Notes

Cross-Domain Self-Supervised Full Geometric Representation Learning pertaining to Real-Scanned Stage Impair Centered Pathological Stride Investigation.
Males experienced a longitudinal increase in spindle density 31% greater than females by 12-14 years (p = 0.006). Females experienced an increase in spindle frequency and fast spindle percent 2% and 41% greater, respectively, than males by 18-22 years (both p = 0.004), while males experienced a 14% greater decline in spindle power by 18-22 years (p = 0.018). Less mature adolescents (86% male) experienced a longitudinal increase in spindle density 36% greater than mature adolescents by 12-14 years (p = 0.002). Overall, males experience greater maturational changes in spindle density in the transition to adolescence, driven by later pubertal development, and sex differences become prominent in early adulthood when females have greater spindle power, frequency, and fast spindle percent.
A subset of primary prostate cancer expresses programmed death-ligand 1 (PD-L1), but whether they have a unique tumor immune microenvironment or genomic features is unclear.

We selected PD-L1-positive high-grade and/or high-risk primary prostate cancer, characterized tumor-infiltrating lymphocytes with multiplex immunofluorescence, and identified genomic alterations in immunogenic and nonimmunogenic tumor foci.

One quarter of aggressive localized prostate cancer cases (29/115) had tumor PD-L1 expression more than 5%. This correlated with increased density of CD8
T cells, a large fraction coexpressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8
PD-1
cells did not express terminal exhaustion markers (TIM3 or LAG3), while a subset expressed TCF1. Consistent with these CD8
PD-1
TCF1
cells being progenitors, they were found in antigen-presenting cell niches in close proximity to MHC-II
cells. CD8 T-cell density in immunogenic prostate cancer and renal ceckpoint inhibitors (ICI). Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of patients with localized prostate cancer.
The efficacy of EZH2 inhibition has been modest in the initial clinical exploration of diffuse large B-cell lymphoma (DLBCL), yet EZH2 inhibitors are well tolerated. Herein, we aimed to uncover genetic and pharmacologic opportunities to enhance the clinical efficacy of EZH2 inhibitors in DLBCL.

We conducted a genome-wide sensitizing CRISPR/Cas9 screen with tazemetostat, a catalytic inhibitor of EZH2. The sensitizing effect of
loss of function was then validated and leveraged for combination treatment with lenalidomide. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing analyses were performed to elucidate transcriptomic and epigenetic changes underlying synergy.

We identified
knockout as the top candidate for sensitizing DLBCL cells to tazemetostat. Treating cells with tazemetostat and lenalidomide, an immunomodulatory drug that selectively degrades IKAROS and AIOLOS, phenocopied the effects of the CRISPR/Cas9 screen. The combined drug treatment triggered either cell-cycle arrest or apoptosis in a broad range of DLBCL cell lines, regardless of
mutational status. Cell-line-based xenografts also showed slower tumor growth and prolonged survival in the combination treatment group. RNA-seq analysis revealed strong upregulation of interferon signaling and antiviral immune response signatures. Gene expression of key immune response factors such as
and
were induced in cells treated with lenalidomide and tazemetostat, with a concomitant increase of H3K27 acetylation at their promoters. Furthermore, transcriptome analysis demonstrated derepression of endogenous retroviruses after combination treatment.

Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Our data underscore the synergistic interplay between IKAROS degradation and EZH2 inhibition on modulating epigenetic changes and ultimately enhancing antitumor effects in DLBCL.
Comorbid medical conditions define a subset of patients with chronic lymphocytic leukemia (CLL) with poor outcomes. However, which comorbidities are most predictive remains understudied.

We conducted a retrospective analysis from 10 academic centers to ascertain the relative importance of comorbidities assessed by the cumulative illness rating scale (CIRS). The influence of specific comorbidities on event-free survival (EFS) was assessed in this derivation dataset using random survival forests to construct a CLL-specific comorbidity index (CLL-CI). Cox models were then fit to this dataset and to a single-center, independent validation dataset.

The derivation and validation sets comprised 570 patients (59% receiving Bruton tyrosine kinase inhibitor, BTKi) and 167 patients (50% receiving BTKi), respectively. Of the 14 CIRS organ systems, three had a strong and stable influence on EFS any vascular, moderate/severe endocrine, moderate/severe upper gastrointestinal comorbidity. These were combined to create the CLL-CI score, which was categorized into 3 risk groups. In the derivation dataset, the median EFS values were 58, 33, and 20 months in the low, intermediate, and high-risk groups, correspondingly. Two-year overall survival (OS) rates were 96%, 91%, and 82%. In the validation dataset, median EFS values were 81, 40, and 23 months (two-year OS rates 97%/92%/88%), correspondingly. Selleck BI-1347 Adjusting for prognostic factors, CLL-CI was significantly associated with EFS in patients treated with either chemo-immunotherapy or with BTKi in each of our 2 datasets.

The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
The CLL-CI is a simplified, CLL-specific comorbidity index that can be easily applied in clinical practice and correlates with survival in CLL.
CD137 agonism and CSF-1R blockade augment stereotactic body radiotherapy (SBRT) and anti-PD1 in pre-clinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF-1R inhibitor).

This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1-4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if less than or equal to33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies.

Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (
=3 grade 3,
=4 grade 4) in the following anatomic cohorts abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months (95% CI 2.9-4.8) and 17.0 months (95% CI 6.8-undetermined), respectively. No patients with elevated pre-SBRT serum interleukin-8 experienced a response.

SBRT to less than or equal to4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest anti-tumor activity.
SBRT to less than or equal to4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest anti-tumor activity.
Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi-ICB interaction in a prostate cancer-specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC.

We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS-STING and DDR signaling in treated cells, and treated a syngeneic androgen-indifferent, prostate cancer model with combined ATR inhibition and anti-programmed death ligand 1 (anti-PD-L1), and performed single-cell RNA sequencing analysis in treated tumors.

ATR inhibitor (ATRi; BAY1895433) directly repressed ATR-CHK1 signaling, activated CDK1-SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS-STING-initiated, IFN-β-mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti-PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell-dependent therapeutic response in our syngeneic mouse model.

This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.
This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.
The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understanding its potential prognostic implications.

We deconvoluted the transcriptomic profiles of 1,779 tumors from the PETACC8 trial and 155 colon cancer cell lines as weighted sums of the four CMSs, using the Weighted In Silico Pathology (WISP) algorithm. We assigned to each tumor and cell line a combination of up to three CMS subtypes with a threshold above 20%.

Over 55% of tumors corresponded to mixtures of at least two CMSs, demonstrating pervasive ITH in colon cancer. Of note, ITH was associated with shorter disease-free survival (DFS) and overall survival, [HR, 1.34; 95% confidence interval (CI; 1.12-1.59), 1.40, 95% CI (1.14-1.71), respectively]. Moreover, we uncoveredS-related cell populations. Transcriptomic ITH deserves further assessment in the context of personalized medicine.
While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.

We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified
chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.

We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation.
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