SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.

Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.

Short-term insomnia disorder in health care workers in an academic medical center before and during COVID-19: rates and predictive factors.

STUDY OBJECTIVES: This study investigated risk factors and estimated rates of acute insomnia disorder in health care workers at the onset of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A Qualtrics survey of more than 2,300 health care providers was conducted in a single academic health system on May 15, 2020, including practicing attending physicians, residents and fellows in training, advanced practice providers, and nurses. Six hundred and sixty-eight responded (29% response rate). The survey employed the Research Diagnostic Criteria for insomnia disorder to diagnose acute insomnia disorder. RESULTS: Five hundred seventy-three respondents had no missing data pertaining to sleep, with a mean age of 43.4 ± 12.5 years and 72% women. The rate of insomnia disorder before COVID-19 was 44.5%, while after COVID-19 it was 64.0%. Of persons with insomnia disorder before COVID-19 10.2% stated it had resolved during COVID-19, while 43.4% of persons who did not have insomnia disorder before COVID-19 developed acute insomnia disorder during COVID-19 (χ² = 145.2; df = 1; P < .0001). New cases of acute insomnia disorder were related positively to female sex, advancing age, and less time spent in direct patient care. CONCLUSIONS: Acute insomnia disorder was exceptionally common in this sample of tertiary care health care workers. The effects of sex and age were similar to what has been generally described as risk factors for insomnia. The surprising finding that less time spent in direct patient care was associated with more cases of acute insomnia disorder might be explained by the poorly understood stresses of working from home during COVID-19.

CDK9 Expression Shows Role as a Potential Prognostic Biomarker in Breast Cancer Patients Who Fail to Achieve Pathologic Complete Response after Neoadjuvant Chemotherapy.

Failure to achieve pathologic complete response is associated with poor prognosis in breast cancer patients following neoadjuvant chemotherapy (NACT). However, prognostic biomarkers for clinical outcome are unclear in this patient population. Cyclin-dependent kinase 9 (CDK9) is often dysregulated in breast cancer, and its deficiency results in genomic instability. We reviewed the records of 84 breast cancer patients from Emory University's Winship Cancer Institute who had undergone surgical resection after NACT and had tissue available for tissue microarray analysis (TMA). Data recorded included disease presentation, treatment, pathologic response, overall survival (OS), locoregional recurrence free survival (LRRFS), distant-failure free survival (DFFS), recurrence-free survival (RFS), and event-free survival (EFS). Immunohistochemistry was performed on patient samples to determine CDK9 expression levels after NACT. Protein expression was linked with clinical data to determine significance. In a Cox proportional hazards model, using a time-dependent covariate to evaluate the risk of death between groups beyond 3 years, high CDK9 expression was significantly associated with an increase in OS (HR: 0.26, 95% CI: 0.07-0.98, p=0.046). However, Kaplan-Meier curves for OS, LRRFS, DFFS, RFS, and EFS did not reach statistical significance. The results of this study indicate that CDK9 may have a potential role as a prognostic biomarker in patients with breast cancer following NACT. However, further validation studies with increased sample sizes are needed to help elucidate the prognostic role for CDK9 in the management of these patients.

SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination.

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.

Sirtuin 2 mutations in human cancers impair its function in genome maintenance.

Sirtuin 2 (SIRT2) is a sirtuin family deacetylase, which maintains genome integrity and prevents tumorigenesis. Although Sirt2 deficiency in mice leads to tumorigenesis, the functional significance of somatic SIRT2 mutations in human tumors is unclear. Using structural insight combined with bioinformatics and functional analyses, we show that naturally occurring cancer-associated SIRT2 mutations at evolutionarily conserved sites disrupt its deacetylation of DNA-damage response proteins by impairing SIRT2 catalytic activity or protein levels but not its localization or binding with substrate. We observed that these SIRT2 mutant proteins fail to restore the replication stress sensitivity, impairment in recovery from replication stress, and impairment in ATR-interacting protein (ATRIP) focus accumulation of SIRT2 deficiency. Moreover, the SIRT2 mutant proteins failed to rescue the spontaneous induction of DNA damage and micronuclei of SIRT2 deficiency in cancer cells. Our findings support a model for SIRT2's tumor-suppressive function in which somatic mutations in SIRT2 contribute to genomic instability by impairing its deacetylase activity or diminishing its protein levels in the DNA-damage response. In conclusion, our work provides a mechanistic basis for understanding the biological and clinical significance of SIRT2 mutations in genome maintenance and tumor suppression.