Synthesis and biological evaluation of α-D-tocopherol derivatives as anticancer agents targeting mitochondrial metabolism.

Cancer, driven by mitochondrial and nuclear DNA mutations, presents opportunities for targeted therapies. Gastric cancer (GC), the 4th leading cause of cancer-related deaths, has poor prognosis due to cancer stem cells (CSCs), which depend on mitochondrial complex II (CII) respiration. Among CSC-enriched subtypes, the aggressive stem-like/EMT/Mesenchymal (SEM) GC subtype exhibits high plasticity, chemotherapy resistance, and metabolic adaptations that promote tumor survival.

PKA-Mediated Phosphorylation of SFRP4 Promotes Wnt/β-Catenin Activation and Cancer Stemness in Gastric Cancer.

Secreted Frizzled-related protein 4 (SFRP4) has been identified as a patient-level biomarker of the stem-like subtype of gastric cancer (GC), which is associated with poor prognosis and resistance to chemotherapy. Although multiple studies have documented the clinical significance of SFRP4 in GC, its mechanistic role in the stem-like subtype remains incompletely understood. In this study, we elucidate how phosphorylation of SFRP4 by protein kinase A (PKA) converts it into a Wnt signaling agonist.

Deep Gaussian process with uncertainty estimation for microsatellite instability and immunotherapy response prediction from histology.

Determining tumor microsatellite status has significant clinical value because tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) respond well to immune checkpoint inhibitors (ICIs) and oftentimes not to chemotherapeutics. We propose MSI-SEER, a deep Gaussian process-based Bayesian model that analyzes H&E whole-slide images in weakly-supervised-learning to predict microsatellite status in gastric and colorectal cancers. We performed extensive validation using multiple large datasets comprised of patients from diverse racial backgrounds.

SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, largely due to the rapid development of chemoresistance in patients. Mitochondrial dynamics play a crucial role in cancer cell survival. Currently, the specific mechanisms underlying gemcitabine resistance in PDAC remain unknown.

Spatial organization of B lymphocytes and prognosis prediction in patients with gastric cancer.

Background: Within the tumor microenvironment (TME), the association of B lymphocytes (B cells) with prognosis and therapy response in gastric cancer (GC) remains poorly characterized. We investigated the predictive and prognostic value of B cells, including their spatial organization within the TME, in one of the largest multi-cohort studies to date.

Methods: Using CD20 immunohistochemistry, we evaluated B cell density in resection specimens from 977 patients with resectable GC across three cohorts, including the randomized phase III Korean CLASSIC trial.

The Current Evidence and Future Direction of Adjuvant Treatment for Gastric Cancer in the Era of Precision Medicine.

Although gastric cancer remains a significant global health burden, its treatment strategies vary across different geographical regions, leading to distinct guidelines. In Asia, particularly in Korea, D2 gastrectomy followed by adjuvant chemotherapy has been established as the standard treatment for stage II/III gastric cancer based on landmark clinical trials. However, this "one-size-fits-all" approach requires refinement as emerging evidence suggests heterogeneous outcomes even within the same stage.

Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer.

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its mA methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC value of 220 nM in a dose-, time- and ubiquitin-dependent fashion.

Targeting ATP2B1 impairs PI3K/Akt/FOXO signaling and reduces SARS-COV-2 infection and replication.

ATP2B1 is a known regulator of calcium (Ca) cellular export and homeostasis. Diminished levels of intracellular Ca content have been suggested to impair SARS-CoV-2 replication. Here, we demonstrate that a nontoxic caloxin-derivative compound (PI-7) reduces intracellular Ca levels and impairs SARS-CoV-2 infection.

Impact of Coronavirus Disease 2019 on Gastric Cancer Diagnosis and Stage: A Single-Institute Study in South Korea.

Purpose: Gastric cancer (GC) is among the most prevalent and fatal cancers worldwide. National cancer screening programs in countries with high incidences of this disease provide medical aid beneficiaries with free-of-charge screening involving upper endoscopy to detect early-stage GC. However, the coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions to routine healthcare access.

Caveolin-1 mediates the utilization of extracellular proteins for survival in refractory gastric cancer.

Despite advances in cancer therapy, the clinical outcome of patients with gastric cancer remains poor, largely due to tumor heterogeneity. Thus, finding a hidden vulnerability of clinically refractory subtypes of gastric cancer is crucial. Here, we report that chemoresistant gastric cancer cells rely heavily on endocytosis, facilitated by caveolin-1, for survival.

SLC38A5 Modulates Ferroptosis to Overcome Gemcitabine Resistance in Pancreatic Cancer.

Pancreatic cancer is characterized by a poor prognosis, with its five-year survival rate lower than that of any other cancer type. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine resistance.

CanISO: a database of genomic and transcriptomic variations in domestic dog (Canis lupus familiaris).

Background: The domestic dog, Canis lupus familiaris, is a companion animal for humans as well as an animal model in cancer research due to similar spontaneous occurrence of cancers as humans. Despite the social and biological importance of dogs, the catalogue of genomic variations and transcripts for dogs is relatively incomplete.

Results: We developed CanISO, a new database to hold a large collection of transcriptome profiles and genomic variations for domestic dogs.

The role of LOXL2 induced by glucose metabolism-activated NF-κB in maintaining drug resistance through EMT and cancer stemness in gemcitabine-resistant PDAC.

Gemcitabine is considered a standard treatment for pancreatic cancer, but developing drug resistance greatly limits the effectiveness of chemotherapy and increases the rate of recurrence. Lysyl oxide-like 2 (LOXL2) is highly expressed in pancreatic cancer and is involved in carcinogenesis and EMT regulation. However, studies on the role of LOXL2 in drug resistance are limited.

PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress.

Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition.

Tumour infiltrating lymphocytes and survival after adjuvant chemotherapy in patients with gastric cancer: post-hoc analysis of the CLASSIC trial.

Background: Only a subset of gastric cancer (GC) patients with stage II-III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit.

Methods: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S).