Re-evaluation of the methodology for estimating the US specialty physician workforce.

Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends.

Extracorporeal Femoro-Carotid Shunt for Transcarotid Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement may be performed with a transcarotid approach when peripheral vascular disease is prohibitive for transfemoral access. In this case, a patient who presented in cardiogenic shock secondary to severe aortic stenosis developed electroencephalographic changes during transcarotid TAVR. A temporary extracorporeal femoro-carotid shunt permitted successful TAVR.

Synergism of dual AAV gene therapy and rapamycin rescues GSDIII phenotype in muscle and liver.

Glycogen storage disease type III (GSDIII) is a rare metabolic disorder due to glycogen debranching enzyme (GDE) deficiency. Reduced GDE activity leads to pathological glycogen accumulation responsible for impaired hepatic metabolism and muscle weakness. To date, there is no curative treatment for GSDIII. We previously reported that 2 distinct dual AAV vectors encoding for GDE were needed to correct liver and muscle in a GSDIII mouse model. Here, we evaluated the efficacy of rapamycin in combination with AAV gene therapy. Simultaneous treatment with rapamycin and a potentially novel dual AAV vector expressing GDE in the liver and muscle resulted in a synergic effect demonstrated at biochemical and functional levels. Transcriptomic analysis confirmed synergy and suggested a putative mechanism based on the correction of lysosomal impairment. In GSDIII mice livers, dual AAV gene therapy combined with rapamycin reduced the effect of the immune response to AAV observed in this disease model. These data provide proof of concept of an approach exploiting the combination of gene therapy and rapamycin to improve efficacy and safety and to support clinical translation.

A critical role for Pol II CTD phosphorylation in heterochromatic gene activation.

How gene activation works in heterochromatin, and how the mechanism might differ from the one used in euchromatin, has been largely unexplored. Previous work has shown that in SIR-regulated heterochromatin of Saccharomyces cerevisiae, gene activation occurs in the absence of covalent histone modifications and other alterations of chromatin commonly associated with transcription.Here we demonstrate that such activation occurs in a substantial fraction of cells, consistent with frequent transcriptional bursting, and this raises the possibility that an alternative activation pathway might be used. We address one such possibility, Pol II CTD phosphorylation, and explore this idea using a natural telomere-linked gene, YFR057w, as a model. Unlike covalent histone modifications, we find that Ser2, Ser5 and Ser7 CTD phosphorylated Pol II is prevalent at the drug-induced heterochromatic gene. Particularly enriched relative to the euchromatic state is Ser2 phosphorylation. Consistent with a functional role for Ser2P, YFR057w is negligibly activated in cells deficient in the Ser2 CTD kinases Ctk1 and Bur1 even though the gene is strongly stimulated when it is placed in a euchromatic context. Collectively, our results are consistent with a critical role for Ser2 CTD phosphorylation in driving Pol II recruitment and transcription of a natural heterochromatic gene - an activity that may supplant the need for histone epigenetic modifications.

Computational modeling of the thermal effects of flow on radio frequency-induced heating of peripheral vascular stents during MRI.

Purpose. The goal of this study was to develop and validate a computational model that can accurately predict the influence of flow on the temperature rise near a peripheral vascular stent during magnetic resonance imaging (MRI).Methods. Computational modeling and simulation of radio frequency (RF) induced heating of a vascular stent during MRI at 3.0 T was developed and validated with flow phantom experiments. The maximum temperature rise of the stent was measured as a function of physiologically relevant flow rates.Results. A significant difference was not identified between the experiment and simulation (P > 0.05). The temperature rise of the stent during MRI was over 10 °C without flow, and was reduced by 5 °C with a flow rate of only 58 ml min-1, corresponding to a reduction of CEM43from 45 min to less than 1 min.Conclusion. The computer model developed in this study was validated with experimental measurements, and accurately predicted the influence of flow on the RF-induced temperature rise of a vascular stent during MRI. Furthermore, the results of this study demonstrate that relatively low flow rates significantly reduce the temperature rise of a stent and the surrounding medium during RF-induced heating under typical scanning power and physiologically relevant conditions.

Ethanol stress induces transient restructuring of the yeast genome yet stable formation of Hsf1 transcriptional condensates.

In mammals, 3D genome topology has been linked to transcriptional states yet whether this link holds for other eukaryotes is unclear. Here we show that in budding yeast, Heat Shock Response (HSR) genes under the control of Heat Shock Factor (Hsf1) rapidly reposition in cells exposed to acute ethanol stress and engage in concerted, Hsf1-dependent intergenic interactions. Accompanying 3D genome reconfiguration is equally rapid formation of Hsf1-containing condensates. However, in contrast to the transience of Hsf1-driven intergenic interactions that peak within 10 min and dissipate within 1 h, Hsf1 condensates are stably maintained for hours. Moreover, under the same conditions, Pol II occupancy of HSR genes and RNA expression are detectable only later in the response and peak much later (>1 h). This contrasts with the coordinate response of HSR genes to thermal stress where Pol II occupancy, transcription, intergenic interactions, and formation of Hsf1 condensates are all rapid yet transient (peak within 2.5-10 min and dissipate within 1 h). Collectively, our data suggest that different stimuli drive distinct transcription, topologic, and phase-separation phenomena dependent on the same transcription factor and that transcription factor-containing condensates represent only part of the ensemble required for gene activation.

Impact of Single-Time-Point Estimates of 177Lu-PRRT Absorbed Doses on Patient Management: Validation of a Trained Multiple-Linear-Regression Model in 159 Patients and 477 Therapy Cycles.

Dosimetry after 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) enables estimation of radiation doses absorbed by normal organs and target lesions. This process is time-consuming and requires multiple posttreatment studies on several subsequent days. In a previous study, we described a newly developed multiple-linear-regression model to predict absorbed doses (ADs) from a single-time-point (STP) posttreatment study acquired 168 h after the first infusion and 24 h after the following ones, with similar results to the standard multiple-time-point (MTP) protocol. The present study aimed to validate this model in a large patient cohort and to assess whether STP dosimetry affects patient management decisions compared with our MTP protocol. Methods: Quantitative 177Lu-DOTATATE SPECT/CT post-PRRT data from 159 consecutive patients (172 therapies, 477 therapy cycles) were retrospectively analyzed. ADs obtained from an STP model were compared with those obtained using an MTP model. We evaluated the impact of the STP model on the decision on whether PRRT should be stopped because of an expected kidney AD exceeding the safety threshold. We hypothesized that patient management based on the STP model does not differ from that based on the MTP model in at least 90% of the cases. Results: There was no difference in management decisions between the MTP and STP models in 170 of 172 therapies (98.8%). A Fisher χ2 test for combined probabilities produced a composite P value of 0.0003. Mean cumulative AD relative differences between the STP and MTP models were 0.8% ± 8.0%, -7.7% ± 4.8%, 0.0% ± 11.4%, -2.8% ± 6.3%, and -2.1% ± 18.4% for kidneys, bone marrow, liver, spleen, and tumors, respectively (Pearson r = 0.99 for all), for patients who underwent 4 therapy cycles. Similar results were obtained with fewer therapy cycles. Conclusion: Estimated radiation ADs and patient management decisions were similar with the STP and MTP models. The STP model can simplify the dosimetry process while also reducing scanner and staff time and improving patient comfort.

Magnetic Resonance Safety Evaluation of a Novel Alumina Matrix Composite Ceramic Knee and Image Artifact Comparison to a Metal Knee Implant of Analogous Design.

Background: Image artifacts caused by metal knee implants in 1.5T and 3T magnetic resonance imaging (MRI) systems complicate imaging-based diagnosis of the peri-implant region after total knee arthroplasty. Alternatively, metal-free knee prostheses could effectively minimize MRI safety hazards and offer the potential for higher quality diagnostic images. Methods: A novel knee arthroplasty device composed of BIOLOX delta, an alumina matrix composite (AMC) ceramic, was tested in a magnetic resonance (MR) environment. American Society for Testing and Materials test methods were used for evaluating magnetically induced displacement force, magnetically induced torque, radiofrequency-induced heating, and MR image artifact. Results: Magnetically induced displacement force and magnetically induced torque results of the AMC ceramic knee indicated that these effects do not pose a known risk in a clinical MR environment, as assessed in a 3T magnetic field. Moreover, minimal radiofrequency-induced heating of the device was observed. In addition, the AMC ceramic knee demonstrated minimal MR image artifacts (7 mm) in comparison to a cobalt-chromium knee (88 mm). The extremely low magnetic susceptibility of AMC (2 ppm) underlines that it is a nonmetallic and nonmagnetic material well suited for the manufacturing of MR Safe orthopaedic implants. Conclusions: The AMC ceramic knee is a novel metal-free total knee arthroplasty device that can be regarded as MR Safe, as suggested by the absence of hazards from the exposure of this implant to a MR environment. The AMC ceramic knee presents the advantage of being scanned with superior imaging results in 3T MRI systems compared to alternative metal implants on the market.

Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) in Appalachia: protocol for a group randomized, delayed intervention trial.

Appalachian regions of Kentucky and Ohio are hotspots for colorectal cancer (CRC) mortality in the USA. Screening reduces CRC incidence and mortality; however, screening uptake is needed, especially in these underserved geographic areas. Implementation science offers strategies to address this challenge. The aim of the current study was to conduct multi-site, transdisciplinary research to evaluate and improve CRC screening processes using implementation science strategies. The study consists of two phases (Planning and Implementation). In the Planning Phase, a multilevel assessment of 12 health centers (HC) (one HC from each of the 12 Appalachian counties) was conducted by interviewing key informants, creating community profiles, identifying HC and community champions, and performing HC data inventories. Two designated pilot HCs chose CRC evidence-based interventions to adapt and implement at each level (i.e., patient, provider, HC, and community) with evaluation relative to two matched control HCs. During the Implementation Phase, study staff will repeat the rollout process in HC and community settings in a randomized, staggered fashion in the remaining eight counties/HCs. Evaluation will include analyses of electronic health record data and provider and county surveys. Rural HCs have been reluctant to participate in research because of concerns about capacity; however, this project should demonstrate that research does not need to be burdensome and can adapt to local needs and HC abilities. If effective, this approach could be disseminated to HC and community partners throughout Appalachia to encourage the uptake of effective interventions to reduce the burden of CRC.

We conducted a multi-site study to evaluate and improve CRC screening processes using implementation science strategies at multiple levels including the patient, provider, health center, and community. Our goals were to increase rates of guideline-recommended CRC screening, follow-up, and referral-to-care in an Appalachian, medically underserved population.

COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Dynamic coalescence of yeast Heat Shock Protein genes bypasses the requirement for actin.

Nuclear actin has been implicated in dynamic chromatin rearrangements in diverse eukaryotes. In mammalian cells, it is required to reposition double-strand DNA breaks to enable homologous recombination repair and to enhance transcription by facilitating RNA Pol II recruitment to gene promoters. In the yeast Saccharomyces cerevisiae, nuclear actin modulates interphase chromosome dynamics and is required to reposition the induced INO1 gene to the nuclear periphery. Here, we have investigated the role of actin in driving intergenic interactions between Heat Shock Factor 1 (Hsf1)-regulated Heat Shock Protein (HSP) genes in budding yeast. These genes, dispersed on multiple chromosomes, dramatically reposition following exposure of cells to acute thermal stress, leading to their clustering within dynamic biomolecular condensates. Using an auxin-induced degradation strategy, we found that conditional depletion of nucleators of either linear or branched F-actin (Bni1/Bnr1 and Arp2, respectively) had little or no effect on heat shock-induced HSP gene coalescence or transcription. In addition, we found that pretreatment of cells with latrunculin A, an inhibitor of both filamentous and monomeric actin, failed to affect intergenic interactions between activated HSP genes and their heat shock-induced intragenic looping and folding. Moreover, latrunculin A pretreatment had little effect on HSP gene expression at either RNA or protein levels. In notable contrast, we confirmed that repositioning of activated INO1 to the nuclear periphery and its proper expression do require actin. Collectively, our work suggests that transcriptional activation and 3D genome restructuring of thermally induced, Hsf1-regulated genes can occur in the absence of actin.

Strong Job Market for Pathologists: Results From the 2021 College of American Pathologists Practice Leader Survey.

CONTEXT.­: There has long been debate about whether and when there may be a shortage of pathologists in the United States. One way to assess this is to survey the hiring experiences of pathology practices. A 2018 survey revealed a strong demand for pathologists, with expectations of continued strength. This study updates that prior analysis using data from a 2021 survey of pathology practice leaders. OBJECTIVE.­: To assess the US pathologist job market and examine implications. DESIGN.­: We analyzed data from the 2021 College of American Pathologists Practice Leader Survey. This survey queried practice leaders, including regarding the hiring of pathologists, the level of experience being sought, success in filling positions, and expectations for hiring in the next 3 years. RESULTS.­: Among the 375 surveyed practice leaders (about one-third of all US pathology practices), 282 provided information about pathologist hiring in 2021. A total of 157 of these 282 practices (55.7%) sought to hire at least 1 pathologist in 2021, up from 116 of 256 practices (45.3%) in 2017; the mean number of pathologists hired per practice also increased. In 2021, a total of 175 of 385 positions (45.5%) were to fill new positions, compared with 95 of 249 positions (38.2%) in 2017. Most practice leaders were comfortable hiring pathologists with less than 2 years of posttraining experience. Practice leaders anticipated continued strong demand for hiring pathologists during the next 3 years. CONCLUSIONS.­: Our analysis confirms that the demand in pathologist hiring is strong and much increased from 2017. We believe, in combination with other job market indicators, that demand may outstrip the supply of pathologists, which is limited by the number of trainees and has remained constant during the past 20 years.

Plasma Progastrin-Releasing Peptide and Chromogranin A Assays for Diagnosing and Monitoring Lung Well-Differentiated Neuroendocrine Tumors: A Brief Report.

INTRODUCTION: The use of chromogranin A (CGA) as a circulating biomarker in lung carcinoids (LCs) is limited by low specificity and sensitivity. This study aimed to evaluate plasma progastrin-releasing peptide (ProGRPp) as an alternative to plasma CGA (CGAp), for the diagnosis and follow-up of LC. METHODS: ProGRPp and CGAp concentrations were measured in 107 patients with LC and 105 patients with benign lung disease (BLD). RESULTS: ProGRPp distinguished patients with LC with active disease in the pretreatment (n = 43) and post-treatment (n = 43) groups from those with BLD: area under the curve for both 0.864 (p < 0.0001); sensitivity 67.4% and 58.1%, respectively; specificity 96.2%; at 64 pg/mL cutoff. CGAp failed to differentiate both LC groups from those with BLD: area under the curve 0.579 and 0.526 (for both p > 0.1); sensitivity 34.9% and 25.6%, respectively; specificity 73.3%; at 104 ng/mL cutoff. Only ProGRPp correlated with the Ki67 proliferation index (r = 0.40, p < 0.001) and was associated with mitotic count (p = 0.025), stage (p = 0.018), grade (p = 0.019), and the expression of thyroid transcription factor-1 (p = 0.005). ProGRPp had a high sensitivity (92.3%) in LC with diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. Abnormal postoperative ProGRPp level was associated with residual disease (p = 0.029). The changes in ProGRPp level during treatment, a decrease greater than 30% and an increase greater than 8%, were associated with image-based outcomes, partial response and disease progression, respectively (p < 0.0001). CGAp did not reflect the disease course. CONCLUSIONS: ProGRPp was superior to CGAp in diagnosing LC with correlations concerning proliferation, grading, staging, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia co-occurrence, and response to treatment. ProGRPp is an optimal emerging biomarker to be further evaluated.

Inducible transcriptional condensates drive 3D genome reorganization in the heat shock response.

Mammalian developmental and disease-associated genes concentrate large quantities of the transcriptional machinery by forming membrane-less compartments known as transcriptional condensates. However, it is unknown whether these structures are evolutionarily conserved or involved in 3D genome reorganization. Here, we identify inducible transcriptional condensates in the yeast heat shock response (HSR). HSR condensates are biophysically dynamic spatiotemporal clusters of the sequence-specific transcription factor heat shock factor 1 (Hsf1) with Mediator and RNA Pol II. Uniquely, HSR condensates drive the coalescence of multiple Hsf1 target genes, even those located on different chromosomes. Binding of the chaperone Hsp70 to a site on Hsf1 represses clustering, whereas an intrinsically disordered region on Hsf1 promotes condensate formation and intergenic interactions. Mutation of both Hsf1 determinants reprograms HSR condensates to become constitutively active without intergenic coalescence, which comes at a fitness cost. These results suggest that transcriptional condensates are ancient and flexible compartments of eukaryotic gene control.

Features of burnout amongst pathologists: A reassessment.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice.

Phase-separation antagonists potently inhibit transcription and broadly increase nucleosome density.

Biomolecular condensates are self-organized membraneless bodies involved in many critical cellular activities, including ribosome biogenesis, protein synthesis, and gene transcription. Aliphatic alcohols are commonly used to study biomolecular condensates, but their effects on transcription are unclear. Here, we explore the impact of the aliphatic dialcohol, 1,6-hexanediol (1,6-HD), on Pol II transcription and nucleosome occupancy in budding yeast. As expected, 1,6-HD, a reagent effective in disrupting biomolecular condensates, strongly suppressed the thermal stress-induced transcription of Heat Shock Factor 1-regulated genes that have previously been shown to physically interact and coalesce into intranuclear condensates. Surprisingly, the isomeric dialcohol, 2,5-HD, typically used as a negative control, abrogated Heat Shock Factor 1-target gene transcription under the same conditions. Each reagent also abolished the transcription of genes that do not detectably coalesce, including Msn2/Msn4-regulated heat-inducible genes and constitutively expressed housekeeping genes. Thus, at elevated temperature (39 °C), HDs potently inhibit the transcription of disparate genes and as demonstrated by chromatin immunoprecipitation do so by abolishing occupancy of RNA polymerase in chromatin. Concurrently, histone H3 density increased at least twofold within all gene coding and regulatory regions examined, including quiescent euchromatic loci, silent heterochromatic loci, and Pol III-transcribed loci. Our results offer a caveat for the use of HDs in studying the role of condensates in transcriptional control and provide evidence that exposure to these reagents elicits a widespread increase in nucleosome density and a concomitant loss of both Pol II and Pol III transcription.

Prognostic Factors in Advanced Adrenocortical Carcinoma: Summary of a National Referral Center's 20 years of Experience.

Context: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination etoposide-doxorubicin-cisplatin-mitotane (EDP-M) is highly toxic and some patients benefit from mitotane monotherapy. However, identification of these patients remains challenging. Objective: We present a summary of the Israeli national referral center's 20 years of experience in treating advanced ACC, with the aim of identifying prognostic factors and assisting in treatment decision making. Methods: We conducted a retrospective multivariate analysis of patients treated for metastatic or locally advanced ACC at Hadassah Medical Center between 2000 and 2020 to determine clinical, pathological, and treatment factors correlated with overall survival (OS). Results: In our cohort of 37 patients, a combination of modified European Network for the study of Adrenal Tumors (mENSAT) staging with either grade and R status, or age and symptoms was validated to stratify prognosis (P = .01 and P = .03, respectively). Patients who underwent R0 resection followed by radiotherapy or metastasectomy for oligometastatic disease had longer OS than patients with residual disease: median OS of 55 months vs 14 months, respectively, hazard ratio 3.1 (CI 1.4-6.7, P = .005). Patients treated with mitotane monotherapy had a significantly better prognosis, yet this result was attenuated in a multivariate analysis controlling for mENSAT and R status. Of patients treated with EDP-M, 41.4% experienced grade 3 or higher adverse events. Conclusion: Patients with advanced ACC achieving R0 status have a better prognosis and might benefit from mitotane monotherapy.

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.