Next generation sequencing-based MSI scoring predict benefit in mismatch repair deficient tumors treated with nivolumab: follow-up on NCI-MATCH arm Z1D.

Purpose: Mismatch repair deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Experimental Design: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-MATCH arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with non-colorectal dMMR tumors.

Tumor-derived CCL2 drives tumor growth and immunosuppression in IDH1- mutant cholangiocarcinoma.

Background And Aims: Isocitrate dehydrogenase 1 ( IDH1 )-mutant cholangiocarcinoma (CCA) is a highly lethal subtype of hepatobiliary cancer that is often resistant to immune checkpoint inhibitor therapies. We evaluated the effects of IDH1 mutations in CCA cells on the tumor immune microenvironment and identified opportunities for therapeutic intervention.

Approach And Results: Analysis of 2606 human CCA tumors using deconvolution of RNA-sequencing data identified decreased CD8+ T cell and increased M2-like tumor-associated macrophage (TAM) infiltration in IDH1 -mutant compared to IDH1 wild-type tumors.

Effects of substance exposure on gametes and pre-implantation embryos: a narrative review.

Substance use refers to the consumption of drugs that have varying degrees of impact on a persons' physical, mental and emotional well-being. While the adverse health effects of drugs have been extensively documented, further research is needed to understand their impact on fertility. Studies have indicated that substance use affects both the male and female reproductive systems.

SpliceMutr Enables Pan-Cancer Analysis of Splicing-Derived Neoantigen Burden in Tumors.

SpliceMutr shows that splicing antigenicity changes in response to ICI therapies and that native modulation of the splicing machinery through mutations increases the contribution of splicing to the neoantigen load of some The Cancer Genome Atlas cancer subtypes. Future studies of the relationship between splicing antigenicity and immune checkpoint inhibitor response pan-cancer are essential to establish the interplay between antigen heterogeneity and immunotherapy regimen on patient response.

Assessment of CMIP6 models and multi-model averaging for temperature and precipitation over Iran.

In this study, the performances of 40 Coupled Model Intercomparison Project Phase 6 are evaluated against observational data at synoptic stations in Iran using various evaluation criteria. The results reveal diverse model accuracy across different climate conditions and criteria, emphasizing particularly notable disparities in the nonstationarity R criterion compared to others. Although according to the ranking of the raw and bias-corrected outputs of CMIP6 GCMs for Iran, the NorESM2-MM, AWI-ESM-1-1-LR, and MPI-ESM1-2-LR models are consistently among the top six ranked models for precipitation in both raw and corrected outputs.

Clinical Applications of Assisted Oocyte Activation in Couples with Various Reproductive Problems: A Systematic Review.

ICSI may face fertilization failure, prompting the use of assisted oocyte activation (AOA) techniques. While AOA is implemented in infertility clinics, its target patients and definitive application remain uncertain. This systematic review adheres to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to assess reproductive outcomes in ICSI-AOA cycles compared to conventional ICSI and evaluate AOA effectiveness in various infertility disorders.

COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.

Topical insulin for refractory persistent corneal epithelial defects.

The aim was clinical evaluation of the efficacy of topical insulin eye drops in patients with refractory persistent epithelial defects (PEDs). This prospective non-randomized investigation was conducted to examine the efficacy of insulin eye drops in treating patients with PEDs that did not respond to conventional therapy. A total of twenty-three patients were included in the study, and they were administered insulin eye drops formulated as 1 U/mL, four times a day.

Immunotherapy for the treatment of biliary tract cancer: an evolving landscape.

Biliary tract cancers (BTCs), consisting of intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer, are an aggressive, heterogeneous malignancy. They are most often diagnosed in the locally advanced or metastatic setting, at which point treatment consists of systemic therapy or best supportive care. Our understanding of the tumor microenvironment and the molecular classification has led to the identification of targetable mutations, such as isocitrate dehydrogenase 1 and fibroblast growth factor receptor 2.

A Short Post-Reattachment Ultrasensitive Window of Time in Human Cancer Cells as Therapeutic Target of Prolonged Low-Dose Administration of Specific Compounds.

Prolonged low-dose administration (PLDA) of several FDA-approved drugs for noncancer conditions or dietary compounds is associated with a lower incidence of specific types of cancers and with the lower formation of metastasis. However, the underlying mechanism is unknown; there is a discrepancy between the concentration of drugs needed to kill cancer cells in vitro and the actual serum levels (10 and >1000 times lower) found in patients. In this study, we evaluated the hypothesis that clonogenicity may be the target of PLDA.

Surgical and local control outcomes after sequential short-course radiation therapy and chemotherapy for rectal cancer.

Background: Total neoadjuvant therapy (TNT) is an accepted approach for the management of locally advanced rectal cancer (LARC) and is associated with a decreased risk of development of metastatic disease compared to standard neoadjuvant therapy. However, questions remain regarding surgical outcomes and local control in patients who proceed to surgery, particularly when radiation is given first in the neoadjuvant sequence. We report on our institution's experience with patients who underwent short-course radiation therapy, consolidation chemotherapy, and surgery.

A phase II study of guadecitabine combined with irinotecan vs regorafenib or TAS-102 in irinotecan-refractory metastatic colorectal cancer patients.

DNA methyltransferase inhibitors (DNMTi) have demonstrated benefit in reversing resistance to systemic therapies for several cancer types. In a phase II trial of guadecitabine and irinotecan compared to regorafenib or TAS-102 in pts with advanced mCRC refractory to irinotecan. Patients with mCRC refractory to irinotecan were randomized 2:1 to guadecitabine and irinotecan (Arm A) vs standard of care regorafenib or TAS-102 (Arm B) on a 28-day cycle.

Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations.

Biliary tract cancers (BTC) are a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC.

CD4 T cell-activating neoantigens enhance personalized cancer vaccine efficacy.

Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8+ T cells to recognize and kill tumor cells. However, the role of CD4+ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8+ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy.

Oxidative stress and signaling through EGFR and PKA pathways converge on the nuclear transport factor RanBP1.

Nuclear protein trafficking requires the soluble transport factor RanBP1. The subcellular distribution of RanBP1 is dynamic, as the protein shuttles between the nucleus and cytoplasm. To date, the signaling pathways regulating RanBP1 subcellular localization are poorly understood.

An application of computable biomedical knowledge to transform patient centered scheduling.

Introduction: Efficient appointment scheduling in the outpatient setting is challenged by two main factors: variability and uncertainty leading to undesirable wait times for patients or physician overtime, and events such as no-shows, cancellations, or walk-ins can result in physician idle time and under-utilization of resources. Some methods have been developed to optimize scheduling and minimize wait and idle times in the inpatient setting but are limited in the outpatient setting.

Methods: People and Organization Development, an internal group of organizational developers, led the development of a solution that selects the optimal group of appointments for a patient that minimizes the time between associated procedures as well as lead time built using a linear integer program.

Barcoding intracellular reverse transcription enables high-throughput phenotype-coupled T cell receptor analyses.

Assays linking cellular phenotypes with T cell or B cell antigen receptor sequences are crucial for characterizing adaptive immune responses. Existing methodologies are limited by low sample throughput and high cost. Here, we present INtraCEllular Reverse Transcription with Sorting and sequencing (INCERTS), an approach that combines molecular indexing of receptor repertoires within intact cells and fluorescence-activated cell sorting (FACS).