Search

Schizophrenia (SZ) is a serious mental illness and neuropsychiatric brain disorder with behavioral symptoms that include hallucinations, delusions, disorganized behavior, and cognitive impairment. Regulation of such behaviors requires utilization of neurotransmitters released to mediate cell-cell communication which are essential to brain functions in health and disease. We hypothesized that SZ may involve dysregulation of neurotransmitters secreted from neurons. To gain an understanding of human SZ, induced neurons (iNs) were derived from SZ patients and healthy control subjects to investigate peptide neurotransmitters, known as neuropeptides, which represent the major class of transmitters. The iNs were subjected to depolarization by high KCl in the culture medium and the secreted neuropeptides were identified and quantitated by nano-LC-MS/MS tandem mass spectrometry. Several neuropeptides were identified from schizophrenia patient-derived neurons, including chromogranin B (CHGB), neurotensin, and natriuretic peptide. Focusing on the main secreted CHGB neuropeptides, results revealed differences in SZ iNs compared to control iN neurons. Lower numbers of distinct CHGB peptides were found in the SZ secretion media compared to controls. Mapping of the peptides to the CHGB precursor revealed peptides unique to either SZ or control, and peptides common to both conditions. Also, the iNs secreted neuropeptides under both KCl and basal (no KCl) conditions. These findings are consistent with reports that chromogranin B levels are reduced in the cerebrospinal fluid and specific brain regions of SZ patients. These findings suggest that iNs derived from SZ patients can model the decreased CHGB neuropeptides observed in human SZ.

The genus Xanthomonas has been primarily studied for pathogenic interactions with plants. However, besides host and tissue-specific pathogenic strains, this genus also comprises nonpathogenic strains isolated from a broad range of hosts, sometimes in association with pathogenic strains, and other environments, including rainwater. Based on their incapacity or limited capacity to cause symptoms on the host of isolation, nonpathogenic xanthomonads can be further characterized as commensal and weakly pathogenic. This study aimed to understand the diversity and evolution of nonpathogenic xanthomonads compared to their pathogenic counterparts based on their cooccurrence and phylogenetic relationship and to identify genomic traits that form the basis of a life history framework that groups xanthomonads by ecological strategies. We sequenced genomes of 83 strains spanning the genus phylogeny and identified eight novel species, indicating unexplored diversity. While some nonpathogenic species have experienced a recent loss of a type III secretion system, specifically the hrp2 cluster, we observed an apparent lack of association of the hrp2 cluster with lifestyles of diverse species. We performed association analysis on a large data set of 337 Xanthomonas strains to explain how xanthomonads may have established association with the plants across the continuum of lifestyles from commensals to weak pathogens to pathogens. Presence of distinct transcriptional regulators, distinct nutrient utilization and assimilation genes, transcriptional regulators, and chemotaxis genes may explain lifestyle-specific adaptations of xanthomonads.

Biallelic mutations in the gene that encodes the enzyme N-glycanase 1 (NGLY1) cause a rare disease with multi-symptomatic features including developmental delay, intellectual disability, neuropathy, and seizures. NGLY1s activity in human neural cells is currently not well understood. To understand how NGLY1 gene loss leads to the specific phenotypes of NGLY1 deficiency, we employed direct conversion of NGLY1 patient-derived induced pluripotent stem cells (iPSCs) to functional cortical neurons. Transcriptomic, proteomic, and functional studies of iPSC-derived neurons lacking NGLY1 function revealed several major cellular processes that were altered, including protein aggregate-clearing functionality, mitochondrial homeostasis, and synaptic dysfunctions. These phenotypes were rescued by introduction of a functional NGLY1 gene and were observed in iPSC-derived mature neurons but not astrocytes. Finally, laser capture microscopy followed by mass spectrometry provided detailed characterization of the composition of protein aggregates specific to NGLY1-deficient neurons. Future studies will harness this knowledge for therapeutic development.

Over the last half-century, discussions on the exact targets for low-density lipoprotein cholesterol (LDL-C) reduction have evolved towards a more aggressive approach with lower LDL-C targets, particularly for high-risk patients with pre-existing atherosclerotic cardiovascular disease (ASCVD). A wealth of cardiovascular outcome trials have shown the efficacy of statin therapy in general, as well as the incremental impact of high-intensity statin therapy in particular. More recent trials have further demonstrated the impact of non-statin therapies, including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and, most recently, bempedoic acid, on reducing ASCVD outcomes. The availability of these and other newer therapies has prompted clinicians to strive for lower LDL-C targets to address residual ASCVD risk after statin therapy. This paper will provide an overview of the historical trends in lipid management and therapeutics and review the current state of evidence for lower LDL-C targets in clinical guidelines and recommendations.

This research explores the integration of creative and expressive arts in a young adult problem-solving court and the perceived benefits of participation. The Young Adult Diversion Court (YADC) was created to help young adults 17 to 20 years of age complete probation requirements. This qualitative study is informed by interpretive interactionism to examine the lived experience of participants. Ethnographic observations were conducted over 20 months, and interpretive interviews were held with 32 young adult participants and 8 program coordinators. Participants described an engaging programmatic design, and felt cared for and supported by staff in the YADC. The use of the creative and expressive arts and spoken-word practices allowed participants to overcome vulnerabilities through self-expression, regulate emotions and process trauma, and consider possible future selves. This research suggests the potential of alternative approaches in the criminal justice system that intervene in the lives of young adults to promote positive change.

Copper (Cu) is the most extensively used bactericide worldwide in many agricultural production systems. However, intensive application of Cu bactericide have increased the selection pressure toward Cu-tolerant pathogens, including Xanthomonas perforans, the causal agent of tomato bacterial spot. However, alternatives for Cu bactericides are limited and have many drawbacks including plant damage and inconsistent effectiveness under field conditions. Also, potential ecological risk on nontarget organisms exposed to field runoff containing Cu is high. However, due to lack of alternatives for Cu, it is still widely used in tomato and other crops around the world in both conventional and organic production systems. In this study, a Cu-tolerant X. perforans strain GEV485, which can tolerate eight tested commercial Cu bactericides, was used in all the field trials to evaluate the efficacy of MgO nanomaterial. Four field experiments were conducted to evaluate the impact of intensive application of MgO nanomaterial on tomato bacterial spot disease severity, and one field experiment was conducted to study the impact of soil accumulation of total and bioavailable Cu, Mg, Mn, and Zn. In the first two field experiments, twice-weekly applications of 200 μg/mL MgO significantly reduced disease severity by 29-38% less in comparison to a conventional Cu bactericide Kocide 3000 and 19-30% less in comparison to the water control applied at the same frequency (p = 0.05). The disease severity on MgO twice-weekly was 12-32% less than Kocide 3000 + Mancozeb treatment. Single weekly applications of MgO had 13-19% higher disease severity than twice weekly application of MgO. In the second set of two field trials, twice-weekly applications of MgO at 1000 μg/mL significantly reduced disease severity by 32-40% in comparison to water control applied at the same frequency (p = 0.05). There was no negative yield impact in any of the trials. The third field experiment demonstrated that application of MgO did not result in significant accumulation of total and bioavailable Mg, Mn, Cu, or Zn in the root-associated soil and in soil farther away from the production bed compared to the water control. However, Cu bactericide contributed to significantly higher Mn, Cu, and Zn accumulation in the soil compared to water control (p = 0.05). This study demonstrates that MgO nanomaterial could be an alternative for Cu bactericide and have potential in reducing risks associated with development of tolerant strains and for reducing Cu load in the environment.

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.

The authors examine the impact of a new online learning system on student performance in a core finance course required of all business majors. They find that the online learning system significantly reduces the number of students that withdraw from the course prior to course completion. Additionally, the benefits of a lower withdrawal rate transcend all modalities of course delivery and are greatest for students with declared majors outside of finance. Finally, though use of the online learning system reduces the withdrawal rate of students, it does not appear to result in significant grade inflation among those students completing the course.

Objective: With high rates of mental health concerns on college campuses, effective positive psychology interventions could greatly improve student well-being and academic outcomes. Participants: Working undergraduates (N = 52). Methods: This preliminary, randomized controlled trial investigated the effects of the 8-week Mindfulness-based strengths practice (MBSP) on Seligman's five domains of well-being, as measured by the PERMA-Profiler, Workplace PERMA-Profiler, and student retention in working undergraduates. Results: Students in the MBSP intervention had significantly higher well-being, engagement, meaning, and health following the MBSP program (P < 0.0042). No such changes were observed in the control group. Students in the intervention group also had modestly higher retention rates in the following academic year than those in the control group. Conclusions: This study provides the first evidence to date that an MBSP program can improve college student well-being and retention.

BackgroundIbrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).Patients and methodsMeasures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization.ResultsWith up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P < .0001). Higher rates of clinically meaningful improvement were demonstrated with ibrutinib versus ofatumumab for FACIT-F and EORTC global health. Greater improvement was observed in disease-related weight loss, fatigue, night sweats, and abdominal discomfort with ibrutinib versus ofatumumab. Hospitalizations in the first 30 days occurred less frequently with ibrutinib than ofatumumab (0.087 vs. 0.184 events/patient; P = .0198). New-onset diarrhea was infrequent with ibrutinib after the first 6 months (47% at ≤6 months vs. 5% at 12-18 months). With ibrutinib, grade ≥ 3 hypertension occurred in 6%, grade ≥ 3 atrial fibrillation in 4%, major hemorrhage in 2%, and tumor lysis syndrome in 1% of patients.ConclusionIbrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18.) Diarrhea was the most common nonhematologic AE (TN 78%, RR 47%); transaminase elevations the most frequent lab-abnormality AE (TN 33.3%, RR 30.9%); and neutropenia the most common ≥grade 3 AE (RR 44%, TN 33%). The overall response rates were 56.4% for RR patients (1.8% CR, 54.5% PR) and 83.3% for TN patients (all PRs); median response duration was 21.0 months in RR patients but was not reached for TN patients. Based upon phase 1 efficacy, pharmacodynamics, and safety, duvelisib 25 mg BID was selected for further investigation in a phase 3 study in RR CLL/SLL.

Patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) with deletion 17p [del(17p)] have poor outcomes with chemoimmunotherapy. Ibrutinib is indicated for the treatment of CLL/SLL, including del(17p) CLL/SLL, and allows for treatment without chemotherapy. This integrated analysis was performed to evaluate outcomes in 230 patients with relapsed/refractory del(17p) CLL/SLL from three ibrutinib studies. With a median of 2 prior therapies (range, 1-12), 18% and 79% of evaluable patients had del(11q) or unmutated IGHV, respectively. With a median follow-up of 28 months, overall response rate was 85% and estimated 30-month progression-free and overall survival rates were 57% [95% confidence interval (CI) 50-64] and 69% (95% CI 61-75), respectively. Patients with normal lactate dehydrogenase or no bulky disease had the most favourable survival outcomes. Sustained haematological improvements in haemoglobin, platelet count and absolute neutrophil count occurred in 61%, 67% and 70% of patients with baseline cytopenias, respectively. New onset severe cytopenias and infections decreased in frequency over time. Progression-free and overall survival with ibrutinib surpass those of other therapies for patients with del(17p) CLL/SLL. These results provide further evidence of the robust clinical activity of ibrutinib in difficult-to-treat CLL/SLL populations.

We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance-KIT, KRAS, and NRAS-exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.

The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large scale manufacturing purposes. Bispecific IgG (BsIgG) based on two antibodies that use an identical common light chain can be combined with a minimal set of Fc mutations to drive heavy chain heterodimerization in order to address these challenges. However, the facile generation of common light chain antibodies with properties similar to traditional monoclonal antibodies has not been demonstrated and they have only been used sparingly. Here, we describe the design of a synthetic human antibody library based on common light chains to generate antibodies with biochemical and biophysical properties that are indistinguishable to traditional therapeutic monoclonal antibodies. We used this library to generate diverse panels of well-behaved, high affinity antibodies toward a variety of epitopes across multiple antigens, including mouse 4-1BB, a therapeutically important T cell costimulatory receptor. Over 200 BsIgG toward 4-1BB were generated using an automated purification method we developed that enables milligram-scale production of BsIgG. This approach allowed us to identify antibodies with a wide range of agonistic activity that are being used to further investigate the therapeutic potential of antibodies targeting one or more epitopes of 4-1BB.

Bleeding events have been observed among a subgroup of chronic lymphocytic leukaemia (CLL) patients treated with ibrutinib. We analysed data from two studies of single-agent ibrutinib to better characterize bleeding events and pattern of anticoagulation and antiplatelet use. Among 327 ibrutinib-treated patients, concomitant anticoagulation (11%) or antiplatelet use (34%) was common, but major bleeding was infrequent (2%). Bleeding events were primarily grade 1, and infrequently (1%) led to discontinuation. Among 175 patients receiving concomitant anticoagulant or antiplatelet agents, 5 had major bleeding events (3%). These events were typically observed in conjunction with other factors, such as coexisting medical conditions and/or concurrent medications.

Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1-12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149-55. ©2017 AACR.