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This study sought to evaluate the impact of telepsychiatry during the COVID-19 pandemic among patients discharged from psychiatric inpatient units in the New York City Health and Hospitals Corporation system. We compared patients discharged to telepsychiatry (April 2020, n = 739) and in-person follow-up (May 2019, n = 527); we collected number, timing and attendance for follow-up appointments and number and timing of emergency room (ER) visits and readmissions. We used logistic regression to evaluate the odds of having these encounters and Kaplan-Meier analyses to compare time to these encounters. Patients discharged in 2020 were more likely to have a follow-up (29.4 vs. 19.9%, p < 0.001) and an ER visit or readmission (40.5 vs. 28.7%, p < 0.001). Kaplan-Meier analyses showed shorter time to first follow-up (chi-square = 14.69, d.f.=1, p < 0.0001, follow-ups = 322) and ER visit or readmission (chi-square = 19.57, d.f.=1, p < 0.0001, ER visits or admissions = 450) in the 2020 cohort. In multivariable analyses, patients discharged in 2020 were more likely to have a follow-up visit (adjusted OR 1.85, 95% confidence interval 1.40, 2.45, p < 0.0001). We found an increase in psychiatric service utilization during the pandemic, with an increase in and shorter time until outpatient visits and ER visits or readmissions. Although increased use of psychiatric services during the height of the COVID-19 pandemic is encouraging, it also points to the depth of the crisis among vulnerable populations; this pattern warrants further exploration and intervention. [ABSTRACT FROM AUTHOR]

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients. Kinase inhibitors are widely used to treat cancer, however patients frequently develop resistance. Here, the authors investigate adaption mechanisms during drug persistence and show that stimulation of the innate immunity sensor RIG-I enhances cancer cell death when combined with kinase inhibition. [ABSTRACT FROM AUTHOR]

Summary Kinase inhibitors represent the backbone of targeted cancer therapy, yet only a limited number of oncogenic drivers are directly druggable. By interrogating the activity of 1,505 kinase inhibitors, we found that BRD4-NUT -rearranged NUT midline carcinoma (NMC) cells are specifically killed by CDK9 inhibition (CDK9i) and depend on CDK9 and Cyclin-T1 expression. We show that CDK9i leads to robust induction of apoptosis and of markers of DNA damage response in NMC cells. While both CDK9i and bromodomain inhibition over time result in reduced Myc protein expression, only bromodomain inhibition induces cell differentiation and a p21-induced cell-cycle arrest in these cells. Finally, RNA-seq and ChIP-based analyses reveal a BRD4-NUT -specific CDK9i-induced perturbation of transcriptional elongation. Thus, our data provide a mechanistic basis for the genotype-dependent vulnerability of NMC cells to CDK9i that may be of relevance for the development of targeted therapies for NMC patients. [ABSTRACT FROM AUTHOR]

The article discusses the identification of RET rearrangements in a broad range of tumors such as lung adenocarcinomas. It suggests that overall response rates in patients treated with RET-targeted drugs are limited. It notes that kinase inhibitors such as AD80 or ponatinib shows extraordinary activity in RET-rearranged cancer models.

MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients. The expression of oncogenic MYC paralogs in small cell lung cancer is mutually exclusive. In this study, the authors show that MYC, but not MYCN or MYCL, represses BCL2, resulting in cells that are uniquely sensitive to apoptosis, and find that CHK1 and AURKA inhibitors may be useful for treating these cancers. [ABSTRACT FROM AUTHOR]