FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer.

Introduction: KRAS G12C targeted therapies, such as sotorasib, represent a major breakthrough, but overall response rates and progression-free survival for patients with KRAS G12C lung cancer are modest due to the emergence of resistance mechanisms involving adaptive reactivation of ERK, which requires wild-type HRAS and NRAS membrane localization.

Methods And Results: Here, we demonstrate that the dual farnesyltransferase and geranylgeranyltransferase-1 inhibitor FGTI-2734 inhibits wild-type RAS membrane localization and sotorasib-induced ERK feedback reactivation, and overcomes sotorasib adaptive resistance. The combination of FGTI-2734 and sotorasib is synergistic at inhibiting the viability and inducing apoptosis of KRAS G12C lung cancer cells, including those highly resistant to sotorasib.

Unveiling the Promise: Navigating Clinical Trials 1978-2024 for PDAC.

Despite many decades of research, pancreatic ductal adenocarcinoma (PDAC) remains one of the most difficult cancers to diagnose and treat effectively. Although there have been improvements in the 5-year overall survival rate, it is still very low at 12.5%.

Robotic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: is there a benefit?

Background: Open cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a therapeutic option for the management of malignancies with peritoneal carcinomatosis and of peritoneal origin. Robotic surgery shows promise as a minimally invasive approach for select patients. We aimed to evaluate the differences in outcomes between robotic versus open CRS/HIPEC and hypothesized less morbidity and faster recovery in the robotic approach group.

Cardiac Atrophy, Dysfunction, and Metabolic Impairments: A Cancer-Induced Cardiomyopathy Phenotype.

Muscle atrophy and weakness are prevalent features of cancer. Although extensive research has characterized skeletal muscle wasting in cancer cachexia, limited studies have investigated how cardiac structure and function are affected by therapy-naive cancer. Herein, orthotopic, syngeneic models of epithelial ovarian cancer and pancreatic ductal adenocarcinoma, and a patient-derived pancreatic xenograft model, were used to define the impact of malignancy on cardiac structure, function, and metabolism.

A Gravid Situation: General Surgery Faculty Support for Pregnant Surgical Residents.

Introduction: The perceptions of teaching faculty toward pregnant general surgery residents have been overlooked despite the daily interactions amongst these groups.

Methods: A 32-question survey designed to measure general surgery teaching faculty perceptions toward pregnant residents was distributed electronically from March 2022 to April 2022 to general surgery teaching faculty in the United States. Descriptive statistics were used to characterize responses and differences in perceptions, and qualitative analysis identified recurring themes from free-text responses.

Cooperation between PRMT1 and PRMT6 drives lung cancer health disparities among Black/African American men.

Lung cancer is the third most common cancer with Black/AA men showing higher risk and poorer outcomes than NHW men. Lung cancer disparities are multifactorial, driven by tobacco exposure, inequities in care access, upstream health determinants, and molecular determinants including biological and genetic factors. Elevated expressions of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis have been observed in many cancers.

Heterogeneity of weight loss and transcriptomic signatures in pancreatic ductal adenocarcinoma.

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss.

Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors.

Unlabelled: Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region.

Cytoplasmic-delivery of polyinosine-polycytidylic acid inhibits pancreatic cancer progression increasing survival by activating Stat1-CCL2-mediated immunity.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective therapies and with poor prognosis, causing 7% of all cancer-related fatalities in the USA. Considering the lack of effective therapies for this aggressive cancer, there is an urgent need to define newer and more effective therapeutic strategies. Polyinosine-polycytidylic acid (pIC) is a synthetic double-stranded RNA (dsRNA) which directly activates dendritic cells and natural killer cells inhibiting tumor growth.

Percutaneous Dilatational Tracheostomy in a Cardiac Surgical Intensive Care Unit: A Single-Center Experience.

Background: A significant proportion of cardiac surgery intensive care unit (CSICU) patients require long-term ventilation, necessitating tracheostomy placement. The goal of this study was to evaluate the long-term postoperative outcomes and complications associated with percutaneous dilatational tracheostomy (PDT) in CSICU patients.

Methods: All patients undergoing PDT after cardiac, thoracic, or vascular operations in the CSICU between January 1, 2013 and January 1, 2021 were identified.

Race and Ethnicity Impacts Overall Survival of Patients with Appendiceal Cancer Who Undergo Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

Appendiceal cancer treatment may include cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We investigated whether patient race/ethnicity influences outcomes and overall survival for patients with appendiceal cancer who undergo CRS/HIPEC. We queried the National Cancer Database for adult patients with appendiceal cancer treated with CRS/HIPEC from 2006 to 2018.

Translocation of Oral Microbiota into the Pancreatic Ductal Adenocarcinoma Tumor Microenvironment.

Oral dysbiosis has long been associated with pancreatic ductal adenocarcinoma (PDAC). In this work, we explore the relationship between the oral and tumor microbiomes of patients diagnosed with PDAC. Salivary and tumor microbiomes were analyzed using a variety of sequencing methods, resulting in a high prevalence and relative abundance of oral bacteria, particularly and , within tumor tissue.

In vivo models of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality rate. Within the next decade, PDAC is projected to become the second leading cause of cancer-associated death in the United States. Understanding the pathophysiology of PDAC tumorigenesis and metastases is crucial toward developing new therapeutics.

Tumor heterogeneity: An oncogenic driver of PDAC progression and therapy resistance under stress conditions.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging disease usually diagnosed at advanced or metastasized stage. By this year end, there are an expected increase in 62,210 new cases and 49,830 deaths in the United States, with 90% corresponding to PDAC subtype alone. Despite advances in cancer therapy, one of the major challenges combating PDAC remains tumor heterogeneity between PDAC patients and within the primary and metastatic lesions of the same patient.

General Surgery Faculty Knowledge and Perceptions of Breast Pumping Amongst Postpartum Surgical Residents.

Background: There is a lack of data regarding the knowledge and perceptions teaching faculty possess about breast pumping among general surgery residents despite breast pumping becoming more common during training. This study aimed to examine faculty knowledge and perceptions of breast pumping amongst general surgery residents.

Methods: A 29-question survey measuring knowledge and perceptions about breast pumping was administered online to United States teaching faculty from March-April 2022.

Call to action: overcoming enrollment disparities in cancer clinical trials with modernized eligibility criteria.

Traditional clinical trial eligibility criteria restrict study populations, perpetuating enrollment disparities. We aimed to assess implementation of modernized eligibility criteria guidelines among pancreatic cancer (PC) clinical trials. Interventional PC trials in the United States since January 1, 2014, were identified via clinicaltrials.

Neighbor-specific gene expression revealed from physically interacting cells during mouse embryonic development.

Development of multicellular organisms is orchestrated by persistent cell-cell communication between neighboring partners. Direct interaction between different cell types can induce molecular signals that dictate lineage specification and cell fate decisions. Current single-cell RNA-seq technology cannot adequately analyze cell-cell contact-dependent gene expression, mainly due to the loss of spatial information.

From Mouth to Muscle: Exploring the Potential Relationship between the Oral Microbiome and Cancer-Related Cachexia.

Cancer cachexia is a multifactorial wasting syndrome associated with skeletal muscle and adipose tissue loss, as well as decreased appetite. It affects approximately half of all cancer patients and leads to a decrease in treatment efficacy, quality of life, and survival. The human microbiota has been implicated in the onset and propagation of cancer cachexia.

Cell Competition in Carcinogenesis.

The majority of human cancers evolve over time through the stepwise accumulation of somatic mutations followed by clonal selection akin to Darwinian evolution. However, the in-depth mechanisms that govern clonal dynamics and selection remain elusive, particularly during the earliest stages of tissue transformation. Cell competition (CC), often referred to as 'survival of the fittest' at the cellular level, results in the elimination of less fit cells by their more fit neighbors supporting optimal organism health and function.

Patient-Derived Pancreatic Cancer Cells Induce C2C12 Myotube Atrophy by Releasing Hsp70 and Hsp90.

Pancreatic cancer (PC) patients are highly prone to cachexia, a lethal wasting syndrome featuring muscle wasting with an undefined etiology. Recent data indicate that certain murine cancer cells induce muscle wasting by releasing Hsp70 and Hsp90 through extracellular vesicles (EVs) to activate p38β MAPK-mediated catabolic pathways primarily through Toll-like receptor 4 (TLR4). However, whether human PC induces cachexia through releasing Hsp70 and Hsp90 is undetermined.

Racial Disparities in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Does Aggressive Surgical Treatment Overcome Cancer Health Inequities?

Background: Advanced cancer states perpetuate health-related disparities. Peritoneal-based cancers are clinically advanced cancers that present a significant clinical dilemma. Peritoneal cancers are managed aggressively with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

A Review of the Clinical Implications of Cachexia, Sarcopenia, and BMI in Patients with Peritoneal Carcinomatosis Receiving Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Peritoneal carcinomatosis (PC) is the dissemination of cancer throughout the peritoneal cavity. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the surgical treatment of choice in highly selected patients. The aim of this narrative review was to assess the impact of cachexia, sarcopenia, and body mass index (BMI) on patient outcomes for patients undergoing CRS and HIPEC for peritoneal carcinomatosis.