 0.419, 95%CI = 0.233–0.754, p = 0.004), rs17100234 (dominant model: crude OR = 0.521, 95%CI = 0.282–0.963, p = 0.038; adjusted OR = 0.520, 95%CI = 0.279–0.970, p = 0.040) and rs7701443 (recessive model: crude OR = 2.736, 95%CI = 1.183–6.331, p = 0.019; adjusted OR = 2.639, 95%CI = 1.116–6.239, p = 0.027) in GR gene, but not for other polymorphisms (p > 0.05). The results of the present study suggest that GR genetic polymorphisms may play a major role in the efficacy of GCs in Chinese population with SLE.

Neurons can maintain stable synaptic connections across adult life. However, the signals that regulate expression of synaptic proteins in the mature brain are incompletely understood. Here, we describe a transcriptional feedback loop between the biosynthesis and repertoire of specific phospholipids and the synaptic vesicle pool in adult Drosophila photoreceptors. Mutations that disrupt biosynthesis of a subset of phospholipids cause degeneration of the axon terminal and loss of synaptic vesicles. Although degeneration of the axon terminal is dependent on neural activity, activation of sterol regulatory element binding protein (SREBP) is both necessary and sufficient to cause synaptic vesicle loss. Our studies demonstrate that SREBP regulates synaptic vesicle levels by interacting with tetraspanins, critical organizers of membranous organelles. SREBP is an evolutionarily conserved regulator of lipid biosynthesis in non-neuronal cells; our studies reveal a surprising role for this feedback loop in maintaining synaptic vesicle pools in the adult brain.

The development of the Drosophila visual system provides a framework for investigating how circuits assemble. A sequence of reciprocal interactions amongst photoreceptors, target neurons and glia creates a precise pattern of connections while reducing the complexity of the targeting process. Both afferent-afferent and afferent-target interactions are required for photoreceptor (R cell) axons to select appropriate synaptic partners. With the identification of some critical cell adhesion and signaling molecules, the logic by which axons make choices amongst alternate synaptic partners is becoming clear. These studies also provide an opportunity to examine the molecular basis of neural circuit evolution.

We investigated whether thrombin, the final activator of coagulation cascade, regulates expression of matrix metalloproteinases (MMP)-9 in human monocytes. We show that thrombin stimulation induced MMP-9 secretion of monocytes dose- and time-dependently as revealed by gelatin zymography. Real-time RT-PCR and Western blot analysis demonstrated that thrombin up-regulated mRNA and protein levels of MMP-9. Pre-incubation with anti-protease-activated receptor (PAR)-1 or anti-PAR-3 antibody partially inhibited the thrombin-induced MMP-9 secretion. Simultaneous incubation with both showed synergistic effect, indicating the involvement of both receptors in this thrombin effect. BAPTA, a Ca2+ chelator, abolished the thrombin-induced MMP-9 secretion, indicating the requirement of Ca2+ mobilization in this process. Inhibition of thrombin-induced MMP-9 secretion by either MEK inhibitor or p38 kinase inhibitor revealed that the thrombin effect was mediated by both ERK1/2 and p38 pathways. The activation of NFκB by thrombin as demonstrated by electromobility shift assay was also shown to be critical to the thrombin-induced MMP-9 up-regulation.

Abstract Described is a deprotonative α-arylation reaction of Meyers’s chiral bicyclic lactams (MCBLs) under palladium catalysis, and a substrate-dependent post-transformation. When the bridgehead carbon of the MCBLs is substituted with a methyl or an ethyl group, the initial arylation product undergoes a further rearrangement reaction to give a conjugated framework. On the other hand, substrates bearing a bridgehead isopropyl or aryl group are converted into the corresponding exo-arylation products. Preliminary studies indicated that the rearrangement pathway was promoted by deprotonation and was independent of palladium catalysis. In addition to mechanistic interests, this study demonstrates a modular and divergent synthesis of functionalized lactams.

Abstract Introduction: IT TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of IL12 in the tumor microenvironment (TME). This study (NCT04526730) evaluated NeoAd TAVO-EP and NIVO. All patients provided a written informed consent (Advarra IRB Pro00041794). Biomarkers of tumoral and systemic immune responses were conducted and correlated with clinical outcomes. Methods: NeoAd phase comprised up to 3 × 4-week cycles of IT TAVO-EP and iv NIVO followed by surgery. Endpoints included pathologic complete response (pCR), near pCR, major response (pMR; pCR + near pCR) and nonresponse (pNR). Biospecimens were collected at screening, C1D8, C2D1 (~30 days from treatment start), pre-surgery (~90 days). Slides cut from FFPE tissue were analyzed by chromogenic immunohistochemistry (IHC) for CD8+ tumor infiltrating lymphocytes (TIL) and PD-L1 (22C3 CDx assay). RNA extracted from FFPE tissue was subjected to NanoString’s IO360 transcriptomic analysis, including Tumor Inflammation Signature (TIS). PBMCs were stained and analyzed via flow cytometry on an LSR Fortessa X-20. Serum samples were analyzed for cytokine levels using Luminex® MAGPIX® platform (15-plex). Results: 16 pts were treated; 1 with PR declined surgery, 1 with early distant PD did not have surgery, 14 had surgery: 2 pNR, 3 near pCR, 9 pCR; pMR rate 12/15 (80%). In tumor, at baseline, 9/11 pts tested had &amp;lt;20% CD8+ TIL, 7/11 &amp;lt;10% PD-L1 tumor proportion score (TPS) and 6/10 TIS of ≤0, predicting non-response to anti-PD-1. In 5 pts with evaluable matched tissue at baseline and C2D1: 5/5 had increased peritumoral CD8+ T cells, 4/5 increased CD8+ TIL, 2/5 increased PD-L1, 4/5 increased TIS at C2D1 compared to baseline. Tumoral transcriptome profile revealed significant upregulation of genes involved in innate and adaptive immune responses (IFN-gamma, APM, granzymes, CD8, PD-L1, JAK1, chemokines, others) at C2D1. In blood, proliferating Ki-67+/PD-1+/CD8+ T cells expanded at C2D1 while total PD1+/CD8+ cells decreased. Decrease of PD1+CD8+ cells and other subtypes in blood at C2D1 coincided with TME infiltration by CD8+ cells. Serum effector cytokines including IL12, IFN-gamma and IL2, showed no biologically meaningful changes following treatment or differences between responders and non-responders. Conclusions: At baseline, most patients exhibited low CD8+ TIL, PD-L1 and TIS, with enhanced immune activation following treatment in the TME and blood including increased immune-related gene expression, CD8+ TIL, peritumoral CD8+ T cells and TIS. Four of 5 pts with negative predictive baseline biomarkers [CD8+TIL/PD-L1/TIS]low experienced pCRs supporting activity of IL12/anti-PD1 based regimens in this setting. Citation Format: Ahmad A. Tarhini, Zeynep Eroglu, Jonathan S. Zager, Ricardo J. Gonzalez, Amod A. Sarnaik, C Wayne Cruse, Deanryan B. De Aquino, Edith Abraham, Diana M. Acevedo, Allison Richards, Michael J. Schell, Denise Kalos, Pei-Ling Chen, Jane L. Messina, David A. Canton, Vernon K. Sondak. Tumoral and systemic immune modulation with neoadjuvant (NeoAd) intratumoral (IT) TAVO-EP (plasmid IL-12 electro gene transfer) and nivolumab (NIVO) in patients (pts) with operable locoregionally advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3734.

Abstract Advances in single-cell multiomic technologies have revolutionized our understanding of how heterogeneous cell types and cell states shape the tumor microenvironment (TME). However, dissociated single cell profiling lacks spatial context. To resolve the organization, cell-cell communication, and granular structures in the TME, new single-cell spatial transcriptomic (ST) characterizations are needed. Here, we dissected the spatial molecular architecture of the melanoma (30 tumors, 30 patients) and transformed cutaneous T-cell lymphoma (tCTCL, 12 tumors, 6 patients) TMEs by Multiplexed Error-Robust FISH (305 gene MERFISH), with benchmarking scRNAseq data from matched tissues (6 melanoma scFFPEseq, 6 tCTCL scVDJ/RNAseq) for cross-platform validation. We profiled 565,122 cells in melanoma and 92584 cells in tCTCL by MERFISH. We interrogated both datasets using a novel computational framework that includes cell typing by Leiden clustering and marker genes, spatial neighborhood and receptor-ligand (R-L) analyses, and spatial/scRNA imputation via deep learning. In the melanoma dataset, we identified tumor cells, major TME cell types, and rare immune cell types (TCF7+ stem-like T-cells and CD3+TCRα+PAX5+CD79a+ B/T dual-expressor lymphocytes enriched in tertiary lymphoid structures). All cell types were validated in scFFPEseq. As immune R-L interactions are critical therapeutic targets, we developed a novel computation method to quantify spatial R-L interactions by accounting for cell-cell distance, identifying spatially informed R-L pairs that differ from dissociation-based inferences. CNV inference from melanoma scFFPEseq revealed intratumoral heterogeneity (ITH). We therefore adapted the conditional variational autoencoder ENVI to simultaneously incorporate scRNA and MERFISH spatial data into a unified latent embedding. ENVI-ITH successfully learned ITH subgroup information, enabling imputation of phylogenetic lineages on spatial MERFISH. CTCL MERFISH data revealed major TME cell types, yet separation of malignant vs benign T-cells by clustering and marker approaches is hindered by their overlapping gene expression. To overcome this barrier, we deployed ENVI to impute patient-specific malignant and benign TCR clonotypes by training on the matched scVDJ/RNA data, yielding an ENVI-TCR pipeline that can delineate malignant vs benign T-cells in situ. We validated the spatial pattern of malignant T-cells by patient-specific in situ TCR probes. In sum, we have interrogated the melanoma and CTCL TME by MERFISH and presented a novel computational framework for robustly co-embedding scRNA data with imaging-based ST to spatially resolve melanoma ITH and malignant/benign T-cell populations. We believe this approach will be highly impactful for melanoma and CTCL and can be broadly applied to other solid tumors and lymphomas. Citation Format: Zichao Liu, Xiaofei Song, Jiang He, Justin He, Jodi Balasi, Jeffrey H. Chuang, Pei-Ling Chen. Dissection of melanoma and cutaneous lymphoma spatial molecular architecture by multimodal single-cell and spatial transcriptomics with generative AI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1143.

Abstract IFx-Hu2.0 was designed to encode part of the Emm55 protein contained within a plasmid in a formulation intended for transfection into mammalian cells. IFx-Hu2.0 promotes both adaptive and innate immune responses in animal studies. Furthermore, previous studies have demonstrated safety/efficacy in equine, canine, and murine species. We present the first-in-human study of IFx-Hu2.0, administered by intralesional injection into melanoma tumors of seven patients with stage III/IV unresectable melanoma. No dose-limiting toxicities attributable to IFx-Hu2.0 were observed. Grade 1/2 injection site reactions were observed in five of seven patients. IgG and IgM responses were seen in the peripheral blood to Emm55 peptides and known melanoma antigens, suggesting that IFx-Hu2.0 acts as an individualized “in-situ vaccine.” Three of four patients previously refractory to anti-PD1 experienced clinical benefit upon subsequent anti-PD1-based treatment. Therefore, this approach is feasible, and clinical/correlative outcomes warrant further investigation for treating metastatic melanoma patients as an immune priming agent.

Abstract To investigate the most efficient way to represent text in reading Chinese on computer displays, three typographic variables, character size (41′ arc/24 pixels and 60′ arc/32 pixels), character spacing (1/4 and 1/8 character width) and font type (Kai and Ming), were manipulated. Results showed that the reading speed for Chinese characters of Kai type in 24 pixels with 1/8 character spacing was the shortest. Character size significantly affected overall reading speed; in specific, text in 24-pixel characters was read faster than text in 32-pixel characters. Further eye-movement analyses revealed that text in smaller-sized characters had longer fixation duration, fewer fixations and fewer regressions than text in larger-sized characters. The interaction between character spacing and font type was observed on overall reading efficiency and on some eye-movement measures, which suggests that different character spacings should be considered in different font types for more efficient reading. Generally, characters in Kai font were easier to read with 1/8 character spacing than with 1/4 character spacing. The relationship between eye-movement measures and overall reading efficiency was further discussed. Keywords: character sizecharacter spacingfont typeeye-movement measures Acknowledgement This research was supported by a grant (NSC 95-2627-E–004-002) from the National Science Council of the Republic of China.

Background Sebaceous carcinoma represents a rare and potentially fatal adnexal malignancy. Poorly‐differentiated sebaceous carcinoma consisting of infiltrative basaloid tumor cells with inapparent lipid vesicles can mimic basal cell carcinoma (BCC). Conversely, other epithelial tumors can exhibit clear cell histopathology and mimic sebaceous carcinoma. At the present time, immunohistochemical markers unique for sebaceous carcinoma are limited. Methods We evaluated the expression of three lipid synthesis/processing protein markers alpha/beta hydrolase domain‐containing protein 5 ( ABHD5 ), progesterone receptor membrane component‐1 ( PGRMC1 ) and squalene synthase (SQS) in sebaceous carcinoma and investigated their utility in differentiating sebaceous tumors from BCC with clear cell features. Immunohistochemistry was performed on 23 sebaceous carcinomas, 14 sebaceomas and 14 BCCs with clear cell features. Results In sebaceous carcinomas, ABHD5 showed dispersed, cytoplasmic punctate and/or vesicular staining (n = 19/23, 83%), while PGRMC1 and SQS each showed vesicular and membranous staining in tumor cells (n = 22/23, 96%). In all sebaceomas, these markers highlighted tightly clustered lipid vesicles in sebocytes. All BCCs with clear cell features were negative for these three markers. Conclusion ABHD5 , PGRMC1 and SQS are novel markers for sebaceous carcinoma and can reliably distinguish sebaceous neoplasms from non‐sebaceous tumors, specifically BCC with clear cell features.

We developed palladium-catalyzed oxidative coupling of olefins with N-acyl 2-aminobiaryls through a sequence of ortho C–H bond activation/alkene insertion/reductive elimination. Furthermore, we controlled the selectivity of mono- and bis-alkenylation products with the solvent effect. The developed protocol was promising for a broad substrate scope ranging from activated olefins with a wide variety of functional groups to unactivated olefins.

Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.

Importance Cutaneous T-cell lymphoma (CTCL) is a group of rare, complex cutaneous malignant neoplasms associated with significant disease burden on patients and the health care system. Currently, the population of patients with CTCL admitted to the hospital remains largely uncharacterized and poorly understood. Objective To characterize the clinical characteristics, course of hospitalization, and mortality outcomes of an inpatient CTCL cohort. Design, Setting, and Participants This multicenter retrospective cohort study reviewed medical records for adult patients (age ≥18 years) with a CTCL diagnosis per National Comprehensive Cancer Network guidelines admitted for inpatient hospitalization at 5 US academic medical centers with inpatient dermatology consult services and CTCL clinics between August 2016 and August 2020. Main Outcomes and Measures Patient demographics, clinical history and findings, hospitalization courses, and mortality outcomes. Results A total of 79 hospitalized patients with CTCL were identified, including 52 (70.3%) men and 22 (29.7%) women, with a median (IQR) age at hospitalization of 62.9 (27-92) years. The majority of admitted patients with CTCL were White (65 patients [82.3%]), had disease classified as mycosis fungoides (48 patients [61.5%]), and had advanced-stage disease (≥IIB, 70 patients [89.7%]). Most hospitalizations were complicated by infection (45 patients [57.0%]) and required intravenous antibiotic therapy (45 patients [57.0%]). In-hospital mortality occurred in 6 patients (7.6%) and was associated with higher body mass index (36.5 vs 25.3), history of thromboembolic disease (50.0% vs 12.3%), and diagnosis of sepsis on admission (66.7% vs 20.5%). At 1-year postdischarge, 36 patients (49.3%) patients had died, and mortality was associated with history of solid organ cancers (27.8% vs 10.8%), wound care as the reason for dermatology consultation (58.3% vs 24.3%), and presence of large cell transformation (58.3% vs 22.9%). Conclusions and Relevance The findings of this cohort study improve the understanding of hospitalized patients with CTCL and lend valuable insight into identifying factors associated with both in-hospital and long-term mortality outcomes. This refined understanding of the inpatient CTCL population provides a foundation for larger, more robust studies to identify causal risk factors associated with mortality, development of prognostic scoring systems to estimate the probability of hospital mortality. Overall, the findings may prompt physicians caring for patients with CTCL to implement preventive strategies to diminish hospitalization and improve clinical management across this unique disease spectrum.

The malignant peripheral nerve sheath tumor is a relatively uncommon type of soft tissue sarcoma arising from a peripheral nerve or extraneural soft tissues and showing nerve sheath differentiation. The diagnosis of malignant peripheral nerve sheath tumor is one of the most challenging tasks in surgical pathology because of its uncommon type (5-10% soft tissue sarcomas), morphologic resemblance to other spindle cell neoplasms and lack of sensitive and specific immunohistochemical markers. The pathologic diagnosis is more straightforward in the clinical setting of neurofibromatosis-1, but problems are mainly centered on the non-neurofibromatosis-1 malignant peripheral nerve sheath tumors. To date, S100 protein is the most widely applied marker in the case of a suspected malignant peripheral nerve sheath tumor, yet its suboptimal sensitivity and its expression in other spindle cell neoplasms, including spindle cell melanoma, clear-cell sarcoma, leiomyosarcoma and monophasic synovial sarcoma, add to the diagnostic conundrum. Growth-associated protein 43 (GAP43), a membrane-associated phosphoprotein expressed in neuronal growth cones and Schwann cell precursors during neural development and axonal regeneration, was applied to a set of nerve sheath and non-nerve sheath spindle cell neoplasms. The findings in this study indicate that GAP43 is expressed in malignant peripheral nerve sheath tumors (n=18/21; 86%) and demonstrates a sensitivity superior to S100 protein (n=13/21; 62%). GAP43 is also positive in neurofibromas (n=17/18; 94%), schwannomas (n=11/12; 92%) and desmoplastic melanomas (n=7/10; 70%). In contrast, it is negative in the non-desmoplastic spindle cell melanomas (n=20/22; 91%). Of the other non-neural soft tissue sarcomas, GAP43 is non-reactive in most leiomyosarcomas (n=14/16; 88%) and clear-cell sarcomas (n=8/8), and only focally positive in monophasic synovial sarcomas (n=3/7; 43%). GAP43 is seemingly a highly sensitive marker for peripheral nerve sheath tumors and may serve as a useful diagnostic adjunct in the diagnosis of malignant peripheral nerve sheath tumor from other spindle cell neoplasms, including spindle cell melanoma.

Abstract We report the first example of Pd(II)‐catalyzed highly step‐ and atom‐economical benzofulvenation through free amine‐directed ortho C−H bond activation of o ‐arylanilines. This paper presents a novel, simple, and efficient approach for the synthesis of benzofulvene derivatives from o ‐arylaniline substrates through C−H bond activation with two diarylacetylenes as an implicit benzofulvene unit. The reactivity of synthesized benzofulvenes toward oxidation was investigated, and they were shown to transform into phenanthridines, oxabenzofulvenes, and fluorescent polycyclics. magnified image

Dengue virus (DENV) infection triggers the activation of autophagy to facilitate the viral replication cycle from various aspects. Although a number of stimulators are proposed to activate autophagy, none of them appears prior to the uncoating process. Given that T-cell immunoglobulin and mucin domain 1 (TIM-1) receptor is a putative DENV receptor and promotes apoptotic body clearance by autophagy induction, it raises the possibility that TIM-1 may participate in the activation of DENV-induced autophagy. In this study, confocal images first revealed the co-localization of TIM-1 with autophagosomes in DENV-induced autophagy rather than rapamycin-induced autophagy, suggesting the co-transportation of TIM-1 with DENV during infection. The treatment of siRNA to knockdown TIM-1 expression in DENV-infected GFP-microtubule-associated protein light chain 3 (LC3)-Huh7.5 cells revealed that TIM-1 is required not only for DENV cellular internalization but also for autophagy activation. Furthermore, knockdown p85, a subunit of phosphoinositide 3-kinases (PI3Ks), which is co-localized with TIM-1 at rab5-positive endosomes caused the reduction of autophagy, indicating that TIM-1-mediated DENV-induced autophagy requires p85. Taken together, the current study uncovered TIM-1 as a novel factor for triggering autophagy in DENV infection through TIM-1-p85 axis, in addition to serving as a DENV receptor.

Four novel coordination polymers: Ag(dpa) I, Co(O3PH)(4,4′-bpy)(H2O) II, Zn(O3PH)(4,4′-bpy)0.5 III and Mn[O2PH(C6H5)]2(4,4′-bpy) IV (dpa=2,2′-dipyridylamine; 4,4′-bpy=4,4′-bipyridine), were synthesized by microwave heating and characterized by X-ray crystallography. I crystallizes in monoclinic space group P21/n with a=11.576(2) Å, b=5.585(2) Å, c=15.243(4) Å, β=109.00(2)°, V=931.8(3) Å3. II crystallizes in monoclinic Cc space group with a=22.477(7) Å, b=5.280(1) Å, c=10.404(4) Å, β=96.08(3)°, V=1227.8(7) Å3. III crystallizes in monoclinic P21/c space group with a=9.758(2) Å, b=7.449(3) Å, c=10.277(2) Å, β=100.02(2)°, V=735.6(4) Å3. IV crystallizes in monoclinic space group P2/c with a=10.174(1) Å, b=11.817(3) Å, c=18.784(4) Å, β=102.14(1)°, V=2207.8(8) Å3. I consists of linear metal–metal chains wrapped by dpa ligands. II and III consist of two-dimensional MII(O3PH) inorganic sheets cross-linked by 4,4′-bpy ligands, while IV is formed by Mn[O2PH(C6H5)]2 sheets cross-linked by 4,4′-bpy ligands. I exhibits two-step thermal decomposition at ~200 and ~250°C, resulting in the reduction of Ag+ to Ag metal. II loses its coordination water at ~100°C, leaving vacant coordination sites at Co2+ ions, while the original framework remains intact. The removal of 4,4′-bpy in II–IV occurs at elevated temperatures above 250, 200 and 400°C respectively.

A palladium-catalyzed C–H functionalization of an external ring of N-acyl 2-aminobiaryl with bicyclo[2.2.1]hept-2-ene (norbornene) via multiple C–H bond activations was developed. This study is the first report of the formation of bis-norbornene annulated biarylamines isomers (syn-3a′/anti-3a′ = 36:64) from multiple C–H bond functionalizations. Additionally, nondirected C–H bond functionalization at the C-4′ position with alkenes rendered complete C–H functionalization of five C–H bonds that formed a stable hexasubstituted benzene ring.

Abstract: The family of blue nevi includes the common blue nevus (BN), cellular blue nevus (CBN), and atypical BN, while melanomas with BN-like morphology can either arise in association with a blue nevus (MABN) or in the de novo setting mimicking cellular blue nevus (MMCBN). Recent molecular and immunohistochemical studies have demonstrated loss of BAP-1 in MABN/MMCBN but not in BN/CBN, suggesting that loss of BAP-1 correlates with a malignant phenotype in these lesions. In this study, we applied anti–BAP-1 antibodies to a series of CBN/BN (n = 11) and MABN/MMCBN (n = 4). Nuclear BAP-1 expression was detected in the majority of CBN/BN (n = 10/11) but was lost in 1 case. Most cases of MABN/MMCBN showed loss of nuclear BAP-1 expression (n = 3/4), with one case of MMCBN showing preserved BAP-1 expression. Demonstration of BAP-1 loss in a single case of CBN and preservation of BAP-1 expression in 1 case of MMCBN may indicate that detection of alterations in BAP-1 protein expression by immunohistochemistry may not be a completely reliable biomarker for the distinction of BN/CBN from MABN/MMCBN. Further investigation of the significance of BAP-1 loss/preservation in BN-like tumors is warranted.

A novel unprecedented triphenylphosphine-mediated [4 + 3] annulation reaction of 2-benzylidene indane-1,3-diones and -diynoates through initial phosphine α-addition was discovered and found to result in biologically interesting indeno[1,2-b]oxepin-4-ylidenes in up to 75% yield. The seven-membered separable Z and E isomeric oxepins were confirmed using single-crystal X-ray diffraction.

Abstract T cell-mediated immunotherapies are promising cancer treatments. However, most patients still fail to respond to these therapies. The molecular determinants of immune resistance are poorly understood. Here, we interrogated the role of loss of expression of the tumor suppressor, PTEN, in immune resistance. In preclinical studies, we found that silencing PTEN in tumor cells inhibited T cell-mediated tumor killing and decreased T cell trafficking into tumors. In clinical studies, we observed that tumors with loss of PTEN had significantly less CD8+ T cell infiltration than PTEN-present tumors. In addition, 26% of melanomas that did not yield successful TIL growth demonstrated PTEN loss, which was more frequent than was observed in tumors that yielded successful TIL growth (11%). We further validated the association between reduced number and impaired function of TIL with PTEN loss using another independent cohort, TCGA dataset for SKCM. More importantly, we analyzed clinical outcomes of metastatic melanoma patients treated with the FDA-approved anti-PD-1 antibodies. Our analysis demonstrates that a greater reduction in tumor burden was achieved by PD-1 blockade in PTEN present patients, when compared with PTEN absent patients. To decipher the factors mediating the immunosuppressive effects of PTEN loss, we determined the expression profiles of tumor cells with or without PTEN expression. Our results indicated that PTEN loss increased the production of immunosuppressive factors, including CCL2 and VEGF. Anti-VEGF blocking antibody improved anti-tumor activity of transferred tumor-reactive T cells and enhanced tumor infiltration of transferred T cells in PTEN-silenced tumors. These results suggest that loss of PTEN can facilitate the resistance of T cell-mediated immune responses by increasing the expression of immunosuppressive factors. Given that PTEN loss results in activation of the PI3K pathway, we evaluated the efficacy of immunotherapy in combination with a selective PI3Kβinhibitor to treat spontaneously developed BRAF mutant, PTEN null melanomas in genetically engineered mouse models. Our result showed that the combination of PI3Kβ inhibitor and anti-PD-1 significantly delayed tumor growth in tumor-bearing mice. Mice treated with this combination had a median survival time of 28 days, which is longer than the survival time of mice treated with either therapy. Increased numbers of T cells at tumor sites were found in mice receiving the combination therapy compared with mice receiving either agent alone. Taken together, our results demonstrate that PTEN loss contributes to the generation of immunosuppressive tumor microenvironment. Notably, this study provides the first direct clinical evidence to support the association between PTEN loss and poor clinical outcome in immunotherapy treated patients. In addition, our study indicates that inhibition of the PI3K-AKT pathway can improve the efficacy of immunotherapy in cancer. Citation Format: Weiyi Peng, Jie Qing Chen, Chengwen Liu, Shruti Malu, Caitlin Creasy, Michael Tetzlaff, Chunyu Xu, Jodi McKenzie, Chunlei Zhang, Xiaoxuan Liang, Leila Williams, Wanleng Deng, Guo Chen, Rina Mbofung, Alexander Lazar, Carlos Torres-Cabala, Zachary Cooper, Pei-Ling Chen, Trang Tieu, Stefani Spranger, Xiaoxing Yu, Chantale Bernatchez, Marie-Andree Forget, Cara Haymaker, Rodabe Amaria, Jennifer McQuade, Isabella Glitza, Tina Cascone, Haiyan Li, Lawrence Kwong, Timothy Heffernan, Jianhua Hu, Roland Bassett, Marcus Bosenberg, Scott Woodman, Willem Overwijk, Gregory Lizée, Jason Roszik, Thomas Gajewski, Jennifer Wargo, Jeffrey Gershenwald, Laszlo Radvanyi, Michael Davies, Patrick Hwu. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4363.

A new class of iptycenes was developed by combining 2-(naphthalen-1-yl)anilines and <italic>p</italic>-benzoquinones through copper(<sc>ii</sc>)-mediated radical cyclisation.

Background: The ideal surgical procedure for interstitial pregnancy remains undetermined. The aim of this study was to assess whether surgical method is a factor in predicting subsequent pregnancy in women with interstitial pregnancy who underwent laparoscopic cornuostomy or laparoscopic wedge resection. Methods: Medical records of all women with interstitial pregnancy who underwent laparoscopic cornuostomy or laparoscopic wedge resection between March 2008 and October 2017 in a medical center were reviewed. Cox regression analysis was performed to identify factors predicting subsequent pregnancy. Results: Forty patients underwent laparoscopic cornuostomy (n = 14) or laparoscopic wedge resection (n = 26) for the treatment of interstitial pregnancy. Twelve women become pregnant during follow-up. Laparoscopic cornuostomy was associated with shorter operation time (coefficient = −19.1 minutes, 95% CI = −36.9 to −1.3 minutes, p = 0.04, multivariable analysis) than that of laparoscopic wedge resection. Furthermore, laparoscopic cornuostomy (hazard ratio = 6.3, p = 0.03), parity (hazard ratio = 0.18, p = 0.008), and preoperative rupture of the cornus (hazard ratio = 13.3, p = 0.005) were independent predictors of subsequent pregnancy. Conclusion: Laparoscopic cornuostomy was associated with a higher probability of subsequent pregnancy and a shorter operation time. Thus, compared with laparoscopic wedge resection, laparoscopic cornuostomy might be a better surgical procedure for women with interstitial pregnancy, particularly for women who wish to become pregnant later. However, because of the retrospective nature and small sample size of this study, some well-defined/designed prospective studies including more patients are needed to verify our results.

<h3>Background</h3> Intratumoral (IT) treatment with TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of IL-12 in the tumor microenvironment. This study (NCT04526730) was designed to evaluate neoadjuvant TAVO-EP in combination with nivolumab followed by surgery and adjuvant nivolumab in patients with operable, locoregionally advanced melanoma. <h3>Methods</h3> The neoadjuvant phase comprised up to 3 x4-week cycles of TAVO-EP on days 1, 8 and 15 (optional) concurrently with 480 mg nivolumab I.V. on day 8 of each cycle. Surgery followed and adjuvant nivolumab was initiated after recovery from surgery for up to one year. Longitudinal samples of tumor biopsies, PBMCs, serum, PAXgene© blood DNA/RNA, and fecal material were collected at screening, C1D8, C2D1, pre-surgery and during adjuvant phase. Patients provided an IRB-approved ( Advarra-IRB Pro00041794) informed consent and were treated at Moffitt Cancer Center. <h3>Results</h3> Ten patients (6 female, 4 male, 1 black, 9 white, 10 cutaneous primary including 1 acral), age 58–88, were treated. Five had Stage IIIB (4N1c, 1N2b), 3 IIIC (1N3b, 1N3c, 1N1c) and 2 IV (M1a). Treatment was well tolerated. Highest-grade treatment-related events to date were limited to one Gr3 hyponatremia possibly related to nivolumab. One patient is currently in the neoadjuvant phase. Among the nine patients who completed the neoadjuvant phase, median number of neoadjuvant cycles was 3; 2 patients received 2 cycles due to near complete clinical response. Preoperative response rate (RECIST, unconfirmed) was 7/9 (77.8%; 95%CI 40.0-97.2); 1PD, 1SD, 4CR, 3 PR. One patient with PR declined surgery. Among 8 patients who had surgery to date, 1 pathologic non-response (Surgery at 4 weeks after initiating treatment due to clinical progression), 1 pathologic major response (pMR; ≤10% viable tumor), 6 pathologic complete response (pCR). The overall pMR rate was 7/8 (87.5%; 95%CI 47.4–99.7), all with no disease recurrence to date, at a median follow up from the date of surgery of 7.08 months (range 0.2–17.5). Transient on-treatment changes in systemic peripheral immune subsets were identified. At C2D1 (week 5), peripheral proliferating CD8+PD-1+ T cells were significantly increased. In addition, memory precursor effector cells (mPECs; CD8+KLRG1-CD127+) were transiently upregulated at same timepoint, while short-lived effector cells (SLECs; CD8+KLRG1+CD127-) were significantly reduced. These peripheral T cell changes coincided with increased intratumoral CD8+ TIL. <h3>Conclusions</h3> Neoadjuvant IT TAVO-EP in combination with nivolumab exhibited promising clinical activity and a favorable safety profile. There was evidence of significantly enhanced immune activation supporting the proposed immune mechanisms. Analyses of additional biomaterials are underway. <h3>Acknowledgements</h3> We are grateful to the participating patients and their family members as well as all research staff supporting the conduct of the clinical trial. <h3>Trial Registration</h3> NCT04526730 <h3>Ethics Approval</h3> All participating patients in this investigator-initiated clinical provided an IRB-approved (Advarra IRB Pro00041794) written informed consent and were treated at Moffitt Cancer Center.

Abstract The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains unclear. Using single-cell RNA or T-cell receptor (TCR) sequencing of 32 619 CD3+CD4+ and CD26+/CD7+ and 29 932 CD3+CD4+ and CD26−/CD7− lymphocytes from the peripheral blood of 7 patients with CTCL, coupled to single-cell ATAC-sequencing of 26,411 CD3+CD4+ and CD26+/CD7+ and 33 841 CD3+CD4+ and CD26−/CD7− lymphocytes, we show that tumor cells in Sézary syndrome and mycosis fungoides (MF) exhibit different phenotypes and trajectories of differentiation. When compared to MF, Sézary cells exhibit narrower repertoires of TCRs and exhibit clonal enrichment. Surprisingly, we identified ≥200 mutations in hematopoietic stem cells from multiple patients with Sézary syndrome. Mutations in key oncogenes were also present in peripheral Sézary cells, which also showed the hallmarks of recent thymic egression. Together our data suggest that CTCL arises from mutated lymphocyte progenitors that acquire TCRs in the thymus, which complete their malignant transformation in the periphery.

The number of scarlet fever occurrences reported between 2000 and 2006 fluctuated considerably in central Taiwan and throughout the nation. Isolates of Streptococcus pyogenes were collected from scarlet fever patients in central Taiwan and were characterized by emm sequencing and a standardized pulsed-field gel electrophoresis (PFGE) method. National weekly report data were collected for investigating epidemiological trends.A total of 23 emm types were identified in 1,218 S. pyogenes isolates. The five most prevalent emm types were emm12 (50.4%), emm4 (23.2%), emm1 (16.4%), emm6 (3.8%) and emm22 (3.0%). PFGE analysis with SmaI suggested that, with a few exceptions, strains with a common emm type belonged to the same clone. There were two large emm12 clones, one with DNA resistant to cleavage by SmaI. Each prevalent emm clone had major PFGE strain(s) and many minor strains. Most of the minor strains emerged in the population and disappeared soon after. Even some major strains remained prevalent for only 2-3 years before declining. The large fluctuation of scarlet fever cases between 2000 and 2006 was associated with the shuffling of six prevalent emm clones. In 2003, the dramatic drop in scarlet fever cases in central Taiwan and throughout the whole country was associated with the occurrence of a severe acute respiratory syndrome (SARS) outbreak that occurred between late-February and mid-June in Taiwan.The occurrences of scarlet fever in central Taiwan in 2000-2006 were primarily caused by five emm types, which accounted for 96.8% of the isolates collected. Most of the S. pyogenes strains (as defined by PFGE genotypes) emerged and lasted for only a few years. The fluctuation in the number of scarlet fever cases during the seven years can be primarily attributed to the shuffling of six prevalent emm clones and to the SARS outbreak in 2003.

Many machine-to-machine (M2M) applications are characterized by the requirement to support a large number of machines for reporting data back to the aggregator for further data processing. While related work has investigated various access barring and de-prioritization approaches for machine-type communications, they fail to work for delay-sensitive M2M applications, where the random access delay needs to be properly constrained or minimized. In this paper, we start from a multi-channel random access network and investigate how its performance can be optimized for minimizing the overall access delay of all machines with bursting traffic. We first propose a novel and simpler approach for analyzing the random access delay involved in such a network, and then propose an approach to minimize the random access delay through intelligent control of the persistence probability used by contending machines. Without resorting to dynamic programming, the proposed approach can effectively determine the optimal value of the persistence probability in constant computation time. Simulation results substantiate that compared to baseline approaches the proposed approach incurs significantly lower computation overheads without noticeable degradation in optimality.

In the diagnosis of late-onset hypogonadism (LOH), the Androgen Deficiency in the Aging Male (ADAM) questionnaire or Aging Males' Symptoms (AMS) scale can be used to assess related symptoms. Subsequently, blood tests are used to measure serum testosterone levels. However, results obtained using ADAM and AMS have revealed no significant correlations between ADAM and AMS scores and LOH, and the rate of misclassification is high. Recently, many studies have reported significant associations between clinical conditions such as the metabolic syndrome, obesity, lower urinary tract symptoms, and LOH. In this study, we sampled 772 clinical cases of men who completed both a health checkup and two questionnaires (ADAM and AMS). The data were obtained from the largest medical center in Taiwan. Two well-known classification techniques, the decision tree (DT) and logistic regression, were used to construct LOH prediction models on the basis of the aforementioned features. The results indicate that although the sensitivity of ADAM is the highest (0.878), it has the lowest specificity (0.099), which implies that ADAM overestimates LOH occurrence. In addition, DT combined with the AdaBoost technique (AdaBoost DT) has the second highest sensitivity (0.861) and specificity (0.842), resulting in having the best accuracy (0.851) among all classifiers. AdaBoost DT can provide robust predictions that will aid clinical decisions and can help medical staff in accurately assessing the possibilities of LOH occurrence.

Objective: The aim of this study was to investigate the associations between HSP90B1 gene polymorphisms and the efficacy of glucocorticoids (GCs) and the improvement of health-related quality of life (HRQoL) in Anhui patients with systemic lupus erythematosus (SLE). Method: A total of 305 patients with SLE were recruited to the study. These patients were treated with GCs for 12 weeks and classified into two groups (sensitivity and insensitivity) according to the response to GCs measured by the scores on SLE disease activity index (SLEDAI). The HRQoL of SLE patients were evaluated by 36-item Short Form Health Survey (SF-36) at baseline and 12 weeks respectively. HapMap database and Haploview software were used to select HSP90B1 gene tag single nucleotide polymorphisms (SNPs). Benjamini & Hochberg (BH) method based on false discovery rate (FDR) was used for multiple testing correction. Results: A total of 291 patients were included in final data analysis with 14 patients excluded due to loss to follow-up. Among these patients, 160 patients were sensitive to GCs and 131 patients were insensitive to GCs. Twelve tag SNPs of HSP90B1 gene were selected. The rs12426382 polymorphism was associated with the efficacy of GCs (dominant model: crude OR=0.514, 95% CI=0.321-0.824, P=0.006; adjusted OR=0.513, 95% CI=0.317-0.831, P=0.007). After BH correction, there was no association between rs12426382 polymorphism and efficacy of GCs (PBH =0.084). In haplotype analysis, the haplotype CCCGAACATCCC (OR=2.273, 95% CI=1.248-4.139, P=0.006) and CTGGGACGTTC (OR=0.436, 95% CI=0.208-0.916, P=0.025) showed significant associations with the efficacy of GCs. After corrected by BH method, CCCGAACATCCC was still associated with the efficacy of GCs (PBH =0.048). The rs3794241, rs1165681, rs2722188, rs3794240 and rs10861147 polymorphisms were associated with the improvement of HRQoL among SLE patients (P < 0.05). But no association existed after the correction of BH method (P > 0.05). Conclusions: The results of this study demonstrated that HSP90B1 genetic polymorphisms might be associated with the efficacy of GCs, but not associated with the improvement of HRQoL in Anhui population with SLE.

To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8-87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p < 0.001). After propensity score-matching, there were 68 patients in each group. Among locally advanced PC patients, treatment with RP had a higher risk of biochemical recurrence compared to the RT group. In multivariate Cox regression analysis, treatment with RT plus ADT significantly decreased the risk of biochemical failure (HR 0.162, p < 0.001), but there was no significant difference in local recurrence, distant metastasis and overall survival (p = 0.470, p = 0.268 and p = 0.509, respectively). This information supported a clinical benefit in BCR control for patients undergoing RT plus long-term ADT compared to RP.

FP-growth is the most famous algorithm for discovering frequent patterns. As the database size growths or the minimum support decreases, however, both of the memory requirement and execution time increase greatly. Many researchers tried to solve this problem by utilizing distributed computing techniques to improve the scalability and execution efficiency. In this paper, we propose a method for discovering frequent patterns from very large database in cloud computing environments. To build the whole FP-Tree, we use the disk as the secondary memory. Because the disk access is much slower than main memory, an efficient data structure for storing and retrieving FP-Tree from disk is also proposed. Through empirical evaluations on various simulation conditions, the proposed method delivers excellent performance in terms of scalability and execution time.

Multi-Project Wafer (MPW) is designed for cost saving and fast prototype but conventional Blade Dicing process is time consuming and high risk to cause die loss because repetitive Blade Dicing process. Stealth Dicing is an alternative solution of Blade Dicing, patterned by Hamamatsu Photonics, which has potential for MPW dicing solution. This paper presents first successful MPW dicing by Stealth Dicing instead of Blade Dicing which FT (Functional Test) yield has been proved. In this study, the team evaluated the process of MPW dicing by Stealth Dicing. During the evaluation, some phenomenon has been observed which damage MPW chips. This study has clarified the phenomenon and found solution for the damage. After solving the problem, the result shows that yield of Stealth Dicing and Blade Dicing are comparable and Stealth Dicing is able to be used on MPW.

Management of cornual gestational trophoblastic neoplasia (GTN) has never been reported. Here, we describe the first case of cornual GTN. A 32-year-old woman was diagnosed with left cornual GTN after evacuation of a complete mole. Laparoscopic cornuostomy was performed with intramural vasopression injection and barbed sutures. Histopathology revealed hydropic chorionic villi. Complete hydatidiform mole was diagnosed, and treated with adjuvant methotrexate, to address the poor decline of β-human chorionic gonadotropin levels during follow-up. The β- human chorionic gonadotropin levels declined to < 1 mIU/mL 9 months after cornuostomy. She successfully conceived 16 months after cornuostomy, and underwent cesarean section at 37 gestational weeks due to concomitant severe preeclampsia. Cornual GTN can be successfully managed with laparoscopic cornuostomy and adjuvant methotrexate.

Meeting abstracts Despite recent advances in the treatment of metastatic melanoma through targeted and immunotherapy, the majority of patients do not achieve a durable response. Research efforts to better understand responses are underway, and numerous molecular mechanisms of resistance to targeted

Because a sense of reality of a stereopicture used to display a real scene is better than that of a two-dimensional image, the former has been widely paid much attention in application. Recently, there are several methods used on three-dimensional sensing. In this study, our system to construct a stereopicture is composed of a single co-axial point-light source associated with a video camera. Different images of a scene could be taken by the camera when the light source was moving away relative to the scene from a point to another one. Based on the inverse square law for light intensity, the depth information of a scene can be obtained by using the pixel ratio obtained from two consecutive frames. Because the gray-level of each pixel in an image taken by the camera is related to an angle made by the line of sight of the pixel with the optical axis, the image plane is bent. Comparison the distance measured from the camera to the object with theoretical data obtained by the inverse square law, we found that their error corresponding to different pixels located at the margin of the image plane is higher than that at the center of the image plane. However, this problem can be improved by making an angular correction. Consequently, a low-pass filter was used to smooth the raw data of the range to reduce the distance error.

Hypertrophic lupus erythematosus is a variant of discoid lupus erythematosus, which manifests as verrucous plaques and/or keratoacanthoma-like nodules on the face and arms. Diagnosis and treatment of hypertrophic lupus erythematosus can be challenging as it can resemble cutaneous squamous cell carcinoma clinically and histopathologically. Furthermore, cutaneous squamous cell carcinoma is a known complication of discoid lupus erythematosus. We present a diagnostically challenging case of a patient with a rapidly enlarging rhinophymatous mass and multiple keratoacanthoma-like lesions of the bilateral upper extremities whose work-up was initially equivocal. CD123 staining helped to elucidate a final diagnosis of cutaneous squamous cell carcinoma arising in a background of occult hypertrophic lupus erythematosus.

Abstract A benzannulation strategy involving activation of two C–H bonds of five-membered heteroarenes was developed. Readily available furans and pyrroles stabilized by synthetically useful electron-withdrawing groups underwent Pd-catalyzed 1:2 annulation reactions with diaryl alkynes. A variety of functional groups, including ester, amide, ketone, aldehyde, and nitrile, on the heterocyclic cores were tolerated in the Pd-catalyzed oxidative reactions. In these reactions, the combination of 2,2-dimethylbutyric acid and its conjugate base facilitated metalation at the heteroaromatic rings and reoxidation of the Pd(0) species using oxygen as the terminal oxidant. This strategy provides fluorescent ­benzofuran and indole derivatives and is expected to allow for further development of functionalized polycyclic heteroaromatic compounds.

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Compared to the cell using standard a-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M19"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="normal">S</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">C</mml:mi></mml:mrow><mml:mrow><mml:mi>x</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>:H(p), the a-Si:H/a-<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M20"><mml:msub><mml:mrow><mml:mi mathvariant="normal">S</mml:mi><mml:mi mathvariant="normal">i</mml:mi></mml:mrow><mml:mrow><mml:mn mathvariant="normal">1</mml:mn><mml:mo>-</mml:mo><mml:mi>y</mml:mi></mml:mrow></mml:msub><mml:msub><mml:mrow><mml:mi mathvariant="normal">G</mml:mi><mml:mi mathvariant="normal">e</mml:mi></mml:mrow><mml:mrow><mml:mi>y</mml:mi></mml:mrow></mml:msub></mml:math>:H tandem cells employing<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M21"><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="normal">S</mml:mi><mml:mi mathvariant="normal">i</mml:mi><mml:mi mathvariant="normal">O</mml:mi></mml:mrow><mml:mrow><mml:mi>x</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>:H(p) deposited with<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M22"><mml:mrow><mml:msub><mml:mrow><mml:mi>R</mml:mi></mml:mrow><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant="normal">H</mml:mi></mml:mrow><mml:mrow><mml:mn mathvariant="normal">2</mml:mn></mml:mrow></mml:msub></mml:mrow></mml:msub></mml:mrow></mml:math>of 167 showed an improved efficiency from 9.3% to 10.3%, with<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M23"><mml:mrow><mml:msub><mml:mrow><mml:mi>V</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">O</mml:mi><mml:mi mathvariant="normal">C</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>of 1.60 V,<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M24"><mml:mrow><mml:msub><mml:mrow><mml:mi>J</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant="normal">S</mml:mi><mml:mi mathvariant="normal">C</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>of 9.3 mA/cm 2 , and FF of 68.9%.

BackgroundPrior quantitative studies have described the diminished health-related quality of life (HRQoL) faced by the overall mycosis fungoides (MF)/Sézary syndrome (SS) population; yet, little is known about how the disease affects HRQoL in skin of color (SOC) patients.This qualitative study sought to explore the lived experiences of SOC patients with MF/SS and gain deeper insights into the impact the disease has on various facets of HRQoL. MethodologyInterviews with SOC patients with MF/SS ≥18 were recruited from a cutaneous lymphoma clinic.A thematic analysis was performed to identify overarching themes. ResultsTen patients were invited to participate from July to September 2021.One patient with SS and seven patients with MF (four in the early stage and four in the advanced stage), with a median age of 60.5 years, agreed to participate.Emerging themes included diagnostic and therapeutic delays frequently due to initial misdiagnoses with other skin conditions.Physical and functional burdens significantly hindered participants' abilities to carry out daily responsibilities and maintain employment, and impacts on physical appearance (e.g., darkened skin) led to increased self-consciousness and lack of social acceptance.Participants regarded family and faith as main sources of support in addition to developing healthy coping strategies, such as self-acceptance and adaptability.All participants reported feeling satisfied with their access to healthcare information and the quality of care received. ConclusionsOur findings provide greater insights into how HRQoL is impacted across SOC patients with MF/SS, which can help raise awareness among healthcare providers and assist with creating interdisciplinary healthcare approaches to better support the needs of this population.

&lt;p&gt;Survival according to CD3 density/mm2 at the periphery (left), center (middle), and hotspot (right) in MCPyV+ MCCs (Top row) versus MCPyV- MCCs (Second row). Survival according to CD8 density/mm2 at the periphery (left), center (middle), and hotspot (right) in MCPyV+ MCCs. (Third Row) versus MCPyV- MCCs (Bottom row). Legend: Patients with cell densities above the median indicated with a dashed line and patients with cell density below the median indicated with a solid line.&lt;/p&gt;

&lt;p&gt;(A) Kaplan-Meier plot for age and disease specific survival applying a cut off of 71y. (B) Kaplan-Meier plot for sex and disease specific survival. (C) Kaplan-Meier plot for MCPyV status and disease specific survival. (D) Kaplan-Meier plot for perineural invasion and disease specific survival.&lt;/p&gt;

&lt;p&gt;Supplemental Table 1. Relationship Between Merkel Cell Polyoma Virus and Clinicopathologic Parameters. Supplemental Table 2. Univariate Logistic Regression Models for Metastasis to Any Site. Supplemental Table 3. Univariate Logistic Regression for Metastasis to Individual Lymph Node Beyond Sentinel Lymph Node. Supplemental Table 4. Univariate Logistic Regression for Metastasis to Sentinel Lymph Node. Supplemental Table 5. Univariate Logistic Regression for Metastasis to Central Nervous System. Supplemental Table 6. Spearman Correlation Between Cell Density and Age, Tumor Size, Depth of Invasion, and Mitotic Figures. Supplemental Table 7. Relationship Between Gender and Immune Infiltrate. Supplemental Table 8. Merkel Cell Polyoma Virus and Immune Infiltrate. Supplemental Table 9. Immune Infiltrate Cell Density: Descriptive Statistics. Supplemental Table 10. Relationship Between Anatomic Site and Immune Infiltrate. Supplemental Table 11. Relationship Between Lymphovascular Invasion (LVI) and Immune Infiltrate. Supplemental Table 12. Relationship Between Perineural Invasion (PNI) and Immune Infiltrate.&lt;/p&gt;

&lt;p&gt;Figure Legend&lt;/p&gt;

&lt;p&gt;Figure Legend&lt;/p&gt;

&lt;p&gt;(A) Kaplan-Meier plot for age and disease specific survival applying a cut off of 71y. (B) Kaplan-Meier plot for sex and disease specific survival. (C) Kaplan-Meier plot for MCPyV status and disease specific survival. (D) Kaplan-Meier plot for perineural invasion and disease specific survival.&lt;/p&gt;

&lt;p&gt;Survival according to CD3 density/mm2 at the periphery (left), center (middle), and hotspot (right) in MCPyV+ MCCs (Top row) versus MCPyV- MCCs (Second row). Survival according to CD8 density/mm2 at the periphery (left), center (middle), and hotspot (right) in MCPyV+ MCCs. (Third Row) versus MCPyV- MCCs (Bottom row). Legend: Patients with cell densities above the median indicated with a dashed line and patients with cell density below the median indicated with a solid line.&lt;/p&gt;

&lt;p&gt;Supplemental Table 1. Relationship Between Merkel Cell Polyoma Virus and Clinicopathologic Parameters. Supplemental Table 2. Univariate Logistic Regression Models for Metastasis to Any Site. Supplemental Table 3. Univariate Logistic Regression for Metastasis to Individual Lymph Node Beyond Sentinel Lymph Node. Supplemental Table 4. Univariate Logistic Regression for Metastasis to Sentinel Lymph Node. Supplemental Table 5. Univariate Logistic Regression for Metastasis to Central Nervous System. Supplemental Table 6. Spearman Correlation Between Cell Density and Age, Tumor Size, Depth of Invasion, and Mitotic Figures. Supplemental Table 7. Relationship Between Gender and Immune Infiltrate. Supplemental Table 8. Merkel Cell Polyoma Virus and Immune Infiltrate. Supplemental Table 9. Immune Infiltrate Cell Density: Descriptive Statistics. Supplemental Table 10. Relationship Between Anatomic Site and Immune Infiltrate. Supplemental Table 11. Relationship Between Lymphovascular Invasion (LVI) and Immune Infiltrate. Supplemental Table 12. Relationship Between Perineural Invasion (PNI) and Immune Infiltrate.&lt;/p&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm&lt;sup&gt;2&lt;/sup&gt;) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.004) and CD8&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8&lt;sup&gt;+&lt;/sup&gt; T-cell density at the tumor periphery associated with improved DSS (&lt;i&gt;P&lt;/i&gt; = 0.049). Stratifying MCCs according to MCPyV status, higher CD3&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.026) and CD8&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV&lt;sup&gt;+&lt;/sup&gt; but not MCPyV&lt;sup&gt;−&lt;/sup&gt; MCC. TCRseq revealed clonal overlap among MCPyV&lt;sup&gt;+&lt;/sup&gt; samples, suggesting an antigen-specific response against a unifying antigen.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. &lt;i&gt;Clin Cancer Res; 22(22); 5553–63. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm&lt;sup&gt;2&lt;/sup&gt;) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.004) and CD8&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8&lt;sup&gt;+&lt;/sup&gt; T-cell density at the tumor periphery associated with improved DSS (&lt;i&gt;P&lt;/i&gt; = 0.049). Stratifying MCCs according to MCPyV status, higher CD3&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.026) and CD8&lt;sup&gt;+&lt;/sup&gt; (&lt;i&gt;P&lt;/i&gt; = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV&lt;sup&gt;+&lt;/sup&gt; but not MCPyV&lt;sup&gt;−&lt;/sup&gt; MCC. TCRseq revealed clonal overlap among MCPyV&lt;sup&gt;+&lt;/sup&gt; samples, suggesting an antigen-specific response against a unifying antigen.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. &lt;i&gt;Clin Cancer Res; 22(22); 5553–63. ©2016 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

&lt;p&gt;Supplementary Table S1a. Patient Cohort Clinical Summary. Supplementary Table S1b. Patient clinical characteristics. Supplementary Table S1c. Immune profiling by IHC sample log. Supplementary Table S1d. Nanostring 54 sample log. Supplementary Table S2. Summary of immune profiling by immunohistochemistry. Supplementary Table S3. Summary of immune profiling by 4 additional myeloid markers. Supplementary Table S4. Summary of immune profiling by IHC of additional CTLA-4 blockade-naïve samples. Supplementary Table S5. Nanostring Gene List. Supplementary Table S6a. Nanostring summary 54 samples. Supplementary Table S6b. Differentially upregulated and downregulated genes in pre-treatment anti-CTLA-4 samples. Supplementary Table S6c. Differentially upregulated and downregulated genes in on-treatment anti-CTLA-4 samples. Supplementary Table S6d. Differentially upregulated and downregulated genes in pre-treatment anti-PD-1 samples. Supplementary Table S6e. Differentially upregulated and downregulated genes in on-treatment anti-PD-1 samples. Supplementary Table S7. Differentially upregulated and downregulated genes from pre- to on-treatment anti-CTLA-4. Supplementary Table S8. Differentially upregulated and downregulated genes from pre- to on-treatment anti-PD-1. Supplementary Table S9a. Nanostring gene list - chip used for comparison of CTLA-4 blockade-experienced vs -naive anti-PD1 samples (28 samples). Supplementary Table S9b. NanoString additional 28 samples to compare CTLA-4 blockade-experienced vs -naive anti-PD1 samples. Supplementary Table S9c. NanoString normalized data of additional 28 samples to compare CTLA-4 blockade-experienced vs -naive anti-PD1 samples. Supplementary Table S10. Commonly differentially regulated genes between pre- to on-treatment CTLA-4 blockade and PD-1 blockade. Supplementary Table S11a. Fold changes of significant change by anti-PD-1 therapy for paired samples. Supplementary Table S11b. Frequency of significant change by anti-PD1 therapy for paired samples.&lt;/p&gt;

&lt;p&gt;Supplementary Figure Legends&lt;/p&gt;

&lt;p&gt;Supplementary Figure 1. Immune profiling of pre-treatment, on-treatment and progression CTLA-4 blockade samples by immunohistochemistry. Supplementary Figure 2. Myeloid cell profiling of pre-treatment, on-treatment and progression CTLA-4 blockade samples by immunohistochemistry. Supplementary Figure 3. Increased contact between CD8 T cells and CD68 myeloid cells in non-responding patients to anti-CTLA-4 and anti-PD-1 therapy at pre-treatment CTLA-4 blockade, pre-treatment PD-1 blockade, and on-treatment PD-1 blockade time points. Supplementary Figure 4. Immune profiling of pre anti-PD-1, on-treatment anti-PD-1 and progression anti-PD-1 samples by immunohistochemistry. Supplementary Figure 5. Longitudinal increase in CD8, PD-1, and PD-L1 expression in responders to anti-PD-1 therapy. Supplementary Figure 6. Relative increase in CD8 T cell infiltrate at tumor center in responders to anti-PD-1 on treatment. Supplementary Figure 7. Significant increase in immune infiltrate between responders and non-responders to PD-1 blockade in absence of prior anti-CTLA-4 therapy. Supplementary Figure 8. Immune profiling of myeloid cells atpre-treatment and on-treatment PD-1 blockade time pointsby immunohistochemistry. Supplementary Figure 9. Heatmap of 54 NanoString samples. Supplementary Figure 10. Gene-specific NanoString concordance with immune profiling by IHC in pre-treatment, on-treatment and progression CTLA-4 blockade samples. Supplementary Figure 11. Gene-specific NanoString concordance with immune profiling by IHC in pre-treatment, on-treatment and progression PD-1 blockade samples. Supplementary Figure 12. Prior CTLA-4 blockade is not required for PD-1 early on-treatment profile. Supplementary Figure 13. Hierarchical clustering of gene expression across 54 samples confirms lack of batch effect.&lt;/p&gt;

&lt;p&gt;Supplementary Tables S1-S5&lt;/p&gt;

&lt;p&gt;Supplementary Figure Legends&lt;/p&gt;

&lt;p&gt;Supplementary Figures S1-S13&lt;/p&gt;

&lt;div&gt;Abstract&lt;p&gt;Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided &lt;i&gt;in situ&lt;/i&gt; evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74.&lt;/p&gt;Significance:&lt;p&gt;Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma.&lt;/p&gt;&lt;p&gt;&lt;i&gt;This article is highlighted in the In This Issue feature, p. 1171&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Data from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Data from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

&lt;div&gt;Abstract&lt;p&gt;Cutaneous T-cell lymphoma (CTCL) is a rare cancer of skin-homing T cells. A subgroup of patients develops large cell transformation with rapid progression to an aggressive lymphoma. Here, we investigated the transformed CTCL (tCTCL) tumor ecosystem using integrative multiomics spanning whole-exome sequencing (WES), single-cell RNA sequencing, and immune profiling in a unique cohort of 56 patients. WES of 70 skin biopsies showed high tumor mutation burden, UV signatures that are prognostic for survival, exome-based driver events, and most recurrently mutated pathways in tCTCL. Single-cell profiling of 16 tCTCL skin biopsies identified a core oncogenic program with metabolic reprogramming toward oxidative phosphorylation (OXPHOS), cellular plasticity, upregulation of MYC and E2F activities, and downregulation of MHC I suggestive of immune escape. Pharmacologic perturbation using OXPHOS and MYC inhibitors demonstrated potent antitumor activities, whereas immune profiling provided &lt;i&gt;in situ&lt;/i&gt; evidence of intercellular communications between malignant T cells expressing macrophage migration inhibitory factor and macrophages and B cells expressing CD74.&lt;/p&gt;Significance:&lt;p&gt;Our study contributes a key resource to the community with the largest collection of tCTCL biopsies that are difficult to obtain. The multiomics data herein provide the first comprehensive compendium of genomic alterations in tCTCL and identify potential prognostic signatures and novel therapeutic targets for an incurable T-cell lymphoma.&lt;/p&gt;&lt;p&gt;&lt;i&gt;This article is highlighted in the In This Issue feature, p. 1171&lt;/i&gt;&lt;/p&gt;&lt;/div&gt;

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Figure from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma

Supplementary Table from Genomic and Single-Cell Landscape Reveals Novel Drivers and Therapeutic Vulnerabilities of Transformed Cutaneous T-cell Lymphoma