Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.

Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs.

UNIK (Urologic Non-Neoplastic Investigation of Kidneys): a machine learning approach to decode benign lesion.

Purpose: Predicting the likelihood of benign neoplasia in patients with suspected renal cell carcinoma (RCC) is a cornerstone of presurgical planning. We sought to create and validate U.N.

Elucidating the genetic mechanisms governing cytosine base editing outcomes through CRISPRi screens.

Cytosine base editors enable programmable and efficient genome editing using an intermediate featuring a U•G mismatch across from a DNA nick. This intermediate facilitates two major outcomes, C•G to T•A and C•G to G•C point mutations, and it is not currently well-understood which DNA repair factors are involved. Here, we couple reporters for cytosine base editing activity with knockdown of 2015 DNA processing genes to identify genes involved in these two outcomes.

Incidence of benign prostatic hyperplasia in testicular cancer survivors in the Veteran's affairs health system.

Introduction: Testosterone and prostatic inflammation have been postulated to influence the development of benign prostatic hyperplasia (BPH). Our study aims to evaluate the incidence of BPH in Testicular Cancer (TCa) survivors, focusing on its association with chemotherapy and post TCa diagnosed hypogonadism.

Methods: We conducted a retrospective cohort analysis of US veterans diagnosed with TCa between 1990 and 2021, using the Veterans affairs database.

Inducible FAK loss but not FAK inhibition in endothelial cells of PYK2-null mice activates p53 tumor suppressor to prevent tumor growth.

Focal adhesion kinase (FAK) and the related tyrosine kinase PYK2 are signaling and scaffolding proteins co-expressed in endothelial cells (ECs) that regulate blood vessel function and tumor growth. As FAK-PYK2 share overlapping cellular roles, we generated PYK2 FAK mice with tamoxifen-inducible EC-specific Cre expression. EC FAK inactivation in PYK2 but not PYK2 mice led to increased heart and lung mass, vascular leakage, and created a tumor microenvironment that was repressive to syngeneic melanoma, breast, and lung carcinoma implanted tumor growth.

Precision genome editing and in-cell measurements of oxidative DNA damage repair enable functional and mechanistic characterization of cancer-associated MUTYH variants.

Functional characterization of genetic variants has the potential to advance the field of precision medicine by enhancing the efficacy of current therapies and accelerating the development of new approaches to combat genetic diseases. MUTYH is a DNA repair enzyme that recognizes and repairs oxidatively damaged guanines [8-oxoguanine (8-oxoG)] mispaired with adenines (8-oxoG·A). While some mutations in the MUTYH gene are associated with colorectal cancer, most MUTYH variants identified in sequencing databases are classified as variants of uncertain significance.

Genome editing with programmable base editors in human cells.

Genome editing has garnered significant attention over the last decade, resulting in a massive expansion of the genome engineering toolbox. Base editors encompass a class of tools that enable installing single-nucleotide changes in genomic DNA without the use of double-strand breaks. With the ever-increasing development of new and/or improved base editor systems, it is easy to be overwhelmed by the abundance of options.

Characteristics and Outcomes of T1a Renal Cell Carcinoma Presenting with Metastasis.

Objectives: The incidence of renal cell carcinoma (RCC) has been rising, largely due to increased incidental detection from widespread imaging. Although synchronous distant metastasis (SM) with a primary renal tumor measuring <4 cm (cT1a) is uncommon, its presence may influence survival outcomes and the utility of cytoreductive nephrectomy. We sought to investigate clinical characteristics, metastatic patterns, treatments, and survival outcomes of patients with T1a RCC.

Trends and Outcomes in Sarcomatoid Renal Cell Carcinoma: Analysis of the National Cancer Data Base.

Background And Objective: Our aim was to determine the clinical characteristics, temporal trends, and survival outcomes for sarcomatoid-dedifferentiated renal cell carcinoma (sRCC), as sRCC has historically had poor prognosis and a contemporary cohort has not been well characterized in a population-based study.

Methods: Data for 302 630 RCC cases from 2010 to 2019 were extracted from the National Cancer Data Base, of which 4.1% (12 329) were sRCC.

ISG15 Drives Immune Pathology and Respiratory Failure during Systemic Lymphocytic Choriomeningitis Virus Infection.

ISG15, an IFN-stimulated gene, plays a crucial role in modulating immune responses during viral infections. Its upregulation is part of the host's defense mechanism against viruses, contributing to the antiviral state of cells. However, altered ISG15 expression can also lead to immune dysregulation and pathological outcomes, particularly during persistent viral infections.

Targeting Human Pancreatic Cancer with a Fluorophore-Conjugated Mucin 4 (MUC4) Antibody: Initial Characterization in Orthotopic Cell Line Mouse Models.

Pancreatic cancer is the third leading cause of death related to cancer. The only possible cure presently is complete surgical resection; however, this is limited by difficulty in clearly defining tumor margins. Enhancement of the visualization of pancreatic ductal adenocarcinoma (PDAC) tumor margins using near-infrared dye-conjugated tumor-specific antibodies was pioneered by using anti-CEA, anti-CA19.

Baseline biomarkers of efficacy and on-treatment immune-profile changes associated with bempegaldesleukin plus nivolumab.

In PIVOT IO 001 (NCT03635983), the combination of the investigational interleukin-2 agonist bempegaldesleukin (BEMPEG) with nivolumab (NIVO) had no added clinical benefit over NIVO monotherapy in unresectable/metastatic melanoma. Pre-defined baseline and on-treatment changes in selected biomarkers were analyzed to explore the potential mechanisms underlying the clinical observations. In each treatment arm, higher baseline tumor mutational burden or immune infiltration/inflammation was associated with improved efficacy compared with lower levels.

Hypersensitivity to type I interferon as a cause of hydrocephalus development.

Ubiquitin specific protease 18 (USP18) serves as a potent inhibitor of Type I interferon (IFN) signaling. Previous studies have shown that Usp18 deficient (homozygous Usp18 gene knockout) mice exhibit hydrocephalus; however, the precise molecular mechanism underlying hydrocephalus development remains elusive. In this study, we demonstrate that mice lacking both type I IFN receptor subunit 1 (Ifnar1) and Usp18 (Ifnar1/Usp18 double knockout mice) are viable and do not display a hydrocephalus phenotype.

Identification of different classes of genome instability suppressor genes through analysis of DNA damage response markers.

Cellular pathways that detect DNA damage are useful for identifying genes that suppress DNA damage, which can cause genome instability and cancer predisposition syndromes when mutated. We identified 199 high-confidence and 530 low-confidence DNA damage-suppressing (DDS) genes in Saccharomyces cerevisiae through a whole-genome screen for mutations inducing Hug1 expression, a focused screen for mutations inducing Ddc2 foci, and data from previous screens for mutations causing Rad52 foci accumulation and Rnr3 induction. We also identified 286 high-confidence and 394 low-confidence diverse genome instability-suppressing (DGIS) genes through a whole-genome screen for mutations resulting in increased gross chromosomal rearrangements and data from previous screens for mutations causing increased genome instability as assessed in a diversity of genome instability assays.

The IRON Study: Investigation of Robot-assisted Versus Open Nephron-sparing Surgery.

Background: Current literature does not provide large-scale data regarding clinical outcomes of robot-assisted (RAPN) versus open (OPN) partial nephrectomy. Moreover, data assessing predictors of long-term oncologic outcomes after RAPN are scarce.

Objective: To compare perioperative, functional, and oncologic outcomes of RAPN versus OPN, and to investigate the predictors of oncologic outcomes after RAPN.

Oncogenic driver FGFR3-TACC3 requires five coiled-coil heptads for activation and disulfide bond formation for stability.

FGFR3-TACC3 represents an oncogenic fusion protein frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Various exon breakpoints of FGFR3-TACC3 have been identified in cancers; these were analyzed to determine the minimum contribution of TACC3 for activation of the FGFR3-TACC3 fusion protein. While TACC3 exons 11 and 12 are dispensable for activity, our results show that FGFR3-TACC3 requires exons 13-16 for biological activity.

Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis.

While immunotherapy has emerged as a breakthrough cancer therapy, it is only effective in some patients, indicating the need of alternative therapeutic strategies. Induction of cancer immunogenic cell death (ICD) is one promising way to elicit potent adaptive immune responses against tumor-associated antigens. Type I interferon (IFN) is well known to play important roles in different aspects of immune responses, including modulating ICD in anti-tumor action.

Post Treatment Mastalgia is a Common Complaint but not an Indication of Recurrence or Second Primary Breast Cancer.

Background: Post-treatment mastalgia is a common complaint in up to 68% of patients after treatment. This symptom is worrisome to patients as many believe it is a sign of recurrence. The current study was performed to evaluate if post-treatment mastalgia is associated with a second breast cancer diagnosis.

Mlh1 interacts with both Msh2 and Msh6 for recruitment during mismatch repair.

Eukaryotic DNA mismatch repair (MMR) initiates through mispair recognition by the MutS homologs Msh2-Msh6 and Msh2-Msh3 and subsequent recruitment of the MutL homologs Mlh1-Pms1 (human MLH1-PMS2). In bacteria, MutL is recruited by interactions with the connector domain of one MutS subunit and the ATPase and core domains of the other MutS subunit. Analysis of the S.

Alvimopan for Enhanced Gastrointestinal Recovery after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Randomized Controlled Trial.

Background: Surgical management of peritoneal metastases with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is associated with prolonged length of stay and time to return of bowel function. Alvimopan is a peripherally acting opioid antagonist that reduces postoperative ileus. We sought to determine the efficacy of alvimopan on return of bowel function in patients undergoing CRS-HIPEC.

Mastalgia is Not An Indication for Mammogram.

METHODS: RESULTS: CONCLUSIONS: