Expert-Guided Large Language Models for Clinical Decision Support in Precision Oncology.

Purpose: Rapidly expanding medical literature challenges oncologists seeking targeted cancer therapies. General-purpose large language models (LLMs) lack domain-specific knowledge, limiting their clinical utility. This study introduces the LLM system Medical Evidence Retrieval and Data Integration for Tailored Healthcare (MEREDITH), designed to support treatment recommendations in precision oncology.

Association of high miR-27a, miR-206, and miR-214 expression with poor patient prognosis and increased chemoresistance in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents the most aggressive breast cancer subtype, associated with early metastasis and recurrence as well as poor patient outcome. TNBC does not or weakly respond to hormonal or HER2-targeted therapies. Therefore, there is a strong need to identify other potential molecular targets for TNBC therapy.

tRNA-derived small RNA 3'U-tRF promotes tumour migration and early progression in ovarian cancer.

Introduction: Despite recent advances in epithelial ovarian cancer (EOC) management, the highly heterogenous histological/molecular tumour background and patients' treatment response obstructs personalised prognosis and therapeutics. Herein, we have studied the role and clinical utility of the novel subclass of tRNA-derived small RNA fragments emerging via 3'-trailer processing of pre-tRNAs (3'U-tRFs) in EOC.

Methods: SK-OV-3 and OVCAR-3 cells were used for in vitro study.

Repression of miR-146a in predicting poor treatment outcome in triple-negative breast cancer.

Objectives: In the era of precision medicine, the highly aggressive and heterogenous triple-negative breast cancer (TNBC) is still characterized by limited options to support personalized prognosis and guide therapeutic interventions. Thereafter, the aim of the present study has been the thorough evaluation of miR-146a as a novel molecular indicator of TNBC prognosis and treatment outcome, utilizing four independent TNBC cohorts.

Design & Methods: miR-146a levels were clinically evaluated in our screening (n = 122) and three external validation TNBC cohorts (de Rinaldis et al.

Herpes simplex virus alters Alzheimer's disease biomarkers - A hypothesis paper.

Introduction: Human herpes simplex virus 1 (HSV1) is discussed to induce amyloid-β (Aβ) accumulation and neurofibrillary tangles of hyperphosphorylated tau (pTau) in Alzheimer's disease (AD) in cell culture and animal models. Aβ appears to be virostatic. We investigated the association between intrathecal antibodies against HSV or cytomegalovirus (CMV) and cerebrospinal fluid (CSF) AD biomarkers.

Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.

Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14).

Platelet mitochondrial membrane depolarization reflects disease severity in patients with preeclampsia.

Background: Thrombocytopenia is a feared complication of preeclampsia (PE) that can additionally complicate the disease course and that carries a poor prognosis. The disease mechanisms of PE on a platelet level are poorly understood and only few platelet-based markers have been investigated. In sepsis, platelet mitochondrial membrane depolarization, a sensitive and early indicator of mitochondrial dysfunction and platelet cell death, correlates with disease severity and outcome as shown in previous studies.

CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer.

Background: Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied.

tRNA-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression.

Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease's clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes.

CX3CL1 Overexpression Prevents the Formation of Lung Metastases in Trastuzumab-Treated MDA-MB-453-Based Humanized Tumor Mice (HTM).

CX3CL1 is a multifunctional chemokine that is involved in numerous biological processes, such as immune cell attraction and enhanced tumor immune cell interaction, but also in enhancing tumor cell proliferation and metastasis. The multifarious activity is partially determined by two CX3CL1 isoforms, a membrane-bound and a soluble version generated by proteolytic cleavage through proteases. Here, we investigated the impact of CX3CL1 overexpression in MDA-MB-453 and SK-BR-3 breast cancer cells.

The prognostic and diagnostic potential of kallikrein-related peptidases in ovarian cancer.

Ovarian cancer is one of the deadliest malignancies among women worldwide. The lack of early diagnostic markers fuels an unfavorable prognosis as most patients are at an advanced stage when the disease is diagnosed for the first time. The role of the kallikrein-related peptidase (KLK) family in ovarian cancer progression and prognosis has been thoroughly investigated in various studies.

The Chemokine CX3CL1 Improves Trastuzumab Efficacy in HER2 Low-Expressing Cancer and .

A crucial mode of action of trastuzumab is the labeling of HER2-positive (HER2) tumor cells for the eradication by natural killer (NK) cells, a process called antibody-dependent cellular cytotoxicity (ADCC). However, despite widespread HER2 expression among cancer entities, only a fraction, with robust HER2 overexpression, benefits from trastuzumab therapy. ADCC requires both sufficient lymphocytic infiltration and close binding of the immune cells to the antibody-tagged tumor cells.

Elevated levels of both microRNA 378 (miR-378) and kallikrein-related peptidase 4 (KLK4) mRNA are associated with an unfavorable prognosis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) patients have the worst outcome among all breast cancer subtypes. In oral squamous carcinoma cells, miR-378 was reported to target the mRNA of kallikrein-related peptidase 4 (KLK4), resulting in inhibition of cell proliferation, migration and invasion, induction of apoptosis, and reduction of tumor growth . Similarly, a miR-378/KLK4 axis has been proposed in prostate cancer.

KLK4 Induces Anti-Tumor Effects in Human Xenograft Mouse Models of Orthotopic and Metastatic Prostate Cancer.

Recent reports have suggested the role of kallikrein-related peptidase 4 (KLK4) to be that of remodeling the tumor microenvironment in many cancers, including prostate cancer. Notably, these studies have suggested a pro-tumorigenic role for KLK4, especially in prostate cancer. However, these have been primarily in vitro studies, with limited in vivo studies performed to date.

Prognostic value of kallikrein-related peptidase 7 (KLK7) mRNA expression in advanced high-grade serous ovarian cancer.

Background: High-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype of ovarian cancer. A growing body of evidence suggests tumor-supporting roles of several members of the kallikrein-related peptidase (KLK) family, including KLK5 and KLK7, in this cancer subtype. In normal physiology, KLK5 and KLK7 are the major proteases involved in skin desquamation.

Prognostic value of kallikrein-related peptidase 12 (KLK12) mRNA expression in triple-negative breast cancer patients.

Background: The serine protease KLK12 belongs to the human fifteen-member family of kallikrein-related peptidases. Differential expression accompanied by either increased or decreased enzymatic activity has been linked to several diseases including cancer. Triple-negative breast cancer (TNBC) represents a very aggressive subgroup of breast cancer with high tumor recurrence rates and poor patient prognosis.

miR-203 is an independent molecular predictor of prognosis and treatment outcome in ovarian cancer: a multi-institutional study.

Ovarian cancer (OC) accounts for the most gynecological cancer-related deaths in developed countries. Unfortunately, the lack of both evident early symptoms and effective asymptomatic population screening results in late diagnosis and inevitably poor prognosis. Hence, it is urgent to identify novel molecular markers to support personalized prognosis.

Proteolytic chemokine cleavage as a regulator of lymphocytic infiltration in solid tumors.

In the past decade, immune-based therapies such as monoclonal antibodies against tumor epitopes or immune checkpoint inhibitors have become an integral part of contemporary cancer treatment in many entities. However, a fundamental prerequisite for the success of such therapies is a sufficient trafficking of tumor-infiltrating lymphocytes into the tumor microenvironment. This infiltration is facilitated by chemokines, a group of about 50 small proteins capable of chemotactically guiding leukocytes.

Elevated tumor tissue protein expression levels of kallikrein-related peptidases KLK10 and KLK11 are associated with a better prognosis in advanced high-grade serous ovarian cancer patients.

Several members of the KLK family have been proposed to modulate various tumor-relevant processes. Previously, we have shown that in advanced high-grade serous ovarian cancer tissue high KLK11 mRNA levels were significantly associated with prolonged overall and progression-free patients' survival. Furthermore, KLK11 mRNA expression positively correlated with KLK10 mRNA.

Prognosis of ovarian cancer is associated with effector memory CD8 T cell accumulation in ascites, CXCL9 levels and activation-triggered signal transduction in T cells.

The accumulation of intratumoral CD8 T cells is associated with the survival of high grade serous ovarian carcinoma patients, but it is unclear which CD8 T cell subsets contribute to this effect and how they are affected by the peritoneal tumor microenvironment. Here, we provide evidence for a functional link between long relapse-free survival, accumulation of CD8 effector memory T (T) cells in peritoneal effusion (ascites), and the level of the CD8 T attracting chemokine CXCL9, produced by macrophages as a major source. We also propose a novel mechanism by which the tumor microenvironment could contribute to T cell dysfunction and shorter survival, i.