Transforming Growth Factor-ß Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy.

BACKGROUND & AIMS: Transforming growth factor-b (TGFb) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating CD8 T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFb inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFß-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFß with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFß blockade was preserved in CD8-depleted or recombination activating gene 2 (RAG2-/-) mice. TGFß blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex vivo revealed that tumor cells treated with TGFß blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFß blockade increased chemotherapy-induced cell death in vivo. CONCLUSIONS: TGFß regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFß blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer.

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

Conducta sexual y anticonceptiva en estudiantes de medicina / Sexual and Contraceptive Behavior in Medical Students

Introducción: estudios previos y la percepción del personal que labora en el Servicio Médico de la Universidad del Valle sugieren un comportamiento sexual poco responsable por parte del estamento estudiantil. Objetivo: el presente estudio describe el comportamiento sexual y anticonceptivo en estudiantes de primer, tercer y último año del programa de Medicina. Resultados: al Programa de Medicina ingresan adolescentes tardíos con proporción creciente de mujeres y, en su mayoría, de estrato socioeconómico medio y alto; los estudiantes hombres inician sus relaciones coitales más precozmente que las mujeres (p<0,001), si bien estas últimas están iniciando cada vez más temprano, al punto de no encontrar diferencias entre los sexos en la cohorte del primer año. Se evidencia un comportamiento sexual similar en los dos sexos, con un pequeño porcentaje de ambos sexos que se mantiene virgen (alrededor del 5,3%). Los métodos anticonceptivos más utilizados son el condón y la píldora. La conducta sexual responsable (uso de anticonceptivo en todas las relaciones coitales) prácticamente no se modifica entre los semestres. Existe un incremento significativo en embarazos, abortos inducidos y enfermedades de transmisión sexual (ETS) entre los estudiantes de un nivel de formación y otro. Los argumentos expuestos para no utilizar siempre un contraceptivo son insensatos.

Introduction: Previous research and data arising from the “Universidad del Valle” medical school Health Service suggest that students exhibit irresponsible sexual behavior. Objective: This paper describes sexual behavior and contraceptive methods commonly used among first, third and last year students. Results: Students entering the program are frequently late adolescents, with a growing female proportion, coming from high and middle social and economic classes. Although male students begin coital contacts earlier than females (p<0.001), in recent years this is tending to balance, showing no differences in the freshmen cohorts. Both genders have similar sexual behavior, with a small percentage remaining virgin until internship. Condom and oral contraceptives are favored as contraceptive methods. Medical students exhibit a high degree of risk-taking behavior, therefore unwanted pregnancies, abortions and STDs are frequent and become more prevalent in upper levels. Reasons exposed to avoid the use of contraceptive methods seem invalid and irrelevant.