Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B).

Purpose: WU-KONG1B (ClinicalTrials.gov identifier: NCT03974022) is a multinational phase II, dose-randomized study to assess the antitumor efficacy of sunvozertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor () exon 20 insertion mutations (exon20ins).

Methods: Eligible patients with advanced-stage exon20ins NSCLC were randomly assigned by 1:1 ratio to receive sunvozertinib 200 mg or 300 mg once daily (200 and 300 mg-rand cohorts).

Efficacy of Stereotactic Ablative Body Radiotherapy (SABR) in uncommon subtypes of primary kidney cancer: An analysis from the International Radiosurgery Oncology Consortium of the Kidney.

Background: While stereotactic ablative body radiotherapy (SABR) is associated with excellent local control for primary renal cell carcinoma (RCC), outcomes based on clear-cell (ccRCC) and non-clear cell (nccRCC) histologies are not well defined.

Methods And Materials: Individual data of adult patient with biopsy confirmed primary RCC receiving SABR between 2007 and 2021 from 16 institutions in Australia, Canda, Germany, Japan and USA pooled. Patients with metastatic disease or upper tract urothelial carcinoma were excluded.

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

Background: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis.

Prospective assessment of prognostic significance of malignant peritoneal cytology in endometrial cancer: An NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol.

Objective: To examine the association between malignant peritoneal cytology and survival outcomes in endometrial cancer.

Methods: This was an ancillary analysis of prospectively collected surgical-pathological data in the NRG Oncology / Gynecologic Oncology Group study on GOG-210 protocol. The study population included 2383 patients with stage I-III endometrial cancer from 2003 to 2011.

CXCR6 promotes dermal CD8+ T cell survival and transition to long-term tissue residence.

Tissue resident memory T cells (TRM) provide protection against local re-infection, and yet the interstitial signals that govern their formation and persistence remain poorly defined. Here, we show that antigen-dependent induction of the chemokine receptor CXCR6, is a conserved adaptation to peripheral tissue infiltration that promotes TRM formation after viral infection. Deficient TRM formation in the absence of CXCR6 was not explained by trafficking as CXCR6 was not required for tissue entry, was dispensable for the early accumulation of antigen-specific CD8+ T cells in skin, and did not restrain their exit.

Current and Emerging Fluorescence-Guided Techniques in Glioma to Enhance Resection.

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged as a valuable tool to enhance intraoperative tumor visualization and optimize resection outcomes.

Development of Mouse-Derived Organoid Lines from Fallopian Tube Epithelial Cells for High Grade Serous Ovarian Carcinoma Modeling.

Effective modeling of diseases in realistic environments is crucial to improve our understanding of diverse pathologies. In this aspect, organoids offer a more faithful environment than their classical two-dimensional counterparts in vitro. Similarly, syngeneic murine models also allow researchers to investigate more complete tumor-host interactions, such as with the immune system, in vivo.

Deep mutational scanning reveals EGFR mutations conferring resistance to the 4th-generation EGFR tyrosine kinase inhibitor BLU-945.

Fourth-generation EGFR tyrosine kinase are in development to overcome common resistance mutations. We performed deep mutational scanning (DMS) of the EGFR kinase domain in the context of L858R by introducing a saturation library of ~17,000 variants into Ba/F3 cells. DMS library-expressing cells were exposed to osimertinib or BLU-945 to identify escape mutations.

Targeting FSP1 triggers ferroptosis in lung cancer.

Pre-clinical and clinical studies have demonstrated how dietary antioxidants or mutations activating antioxidant metabolism promote cancer, highlighting a central role oxidative stress in tumorigenesis. However, it is unclear if oxidative stress ultimately increases to a point of cell death. Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death triggered by uncontrolled lipid peroxidation.

Automating the Referral of Bone Metastases Patients With and Without the Use of Large Language Models.

Background And Objectives: Bone metastases, affecting more than 4.8% of patients with cancer annually, and particularly spinal metastases require urgent intervention to prevent neurological complications. However, the current process of manually reviewing radiological reports leads to potential delays in specialist referrals.

ApaH decaps NpN-capped RNAs in two alternative orientations.

Enigmatic dinucleoside tetraphosphates, known as 'alarmones' (NpNs), have recently been shown to function in bacteria as precursors to Np caps on transcripts, likely influencing RNA longevity and cellular adaptation to stress. In proteobacteria, ApaH is the predominant enzyme that hydrolyzes NpNs and decaps Np-capped RNAs to initiate their 5'-end-dependent degradation. Here we conducted a biochemical and structural study to uncover the catalytic mechanism of Escherichia coli ApaH, a prototypic symmetric NpN hydrolase, on various NpNs and Np-capped RNAs.

Dual Immune Check Point Blockade in -Unmethylated Newly Diagnosed Glioblastoma: NRG Oncology BN007, a Randomized Phase II/III Clinical Trial.

Purpose: New therapies for glioblastoma are needed, especially -unmethylated (u) disease. NRG Oncology BN002 (phase I) demonstrated safety and suggested efficacy of ipilimumab (ipi) with nivolumab (nivo) in newly diagnosed glioblastoma, leading to this phase II/III trial.

Methods: Adults with newly diagnosed u glioblastoma and Karnofsky performance status (KPS) ≥70 were randomly assigned to radiotherapy with either immunotherapy (ipi and nivo) or temozolomide (TMZ), stratified by recursive partitioning analysis (RPA) class and intention to use tumor treating fields.

Netrin-1 promotes pancreatic tumorigenesis and innervation through NEO1.

Nerves have been shown to regulate cancer progression. However, a clear demonstration of a role for axon guidance molecules in pancreatic tumorigenesis, innervation, and metastasis has been lacking. Using murine -mutant pancreatic organoids, we screened axon guidance molecules by qRT-PCR, identified upregulation, and then verified its upregulation during pancreatic tumorigenesis in humans and mice.

Inhibition of HDAC6 alters fumarate hydratase activity and mitochondrial structure.

Fumarate hydratase (FH), a key node of mitochondrial metabolism, is also a tumour suppressor. Despite its prominent roles in tumourigenesis and inflammation, its regulation remains poorly understood. Herein, we show that histone deacetylase 6 (HDAC6) regulates FH activity.

A Phase I Dose-Escalation Clinical Trial of Bronchoscopic Cryoimmunotherapy in Advanced-Stage NSCLC.

Introduction: Outcomes for NSCLC remain suboptimal. Recent data suggest that cryoablation can generate antitumor immune effects. In this first-in-human phase I clinical trial, we investigated the safety and feasibility of bronchoscopic cryoimmunotherapy (BCI) delivered during standard-of-care bronchoscopy and explored associated systemic immune responses.

Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma.

DNA damage from routine cellular processes or exogenous insults can have a lasting impact on gene regulation beyond genetic mutations. The prevailing paradigm for the consequences of DNA damage repair revolves around restoration of the original genetic sequence, but long-term changes in chromatin configuration, gene expression and DNA modifications have not been analyzed. We introduced numerous, simultaneous Cas9-mediated DNA double strand breaks (DSBs) at defined locations in human glioblastoma cells and tracked both non-genetic and genetic alterations over time.

T lymphocyte-specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4 T cells and impairs antitumor response.

SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role.

mtgRNA-db: An annotated database of multi-target CRISPR-Cas9 guide-RNAs in the human genome.

CRISPR-Cas9 guide-RNA design tools can be used to identify guide-RNAs that target single human genomic loci. However, these approaches limit their effect to a single locus. Here, we generate a database of potential individual guide-RNAs that target multiple sites in the genome at once.

Coenzyme Q headgroup intermediates can ameliorate a mitochondrial encephalopathy.

Decreased brain levels of coenzyme Q (CoQ), an endogenously synthesized lipophilic antioxidant, underpin encephalopathy in primary CoQ deficiencies and are associated with common neurodegenerative diseases and the ageing process. CoQ supplementation does not increase CoQ pools in the brain or in other tissues. The recent discovery of the mammalian CoQ headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ headgroup precursor 4-hydroxybenzoate (4-HB), offers an opportunity to pharmacologically restore CoQ synthesis and mechanistically treat CoQ deficiencies.

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4 T cell suppression.

A CXCR4 partial agonist improves immunotherapy by targeting immunosuppressive neutrophils and cancer-driven granulopoiesis.

Pathologically activated immunosuppressive neutrophils impair cancer immunotherapy efficacy. The chemokine receptor CXCR4, a central regulator of hematopoiesis and neutrophil biology, represents an attractive target. Here, we fuse a secreted CXCR4 partial agonist, trefoil factor 2 (TFF2), to mouse serum albumin (MSA) and demonstrate that TFF2-MSA peptide synergizes with anti-PD-1 to inhibit primary tumor growth and distant metastases and prolongs survival in gastric cancer (GC) mouse models.

Microbial contribution to metabolic niche formation varies across the respiratory tract.

Variations in the airway microbiome are associated with inflammatory responses in the lung and pulmonary disease outcomes. Regional changes in microbiome composition could have spatial effects on the metabolic environment, contributing to differences in the host response. Here, we profiled the respiratory microbiome (metagenome/metatranscriptome) and metabolome of a patient cohort, uncovering topographical differences in microbial function, which were further delineated using isotope probing in mice.

Artificial Intelligence Algorithm Predicts Response to Immune Checkpoint Inhibitors.

Purpose: Cancer treatment has been revolutionized by immune checkpoint inhibitors (ICI). However, a subset of patients do not respond and/or they experience significant adverse events. Attempts to integrate reliable biomarkers of ICI response as part of standard care have been hampered by limited generalizability.

Uncovering Novel lncRNAs Linked to Melanoma Growth and Migration with CRISPR Inhibition Screening.

Unlabelled: Melanoma being one of the most common and deadliest skin cancers has been increasing since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays, the standard of care of advanced melanoma is resection, followed by immune checkpoint inhibition-based immunotherapy.