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Lung cancer is the leading cause of cancer deaths in the United States. New targeted therapies against the once-deemed undruggable oncogenic KRAS are changing current therapeutic paradigms. However, resistance to targeted KRAS inhibitors almost inevitably occurs; resistance can be driven by tumor cell-intrinsic changes or by changes in the microenvironment. Here, we utilized a genetically engineered mouse model of KRASG12D-driven lung cancer that allows for inducible and reversible expression of the oncogene: activation of oncogenic KRASG12D induces tumor growth; conversely, inactivation of KRASG12D causes tumor regression. We showed that in addition to regulating cancer cell growth and survival, oncogenic KRAS regulated the transcriptional status of cancer-associated fibroblasts and macrophages in this model. Utilizing ex vivo approaches, we showed that secreted factors from cancer cells induced the expression of multiple cytokines in lung fibroblasts, and in turn drove expression of immunosuppressive factors, such as arginase 1, in macrophages. In summary, fibroblasts emerged as a key source of immune regulatory signals, and a potential therapeutic target for improving the efficacy of KRAS inhibitors in lung cancer.

Background/Objective: Hepatocellular carcinoma (HCC) is an aggressive disease that is known to be resistant to conventional chemotherapy and radiotherapy. While surgical resection and transarterial therapy can improve overall survival, the biological aspects of HCC contribute to the complexity of its management and limit the effectiveness of current treatment options. The purpose of this scoping review is to identify the limitations of the currently available therapies for HCC and explore the emerging role that histotripsy could play in addressing these limitations, with the intent of informing the direction of future research and clinical management. Methods: The PRISMA checklist for scoping reviews was followed to structure this review, and a systematic search was conducted in the following online databases: PubMed/MEDLINE (National Library of Medicine), Embase (Elsevier), and Scopus (Elsevier). Results: The current evidence supports that histotripsy offers several key advantages that address the limitations of the current treatment strategies for HCC. Clinical trials have highlighted the ability of this technology to destroy solid tumors and induce remission with minimal side effects. In addition, current preclinical studies point to the potent immunostimulatory effects of histotripsy, including the induction of abscopal effects. This poses significant promise in treating tumor metastasis as well as improving clinical regimens by combining histotripsy with immunotherapy. Future research should aim to overcome the current limitations of histotripsy and enhance clinical outcomes for patients. This review examines existing treatments for HCC, emphasizing the promising potential of combining histotripsy with immunotherapy to target the metastatic and advanced stages of the disease.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.

This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.Competing Interest StatementThe authors have declared no competing interest.Footnotes* This version of the manuscript provides updated affiliations for M Robotti.

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine-mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

Heterogeneity in human immune responses is difficult to model in standard laboratory mice. To understand how host variation affects Bacillus Calmette Guerin-induced (BCG-induced) immunity against Mycobacterium tuberculosis, we studied 24 unique collaborative cross (CC) mouse strains, which differ primarily in the genes and alleles they inherit from founder strains. The CC strains were vaccinated with or without BCG and challenged with aerosolized M. tuberculosis. Since BCG protects only half of the CC strains tested, we concluded that host genetics has a major influence on BCG-induced immunity against M. tuberculosis infection, making it an important barrier to vaccine- mediated protection. Importantly, BCG efficacy is dissociable from inherent susceptibility to tuberculosis (TB). T cell immunity was extensively characterized to identify components associated with protection that were stimulated by BCG and recalled after M. tuberculosis infection. Although considerable diversity is observed, BCG has little impact on the composition of T cells in the lung after infection. Instead, variability is largely shaped by host genetics. BCG-elicited protection against TB correlated with changes in immune function. Thus, CC mice can be used to define correlates of protection and to identify vaccine strategies that protect a larger fraction of genetically diverse individuals instead of optimizing protection for a single genotype.

The use of a polygenic risk score to screen for prostate cancer was assessed. Of the 468 persons in at least the 90th percentile of genetic risk who underwent MRI and prostate biopsy, 187 (40.0%) had prostate cancer.

Pain following surgery for cardiac disease is ubiquitous, and optimal management is important. Despite this, there is large practice variation. To address this, the Paediatric Acute Care Cardiology Collaborative undertook the effort to create this clinical practice guideline. A panel of experts consisting of paediatric cardiologists, advanced practice practitioners, pharmacists, a paediatric cardiothoracic surgeon, and a paediatric cardiac anaesthesiologist was convened. The literature was searched for relevant articles and Collaborative sites submitted centre-specific protocols for postoperative pain management. Using the modified Delphi technique, recommendations were generated and put through iterative Delphi rounds to achieve consensus. 60 recommendations achieved consensus and are included in this guideline. They address guideline use, pain assessment, general considerations, preoperative considerations, intraoperative considerations, regional anaesthesia, opioids, opioid-sparing, non-opioid medications, non-pharmaceutical pain management, and discharge considerations. Postoperative pain among children following cardiac surgery is currently an area of significant practice variability despite a large body of literature and the presence of centre-specific protocols. Central to the recommendations included in this guideline is the concept that ideal pain management begins with preoperative counselling and continues through to patient discharge. Overall, the quality of evidence supporting recommendations is low. There is ongoing need for research in this area, particularly in paediatric populations.

Abstract The laboratory mouse is the most widely used animal model for biomedical research, due in part to its well-annotated genome, wealth of genetic resources, and the ability to precisely manipulate its genome. Despite the importance of genetics for mouse research, genetic quality control (QC) is not standardized, in part due to the lack of cost-effective, informative, and robust platforms. Genotyping arrays are standard tools for mouse research and remain an attractive alternative even in the era of high-throughput whole-genome sequencing. Here, we describe the content and performance of a new iteration of the Mouse Universal Genotyping Array (MUGA), MiniMUGA, an array-based genetic QC platform with over 11,000 probes. In addition to robust discrimination between most classical and wild-derived laboratory strains, MiniMUGA was designed to contain features not available in other platforms: (1) chromosomal sex determination, (2) discrimination between substrains from multiple commercial vendors, (3) diagnostic SNPs for popular laboratory strains, (4) detection of constructs used in genetically engineered mice, and (5) an easy-to-interpret report summarizing these results. In-depth annotation of all probes should facilitate custom analyses by individual researchers. To determine the performance of MiniMUGA, we genotyped 6899 samples from a wide variety of genetic backgrounds. The performance of MiniMUGA compares favorably with three previous iterations of the MUGA family of arrays, both in discrimination capabilities and robustness. We have generated publicly available consensus genotypes for 241 inbred strains including classical, wild-derived, and recombinant inbred lines. Here, we also report the detection of a substantial number of XO and XXY individuals across a variety of sample types, new markers that expand the utility of reduced complexity crosses to genetic backgrounds other than C57BL/6, and the robust detection of 17 genetic constructs. We provide preliminary evidence that the array can be used to identify both partial sex chromosome duplication and mosaicism, and that diagnostic SNPs can be used to determine how long inbred mice have been bred independently from the relevant main stock. We conclude that MiniMUGA is a valuable platform for genetic QC, and an important new tool to increase the rigor and reproducibility of mouse research.

Physicians are increasingly becoming salaried employees of hospitals or large physician groups. Yet few published reports have evaluated provider-driven quality incentive programs for salaried physicians. In 2006 the Massachusetts General Physicians Organization began a quality incentive program for its salaried physicians. Eligible physicians were given performance targets for three quality measures every six months. The incentive payments could be as much as 2 percent of a physician's annual income. Over thirteen six-month terms, the program used 130 different quality measures. Although quality-of-care improvements and cost reductions were difficult to calculate, anecdotal evidence points to multiple successes. For example, the program helped physicians meet many federal health information technology meaningful-use criteria and produced $15.5 million in incentive payments. The program also facilitated the adoption of an electronic health record, improved hand hygiene compliance, increased efficiency in radiology and the cancer center, and decreased emergency department use. The program demonstrated that even small incentives tied to carefully structured metrics, priority setting, and clear communication can help change salaried physicians' behavior in ways that improve the quality and safety of health care and ease the physicians' sense of administrative burden.Physicians are increasingly becoming salaried employees of hospitals or large physician groups. Yet few published reports have evaluated provider-driven quality incentive programs for salaried physicians. In 2006 the Massachusetts General Physicians Organization began a quality incentive program for its salaried physicians. Eligible physicians were given performance targets for three quality measures every six months. The incentive payments could be as much as 2 percent of a physician's annual income. Over thirteen six-month terms, the program used 130 different quality measures. Although quality-of-care improvements and cost reductions were difficult to calculate, anecdotal evidence points to multiple successes. For example, the program helped physicians meet many federal health information technology meaningful-use criteria and produced $15.5 million in incentive payments. The program also facilitated the adoption of an electronic health record, improved hand hygiene compliance, increased efficiency in radiology and the cancer center, and decreased emergency department use. The program demonstrated that even small incentives tied to carefully structured metrics, priority setting, and clear communication can help change salaried physicians' behavior in ways that improve the quality and safety of health care and ease the physicians' sense of administrative burden.