Peptriever: a Bi-Encoder approach for large-scale protein-peptide binding search.

MOTIVATION: Peptide therapeutics hinge on the precise interaction between a tailored peptide and its designated receptor while mitigating interactions with alternate receptors is equally indispensable. Existing methods primarily estimate the binding score between protein and peptide pairs. However, for a specific peptide without a corresponding protein, it is challenging to identify the proteins it could bind due to the sheer number of potential candidates. RESULTS: We propose a transformers-based protein embedding scheme in this study that can quickly identify and rank millions of interacting proteins. Furthermore, the proposed approach outperforms existing sequence- and structure-based methods, with a mean AUC-ROC and AUC-PR of 0.73. AVAILABILITY: Training data, scripts, and fine-tuned parameters are available at https://github.com/RoniGurvich/Peptriever. The proposed method is linked with a web application available for customized prediction at https://peptriever.app/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Assessing the effect of metastasis-directed therapy in oligometastatic disease using the restricted mean survival time.

BACKGROUND: Metastasis-directed therapy (MDT) with stereotactic body radiotherapy (SBRT) is emerging as an effective therapeutic option for oligometastatic disease (OMD). However, a lack of phase III data, consensus guidelines, and toxicity concerns limit its widespread use. Randomized controlled trials (RCTs) routinely report hazard ratios (HRs) and medians that lack clear clinical and robust interpretation. Restricted-mean survival time (RMST) is the duration of time a patient is expected to survive over the follow-up period, providing a robust and interpretable alternative. We analyzed the efficacy of SBRT using RMST. METHODS: All registered RCTs of ablative radiotherapy in OMD in ClinicalTrials.gov through 2022 were identified. Data were reconstructed from Kaplan-Meier curves, and the HRs and RMST differences were estimated for surrogate endpoints (SEs) and overall survival (OS). RESULTS: Six studies comprising 426 patients met the inclusion criteria. The RMST differences for SEs ranged from 4.6 months in a study by Iyengar et al. to 11.1 months in SABR-COMET. The RMST differences for OS in SABR-COMET, Gomez et al., and SINDAS studies were 12.6, 15 and 7.9 months, respectively. CONCLUSION: RMST demonstrates the efficacy of local treatment in OMD. Representing the expected survival time, this method effectively communicates outcomes to patients and clinicians.

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness.

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction. Besides established regulators, we uncover genes controlling T cell fitness either specifically or commonly upon differential stimulation. Dap5 ablation, ranking highly in all three screens, increases translation while enhancing tumor killing. Loss of Icam1-mediated homotypic T cell clustering amplifies cell expansion and effector functions after both acute and intense stimulation. Lastly, Ctbp1 inactivation induces functional T cell persistence exclusively upon chronic stimulation. Our results functionally annotate fitness regulators based on their unique or shared contribution to traits limiting T cell antitumor activity.

Projecting complete redaction of clinical trial protocols (RAPTURE): redacted cross sectional study.

OBJECTIVES: To characterise redactions in clinical trials and estimate a time when all protocols are fully removed (RAPTURE). DESIGN: Redacted cross sectional study. SETTING: Published phase 3 randomised controlled trials from 1 January 2010 to ██████████████. PARTICIPANTS: New England Journal of Medicine, ██████████, and Journal of the American Medical Association. MAIN OUTCOME MEASURES: █████ ████████ ██████████████ ██████ ██████████ ████████ ████████ ██████████ ███████████ ████████████ ████████████ ████████████████████████ ██████████████████ RESULTS: ████████████████████ met the inclusion criteria, with 268 (56.7%) research protocols available and accessible. The rate of redactions in protocols has increased from 0 in 2010 to 60.8% in 2021 (P<0.001). The degree of data redaction has also increased, with the average cumulative redactions among industry funded trials rising from 0 in 2010 to 3.5 pages in 2021 (P<0.001). Modelling predicts that RAPTURE is expected to occur between 2073 and 2136. Redactions featured predominantly in ████████ sponsored trials and mostly occurred in the statistical design. CONCLUSIONS: This study highlights the rise in protocol redactions and predicts that, ██████████████████████████████████████████ will be entirely redacted between 2073 and 2136. A legitimate rationale for the redactions could ███ be found. A multipronged strategy against protocol redactions is required to maintain the integrity of science. AVAILABILITY: This paper is partially redacted, but for the sake of ███████████, a version without any redactions can be found in the supplementary material.

Gender Gap in Leadership of Clinical Trials.

This cross-sectional study investigates representation of women as principal investigators of clinical trials by study phase, medical specialty, and representation of women trial participants.

MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2.

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNγ and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNγ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the control of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagenesis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNγ responsiveness of melanomas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma - A real-world experience from Israel.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods: The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade _3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion: This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer.

A major effort in cancer research is to organize the complexities of the disease into fundamental traits. Despite conceptual progress in the last decades and the synthesis of hallmark features, no organizing principles governing cancer beyond cellular features exist. We analyzed experimentally determined structures harboring the most significant and prevalent driver missense mutations in human cancer, covering 73% (n = 168178) of the Catalog of Somatic Mutation in Cancer tumor samples (COSMIC). The results reveal that a single structural element-κ-helix (polyproline II helix)-lies at the core of driver point mutations, with significant enrichment in all major anatomical sites, suggesting that a small number of molecular traits are shared by most and perhaps all types of cancer. Thus, we uncovered the lowest possible level of organization at which carcinogenesis takes place at the protein level. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.

Primary cemiplimab treatment for orbital squamous cell carcinoma is effective and may alleviate the need for orbital exenteration.

PURPOSE: To evaluate the effectiveness of cemiplimab, a Programmed-cell-death-1(PD-1) protein inhibitor, for the treatment of cutaneous periocular-locally-advanced squamous-cell-carcinoma (POLA-SCC) with orbital-invasion. METHODS: Multicentre real-world retrospective study. Demographic and clinical data were collected and analysed for patients with biopsy-proven POLA-SCC(AJCC-T4) with orbital-invasion who were treated with cemiplimab at one of four tertiary medical centres in 2019-2022. RESULTS: The cohort included 13 patients, 8 males and 5 females, of median age 76 years (IQR65-86). The median duration of treatment was 5.0months (IQR3.5-10.5) and the median follow-up time, 15.0 months (IQR10.5-30). The overall response rate was 69.2%. Complete response was documented in seven patients (53.8%), partial response in two (15.4%), stable disease in one (7.7%), and progressive disease in two (15.4%); in one patient (7.7%), response was not evaluable. Six complete responders (46.1% of the cohort) received no further treatment and did not have a recurrence during an average follow-up of 6.14 (±6.9) months from treatment cessation. None of the patients underwent orbital-exenteration. The majority of adverse events were mild (grade-1), except for a moderate increase in creatinine level (grade-2), severe bullous dermatitis (grade-3), and myocarditis (grade-5) in one patient each. Four patients (30.7%) died during the follow-up period, all of whom had an Eastern-Cooperative-Oncology-Group score of 4 at presentation. CONCLUSIONS: To our knowledge, this is the largest study to date on cemiplimab therapy for cutaneous POLA-SCC with orbital-invasion. Treatment was shown to be effective, with an overall response rate of 69.2%. Cemiplimab holds promise for the treatment of patients with tumours invading the orbit as it may alleviate the need for orbital exenteration.

Systemic review of the robustness of randomized controlled trials for the treatment of cholangiocarcinoma in three domains: survival-inferred fragility index, restricted mean survival time, and the spin effect.

Background: The vast majority of patients with cholangiocarcinoma (CC) have advanced disease at diagnosis and are candidates for palliative treatment only. The robustness of the randomized controlled trials regarding the treatment of CC are assessed. Methods: A systematic review of all randomized control trials (RCT) of treatments for both intra- and extrahepatic CC between 2010 and 2020 was performed. The survival-inferred fragility index (SIFI; the minimum number of reassignments of the best survivors between arms that would overturn the statistical outcomes) was calculated. In addition, the gain, or loss, in survival in RCTs was evaluated by the restricted mean survival time (RMST) difference. Finally, the level of spin i.e., misrepresentation of study outcomes, was measured in inconclusive studies to assess distorted reporting strategies. Results: Out of 6,167 studies retrieved, 11 could be retained for full text revision (7 with both intra- and extrahepatic CC, 3 with peri-hilar CC, and 1 with peri-hilar or distal CC). Only 3 studies included resected patients (2 with both intra- and extrahepatic CC and 1 with peri-hilar or distal CC). Nine studies investigated systemic chemotherapy (including 3 after surgical resection), one study evaluated photodynamic therapy, and another investigated the use of an endoscopically inserted stent in the biliary tract. The median SIFI was -2 [interquartile range (IQR): -6.25, -0.25] across all studies. Overall, the median RMST difference was 0.56 months (IQR: 0.10, 0.95). Finally, for inconclusive studies, the level of spin was high, moderate, and low in respectively 12.5%, 25%, and 62.5% of the studies. Conclusions: RCTs of CC showed a low degree of robustness with a frequent proportion of associated spin.

Analysis of new treatments proposed for malignant pleural mesothelioma raises concerns about the conduction of clinical trials in oncology.

In this commentary, using existing clinical trial data and FDA approvals we propose that there is currently a critical need for an appropriate balancing between the financial impact of new cancer drugs and their actual benefit for patients. By adopting "pleural mesothelioma" as our clinical model we summarize the most relevant pertinent and available literature on this topic, and use an analysis of the reliability of the trials submitted for registration and/or recently published as a case in point to raise concerns with respect to appropriate trial design, biomarker based stratification and to highlight the ongoing need for balancing the benefit/cost ratio for both patients and healthcare providers.

Trends in Women's Leadership of Oncology Clinical Trials.

It has been widely reported that women are underrepresented in leadership positions within academic medicine. This study aimed to assess trends in women representation as principal investigators (PIs) in oncology clinical trials and to characterize trends in women's leadership in such trials conducted between 1999 and 2019. The gender of 39,240 PIs leading clinical trials was determined using the gender prediction software Genderize.io. In total, 11,516 (27.7%) women served as PIs. Over the past 20 years, an annual increase of 0.65% in women PIs was observed. Analysis by geographic distribution revealed higher women representation among PIs in North America and Europe compared to Asia. Industry-funded trials were associated with lower women PI representation than academic-funded trials (31.4% vs. 18.8%, p<0.001). Also, women PIs were found to be underrepresented in late-phase as compared to early-phase studies (27.9%, 25.7%, 21.6%, and 22.4% in phase I, II, III, and IV, respectively; Cochran-Armitage test for trend, p<0.001). Furthermore, an association was found between the PI's gender and enrolment of female subjects (50% vs. 43% female participants led by women vs men PIs, respectively, p<0.001). Taken together, while the gender gap in women's leadership in oncology trials has been steadily closing, prominent inequalities remain in non-Western countries, advanced study phases, industry-funded trials and appear to be linked to a gender gap in patient accrual. These observations can serve for the development of strategies to increase women's representation and to monitor progress toward gender equality in PIs of cancer clinical trials.

Adenosine-Deaminase-Acting-on-RNA-1 Facilitates T-cell Migration toward Human Melanoma Cells.

The effect of tumor/T-cell interactions on subsequent immune infiltration is undefined. Here, we report that preexposure of melanoma cells to cognate T cells enhanced the chemotaxis of new T cells in vitro. The effect was HLA class I-restricted and IFNγ-dependent, as it was abolished by ß2M-knockdown, MHC-blocking antibodies, JAK1 inhibitors, JAK1-silencing and IFNgR1-blocking antibodies. RNA sequencing (RNA-seq) of 73 melanoma metastases showed a significant correlation between the interferon-inducible p150 isoform of adenosine-deaminase-acting-on-RNA-1 (ADAR1) enzyme and immune infiltration. Consistent with this, cocultures of cognate melanoma/T-cell pairs led to IFNγ-dependent induction of ADAR1-p150 in the melanoma cells, as visualized in situ using dynamic cell blocks, in ovo using fertilized chick eggs, and in vitro with Western blots. ADAR1 staining and RNA-seq in patient-derived biopsies following immunotherapy showed a rise in ADAR1-p150 expression concurrently with CD8+ cell infiltration and clinical response. Silencing ADAR1-p150 abolished the IFNγ-driven enhanced T-cell migration, confirming its mechanistic role. Silencing and overexpression of the constitutive isoform of ADAR1, ADAR1-p110, decreased and increased T-cell migration, respectively. Chemokine arrays showed that ADAR1 controls the secretion of multiple chemokines from melanoma cells, probably through microRNA-mediated regulation. Chemokine receptor blockade eliminated the IFNγ-driven T-cell chemotaxis. We propose that the constitutive ADAR1 downregulation observed in melanoma contributes to immune exclusion, whereas antigen-specific T cells induce ADAR1-p150 by releasing IFNγ, which can drive T-cell infiltration.

Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma.

Importance: Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments. Objective: To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003. Design, Setting, and Participants: This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021. Main Outcomes and Measures: Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT. Results: A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048). Conclusions and Relevance: This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.

The common sense behind clinical trial names: An empirical study of trial acronyms.

The use of acronyms to name clinical trials, some of which might be manipulative or even coercive, is increasingly popular yet controversial. We aimed to evaluate whether trial acronyms are associated with appealing linguistic cues born of marketing psychology using trade names of perfumes. The proportion of trials (730 clinical trials) titled with an acronym was 61%. Among acronym-named trials, 70% have matching trade names of perfumes, i.e., - alluring names. Industry-sponsored trials were more likely to use acronyms (OR 1.61; 95% CI 1.15-2.26; p = 0.006) and alluring acronyms (OR 2.58; 95% CI 1.61-4.12; p < 0.001). During the period from 2000 to 2020, the proportion of alluring trials increased both for industry and academic funding, from 50% to 77% and from 0% to 57% , respectively. Also, trials with alluring acronyms were cited more often (relative rate of citation, 1.37; 95% CI 1.13-1.66; p = 0.001). The growing use of acronyms coincides with a noticeable increase in manipulative names. Through overt or subliminal enticement, inspirational acronyms that downplay the risks or raise expectations to patients with life-threatening illnesses, may exert undue influence. The observed relationship between manipulative acronyms and sponsorship by the pharmaceutical industry enhances this concern.