QSAR modeling for anti-human African trypanosomiasis activity of substituted 2-phenylimidazopyridines

In the present work, sixty substituted 2-Phenylimidazopyridines previously reported with potent anti-human African trypanosomiasis (HAT) activity were selected to build genetic algorithm (GA) based QSAR models to determine the structural features that have significant correlation with the activity. Multiple QSAR models were built using easily interpretable descriptors that are directly associated with the presence or the absence of a structural scaffold, or a specific atom. All the QSAR models have been thoroughly validated according to the OECD principles. All the QSAR models are statistically very robust (R2 = 0.80–0.87) with high external predictive ability (CCCex = 0.81–0.92). The QSAR analysis reveals that the HAT activity has good correlation with the presence of five membered rings in the molecule

Influence of cranial radiotherapy on outcome in children with acute lymphoblastic leukemia treated with contemporary therapy

Purpose We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). Patients and Methods We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0%to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm metaanalysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. Results Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). Conclusion CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols

Hidden spin-texture at topological domain walls drive exchange bias in a Weyl semimetal

Exchange bias is a phenomenon critical to solid-state technologies that require spin valves or non-volatile magnetic memory. The phenomenon is usually studied in the context of magnetic interfaces between antiferromagnets and ferromagnets, where the exchange field of the former acts as a means to pin the polarization of the latter. In the present study, we report an unusual instance of this phenomenon in the topological Weyl semimetal Co3Sn2S2, where the magnetic interfaces associated with domain walls suffice to bias the entire ferromagnetic bulk. Remarkably, our data suggests the presence of a hidden order parameter whose behavior can be independently tuned by applied magnetic fields. For micron-size samples, the domain walls are absent, and the exchange bias vanishes, suggesting the boundaries are a source of pinned uncompensated moment arising from the hidden order. The novelty of this mechanism suggests exciting opportunities lie ahead for the application of topological materials in spintronic technologies.Comment: Main text: 11 pages, 4 figures. Supplementary information: 7 pages, 6 figures. Supplementary videos:

Global effect of the COVID-19 pandemic on paediatric cancer care: a cross-sectional study

BACKGROUND: Although mortality due to COVID-19 has been reportedly low among children with cancer, changes in health-care services due to the pandemic have affected cancer care delivery. This study aimed to assess the effect of the COVID-19 pandemic on childhood cancer care worldwide. METHODS: A cross-sectional survey was distributed to paediatric oncology providers worldwide from June 22 to Aug 21, 2020, through the St Jude Global Alliance and International Society for Paediatric Oncology listservs and regional networks. The survey included 60 questions to assess institution characteristics, the number of patients diagnosed with COVID-19, disruptions to cancer care (eg, service closures and treatment abandonment), adaptations to care, and resources (including availability of clinical staff and personal protective equipment). Surveys were included for analysis if respondents answered at least two thirds of the items, and the responses were analysed at the institutional level. FINDINGS: Responses from 311 health-care professionals at 213 institutions in 79 countries from all WHO regions were included in the analysis. 187 (88%) of 213 centres had the capacity to test for SARS-CoV-2 and a median of two (range 0-350) infections per institutution were reported in children with cancer. 15 (7%) centres reported complete closure of paediatric haematology-oncology services (median 10 days, range 1-75 days). Overall, 2% (5 of 213) of centres were no longer evaluating new cases of suspected cancer, while 43% (90 of 208) of the remaining centers described a decrease in newly diagnosed paediatric cancer cases. 73 (34%) centres reported increased treatment abandonment (ie, failure to initiate cancer therapy or a delay in care of 4 weeks or longer). Changes to cancer care delivery included: reduced surgical care (153 [72%]), blood product shortages (127 [60%]), chemotherapy modifications (121 [57%]), and interruptions to radiotherapy (43 [28%] of 155 institutions that provided radiotherapy before the pandemic). The decreased number of new cancer diagnoses did not vary based on country income status (p=0·14). However, unavailability of chemotherapy agents (p=0·022), treatment abandonment (p<0·0001), and interruptions in radiotherapy (p<0·0001) were more frequent in low-income and middle-income countries than in high-income countries. These findings did not vary based on institutional or national numbers of COVID-19 cases. Hospitals reported using new or adapted checklists (146 [69%] of 213), processes for communication with patients and families (134 [63%]), and guidelines for essential services (119 [56%]) as a result of the pandemic. INTERPRETATION: The COVID-19 pandemic has considerably affected paediatric oncology services worldwide, posing substantial disruptions to cancer diagnosis and management, particularly in low-income and middle-income countries. This study emphasises the urgency of an equitably distributed robust global response to support paediatric oncology care during this pandemic and future public health emergencies. FUNDING: American Lebanese Syrian Associated Charities. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section

Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children

There is increasing evidence from genome-wide association studies for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children, yet the effects of protein-coding variants on ALL risk have not been systematically evaluated. Here we show a missense variant in CDKN2A associated with the development of ALL at genome-wide significance (rs3731249, P=9.4 × 10(-23), odds ratio=2.23). Functional studies indicate that this hypomorphic variant results in reduced tumour suppressor function of p16(INK4A), increases the susceptibility to leukaemic transformation of haematopoietic progenitor cells, and is preferentially retained in ALL tumour cells. Resequencing the CDKN2A-CDKN2B locus in 2,407 childhood ALL cases reveals 19 additional putative functional germline variants. These results provide direct functional evidence for the influence of inherited genetic variation on ALL risk, highlighting the important and complex roles of CDKN2A-CDKN2B tumour suppressors in leukaemogenesis.Heng Xu, Hui Zhang, Wenjian Yang, Rachita Yadav, Alanna C. Morrison, Maoxiang Qian, Meenakshi Devidas, Yu Liu, Virginia Perez-Andreu, Xujie Zhao, Julie M. Gastier-Foster, Philip J. Lupo, Geoff Neale, Elizabeth Raetz, Eric Larsen, W. Paul Bowman, William L. Carroll, Naomi Winick, Richard Williams, Torben Hansen, Jens-Christian Holm, Elaine Mardis, Robert Fulton, Ching-Hon Pui, Jinghui Zhang, Charles G. Mullighan, William E. Evans, Stephen P. Hunger, Ramneek Gupta, Kjeld Schmiegelow, Mignon L. Loh, Mary V. Relling, Jun J. Yan

The Global COVID-19 Observatory and Resource Center for Childhood Cancer: A response for the pediatric oncology community by SIOP and St. Jude Global

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3–2·4]; p=0·0001), and intensive treatment (1·8 [1·3–2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3–0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3–0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3–2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1–2·3]; p=0·020). Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute.Fil: Mukkada, Sheena. St Jude Children's Research Hospital; Estados UnidosFil: Bhakta, Nickhill. St Jude Children's Research Hospital; Estados UnidosFil: Chantada, Guillermo Luis. Hospital Sant Joan de Déu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chen, Yichen. St Jude Children's Research Hospital; Estados UnidosFil: Vedaraju, Yuvanesh. St Jude Children's Research Hospital; Estados UnidosFil: Faughnan, Lane. St Jude Children's Research Hospital; Estados UnidosFil: Homsi, Maysam R. St Jude Children's Research Hospital; Estados UnidosFil: Muniz Talavera, Hilmarie. St Jude Children's Research Hospital; Estados UnidosFil: Ranadive, Radhikesh. St Jude Children's Research Hospital; Estados UnidosFil: Metzger, Monika. St Jude Children's Research Hospital; Estados UnidosFil: Friedrich, Paola. St Jude Children's Research Hospital; Estados UnidosFil: Agulnik, Asya. St Jude Children's Research Hospital; Estados UnidosFil: Jeha, Sima. St Jude Children's Research Hospital; Estados UnidosFil: Lam, Catherine G.. St Jude Children's Research Hospital; Estados UnidosFil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; IndiaFil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de ÁfricaFil: Moreira, Daniela. St Jude Children's Research Hospital; Estados UnidosFil: Santana, Victor M. St Jude Children's Research Hospital; Estados UnidosFil: Sullivan, Michael. University of Melbourne; AustraliaFil: Bouffet, Eric. University Of Toronto. Hospital For Sick Children; CanadáFil: Caniza, Miguela A.. St Jude Children's Research Hospital; Estados UnidosFil: Devidas, Meenakshi. St Jude Children's Research Hospital; Estados UnidosFil: Pritchard Jones, Kathy. UCL Great Ormond Street Institute of Child Health; Reino UnidoFil: Rodriguez Galindo, Carlos. St Jude Children's Research Hospital; Estados Unido

Global characteristics and outcomes of SARS-CoV-2 infection in children and adolescents with cancer (GRCCC): a cohort study

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (<19 years) with cancer or having received a haematopoietic stem-cell transplantation. There were no centre-specific exclusion criteria. The registry was disseminated through professional networks through email and conferences and health-care providers were invited to submit all qualifying cases. Data for demographics, oncological diagnosis, clinical course, and cancer therapy details were collected. Primary outcomes were disease severity and modification to cancer-directed therapy. The registry remains open to data collection. Findings: Of 1520 submitted episodes, 1500 patients were included in the study between April 15, 2020, and Feb 1, 2021. 1319 patients had complete 30-day follow-up. 259 (19·9%) of 1301 patients had a severe or critical infection, and 50 (3·8%) of 1319 died with the cause attributed to COVID-19 infection. Modifications to cancer-directed therapy occurred in 609 (55·8%) of 1092 patients receiving active oncological treatment. Multivariable analysis revealed several factors associated with severe or critical illness, including World Bank low-income or lower-middle-income (odds ratio [OR] 5·8 [95% CI 3·8–8·8]; p<0·0001) and upper-middle-income (1·6 [1·2–2·2]; p=0·0024) country status; age 15–18 years (1·6 [1·1–2·2]; p=0·013); absolute lymphocyte count of 300 or less cells per mm3 (2·5 [1·8–3·4]; p<0·0001), absolute neutrophil count of 500 or less cells per mm3 (1·8 [1·3–2·4]; p=0·0001), and intensive treatment (1·8 [1·3–2·3]; p=0·0005). Factors associated with treatment modification included upper-middle-income country status (OR 0·5 [95% CI 0·3–0·7]; p=0·0004), primary diagnosis of other haematological malignancies (0·5 [0·3–0·8]; p=0·0088), the presence of one of more COVID-19 symptoms at the time of presentation (1·8 [1·3–2·4]; p=0·0002), and the presence of one or more comorbidities (1·6 [1·1–2·3]; p=0·020). Interpretation: In this global cohort of children and adolescents with cancer and COVID-19, severe and critical illness occurred in one fifth of patients and deaths occurred in a higher proportion than is reported in the literature in the general paediatric population. Additionally, we found that variables associated with treatment modification were not the same as those associated with greater disease severity. These data could inform clinical practice guidelines and raise awareness globally that children and adolescents with cancer are at high-risk of developing severe COVID-19 illness. Funding: American Lebanese Syrian Associated Charities and the National Cancer Institute.Fil: Mukkada, Sheena. St Jude Children's Research Hospital; Estados UnidosFil: Bhakta, Nickhill. St Jude Children's Research Hospital; Estados UnidosFil: Chantada, Guillermo Luis. Hospital Sant Joan de Déu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Chen, Yichen. St Jude Children's Research Hospital; Estados UnidosFil: Vedaraju, Yuvanesh. St Jude Children's Research Hospital; Estados UnidosFil: Faughnan, Lane. St Jude Children's Research Hospital; Estados UnidosFil: Homsi, Maysam R. St Jude Children's Research Hospital; Estados UnidosFil: Muniz Talavera, Hilmarie. St Jude Children's Research Hospital; Estados UnidosFil: Ranadive, Radhikesh. St Jude Children's Research Hospital; Estados UnidosFil: Metzger, Monika. St Jude Children's Research Hospital; Estados UnidosFil: Friedrich, Paola. St Jude Children's Research Hospital; Estados UnidosFil: Agulnik, Asya. St Jude Children's Research Hospital; Estados UnidosFil: Jeha, Sima. St Jude Children's Research Hospital; Estados UnidosFil: Lam, Catherine G.. St Jude Children's Research Hospital; Estados UnidosFil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; IndiaFil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de ÁfricaFil: Moreira, Daniela. St Jude Children's Research Hospital; Estados UnidosFil: Santana, Victor M. St Jude Children's Research Hospital; Estados UnidosFil: Sullivan, Michael. University of Melbourne; AustraliaFil: Bouffet, Eric. University Of Toronto. Hospital For Sick Children; CanadáFil: Caniza, Miguela A.. St Jude Children's Research Hospital; Estados UnidosFil: Devidas, Meenakshi. St Jude Children's Research Hospital; Estados UnidosFil: Pritchard Jones, Kathy. UCL Great Ormond Street Institute of Child Health; Reino UnidoFil: Rodriguez Galindo, Carlos. St Jude Children's Research Hospital; Estados Unido

PRC2 loss induces chemoresistance by repressing apoptosis in T cell acute lymphoblastic leukemia

The tendency of mitochondria to undergo or resist BCL2-controlled apoptosis (so-called mitochondrial priming) is a powerful predictor of response to cytotoxic chemotherapy. Fully exploiting this finding will require unraveling the molecular genetics underlying phenotypic variability in mitochondrial priming. Here, we report that mitochondria) apoptosis resistance in T cell acute lymphoblastic leukemia (T-ALL) is mediated by inactivation of polycomb repressive complex 2 (PRC2). In T-ALL clinical specimens, loss-of-function mutations of PRC2 core components (EZH2, FED, or SUZ12) were associated with mitochondrial apoptosis resistance. In T-ALL cells, PRC2 depletion induced resistance to apoptosis induction by multiple chemotherapeutics with distinct mechanisms of action. PRC2 loss induced apoptosis resistance via transcriptional up-regulation of the LIM domain transcription factor CRIP2 and downstream up-regulation of the mitochondrial chaperone TRAP1. These findings demonstrate the importance of mitochondrial apoptotic priming as a prognostic factor in T-ALL and implicate mitochondrial chaperone function as a molecular determinant of chemotherapy response