tbuckley/cabot-search huggingface dataset:
Association of Hypothyroidism and Clinical Depression
Authors: Henry Bode, Beatrice Ivens, Tom Bschor, Guido Schwarzer, Jonathan Henssler, Christopher Baethge
Journal: JAMA Psychiatry (2021)

Hypothyroidism is considered a cause of or a strong risk factor for depression, but recent studies provide conflicting evidence regarding the existence and the extent of the association. It is also unclear whether the link is largely due to subsyndromal depression or holds true for clinical depression.To estimate the association of hypothyroidism and clinical depression in the general population.PubMed, PsycINFO, and Embase databases were searched from inception until May 2020 for studies on the association of hypothyroidism and clinical depression.Two reviewers independently selected epidemiologic and population-based studies that provided laboratory or International Statistical Classification of Diseases and Related Health Problems diagnoses of hypothyroidism and diagnoses of depression according to operationalized criteria (eg, Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases and Related Health Problems) or cutoffs in established rating scales.Two reviewers independently extracted data and evaluated studies based on the Newcastle-Ottawa Scale. Summary odds ratios (OR) were calculated in random-effects meta-analyses.Prespecified coprimary outcomes were the association of clinical depression with either hypothyroidism or autoimmunity.Of 4350 articles screened, 25 studies were selected for meta-analysis, including 348 014 participants. Hypothyroidism and clinical depression were associated (OR, 1.30 [95% CI, 1.08-1.57]), while the OR for autoimmunity was inconclusive (1.24 [95% CI, 0.89-1.74]). Subgroup analyses revealed a stronger association with overt than with subclinical hypothyroidism, with ORs of 1.77 (95% CI, 1.13-2.77) and 1.13 (95% CI, 1.01-1.28), respectively. Sensitivity analyses resulted in more conservative estimates. In a post hoc analysis, the association was confirmed in female individuals (OR, 1.48 [95% CI, 1.18-1.85]) but not in male individuals (OR, 0.71 [95% CI, 0.40-1.25]).In this systematic review and meta-analysis, the effect size for the association between hypothyroidism and clinical depression was considerably lower than previously assumed, and the modest association was possibly restricted to overt hypothyroidism and female individuals. Autoimmunity alone may not be the driving factor in this comorbidity.
Association of Medicaid expansion under the Affordable Care Act and early mortality following lung cancer surgery.
Authors: Leticia Nogueira, Ahmedin Jemal, Xuesong Han, K. Robin Yabroff
Journal: Journal of Clinical Oncology (2021)

76 Background: Medicaid expansion under the Affordable Care Act is associated with gains in health insurance coverage and a shift towards earlier stage diagnosis among patients with cancer. However, the association between Medicaid expansion and cancer mortality has not been well characterized. The aim of this study was to evaluate the association of Medicaid expansion with changes in early mortality, defined as death within 30 days after major NSCLC surgery, among adults discharged following major surgery for non-small cell lung cancer (NSCLC), a setting where access to care is a major determinant of death. Methods: Of the 11,627 patients selected from the National Cancer Database who were aged 45-64 (more likely to be diagnosed and die from NSCLC and not age-eligible for Medicare coverage) and were discharged from the hospital following major surgery for treatment of NSCLC between 2009 and 2018, 7,294 patients lived in expansion states and 4,333 lived in non-expansion states. Differences-in-differences (DD) analyses were used to evaluate the impact of Medicaid expansion on early mortality pre-(2009- 2013) and post-ACA (2014- 2018). Results: Early mortality among patients discharged from the hospital following NSCLC surgery statistically significantly decreased from 2.4% pre-ACA to 0.8% post-ACA among patients in Medicaid expansion states (1.6 percentage point decrease, p &lt;.0001), but not in patients living in non-expansion states (from 2.1% to 1.6%, p = 0.2), leading to a DD of 1.1 percentage points (95% Confidence Interval = 0.1, 2.1; p = 0.03). Conclusions: This study found a decrease in early mortality following hospital discharge after NSCLC surgery post-ACA among patients living in Medicaid expansion states and no change in patients residing in non-expansion states. Medicaid expansion may be an effective strategy for improving access to care and cancer outcomes among older adults who are not age-eligible for Medicare.
Minimal residual disease, long-term outcome, and IKZF1 deletions in children and adolescents with Down syndrome and acute lymphocytic leukaemia: a matched cohort study
Authors: Naomi Michels, Judith M Boer, Amir Enshaei, Rosemary Sutton, Mats Heyman, Sabine Ebert, Marta Fiocco, Hester A de Groot-Kruseman, Vincent H J van der Velden, Gisela Barbany, Gabriele Escherich, Ajay Vora, Toby Trahair, Luciano Dalla-Pozza, Rob Pieters, Udo zur Stadt, Kjeld Schmiegelow, Anthony V Moorman, C Michel Zwaan, Monique L den Boer
Journal: The Lancet Haematology (2021)

Patients with Down syndrome and acute lymphocytic leukaemia are at an increased risk of treatment-related mortality and relapse, which is influenced by unfavourable genetic aberrations (eg, IKZF1 deletion). We aimed to investigate the potential underlying effect of Down syndrome versus the effects of adverse cancer genetics on clinical outcome.
Oncologists’ knowledge and perspectives on the use of biosimilars.
Authors: John Peipert, Karen Kaiser, Sheetal Mehta Kircher, George J. Greene, Sara Shaunfield, Katherina KY Hauner, David Cella, Dan Mroczek
Journal: Journal of Clinical Oncology (2021)

35 Background: Despite the increasing availability of biosimilar cancer treatments, little is known about oncologists’ knowledge and concerns about biosimilar use in the United States. We conducted a survey of oncologists to examine their knowledge, attitudes, and experience with biosimilars. Methods: Using the ASCO Survey Research Pool (10-6-20 to 11-16-20), clinical oncologists completed a 29-question survey designed with structured input from clinical and health care system experts and literature review. Results: Of the 269 respondents, most ( n= 236, 88%) treated with biosimilars and reported that biosimilars were required at their institution. The table summarizes participants’ knowledge, barriers to use, preferences for and access to information around biosimilars, and interest in training. Conclusions: Despite high uptake of biosimilars, knowledge about basic features of biosimilars was low, and oncologists in community and private practice settings were more often concerned about safety and efficacy than those in academic practices. This information provides targets for future education about biosimilars.[Table: see text]
P13.08 Novel Thioridazine derivates: Antiproliferative and apoptosis-inducing activity on glioblastoma cells <i>in vitro</i>
Authors: S G Schwab, K Sarnow, E Alme, R Goldbrunner, H Bjørsvik, R Bjerkvig
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Although withdrawn from the market due to cardiotoxicity, we have shown that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of the presented project was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. MATERIAL AND METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay as well as a real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p&amp;lt;0,0001, U251 p&amp;lt;0,0001, LN18 p=0,0004) as well as on glioma stem cells (GSC) (P3 p&amp;lt;0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in the GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg. CONCLUSION We have developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.
Exosomes-mediated tumor treatment: One body plays multiple roles
Authors: Na Xu, Ranran Guo, Xiaotong Yang, Ning Li, Jia Yu, Peng Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2021)

Exosomes are vesicles secreted by a variety of living cells, containing proteins, RNA and other components, which are nanoscale capsules commonly existed in the body. Exosomes play important roles in a variety of physiological and pathological processes by participating in material and information exchange between cells, which can play multiple roles in tumor treatment. On the one hand, exosomes can be used as carriers and biomarkers, participate in the apoptosis signaling pathway and improve chemotherapy resistance, thus playing beneficial roles in tumor treatment. On the other hand, exosomes play unfavorable roles in tumor treatment. Tumor cell exosomes contain PD-L1, which is a nuclear weapon for tumor growth, metastasis, and immunosuppression. In addition, exosomes can not only promote the epithelial-mesenchymal transition process, tumor angiogenesis and chemoresistance, but also participate in the autocrine pathway. In this review, the multiple roles of exosomes and their prospects in the treatment of tumor were reviewed in detail.
Cardiovascular disease and COVID-19: a consensus paper from the ESC Working Group on Coronary Pathophysiology &amp; Microcirculation, ESC Working Group on Thrombosis and the Association for Acute CardioVascular Care (ACVC), in collaboration with the European Heart Rhythm Association (EHRA)
Authors: Edina Cenko, Lina Badimon, Raffaele Bugiardini, Marc J Claeys, Giuseppe De Luca, Cor de Wit, Geneviève Derumeaux, Maria Dorobantu, Dirk J Duncker, Etto C Eringa, Diana A Gorog, Christian Hassager, Frank R Heinzel, Kurt Huber, Olivia Manfrini, Davor Milicic, Evangelos Oikonomou, Teresa Padro, Danijela Trifunovic-Zamaklar, Zorana Vasiljevic-Pokrajcic, Marija Vavlukis, Gemma Vilahur, Dimitris Tousoulis
Journal: Cardiovascular Research (2021)

The cardiovascular system is significantly affected in coronavirus disease-19 (COVID-19). Microvascular injury, endothelial dysfunction, and thrombosis resulting from viral infection or indirectly related to the intense systemic inflammatory and immune responses are characteristic features of severe COVID-19. Pre-existing cardiovascular disease and viral load are linked to myocardial injury and worse outcomes. The vascular response to cytokine production and the interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and angiotensin-converting enzyme 2 receptor may lead to a significant reduction in cardiac contractility and subsequent myocardial dysfunction. In addition, a considerable proportion of patients who have been infected with SARS-CoV-2 do not fully recover and continue to experience a large number of symptoms and post-acute complications in the absence of a detectable viral infection. This conditions often referred to as 'post-acute COVID-19' may have multiple causes. Viral reservoirs or lingering fragments of viral RNA or proteins contribute to the condition. Systemic inflammatory response to COVID-19 has the potential to increase myocardial fibrosis which in turn may impair cardiac remodelling. Here, we summarize the current knowledge of cardiovascular injury and post-acute sequelae of COVID-19. As the pandemic continues and new variants emerge, we can advance our knowledge of the underlying mechanisms only by integrating our understanding of the pathophysiology with the corresponding clinical findings. Identification of new biomarkers of cardiovascular complications, and development of effective treatments for COVID-19 infection are of crucial importance.
<i>Notes from the Field</i>: Xylazine, a Veterinary Tranquilizer, Identified as an Emerging Novel Substance in Drug Overdose Deaths — Connecticut, 2019–2020
Authors: Shobha Thangada, Heather A. Clinton, Sarah Ali, Jacqueline Nunez, James R. Gill, Robert F. Lawlor, Susan B. Logan
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Xylazine, a clonidine analog, is a nonopioid veterinary tranquilizer not intended for human use.Recreational drugs such as cocaine, heroin, and fentanyl are often adulterated with agents such as xylazine to enhance drug effects or increase street value by increasing net weight (1).Xylazine is known to cause hypotension and bradycardia when used in humans (2).Although not a controlled substance in the United States, xylazine cannot be purchased without a veterinary license.Misuse of xylazine was reported in Puerto Rico in the early 2000s (3).Recreational use of xylazine can occur via oral ingestion, inhalation or sniffing, or intravenous injection; however, injection is the most common route of administration (2).The effects of xylazine when used contemporaneously with other illicit drugs such as heroin, cocaine, and fentanyl are still not widely known (2).No antidote is recommended for the effects of xylazine overdose (4).One recent study suggests that high doses of naloxone might reverse the effects of a clonidine overdose (5).However, given that this finding is from a single study of a small cohort of pediatric patients, it might not be generalizable to the broader population (5).Furthermore, no reports specific to xylazine and naloxone exist regarding reversal of effects.Routine drug screening is conducted for all suspected drug overdose deaths investigated by the Connecticut Office of the Chief Medical Examiner, and xylazine has been included in toxicology panels since 2013.Antemortem and postmortem specimens are collected by the Office of the Chief Medical Examiner; toxicology analysis is performed using liquid chromatography time-of-flight mass spectrometry and liquid chromatography-tandem mass spectrometry by National Medical Services Laboratories in Horsham, Pennsylvania.During 2019, a total of 1,200 deaths from unintentional drug overdoses were reported in Connecticut; test results for 70 (5.8%)decedents were positive for xylazine.During January-July 2020, 666 deaths from drug overdoses were reported in Connecticut; test results for 76 (11.4%) were positive for xylazine.Among 146 xylazine-positive deaths during 2019 and 2020 (Table ), test results for all but one (99.3%)were positive for fentanyl.Xylazine-associated deaths occurred primarily among males (80.9%) and non-Hispanic White
Review of Ongoing Clinical Trials in Non–Small-Cell Lung Cancer: A Status Report for 2012 from the ClinicalTrials.gov Web Site
Authors: Janakiraman Subramanian, Thomas Regenbogen, Gayathri Nagaraj, Alex Lane, Siddhartha Devarakonda, Gongfu Zhou, Ramaswamy Govindan
Journal: Journal of Thoracic Oncology (2013)
Diagnostic Accuracy of FEC-PET/CT, FDG-PET/CT, and Diffusion-Weighted MRI in Detection of Nodal Metastases in Surgically Treated Endometrial and Cervical Carcinoma
Authors: Andrea G. Rockall, Tara D. Barwick, William Wilson, Naveena Singh, Nishat Bharwani, Aslam Sohaib, Marielle Nobbenhuis, Victoria Warbey, Marc Miquel, Dow-Mu Koh, Katja N. De Paepe, Pierre Martin-Hirsch, Sadaf Ghaem-Maghami, Christina Fotopoulou, Helen Stringfellow, Sudha Sundar, Ranjit Manchanda, Anju Sahdev, Allan Hackshaw, Gary J. Cook
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Preoperative nodal staging is important for planning treatment in cervical cancer and endometrial cancer, but remains challenging. We compare nodal staging accuracy of 18F-ethyl-choline-(FEC)-PET/CT, 18F-fluoro-deoxy-glucose-(FDG)-PET/CT, and diffusion-weighted-MRI (DW-MRI) with conventional morphologic MRI. Experimental Design: A prospective, multicenter observational study of diagnostic accuracy for nodal metastases was undertaken in 5 gyne-oncology centers. FEC-PET/CT, FDG-PET/CT, and DW-MRI were compared with nodal size and morphology on MRI. Reference standard was strictly correlated nodal histology. Eligibility included operable cervical cancer stage ≥ 1B1 or endometrial cancer (grade 3 any stage with myometrial invasion or grade 1–2 stage ≥ II). Results: Among 162 consenting participants, 136 underwent study DW-MRI and FDG-PET/CT and 60 underwent FEC-PET/CT. In 118 patients, 267 nodal regions were strictly correlated at histology (nodal positivity rate, 25%). Sensitivity per patient (n = 118) for nodal size, morphology, DW-MRI, FDG- and FEC-PET/CT was 40%*, 53%, 53%, 63%*, and 67% for all cases (*, P = 0.016); 10%, 10%, 20%, 30%, and 25% in cervical cancer (n = 40); 65%, 75%, 70%, 80% and 88% in endometrial cancer (n = 78). FDG-PET/CT outperformed nodal size (P = 0.006) and size ratio (P = 0.04) for per-region sensitivity. False positive rates were all &amp;lt;10%. Conclusions: All imaging techniques had low sensitivity for detection of nodal metastases and cannot replace surgical nodal staging. The performance of FEC-PET/CT was not statistically different from other techniques that are more widely available. FDG-PET/CT had higher sensitivity than size in detecting nodal metastases. False positive rates were low across all methods. The low false positive rate demonstrated by FDG-PET/CT may be helpful in arbitration of challenging surgical planning decisions.
Treatment selection in cml: Effect of online education on clinician knowledge and confidence
Authors: A. Taylor, S. Koekkoek, C. Scot-Smith, J. Apperley
Journal: HemaSphere (2021)

Background: Despite the improvement in patient outcomes with the implementation of TKIs, patients still relapse on or are intolerant of initial treatment and an associated impact on quality of life. Physician choice of 2nd and 3rd line treatment is currently essentially limited to the same TKIs as are available for front-line treatment, with the exception of ponatinib. Thus physician's choice of 2nd or 3rd line therapy is not only predicated on patient disease, social and clinical characteristics, but also by which TKI the patient received previously, challenging them to make choices from a decreasing pool of options. Aims: This study determined whether online continuing medical education could improve the knowledge and confidence of clinicians in best-practice sequencing strategies for patients with CML after front line therapy with a tyrosine kinase inhibitor (TKI), using a case-based approach. Methods: A 30-minute online video panel discussion was launched for countries outside the USA in June 2020. Data were collected to September 2020. Educational effect assessed with repeated-pairs pre-/ post-activity, where individual participants served as their own control. 3 multiple-choice, knowledge questions and 1 self-efficacy, 5-point Likert scale confidence question were analyzed. Chi-squared test assessed pre- to post-activity change (5% significance level, P  .26=Extensive). Results: 52 hematologist/oncologists completed pre- and post-activity questions. A considerable educational effect was observed (V=.181, P<.0001) with average % of correct responses increasing from 34 to 52%. Clinicians with 3/3 answers correct increased post-activity (4 to 12%) and for 2/3 answers correct post-activity (29-46%). Improvements in % of correct responses post-activity were seen for questions on: the patient population with the best outcomes related to clinical trials data, the application of the ELN guideline recommendations for defining response to TKI treatment, and the selection of an appropriate alternative TKI for a patient case (relative improvements, 25%, 56%, and 85%). 52% of haematologist/oncologist responses were improved or reinforced post-activity. 48% of all participants stated they would modify treatment plans. 31% had a measurable increase in confidence in selecting an appropriate BCR-ABL TKI for individual patients with CML who have failed prior lines of therapy with a total average confidence shift of 9.6%. Summary/Conclusion: This on-demand, online video panel discussion resulted in a considerable educational impact. Online medical education is valuable in improving knowledge and confidence, as well as identifying areas of continued educational need and potentially improving patient outcomes, of particular importance during the COVID-19 pandemic where in-person conference learning is inaccessible.
Abstract 12698: Role of Rictor in Cardiac Cell Survival
Authors: Xiangzhen Sui, Christophe Depre
Journal: Circulation (2010)

The mammalian target of rapamycin (mTOR), acting downstream phosphatidylinositol-3-phosphate kinase (PI3K) and Akt, binds raptor to form an mTOR complex mTORC1 that activates S6 kinase-1 (S6K1) and...
IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice
Authors: Larisa V. Kovtonyuk, Francisco Caiado, Santiago Garcia-Martin, Eva-Maria Manz, Patrick Helbling, Hitoshi Takizawa, Steffen Boettcher, Fatima Al-Shahrour, Cesar Nombela-Arrieta, Emma Slack, Markus G. Manz
Journal: Blood (2021)

Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness in the hematopoietic stem cell (HSC) population and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice in contrast to young SPF mice produce more interleukin-1a and interleukin-1b (IL-1a/b) in steady-state bone marrow (BM), with most of the IL-1a/b being derived from myeloid BM cells. Furthermore, blood from steady-state older SPF WT mice contains higher levels of microbe-associated molecular patterns, specifically TLR4 and TLR8 ligands. In addition, BM myeloid cells from older mice produce more IL-1b in vitro, and older mice show higher and more durable IL-1a/b responses upon stimulation with lipopolysaccharide in vivo. To test whether HSC aging is driven by IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knockout (KO) mice. Indeed, older HSCs from IL-1R1KO mice show significantly mitigated aging-associated inflammatory signatures. Moreover, HSCs from older IL-1R1KO and from germ-free mice maintain unbiased lymphomyeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in older WT mice was similarly sufficient to reverse myeloid-biased output of their HSC populations. Collectively, our data define the microbiome/IL-1/IL-1R1 axis as a key, self-sustaining and also therapeutically partially reversible driver of HSC inflammaging.