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curriculum content, which we have made publicly available in order to encourage broader implementation, and its effect on participating fellows and the nephrology educators who facilitated it.
Immune checkpoint blockade therapy has clearly shown clinical activity in patients with triple-negative breast cancer, but less than half of the patients benefit from the treatments. While a number of ongoing clinical trials are investigating different combinations of checkpoint inhibitors and chemotherapeutic agents, predictive biomarkers that identify patients most likely to benefit remains one of the major challenges. Here we present a modular quantitative systems pharmacology (QSP) platform for immuno-oncology that incorporates detailed mechanisms of immune-cancer cell interactions to make efficacy predictions and identify predictive biomarkers for treatments using atezolizumab and nab-paclitaxel.

A QSP model was developed based on published data of triple-negative breast cancer. With the model, we generated a virtual patient cohort to conduct in silico virtual clinical trials and make retrospective analyses of the pivotal IMpassion130 trial that led to the accelerated approval of atezolizumab and nablinical trial designs.
This study provides a QSP platform, which can be used to generate virtual patient cohorts and conduct virtual clinical trials. Our findings demonstrate its potential for making efficacy predictions for immunotherapies and chemotherapies, identifying predictive biomarkers, and guiding future clinical trial designs.Metastatic colorectal cancers (mCRC) harboring microsatellite instability (MSI) are sensitive to immune checkpoint inhibitors (ICIs), but the mechanisms of resistance to ICIs remain unclear. Dissociated responses in patients with ICI-treated cancer suggest that certain organs may serve as sanctuary sites due to the tumor microenvironment. This case series describes five patients with ICI-treated MSI mCRC with disease progression limited to the adrenal glands. At ICI initiation, three patients were free of metastasis in the adrenal glands. Four patients experienced objective response per RECIST (Response Evaluation Criteria in Solid Tumors) while treated with ICI. ICI treatment was discontinued due to progressive disease limited to the adrenal glands (n=3) or toxicity (n=2). https://www.selleckchem.com/mTOR.html The time between ICI initiation and progression in the adrenal glands ranged from 11 to 39 months. Adrenalectomy (n=3) and stereotactic body radiation therapy (n=2) were performed. At the last follow-up, all patients were alive and progression free. https://www.selleckchem.com/mTOR.html Molecular analyses were performed in one patient. A significant impairment of the antigen presentation pathway was observed in the ICI-resistant lesion of the adrenal gland, which could be explained by the presence of glucocorticoids in the adrenal gland microenvironment. We also detected an overexpression of TSC22D3, a glucocorticoid-target gene that functions as a mediator of anti-inflammation and immunosuppression. link= https://www.selleckchem.com/mTOR.html This case series suggests that the adrenal glands may be the sanctuary sites for ICI-treated MSI mCRC through the glucocorticoid-induced impairment of the antigen presentation machinery.
CKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), a programmed death-ligand 1 (PD-L1) regulator, is widely expressed in various tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of CMTM6 in colorectal cancer (CRC) are still unknown. In this study, we aimed to elaborate the expression patterns of CMTM6 and PD-L1 in CRC and investigate their relationship with the infiltration of T cells and the prognosis of patients with CRC.

Analysis of CMTM6 mRNA levels, gene ontology enrichment analysis and single-sample gene set enrichment analysis were performed in a The Cancer Genome Atlas colon cancer cohort. The expression of CMTM6 and PD-L1 and the infiltration of T cells in tumor tissues from our cohort containing 156 patients with CRC receiving adjuvant chemotherapy and 77 patients with CRC without chemotherapy were examined by immunohistochemistry assay.

CMTM6 expression was upregulated in CRC compared with normal colon tissues, and Cd PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with CRC, especially for patients receiving adjuvant chemotherapy. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for CRC in the future.
CMTM6 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for CRC. The coexpression status of CMTM6 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with CRC, especially for patients receiving adjuvant chemotherapy. These findings may provide insights into improving responses to immunotherapy-included comprehensive treatment for CRC in the future.Background Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. link2 link2 A common feature, however, is the host's inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8+ T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment.Methods To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy.Results Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. link3 In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8+ T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA.Conclusion Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8+ T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.Sexsomnia is a non-rapid eye movement parasomnic behavior characterized by sexual activity during sleep. Recognized in the most recent editions of the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Sleep Disorders, sexsomnia is likely to arise with increasing frequency in court as a potential explanation for sexual offending. The forensic psychiatrist has a unique role in the evaluation and management of sexsomnia. The psychosexual evaluation may elucidate the presence or absence of paraphilias and paraphilic disorders and identify any overlap between the alleged sexsomnic behavior and paraphilic interest. In addition, forensic psychiatrists may assess for malingered sexsomnia, provide an opinion regarding criminal responsibility, or evaluate the risk for committing future sexual offenses. Forensic psychiatrists should therefore understand basic information regarding the disorder, as well as how to conduct a psychosexual evaluation effectively in cases of alleged sexsomnia. This article describes the various considerations involved in the forensic evaluation of sexsomnia.The introduction of psychiatric genetic evidence in court proceedings to terminate parental rights raises concerns that such information will result in misconceived assumptions about the child's mental health trajectory and unjust rulings on termination of parental rights. We conducted an online vignette-based survey with a nationally representative sample of adults from the general public (n = 300 respondents) to assess their views on how evidence about a child's psychiatric genetic makeup may affect key decisions in termination proceedings. Our findings indicate that genetic evidence increased the child's labeling as having a psychiatric disorder, regardless of the presence of symptoms, treatment recommendations, evaluation of prescription medication, and beliefs in treatment efficacy. Genetic evidence alone did not affect whether participants would terminate parental rights, but participants who thought that the child did not have a psychiatric disorder were more likely to terminate in the presence of genetic test results. We conclude that psychiatric genetic evidence in termination proceedings may have unintended consequences, and that measures should be taken to ensure that it does not unfairly affect outcomes.Trauma and posttraumatic stress disorder (PTSD) are common among psychiatric and criminal populations, yet there have been few studies among forensic psychiatric populations and no known studies have specifically examined insanity acquittees. This study aimed to identify the prevalence of trauma and to assess recognition of PTSD in forensic settings. Using a cross-sectional self-report survey methodology, we examined traumas, adverse childhood experiences (ACEs), and PTSD in insanity acquittees (n = 107). Most insanity acquittees experienced trauma (86%, averaging 11 events) and ACEs (76%, averaging 3 types). The most commonly experienced traumas were sudden death of a loved one, witnessed death or serious injury, adult physical assault, and motor vehicle accident. Women were significantly more likely to experience any ACE (especially witnessing domestic violence, household members with mental illness, emotional abuse, and emotional neglect) and adult sexual assault. PTSD prevalence was 25 percent, with 97 percent of cases being previously undiagnosed. Sexual traumas and younger age were significantly associated with PTSD. These results suggest that insanity acquittees have high levels of trauma, ACEs, and PTSD. link3 While PTSD was about seven times more common than in previous findings in the general population, it frequently goes undiagnosed in forensic settings. Potential explanations and implications of our findings are discussed.Civil commitment for substance use disorders is an increasingly used intervention to mitigate the risks associated with severe substance use. Although court clinicians play a vital role in helping courts determine whether respondents meet statutory requirements for commitment, little is known about their experiences conducting these evaluations. In this pilot study, we surveyed all court clinicians who perform evaluations for civil commitment for substance use disorders in Massachusetts, a state with one of the highest rates of such commitments nationally. Court clinicians reported that these evaluations are most frequently ordered for individuals who use heroin and other opioids, alcohol, and cannabis. They reported a recent suicide attempt or drug overdose, intentional physical harm to another, use of dangerous weapon, and driving while intoxicated as the behaviors most likely to satisfy the statutory requirement of imminent risk. At the same time, many court clinicians consider a much broader range of behaviors as constituting imminent risk, and many reported having endorsed commitment on one or more occasions in the absence of statutory criteria being satisfied.
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