Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response.

KRAS inhibitors have demonstrated exciting preclinical and clinical responses, although resistance occurs rapidly. Here, we investigate the effects of KRAS-targeting therapies on the tumor microenvironment using a library of KrasG12D, p53-mutant, murine pancreatic ductal adenocarcinoma-derived cell lines (KPCY) to leverage immune-oncology combination strategies for long-term tumor efficacy. Our findings show that SOS1 and MEK inhibitors (SOS1i+MEKi) suppressed tumor growth in syngeneic models and increased intratumoral CD8+ T cells without durable responses. Single-cell RNA sequencing revealed an increase in inflammatory cancer-associated fibroblasts (iCAF), M2 macrophages, and a decreased dendritic cell (DC) quality that ultimately resulted in a highly immunosuppressive microenvironment driven by IL6+ iCAFs. Agonist CD40 treatment was effective to revert macrophage polarization and overcome the lack of mature antigen-presenting DCs after SOS1i+MEKi therapy. Treatment increased the overall survival of KPCY tumor-bearing mice. The addition of checkpoint blockade to SOS1i+MEKi combination resulted in tumor-free mice with established immune memory. Our data suggest that KRAS inhibition affects myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong antitumor effects. SIGNIFICANCE: Combination of SOS1 and MEK inhibitors increase T cell infiltration while blunting pro-immune myeloid cell maturation and highlights the need for combining KRAS cancer-targeted therapy with myeloid activation to enhance and prolong anti-tumor effects.

Algal bloom-associated disease outbreaks among users of freshwater lakes--United States, 2009-2010.

Harmful algal blooms (HABs) are excessive accumulations of microscopic photosynthesizing aquatic organisms (phytoplankton) that produce biotoxins or otherwise adversely affect humans, animals, and ecosystems. HABs occur sporadically and often produce a visible algal scum on the water. This report summarizes human health data and water sampling results voluntarily reported to CDC's Waterborne Disease and Outbreak Surveillance System (WBDOSS) via the National Outbreak Reporting System (NORS) and the Harmful Algal Bloom-Related Illness Surveillance System (HABISS)* for the years 2009-2010. For 2009-2010, 11 waterborne disease outbreaks associated with algal blooms were reported; these HABs all occurred in freshwater lakes. The outbreaks occurred in three states and affected at least 61 persons. Health effects included dermatologic, gastrointestinal, respiratory, and neurologic signs and symptoms. These 11 HAB-associated outbreaks represented 46% of the 24 outbreaks associated with untreated recreational water reported for 2009-2010, and 79% of the 14 freshwater HAB-associated outbreaks that have been reported to CDC since 1978. Clinicians should be aware of the potential for HAB-associated illness among patients with a history of exposure to freshwater.

Food worker experiences with and beliefs about working while ill.

Transmission of foodborne pathogens from ill food workers to diners in restaurants is an important cause of foodborne illness outbreaks. The U.S. Food and Drug Administration recommends that food workers with vomiting or diarrhea (symptoms of foodborne illness) be excluded from work. To understand the experiences and characteristics of workers who work while ill, workplace interviews were conducted with 491 food workers from 391 randomly selected restaurants in nine states that participated in the Environmental Health Specialists Network of the Centers for Disease Control and Prevention. Almost 60% of workers recalled working while ill at some time. Twenty percent of workers said that they had worked while ill with vomiting or diarrhea for at least one shift in the previous year. Factors significantly related to workers having said that they had worked while ill with vomiting or diarrhea were worker sex, job responsibilities, years of work experience, concerns about leaving coworkers short staffed, and concerns about job loss. These findings suggest that the decision to work while ill with vomiting or diarrhea is complex and multifactorial.

Characteristics and predictive value of blood transcriptome signature in males with autism spectrum disorders.

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.

Restaurant food cooling practices.

Improper food cooling practices are a significant cause of foodborne illness, yet little is known about restaurant food cooling practices. This study was conducted to examine food cooling practices in restaurants. Specifically, the study assesses the frequency with which restaurants meet U.S. Food and Drug Administration (FDA) recommendations aimed at reducing pathogen proliferation during food cooling. Members of the Centers for Disease Control and Prevention's Environmental Health Specialists Network collected data on food cooling practices in 420 restaurants. The data collected indicate that many restaurants are not meeting FDA recommendations concerning cooling. Although most restaurant kitchen managers report that they have formal cooling processes (86%) and provide training to food workers on proper cooling (91%), many managers said that they do not have tested and verified cooling processes (39%), do not monitor time or temperature during cooling processes (41%), or do not calibrate thermometers used for monitoring temperatures (15%). Indeed, 86% of managers reported cooling processes that did not incorporate all FDA-recommended components. Additionally, restaurants do not always follow recommendations concerning specific cooling methods, such as refrigerating cooling food at shallow depths, ventilating cooling food, providing open-air space around the tops and sides of cooling food containers, and refraining from stacking cooling food containers on top of each other. Data from this study could be used by food safety programs and the restaurant industry to target training and intervention efforts concerning cooling practices. These efforts should focus on the most frequent poor cooling practices, as identified by this study.