We previously found that QNBC tumors are more frequent in African Americans compared to TNBC tumors. To characterize this subtype further, we sought to determine the miRNA–mRNA profile in QNBC patients based on race. Both miRNA and mRNA expression data were analyzed from TCGA and validated using datasets from the METABRIC, TCGA proteomic, and survival analysis by KMPLOT. miRNA–mRNAs which include FOXA1 and MYC (mir-17/20a targets); GATA3 and CCNG2 (mir-135b targets); CDKN2A, CDK6, and B7-H3 (mir-29c targets); and RUNX3, KLF5, IL1-β, and CTNNB1 (mir-375 targets) were correlated with basal-like and immune subtypes in QNBC patients and associated with a worse survival. Thus, QNBC tumors have an altered gene signature implicated in racial disparity and poor survival.

Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm ("secDrugs") to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a 'Double-Hit' drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness-related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/'scratch' assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.

Takotsubo cardiomyopathy (TC), an acute cardiac event is often associated with acute emotional stress, usually in the setting of cardiovascular risk factors. This case report attempts to review one of the triggers of TC beer potomania-induce hyponatremia with imaging findings that shows the link between severe hyponatremia and TC.

Increased body mass index (BMI) and metabolic syndrome (MS) are associated with increased breast cancer recurrence risk. Whether this is due to intrinsic tumor biology or modifiable factors of the obese state remains incompletely understood. Oncotype DX Recurrence Scores of 751 patients were stratified by BMI to assess association with tumor-intrinsic recurrence risk. Cellular proliferation by Ki67 after 10-21days of presurgical letrozole treatment was used to stratify endocrine therapy response (sensitive-ln(Ki67) < 1; intermediate-ln(Ki67)1-2; resistant-ln(Ki67) > = 2). BMI at the time of surgery and MS variables were collected retrospectively for 143 patients to analyze association between therapy response and BMI/MS. Additionally, PI3K pathway signaling was evaluated by immunohistochemistry of phosphorylated Akt and S6. There was no significant association between BMI and recurrence score (p = 0.99), and risk score distribution was similar across BMI groups. However, BMI was associated with short-term endocrine therapy resistance, with a significant enrichment of intermediate and resistant tumors in patients with obesity (55%, p = 0.0392). Similarly, the relative risk of an endocrine therapy-resistant tumor was 1.4-fold greater for patients with MS (p = 0.0197). In evaluating PI3K pathway mediators, we found patients with 3 or more MS criteria had more tumors with pAkt scores above the median (p = 0.0436). There were no significant differences in S6 activation. Our findings suggest the association between obesity/metabolic syndrome and breast cancer recurrence is better reflected by response to treatment than tumor-intrinsic properties, suggesting interventions to reverse obesity and/or MS may improve outcomes for breast cancer recurrence.

Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. NCT03517007.

MAA have higher rates of prostate cancer incidence and mortality, however, are severely underrepresented in genomic studies. This is the first study utilizing whole-exome sequencing in NG men to identify West African ancestry-linked variant patterns that impact DNA damage repair pathways.

Takotsubo Cardiomyopathy (TC), an acute cardiac event accounting for about 1-2% of all acute coronary syndromes is often associated with acute emotional stress usually in the setting of the other cardiovascular risk factors.This case report reviews a trigger of TC (severe hyponatremia) and the link between them.

ABSTRACTMetastatic prostate cancer is the second leading cause of cancer deaths in US men. Resistance to standard medical castration and secondary taxane-based chemotherapy is nearly universal. Further, presence of cancer stem-like cells (EMT/epithelial to mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/advanced/lethal variants of PCa (AVPC).In this study, first we used single-cell RNA sequencing (scRNAseq) analysis to demonstrate that ARlow PCa cells in metastatic prostate cancer, including castration-sensitive tumors, harbored signatures of EMT, and ‘cancer stemness’. Next, we introduced a novel pharmacogenomics data-driven computational approach and identified several potential agents that can be re-purposed as novel secondary drugs (“secDrugs”) to treat advance variants of Prostate cancer. Using scRNAseq as a biomarker-based drug screen, we demonstrated that a majority of the single-cell subclones in mCRPC and mCSPC cell lines also showed significantly high expression of the NAMPT pathway genes, indicating that the secDrug FK866, which targets NAMPT, is potentially effective against drug-resistant and stem-cell-like subpopulation cluster. Next, we showed significant in vitro cytotoxicity of FK866 as single-agent and in combination with the taxanes or Enzalutamide against models of clinically-advanced PCa. We performed bulk- and single-cell RNAseq to identify several pathways underlining FK866 mechanism of action and found that in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes HES1 and CD44. Further, we performed a microfluidic chip-based cell migration assay that demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using multiple PCa patient datasets, we showed that FK866 is potentially capable of reversing expression of several genes associated with biochemical recurrence and inter-ethnic differences, including IFITM3 and LTB4R.Thus, using FK866 as a proof-of-concept drug, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.

To derive and validate a risk score that accurately predicts 1-year mortality after heart transplantation (HT) in patients bridged to transplant (BTT) with a left ventricular assist device (LVAD). The UNOS database was queried to identify patients BTT with an LVAD between 2008 and 2018. Patients with ⩾1-year follow up were randomly divided into derivation (70%) and validation (30%) cohorts. The primary endpoint was 1-year mortality. A simple additive risk score was developed based on the odds of 1-year mortality after HT. Risk groups were created, and survival was estimated and compared. A total of 7759 patients were randomly assigned to derivation (n = 5431) and validation (n = 2328) cohorts. One-year post-transplant mortality was 9.8% (n = 760). A 33-point scoring was created from six recipient variables and two donor variables. Risk groups were classified as low (0-5), intermediate (6-10), and high (>10). In the validation cohort, the predicted 1-year mortality was significantly higher in the high-risk group than the intermediate and low-risk groups, 14.7% versus 9% versus 6.1% respectively (log-rank test: p < 0.0001). The BTT-LVAD Score can serve as a clinical decision tool to guide therapeutic decisions in advanced heart failure patients.

BackgroundSepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. We conducted a randomized controlled trial (NCT03517007) of an opt-out protocol to decrease unnecessary antibiotics in selected patients with suspected sepsis.MethodsWe evaluated non-ICU adults remaining on broad-spectrum antibiotics with negative blood cultures at 48-96 hours at ten U.S. hospitals during September 2018-May 2020. A 23-item safety check excluded patients with ongoing signs of infection, concerning or inadequate microbiologic data, or high-risk conditions (Figure 1). Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted by a pharmacist or physician to encourage antibiotic discontinuation or de-escalation using opt-out language, discuss rationale for continuing antibiotics, working diagnosis, and de-escalation and duration plans. Hurdle models separately compared the odds of antibiotic continuation and DOT distributions among those who continued antibiotics.Components of the De-Escalating Empiric Therapy: Opting-OUt of Rx in Selected patients with Suspected Sepsis (DETOURS) Trial Protocol ResultsAmong 9606 screened, 767 (8%) were enrolled (Figure 2). Common reasons for exclusion were antibiotics given prior to blood culture (35%), positive culture from non-blood sites (26%), and increased oxygen requirement (21%). Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval [0.47, 0.98]). DOT distributions among those who continued antibiotics were similar (ratio of means 1.06 [0.88-1.26], Figure 3). Fewer intervention patients were exposed to extended-spectrum agents (38% vs. 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was not safe (31%). Safety outcomes such as mortality, readmission, sepsis relapse, C. difficile, and length of stay did not differ.DETOURS Trial Flow Diagram Flow of participants through the DETOURS Trial.Observed Days of Antibiotic Therapy Among Intervention and Control Subjects in the DETOURS Trial Post-enrollment days of antibiotic therapy among 767 DETOURS Trial participants in 10 US acute care hospitals within 30 days after enrollment. Dark pink color indicates percent overlap between intervention (purple) and control (light pink) groups.ConclusionIn this patient-level randomized trial of a stewardship intervention, the opt-out de-escalation protocol targeting selected patients with suspected sepsis resulted in more antibiotic discontinuations but did not affect safety events.Disclosures Rebekah W. Moehring, MD, MPH, UpToDate, Inc. (Other Financial or Material Support, Author Royalties) Michael Z. David, MD PhD, GSK (Board Member) Michael Klompas, MD, MPH, UpToDate (Other Financial or Material Support, Chapter Author)