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To investigate genetic mutations in patients with dilated nonischemic cardiomyopathy (NICM) and history of left ventricular assist device (LVAD) implant. 76 patients were included in this retrospective study. Clinical data was obtained to determine environmental exposures (i.e. infectious, chemotherapy, pregnancy, significant alcohol and drug use), family history, native heart function, and the attributed etiology of their cardiomyopathy as determined by each patient's cardiologist. Genetic testing was obtained using a third-party 168-gene cardiomyopathy panel. Variants were classified into five categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign. The VUS were investigated with population allele frequencies from Gnomad or Varsome databases and two modeling scores, Rare Exome Variant Ensemble Learner (Revel) and Combined Annotation Dependent Depletion (CADD), to investigate the likely pathogenicity. The patients were majority male (68%) and racially diverse, with 59% Black, 21% Hispanic, 17% White, and 3% Asian. Family history of heart failure was positive in 29% of the sample. The possible etiology of heart failure was 16% environmental, 8% familial, and 75% idiopathic or unknown. Regarding genetic testing results, 67 (88%) patients had variants identified; the remaining 9 patients (12%) had negative results. There were a total 170 variants for those 67 patients, with an average of 2.6 variants per patient. Of the 170 variants, 14 (8%) were pathogenic/likely pathogenic and 7 of these were titin (TTN) mutations. 151 (89%) of variants were VUS. Allele frequencies were not found for 17% of the VUS, and the remaining variants had total population and race-specific allele frequencies less than 1%. 83 (55%) of VUS were among the top 1% deleterious substitutions by CADD scores, and 27 (18%) of VUS had a Revel score > 0.5, on a scale of 0 to 1, suggesting more likely pathogenic variants. Patients with end-stage dilated NICM undergoing LVAD are likely to have genetic variants. The most frequent pathogenic variants were in TTN but most results are VUS. Due to the high frequency of VUS, augmenting genetic testing in this population may contribute to identification of additional pathogenic variants. [ABSTRACT FROM AUTHOR]

Objective: The current study examined the effects of partial and total sleep deprivation on emotional reactivity.Methods: Twenty-eight partially sleep-deprived participants and 31 totally sleep-deprived participants rated their valence and arousal responses to positive and negative pictures across four testing sessions during the day following partial sleep deprivation or during the night under total sleep deprivation.Results: The results suggest that valence and arousal ratings decreased under both sleep deprivation conditions. In addition, partial and total sleep deprivation had a greater negative effect on positive events than negative events.Conclusion: These results suggest that sleep-deprived persons are more likely to respond less to positive events than negative events. One explanation for the current findings is that negative events could elicit more attentive behavior and thus stable responding under sleep deprivation conditions. As such, sleep deprivation could impact reactivity to emotional stimuli through automated attentional and self-regulatory processes. [ABSTRACT FROM AUTHOR]

Background: Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. Patients and methods: We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. Results: CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. Conclusions: In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis. [ABSTRACT FROM AUTHOR]

Purpose: (1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial-mesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment. Methods: Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0-300 mg/m/week) given concurrently with cetuximab (400 mg/m loading dose, 250 mg/m weekly maintenance dose) and abdominal irradiation (50.4 Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens. Results: Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1-2 adverse events was 96%, and incidence of 3-4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5 months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients. Conclusions: Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300 mg/m/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: TRA-8 is a murine agonist monoclonal antibody to death receptor 5 (DR5), which is able to trigger apoptosis in DR5 positive human tumor cells without the aid of crosslinking. It has demonstrated cytotoxicity in vitro and in vivo antitumor efficacy to a wide range of solid tumors in murine xenograft models. Tigatuzumab is a humanized IgG1 monoclonal antibody derived from TRA-8.Methods: A phase I trial of tigatuzumab in patients with relapsed/refractory carcinomas (n = 16) or lymphoma (n = 1) was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety. Three to six (3-6) patients were enrolled in successive escalating cohorts at doses ranging from 1 to 8 mg/kg weekly.Results: Seventeen (17) patients enrolled, 9 in the 1-, 2-, and 4-mg/kg dose cohorts (3 in each cohort) and 8 in the 8-mg/kg dose cohort. Tigatuzumab was well tolerated with no DLTs observed, and the MTD was not reached. There were no study-drug-related grade 3 or 4, renal, hepatic, or hematologic toxicities. Plasma half-life was 6-10 days, and no anti-tigatuzumab responses were detected. Seven (7) patients had stable disease, with the duration of response ranging from 81 to 798 days.Conclusions: Tigatuzumab is well tolerated, and the MTD was not reached. The high number of patients with stable disease suggests antitumor activity. [ABSTRACT FROM AUTHOR]