tbuckley/cabot-search huggingface dataset:
Evolution of Functional Diversity in the Holozoan Tyrosine Kinome
Authors: Wayland Yeung, Annie Kwon, Rahil Taujale, Claire Bunn, Aarya Venkat, Natarajan Kannan
Journal: Molecular Biology and Evolution (2021)

The emergence of multicellularity is strongly correlated with the expansion of tyrosine kinases, a conserved family of signaling enzymes that regulates pathways essential for cell-to-cell communication. Although tyrosine kinases have been classified from several model organisms, a molecular-level understanding of tyrosine kinase evolution across all holozoans is currently lacking. Using a hierarchical sequence constraint-based classification of diverse holozoan tyrosine kinases, we construct a new phylogenetic tree that identifies two ancient clades of cytoplasmic and receptor tyrosine kinases separated by the presence of an extended insert segment in the kinase domain connecting the D and E-helices. Present in nearly all receptor tyrosine kinases, this fast-evolving insertion imparts diverse functionalities, such as post-translational modification sites and regulatory interactions. Eph and EGFR receptor tyrosine kinases are two exceptions which lack this insert, each forming an independent lineage characterized by unique functional features. We also identify common constraints shared across multiple tyrosine kinase families which warrant the designation of three new subgroups: Src module (SrcM), insulin receptor kinase-like (IRKL), and fibroblast, platelet-derived, vascular, and growth factor receptors (FPVR). Subgroup-specific constraints reflect shared autoinhibitory interactions involved in kinase conformational regulation. Conservation analyses describe how diverse tyrosine kinase signaling functions arose through the addition of family-specific motifs upon subgroup-specific features and coevolving protein domains. We propose the oldest tyrosine kinases, IRKL, SrcM, and Csk, originated from unicellular premetazoans and were coopted for complex multicellular functions. The increased frequency of oncogenic variants in more recent tyrosine kinases suggests that lineage-specific functionalities are selectively altered in human cancers.
Comparative Genomics Sheds Light on the Convergent Evolution of Miniaturized Wasps
Authors: Hongxing Xu, Xinhai Ye, Yajun Yang, Yi Yang, Yu H Sun, Yang Mei, Shijiao Xiong, Kang He, Le Xu, Qi Fang, Fei Li, Gongyin Ye, Zhongxian Lu
Journal: Molecular Biology and Evolution (2021)

Miniaturization has occurred in many animal lineages, including insects and vertebrates, as a widespread trend during animal evolution. Among Hymenoptera, miniaturization has taken place in some parasitoid wasp lineages independently, and may have contributed to the diversity of species. However, the genomic basis of miniaturization is little understood. Diverged approximately 200 Ma, Telenomus wasps (Platygastroidea) and Trichogramma wasps (Chalcidoidea) have both evolved to a highly reduced body size independently, representing a paradigmatic example of convergent evolution. Here, we report a high-quality chromosomal genome of Telenomus remus, a promising candidate for controlling Spodoptera frugiperda, a notorious pest that has recently caused severe crop damage. The T. remus genome (129 Mb) is characterized by a low density of repetitive sequence and a reduction of intron length, resulting in the shrinkage of genome size. We show that hundreds of genes evolved faster in two miniaturized parasitoids Trichogramma pretiosum and T. remus. Among them, 38 genes exhibit extremely accelerated evolutionary rates in these miniaturized wasps, possessing diverse functions in eye and wing development as well as cell size control. These genes also highlight potential roles in body size regulation. In sum, our analyses uncover a set of genes with accelerated evolutionary rates in Tri. pretiosum and T. remus, which might be responsible for their convergent adaptations to miniaturization, and thus expand our understanding on the evolutionary basis of miniaturization. Additionally, the genome of T. remus represents the first genome resource of superfamily Platygastroidea, and will facilitate future studies of Hymenoptera evolution and pest control.
Incidence of and Factors Associated With Nonfatal Self-injury After a Cancer Diagnosis in Ontario, Canada
Authors: Christopher W. Noel, Antoine Eskander, Rinku Sutradhar, Alyson Mahar, Simone N. Vigod, Elie Isenberg-Grzeda, James Bolton, Julie Deleemans, Wing C. Chan, Ravleen Vasdev, Victoria Zuk, Barbara Haas, Stephanie Mason, Natalie G. Coburn, Julie Hallet, Christopher W Noel, Antoine Eskander, Rinku Sutradhar, Alyson Mahar, Simone N Vigod, Elie Isenberg-Grzeda, James Bolton, Wing Chan, Julie Deleemans, Ravleen Vasdev, Victora Zuk, Barbara Haas, Stephanie Mason, Natalie G Coburn, Julie Hallet
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Psychological distress is a key component of patient-centered cancer care. While a greater risk of suicide among patients with cancer has been reported, more frequent consequences of distress, including nonfatal self-injury (NFSI), remain unknown. <h3>Objective</h3> To examine the risk of NFSI after a cancer diagnosis. <h3>Design, Setting, and Participants</h3> This population-based retrospective cohort study used linked administrative databases to identify adults diagnosed with cancer between 2007 and 2019 in Ontario, Canada. <h3>Exposures</h3> Demographic and clinical factors. <h3>Main Outcomes and Measures</h3> Cumulative incidence of NFSI, defined as emergency department presentation of self-injury, was computed, accounting for the competing risk of death from all causes. Factors associated with NFSI were assessed using multivariable Fine and Gray models. <h3>Results</h3> In total, 806 910 patients met inclusion criteria. The mean (SD) age was 65.7 (14.3) years, and 405 161 patients (50.2%) were men. Overall, 2482 (0.3%) had NFSI and 182 (&lt;0.1%) died by suicide. The 5-year cumulative incidence of NFSI was 0.27% (95% CI, 0.25%-0.28%). After adjusting for key confounders, prior severe psychiatric illness, whether requiring inpatient care (subdistribution hazard ratio [sHR], 12.6; 95% CI, 10.5-15.2) or outpatient care (sHR, 7.5; 95% CI, 6.5-8.8), and prior self-injury (sHR, 6.6; 95% CI, 5.5-8.0) were associated with increased risk of NFSI. Young adults (age 18-39 years) had the highest NFSI rates relative to individuals aged 70 years or older (sHR, 5.4; 95% CI, 4.5-6.5). The magnitude of association between prior inpatient psychiatric illness and NFSI was greatest for young adults (sHR, 17.6; 95% CI, 12.0-25.8). Certain cancer subsites were also associated with increased risk, including head and neck cancer (sHR, 1.5; 95% CI, 1.2-1.9). <h3>Conclusions and Relevance</h3> In this study, patients with cancer had a higher incidence of NFSI than suicide after diagnosis. Younger age, history of severe psychiatric illness, and prior self-injury were independently associated with risk of NFSI. These exposures appeared to act synergistically, placing young adults with a prior mental health history at the greatest risk of NFSI. These factors should be used to identify at-risk patients.
Mobile-health tool for timely management of cancer treatment toxicity.
Authors: Amit Sanyal, Sara Mistretta, Morgan Fulton, Clemens walter Janssen
Journal: Journal of Clinical Oncology (2021)

321 Background: Treatment related side effects after chemotherapy are common, with significant toxicities seen in 78.2% to 98.3% of patients allocated to two study arms of a lymphoma trial [1] . While most oncology clinics provide patient education before treatment, onetime delivery of large amounts of information without reiteration of crucial facts results in information gaps, delay in seeking care, culminating in potentially avoidable ED visits and hospitalizations. Technology based symptom monitoring can facilitate early detection of complications, reduce symptom burden and cost of care. Here we update our study [2] of utility of a mobile-health tool for timely management of cancer treatment related toxicities in a community-based oncology practice. Methods: A web-based mobile application consisting of a patient interface, a provider interface and an embedded analytic platform was developed. Patient ‘check-ins’ incorporating a brief introduction and chemotherapy toxicity questionnaires are delivered through automated text or email. Toxicity questionnaires are based on the NCI-PRO-CTCAE ITEMS-ENGLISH form builder. The provider interface incorporates a ‘patient records summary’ page and a ‘tracker’ page, allowing the oncology care team to monitor responses in real-time. Responses exceeding pre-specified thresholds generate a color-coded ‘flag’ and are marked for follow up. Flags result in a phone call followed by in-person evaluation if necessary. All interventions are time stamped. Patient experience is measured concurrently using a Likert-scale as well as free-text response box. Results: 310 patients were enrolled as of January 21, 2021. Median age was 64 years. There were 49% females.8916 check-ins were sent out and 2963 responses recorded for an overall response rate of 33.23%. 531 responses provided by 109 unique patients were flagged for follow up, amounting to 6% of all responses. Fatigue was the most common symptom flagged for follow-up (454), followed by nausea/vomiting or diarrhea (167), abdominal pain (140), cough/dyspnea (140) and numbness/tingling (138). Follow up was prompt, with 60% of patient symptoms followed up on the same day and of these, 84% followed-up within 4 hours of patient reported symptom. Patient experience was consistently favorable. 72% of patients reported an experience score of ≥ 4 (1-5 scale, 5 being the most favorable). Conclusions: Electronic capture of symptoms using connected technology is feasible and can be used for timely management of treatment related complications. References: Bartlett, N.L., et al., Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol, 2019. 37(21): p. 1790-1799. Sanyal, A. Mobile health tool for monitoring cancer treatment complications. 2020. ASCO Quality Care Symposium: American Society of Clinical Oncology.
Delay in the diagnosis of acute myeloid leukemia, comparison before and after SARS-COV-2: A single centre study
Authors: C. Alburquerque-Prieto, M. C. Mateos, A. Torres-López, I. Peris, M. D. Odero, C. Ceballos-Bolaños, J. M. Sánchez-Iglesias, I. Múgica-Muñagorri, Ttta M. Redondo-Izal
Journal: HemaSphere (2021)

Background: Since the first case of severe acute respiratory infection by coronavirus 2 (SARS-CoV-2), Coronavirus Disease 2019 (COVID- 19) has been the priority in any centre. This situation has produced collateral damage in patients with other acute diseases, with a delay in diagnosis and associated poorer outcomes. Acute myeloid leukemia (AML) is considered a hematologic emergency and delayed induction chemotherapy can harm these patients. Aims: To analyse the impact of the COVID-19 epidemic outbreak on patients diagnosed with AML. We examined the impact on the times from symptom onset to hospital admission, performance status, possibility of administrating treatment and short-term outcome. Methods: Patients diagnosed with AML between January 1, 2019 and December 31, 2020 were included. Cases were grouped into two periods, depending on the year. Demographic and clinical data were recorded including age, sex, detection of symptoms to diagnosis, Eastern Cooperative Oncology Group (ECOG) performance status, diagnoses using World Health Organization (WHO) classification, treatment administered, overall survival, and mortality. Comparisons between groups were made using chi-square tests to compare categorical variables and the Student test for continuous variables;with Kaplan-Meier estimates and Log-Rank test for survival analysis. Results: In total 17 patients with AML were studied (male 9;52.94%;median age 66;interquartile range (IQR) 59-74). Table 1 shows the comparison of baseline characteristics of the patients between the two years. In 2020 there was an increase in the time until the admission to the hospital (30.55 days vs 11.55 days, p=0.0419), with a worsening in ECOG punctuation on arrival statistically significant (Xi2=7.8254, p=0.020). In 2019, all the patients received treatment;and in 2020, 3 patients due to their status;did not received treatment, just best supportive care. Overall survival time was inferior in the cohort of 2020 (3.064 vs 14.028 months;p=0.045). Summary/Conclusion: This retrospective study realized in our centre illustrates the collateral damage caused by the COVID-19 pandemic. Delay in seeking medical attention in a time-course-dependent pathology such as AML;it is followed by an increase in morbidity and mortality.
Clinical practice patterns for advanced breast cancer patients on CDK4/6 inhibitors receiving palliative radiation therapy.
Authors: Neda Stjepanovic, Sonal Gandhi, William Tran, Alia Thawer, Ellen Warner
Journal: Journal of Clinical Oncology (2021)

269 Background: Patients with hormone-receptor positive advanced breast cancer (ABC) often require palliative radiation therapy (RT) while receiving systemic treatment with CDK4/6 inhibitors (CDK4/6i). There are conflicting reports in the literature regarding whether concurrent administration of CDK4/6i and RT increases RT or hematologic toxicity and there are currently no formal guidelines for this realm. A Canadian national survey was conducted to evaluate local practice patterns of CDK4/6i management during palliative RT. Methods: An anonymized online survey was distributed to 162 Canadian breast cancer health care professionals between November 2020 and January 2021. The survey collected provider demographics and questions regarding practice, experiences and opinions on CDK4/6i management during palliative RT for ABC. Results: The survey was completed by 76 (47%) of the invited participants: 40% were medical oncologists, 26% radiation oncologists, 16% pharmacists and 18% nurses, physician assistants or radiation therapists. Nine provinces were represented. The respondents' clinical practice settings were predominantly at an academic/cancer centre (84%), while 16% of clinicians were based at a community setting. Interrupting the CDK4/6i during RT was recommended always by 21% of respondents, sometimes by 46% and never by 9%, while 24% had no opinion. The majority of opinions were based on personal experience (55%), colleagues’ practice (37%), medical literature (33%) and experience with chemotherapy agents (18%). Unexpected RT toxicity observed in patients on concomitant CDK4/6i was reported by 9% of respondents and prolonged cytopenias by 15%. Among responders who always or sometimes interrupt CDK4/6i during palliative RT, the timeframe to hold CDK4/6i prior to RT was 4-7 days 45%, 1-3 days 32%, 8-14 days 13% and 10% were unsure. Responses were similar for the timeframe used to resume the drug after RT. The majority (94%) thought that advising the patient on what to do with the CDK4/6i during RT was the role of the Medical Oncologist, while 48% also thought it was the role of the Radiation Oncologist. 23% of respondents though the patient should always be reassessed prior to restarting the CDK4/6i; 45% said sometimes, and 29% said not necessary. 82% of respondents indicated a standardized protocol or guideline would be valuable in this setting. Conclusions: Two thirds of Canadian breast cancer specialists sometimes or routinely interrupt CDK4/6i treatment during RT with 15% having observed increased toxicity with concurrent administration. Consensus guidelines for the management of CDK4/6i and RT are necessary to reduce treatment variability and improve the quality and safety of care for these patients.
Microvascular changes that stagger the mind
Authors: Frank M. Faraci
Journal: Journal of Clinical Investigation (2021)

Hypertension is a leading cause of cognitive impairment and dementias. Such loss of brain health has a vascular component, but the mechanisms involved are poorly defined. In this issue of the JCI, Koide et al. provide evidence that end-organ effects of hypertension on capillary endothelium and inward-rectifier K+ channels (Kir2.1) impair integrated propagation of electrical signals and vasodilation upstream, resulting in reduced neurovascular coupling (NVC) despite neural activation. NVC was partly restored by amlodipine, but not losartan. Moreover, NVC was improved by eplerenone in the presence of losartan, suggesting a role for aldosterone. These findings support the concept that endothelial cells and Kir2.1 are potential therapeutic targets to prevent or reverse the loss of NVC and the vascular component of cognitive deficits that occur with increased frequency during hypertension.
Covid-19: Migrants face barriers accessing healthcare during the pandemic, report shows
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: Migrants face barriers accessing healthcare during the pandemic, report shows Jacqui WiseThe covid-19 pandemic exacerbated existing inequalities for refugees, asylum seekers, and migrants, who reported higher levels of bad health and inadequate housing as well as difficulties accessing health services, a report from the University of Birmingham has shown.
Nationally representative estimates of the participation of cancer patients in clinical research studies according to the commission on cancer.
Authors: Joseph M. Unger, Mark Fleury
Journal: Journal of Clinical Oncology (2021)

74 Background: The successful conduct of cancer clinical trials hinges on the willingness of patients to participate. The rate of adult clinical trial participation has been regarded as being &lt; 5%. However, national estimates of trial participation are nearly two decades old, and no evidence based on original data sources has been examined for many years. Moreover, studies about trial participation have focused solely on enrollment to treatment trials, which does not reflect the willingness of patients to contribute to other key elements of clinical research, such as quality of life or biorepository studies. We determined inclusive, contemporary estimates of clinical trial participation for adults with cancer using a national sample of data from 1,200 institutions. Methods: The data were from the Commission on Cancer (CoC), a consortium of cancer-related organizations providing accreditation for both academic and community cancer care facilities across the U.S. CoC enrollment data represent 70% of all cases of cancer diagnosed each year. Deidentified, institution-level aggregate counts of annual enrollment to treatment, biorepository, diagnostic, economic, genetic, prevention, quality of life, registry, and screening studies were examined. Overall, study-type estimates for the period 2013-2017 were estimated. Multiple imputation by chained equations was used to account for missing data, with summary estimates calculated separately by type of program (e.g., NCI-designated cancer programs) and pooled. Results: Across the entire U.S. system, the estimated participation rate to cancer treatment trials was 6.3%. Enrollment to treatment trials was highest at NCI-designated comprehensive cancer centers (18.9%), while for community cancer programs (CCPs) and comprehensive CCPs, treatment trial rates were 4.4% and 3.6%, respectively. Nearly 1 in 7 patients participated in biorepository studies (13.4%), including 39.4% at NCI cancer centers. Patients participated in a wide variety of other study types, including registry (8.1%), prevention (6.4%), genetic (3.6%), quality of life (2.9%), economic (2.7%), diagnostic (2.7%), and screening studies (1.8%). At least 25.4% of adult cancer patients were estimated to participate in one or more cancer clinical research studies. Conclusions: In a first-time use of nationally representative enrollment data from the CoC, enrollment to cancer treatment trials was 6.3%, higher than historical estimates of &lt; 5%. Patients participated in a diverse set of other study types, and taken together, at least one quarter of patients participated in a study. Contributions of adult patients with cancer to clinical research is much more comprehensive than previously understood.
Amended <scp>STRONG‐HF</scp> study design
Authors: Gad Cotter, Beth Davison, Marco Metra, Karen Sliwa, Adriaan A. Voors, Faouzi Addad, Jelena Celutkiene, Ovidiu Chioncel, Alain Cohen Solal, Rafael Diaz, Albertino Damasceno, Hans‐Dirk Duengen, Gerasimos Filippatos, Eva Goncalvesova, Imad Merai, Piotr Ponikowski, Dmitry Privalov, Mahmoud U. Sani, Koji Takagi, Zaur Shogenov, Hadiza Saidu, Alexandre Mebazaa
Journal: European Journal of Heart Failure (2021)
Trends in Outpatient Antibiotic Prescriptions in the United States During the COVID-19 Pandemic in 2020
Authors: Deanna J. Buehrle, Marilyn M. Wagener, M. Hong Nguyen, Cornelius J. Clancy
Journal: JAMA Network Open (2021)

azithromycin, amoxicillin, amoxicillin-clavulanate, and levofloxacin prescription fills did not rebound significantly. 1 In this cross-sectional study, we measured prescription fills of commonly prescribed outpatient antibiotics in the US through the end of 2020. MethodsThis cross-sectional study was found exempt by the institutional review board at the University of Pittsburgh.Informed consent was waived because data was deidentified.This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.During each quarter, the mean monthly prescription fills for 9 of the 10 most commonly prescribed US outpatient antibiotics (excluding sulfamethoxazole-trimethoprim) was found from IQVIA National Prescription Audit data (Figure). 1A nonlinear least squares regression model was used to anticipate mean monthly prescription fills during quarters of 2020 based on 2015 to 2019 data.Anticipated and actual mean monthly fills each quarter were compared by a 2-tailed t test.Statistical significance was set at P < .05.STATA/SE version 16.1 (StataCorp) was used for statistical analysis. ResultsIn quarter 1 of 2020 (ie, January-March), the mean monthly prescription fills of each agent did not significantly differ from anticipated values (Table ).In quarter 2 (ie, April-June), quarter 3 (ie, July-September), and quarter 4 (ie, October-December 2020), the mean monthly amoxicillin, amoxicillin-clavulanate, and doxycycline fills were significantly lower than anticipated (amoxicillin: 25.3%-44.1%;P = .003-.03; amoxicillin-clavulanate: 30.1%-40.0%;P = .005-.02; doxycycline: 17.8%-20.7%;P = .008-.01).Azithromycin fills were significantly lower than anticipated in quarters 2 and quarter 4 (quarter 2: 35.4% decrease; P = .02;quarter 4: 31.8%decrease; P = .03).The decrease in quarter 3 was not significant (22.1% decrease; P = .06).Mean monthly cephalexin fills were 10.1% lower than anticipated in quarter 4 (P = .05);those of clindamycin were 4.8% lower than anticipated in quarter 3 (P = .04).Mean monthly ciprofloxacin fills were 12.2% and 14.3% higher than anticipated in quarters 3 and 4, respectively (P = .001and P = .04).Nitrofurantoin and levofloxacin fills were not significantly different from projections in quarter 2, 3, and 4.