Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism

Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase

Loneliness, coping, suicidal thoughts and self-harm during the COVID-19 pandemic: a repeat cross-sectional UK population survey

Objectives: There has been speculation on the impact of the COVID-19 pandemic and the associated lockdown on suicidal thoughts and self-harm and the factors associated with any change. We aimed to assess the effects and change in effects of risk factors including loneliness and coping, as well as pre-existing mental health conditions on suicidal thoughts and self-harm during the COVID-19 pandemic. Design: This study was a repeated cross-sectional online population-based survey. Participants and measures: Non-probability quota sampling was adopted on the UK adult population and four waves of data were analysed during the pandemic (17 March 2020 to 29 May 2020). Outcomes were suicidal thoughts and self-harm associated with the pandemic while loneliness, coping, pre-existing mental health conditions, employment status and demographics were covariates. We ran binomial regressions to evaluate the adjusted risks of the studied covariates as well as the changes in effects over time. Results: The proportion of individuals who felt lonely increased sharply from 9.8% to 23.9% after the UK lockdown began. Young people (aged 18–24 years), females, students, those who were unemployed and individuals with pre-existing mental health conditions were more likely to report feeling lonely and not coping well. 7.7%–10.0% and 1.9%–2.2% of respondents reported having suicidal thoughts and self-harm associated with the pandemic respectively throughout the period studied. Results from cross-tabulation and adjusted regression analyses showed young adults, coping poorly and with pre-existing mental health conditions were significantly associated with suicidal thoughts and self-harm. Loneliness was significantly associated with suicidal thoughts but not self-harm. Conclusions: The association between suicidality, loneliness and coping was evident in young people during the early stages of the pandemic. Developing effective interventions designed and coproduced to address loneliness and promote coping strategies during prolonged social isolation may promote mental health and help mitigate suicidal thoughts and self-harm associated with the pandemic

Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.

The role of lymphoid tissue as a potential source of HIV-1 rebound following interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during treatment interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical treatment interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent treatment interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination

Pregnancy outcomes related to the treatment of sarcomas with anthracyclines and/or ifosfamide during pregnancy

BACKGROUND: Sarcomas are rare diagnoses but are seen with relative frequency in adolescents and young adults and thus can present in pregnancy. We sought to study the administration of anthracyclines and/or ifosfamide in pregnancy-associated sarcomas. PATIENTS AND METHODS: We conducted a multi-institutional retrospective study, identifying sarcoma patients who received anthracyclines and/or ifosfamide during pregnancy. Chart review identified variables related to demographics, cancer diagnosis, therapies, and outcome of the patient and fetus. Wilcoxon rank-sum test compared two independent samples. RESULTS: We identified 13 patients at seven institutions with sarcoma who received anthracyclines and/or ifosfamide during pregnancy, including four bone sarcomas and nine soft tissue sarcomas diagnosed at a mean gestational age of 16.7 ± 5.9 weeks. Only nine patients had live births (9/13, 69.2%), with mean gestational age of 30.8 ± 3.8 weeks at delivery. The four patients with pregnancy loss all received both doxorubicin and ifosfamide, with chemotherapy initiated at 15.5 weeks as compared with 21.3 weeks for those patients with live births (p = 0.016). CONCLUSION: In this multi-institutional study of sarcoma chemotherapy regimens administered during pregnancy, we found a high rate of fetal demise that was seen only in patients receiving both doxorubicin and ifosfamide and statistically more likely with chemotherapy initiation earlier in the second trimester. While limited by a small sample size, our study represents the largest study of sarcoma patients that received anthracyclines and/or ifosfamide in pregnancy thus far reported and supports development of an international registry to study concerns raised by our study

Phase Ib study of unesbulin (PTC596) plus dacarbazine for the treatment of locally recurrent, unresectable or metastatic, relapsed or refractory leiomyosarcoma

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/

Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

PURPOSE: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate-limiting enzyme of arginine biosynthesis. This deficiency causes arginine auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 reexpression. This study examines the role of ASS1 silencing on tumor growth and initiation and identifies a noncanonical mechanism of resistance, aiming to improve clinical responses to ADI-PEG20. EXPERIMENTAL DESIGN: Tumor initiation and growth rates were measured for a spontaneous Ass1 knockout (KO) murine sarcoma model. Tumor cell lines were generated, and resistance to arginine deprivation therapy was studied in vitro and in vivo. RESULTS: Conditional Ass1 KO affected neither tumor initiation nor growth rates in a sarcoma model, contradicting the prevalent idea that ASS1 silencing confers a proliferative advantage. Ass1 KO cells grew robustly through arginine starvation in vivo, while ADI-PEG20 remained completely lethal in vitro, evidence that pointed toward a novel mechanism of resistance mediated by the microenvironment. Coculture with Ass1-competent fibroblasts rescued growth through macropinocytosis of vesicles and/or cell fragments, followed by recycling of protein-bound arginine through autophagy/lysosomal degradation. Inhibition of either macropinocytosis or autophagy/lysosomal degradation abrogated this growth support effect in vitro and in vivo. CONCLUSIONS: Noncanonical, ASS1-independent tumor resistance to ADI-PEG20 is driven by the microenvironment. This mechanism can be targeted by either the macropinocytosis inhibitor imipramine or the autophagy inhibitor chloroquine. These safe, widely available drugs should be added to current clinical trials to overcome microenvironmental arginine support of tumors and improve patient outcomes

Mental health in the pandemic: a repeated cross-sectional mixed-method study protocol to investigate the mental health impacts of the coronavirus pandemic in the UK.

Funder: MQ: Transforming Mental Health; Grant(s): MQBF/3INTRODUCTION: The WHO declared a global pandemic on 11 March 2020. Since then, the world has been firmly in the grip of the COVID-19. To date, more than 211 730 035 million confirmed cases and more than 4 430 697 million people have died. While controlling the virus and implementing vaccines are the main priorities, the population mental health impacts of the pandemic are expected to be longer term and are less obvious than the physical health ones. Lockdown restrictions, physical distancing, social isolation, as well as the loss of a loved one, working in a frontline capacity and loss of economic security may have negative effects on and increase the mental health challenges in populations around the world. There is a major demand for long-term research examining the mental health experiences and needs of people in order to design adequate policies and interventions for sustained action to respond to individual and population mental health needs both during and after the pandemic. METHODS AND ANALYSIS: This repeated cross-sectional mixed-method study conducts regular self-administered representative surveys, and targeted focus groups and semi-structured interviews with adults in the UK, as well as validation of gathered evidence through citizens' juries for contextualisation (for the UK as a whole and for its four devolved nations) to ensure that emerging mental health problems are identified early on and are properly understood, and that appropriate policies and interventions are developed and implemented across the UK and within devolved contexts. STATA and NVIVO will be used to carry out quantitative and qualitative analysis, respectively. ETHICS AND DISSEMINATION: Ethics approval for this study has been granted by the Cambridge Psychology Research Ethics Committee of the University of Cambridge, UK (PRE 2020.050) and by the Health and Life Sciences Research Ethics Committee of De Montfort University, UK (REF 422991). While unlikely, participants completing the self-administered surveys or participating in the virtual focus groups, semi-structured interviews and citizens' juries might experience distress triggered by questions or conversations. However, appropriate mitigating measures have been adopted and signposting to services and helplines will be available at all times. Furthermore, a dedicated member of staff will also be at hand to debrief following participation in the research and personalised thank-you notes will be sent to everyone taking part in the qualitative research.Study findings will be disseminated in scientific journals, at research conferences, local research symposia and seminars. Evidence-based open access briefings, articles and reports will be available on our study website for everyone to access. Rapid policy briefings targeting issues emerging from the data will also be disseminated to inform policy and practice. These briefings will position the findings within UK public policy and devolved nations policy and socioeconomic contexts in order to develop specific, timely policy recommendations. Additional dissemination will be done through traditional and social media. Our data will be contextualised in view of existing policies, and changes over time as-and-when policies change

Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma

Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal α-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorder