tbuckley/cabot-search huggingface dataset:
Folate pathway gene expression in metastatic colorectal cancer patients treated with arfolitixorin/5-FU-based chemotherapy.
Authors: Roger Tell, Alessandro Di Cara, Elisabeth Odin, Göran Ulf Carlsson, Yvonne Wettergren
Journal: Journal of Clinical Oncology (2021)

99 Background: Arfolitixorin is the natural, biologically active form of the marketed folates and is expected to be efficacious in a larger proportion of patients with less inter- and intra-individual variability compared with e.g. leucovorin. We have previously found a positive correlation between survival and expression of folate pathway genes in stage III/IV CRC treated with 5-fluorouracil/leucovorin (5-FU/LV). Low expression of folate-related genes may lead to poor response to 5-FU/LV-based treatment, since suboptimal transport and metabolization of LV yield insufficient active [6R]-5,10-methylenetetrahydrofolate and weak inhibition of the target enzyme thymidylate synthase (TYMS). The aim of the present study was to investigate possible confounders and biomarkers of arfolitixorin/5-FU-based treatment in relation to safety and response in a phase I/IIa metastatic colorectal cancer (mCRC) trial. Methods: ISO-CC-005 is a multi-center, phase I/IIa study in mCRC patients eligible for 5-FU/folate therapy alone or in combination with irinotecan or oxaliplatin ± bevacizumab. Patients were also treated with different doses of arfolitixorin as a single or double bolus. The study investigated safety and tolerability of arfolitixorin, and anti-tumor activity was evaluated by overall response rate (ORR) per RECIST v1.1 after 4 cycles of chemotherapy. RNA was prepared from FFPE tumor tissue, reverse transcribed and used for gene expression profiling. The following genes of interest were evaluated: ABCC3, MTHFD2, SLC46A1, SLC19A1, SLC25A32 and TYMS. An ANOVA test was used to rule out potential biases in the baseline expression levels of the genes and to assess the potential association with clinical response. Results: Eighty-one (77.1%) of 105 patients provided material for this analysis. A lower pre-treatment expression of TYMS was associated with clinical benefit (PR and SD; p = 0.021). No clear association was identified between the gene expression markers and the number of adverse events. Gender was not significantly associated with differences in gene expression. Conclusions: Low pre-treatment expression levels of TYMS were associated with clinical benefit (PR and SD) following treatment. Given the role of this gene in the folate metabolic pathways we plan to further assess its predictive potential on a larger cohort during our ongoing global phase III AGENT study. In parallel an assessment of the expression of the other candidate genes on specific patient sub-groups is currently ongoing. These studies will provide additional cues on the use of these genes as predictive markers for treatment outcome and their role in the mode of action of the drug. Clinical trial information: NCT02244632.
Human oral microbiome dysbiosis as a novel tool for detecting noninvasive biomarkers for colorectal cancer.
Authors: Cheng Kong
Journal: Journal of Clinical Oncology (2021)

23 Background: The oral microbiome may play an important role in colorectal carcinogenesis. However, few studies have investigated the association between oral microbiome and the development of colorectal cancer (CRC). We aimed to investigate whether oral health–colorectal tumor association has an underlying microbial basis, in the quest for novel non-invasive biomarkers for CRC. Methods: We collected oral swab samples from 161 patients with CRC, 34 patients with colorectal adenoma (CRA), and 58 healthy volunteers. The oral microbiota was assessed using 16S rRNA sequencing. The oral microbiome was characterized, microbial markers were identified, and colorectal tumor (CRA and CRC) classifiers were constructed and validated. Results: Oral microbial composition and diversity were significantly different among the three groups; the CRA group had the highest diversity. Analysis of the functional potential of oral microbiota demonstrated that the pathway involving cell motility was overrepresented in the CRA and CRC groups relative to that in the healthy controls. Moreover, a random forest model was constructed based on oral microbial markers, which could distinguish the colorectal tumor groups from the healthy controls and achieve a powerful classification potential in the discovery and validation cohorts. Conclusions: This study suggests a potential association between oral microbiome dysbiosis and colorectal cancer. Oral microbiota-based biomarkers may be helpful in predicting the risk of developing CRA and CRC.
Oncogenic Ras Disrupts Epithelial Integrity by Activating the Transmembrane Serine Protease Hepsin
Authors: Topi A. Tervonen, Shishir M. Pant, Denis Belitškin, Johanna I. Englund, Katja Närhi, Caj Haglund, Panu E. Kovanen, Emmy W. Verschuren, Juha Klefström
Journal: Cancer Research (2021)

Abstract Ras proteins play a causal role in human cancer by activating multiple pathways that promote cancer growth and invasion. However, little is known about how Ras induces the first diagnostic features of invasion in solid tumors, including loss of epithelial integrity and breaching of the basement membrane (BM). In this study, we found that oncogenic Ras strongly promotes the activation of hepsin, a member of the hepsin/TMPRSS type II transmembrane serine protease family. Mechanistically, the Ras-dependent hepsin activation was mediated via Raf–MEK–ERK signaling, which controlled hepsin protein stability through the heat shock transcription factor-1 stress pathway. In Ras-transformed three-dimensional mammary epithelial culture, ablation of hepsin restored desmosomal cell–cell junctions, hemidesmosomes, and BM integrity and epithelial cohesion. In tumor xenografts harboring mutant KRas, silencing of hepsin increased local invasion concomitantly with accumulation of collagen IV. These findings suggest that hepsin is a critical protease for Ras-dependent tumorigenesis, executing cell–cell and cell–matrix pathologies important for early tumor dissemination. Significance: These findings identify the cell-surface serine protease hepsin as a potential therapeutic target for its role in oncogenic Ras-mediated deregulation of epithelial cell–cell and cell–matrix interactions and cohesion of epithelial structure.
Inflammatory Leptomeningeal Cytokines Mediate COVID-19 Neurologic Symptoms in Cancer Patients
Authors: Jan Remsik, Jessica A. Wilcox, N. Esther Babady, Tracy A. McMillen, Behroze A. Vachha, Neil A. Halpern, Vikram Dhawan, Marc Rosenblum, Christine A. Iacobuzio-Donahue, Edward K. Avila, Bianca Santomasso, Adrienne Boire
Journal: Cancer Cell (2021)
HCMV-controlling NKG2C+ NK cells originate from novel circulating inflammatory precursors
Authors: Federica Bozzano, Mariella Della Chiesa, Andrea Pelosi, Francesca Antonini, Maria Libera Ascierto, Genny Del Zotto, Francesca Moretta, Letizia Muccio, Anna Luganini, Giorgio Gribaudo, Giovanni Cenderello, Chiara Dentone, Laura Nicolini, Alessandro Moretta, Lorenzo Moretta, Andrea De Maria
Journal: Journal of Allergy and Clinical Immunology (2021)
COVID-19 Cases and Transmission in 17 K–12 Schools — Wood County, Wisconsin, August 31–November 29, 2020
Authors: Amy Falk, Alison Benda, Peter Falk, Sarah Steffen, Zachary Wallace, Tracy Beth Høeg
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

The coronavirus disease 2019 (COVID-19) pandemic has disrupted in-person learning in the United States, with approximately one half of all students receiving online-only instruction since March 2020.*Discontinuation of in-person schooling can result in many hardships (1) and disproportionately affects families of lower socioeconomic status (2).Current evidence suggests that transmission of SARS-CoV-2, the virus that causes COVID-19, in kindergarten through grade 12 (K-12) schools might not significantly contribute to COVID-19 spread nationwide (3).During August 31-November 29, 2020, COVID-19 cases, spread, and compliance with mask use were investigated among 4,876 students and 654 staff members who participated in in-person learning in 17 K-12 schools in rural Wisconsin.School-attributable COVID-19 case rates were compared with rates in the surrounding community.School administration and public health officials provided information on COVID-19 cases within schools.During the study period, widespread community transmission was observed, with 7%-40% of COVID-19 tests having positive results.Masking was required for all students and staff members at all schools, and rate of reported student mask-wearing was high (>92%).COVID-19 case rates among students and staff members were lower (191 cases among 5,530 persons, or 3,453 cases per 100,000) than were those in the county overall (5,466 per 100,000).Among the 191 cases identified in students and staff members, one in 20 cases among students was linked to in-school transmission; no infections among staff members were found to have been acquired at school.These findings suggest that, with proper mitigation strategies, K-12 schools might be capable of opening for in-person learning with minimal in-school transmission of SARS-CoV-2.Among 18 selected schools in Wood County, Wisconsin, 17 agreed to participate in this study of COVID-19 in schools and compliance with mask use.One school opted not to participate based on teacher preference.Surveillance was initiated by a small group of physician and medical student researchers.Participating schools were from three public school districts, one private school district, and one independent private school.Eight schools were elementary (grades K-6) with 1,529 students attending in-person, and nine were
CBT for Prolonged Grief in Children and Adolescents: A Randomized Clinical Trial
Authors: Paul A. Boelen, Lonneke I.M. Lenferink, Mariken Spuij
Journal: American Journal of Psychiatry (2021)

Prolonged grief disorder was newly included in ICD-11 and resembles persistent complex bereavement disorder, newly included in DSM-5. Although prolonged grief disorder in adults can be successfully treated by cognitive-behavioral therapy (CBT), there is no evidence yet that CBT interventions can successfully alleviate the disorder in children and adolescents. The goal of this randomized clinical trial was to examine the effects of a CBT program, CBT Grief-Help, for prolonged grief disorder in children and adolescents in comparison with the effects of nondirective supportive counseling.A total of 134 children and adolescents with prolonged grief disorder (mean age, 13.10 years [SD=2.84], bereaved a mean of 37.79 months [SD=36.23] earlier) were randomly assigned to receive either CBT Grief-Help (N=74) or supportive counseling (N=60). Both treatment conditions encompassed nine individual sessions with children and adolescents paralleled by five counseling sessions with parents or caretakers. Children and adolescents completed measures of prolonged grief disorder, depression, and posttraumatic stress disorder (PTSD), and their parents or caretakers completed measures of their children's problem behavior before treatment, immediately after treatment, and 3, 6, and 12 months after treatment.Both treatments yielded moderate to large effect sizes across prolonged grief disorder and most other outcome measures. Compared with supportive counseling, CBT Grief-Help resulted in significantly greater reductions in prolonged grief disorder symptoms at all posttreatment assessments, and it was more successful in alleviating depression, PTSD symptoms, and internalizing problems 6 and 12 months after treatment.Prolonged grief disorder and its symptoms in bereaved children and adolescents can be effectively treated by CBT interventions. The superior long-term effects of CBT Grief-Help relative to supportive counseling suggest that this treatment successfully strengthens children and adolescents in facing challenges brought about by bereavement.
Medium- and Large-Vessel Vasculitis
Authors: David Saadoun, Mathieu Vautier, Patrice Cacoub
Journal: Circulation (2021)

Systemic vasculitides are multisystem blood vessel disorders, which are defined by the size of the vessel predominantly affected, namely small, medium, or large vessels. The term “large vessel” relates to the aorta and its major branches; “medium vessel” refers to the main visceral arteries and veins and their initial branches. The most common causes of large-vessel vasculitis are giant cell arteritis and Takayasu arteritis, and those of medium-vessel arteritis are polyarteritis nodosa and Kawasaki disease. However, there is some overlap, and arteries of any size can potentially be involved in any of the 3 main categories of dominant vessel involvement. In addition to multisystem vasculitides, other forms of vasculitis have been defined, including single-organ vasculitis (eg, isolated aortitis). Prompt identification of vasculitides is important because they are associated with an increased risk of mortality. Left undiagnosed or mismanaged, these conditions may result in serious adverse outcomes that might otherwise have been avoided or minimized. The ethnic and regional differences in the incidence, prevalence, and clinical characteristics of patients with vasculitis should be recognized. Because the clinical presentation of vasculitis is highly variable, the cardiovascular clinician must have a high index of suspicion to establish a reliable and prompt diagnosis. This article reviews the pathophysiology, epidemiology, diagnostic strategies, and management of vasculitis.
Biological Aspects of Cancer Health Disparities
Authors: Jennifer A. Freedman, Muthana Al Abo, Tyler A. Allen, Sean A. Piwarski, Kara Wegermann, Steven R. Patierno
Journal: Annual Review of Medicine (2021)

Racial and ethnic disparities span the continuum of cancer care and are driven by a complex interplay among social, psychosocial, lifestyle, environmental, health system, and biological determinants of health. Research is needed to identify these determinants of cancer health disparities and to develop interventions to achieve cancer health equity. Herein, we focus on the overall burden of ancestry-related molecular alterations, the functional significance of the alterations in hallmarks of cancer, and the implications of the alterations for precision oncology and immuno-oncology. In conclusion, we reflect on the importance of estimating ancestry, improving diverse racial and ethnic participation in cancer clinical trials, and examining the intersection among determinants of cancer health disparities.
Root Cause Analysis
Authors: Megan Paulsen
Journal: JAMA (2021)

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Fortnightly review: Medical management of menorrhagia
Authors: A. Prentice
Journal: BMJ (1999)

Excessive menstrual loss, or menorrhagia, is a significant healthcare problem in the developed world (box ​(boxB1).B1). In the United Kingdom, 5% of women of reproductive age will seek help for this symptom annually1; by the end of reproductive life the risk of hysterectomy (primarily for menstrual disorders) is 20%.2 This is also the situation in New Zealand.3 Objectively, menorrhagia is defined as a menstrual loss of 80 ml per month. Population studies have shown that this amount of loss is present in 10% of the population4 yet nearly a third of all women consider their menstruation to be excessive.5 This symptom thus creates a significant workload for health services. 



Box 1

: Indications for referral to a gynaecologist or for surgical management




In clinical medicine the paradigm of evidence based medicine currently holds sway. Evidence based medicine implies not only the application of effective treatments but their rational use within a rational overall management framework. In the management of excessive menstrual loss there is good evidence that many doctors do not necessarily prescribe the most effective treatments. In the United Kingdom, for example, more than a third of general practitioners prescribe norethisterone—arguably the least effective option—as first line treatment, whereas only 1 in 20 prescribe tranexamic acid—probably the most effective first line treatment.6 The problem is not confined to primary care. In New Zealand, where the use of tranexamic acid is restricted to secondary care, 50% of gynaecologists still use luteal phase progestogens, and less than 10% use tranexamic acid.7


Summary points


Menorrhagia is an important healthcare issue


Despite widely available evidence inappropriate treatments are being prescribed


Guidelines exist for the appropriate management of menorrhagia


Appropriate treatments enhance patient choice and may increase patient satisfaction


Medical treatments may provide an effective alternative to surgery








Methods
This review attempts to provide a rational overview of the diagnostic and therapeutic management of menorrhagia, relying on the systematic reviews presented in three papers—two guidelines for the management of excessive menstrual loss published in 19988,9 and a consensus view published in 199510—and the Cochrane library for the source literature.
Vertebral Ischemic Necrosis in Diabetic Lumbosacral Radiculoplexus Neuropathy
Authors: Ari Breiner, Thanh B. Nguyen, Bibianna Purgina, Pierre R. Bourque
Journal: Diabetes Care (2021)

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN), or diabetic amyotrophy, is an infrequent neurovascular complication of diabetes thought to result from immune-mediated infarction of peripheral nerve branches (1). DLRPN has not previously been reported in association with infarction of the vertebral bone, which itself is a rare occurrence, typically in the setting of aortic surgery and spinal cord infarction (2). We report a case of simultaneous DLRPN and vertebral bony infarction in a patient with type 2 diabetes, highlighting the unifying vascular etiology responsible for both these uncommon pathologies.

A 47-year-old man of Nepalese origin presented to hospital with a 2-week history of relatively acute-onset left lumbar pain, numbness and paresthesia in the left obturator and saphenous nerve distributions, and marked proximal left leg weakness. His past health was notable for a 4-year history of type 2 diabetes, well controlled with sitagliptin, canagliflozin, and metformin. On examination, there was Medical Research Council (MRC) grade 2/5 paresis of the left hip flexor and hip adductor muscles, with grade 1/5 power of knee extension. The left patellar reflex was absent. Electrodiagnostic studies showed a reduced left femoral motor potential and denervation at the …
CHecklist for statistical Assessment of Medical Papers: the CHAMP statement
Authors: Mohammad Ali Mansournia, Gary S Collins, Rasmus Oestergaard Nielsen, Maryam Nazemipour, Nicholas P Jewell, Douglas G Altman, Michael J Campbell
Journal: British Journal of Sports Medicine (2021)

Despite efforts to improve the statistical quality of research articles in medical journals, serious statistical errors or deficiencies in the design, analysis, reporting and interpretation still occur, even in highly ranked journals.1 Flawed statistics and methodology will negatively affect the study results and could consequently impact public health and patient care.2 Despite numerous educational papers on biostatistics as well as reporting guidelines including CONsolidated Standards Of Reporting Trials, STrengthening the Reporting of OBservational studies in Epidemiology, STAndards for the Reporting of Diagnostic accuracy studies, REporting recommandations for tumor MARKer prognostic studies, and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (and others as listed in the Enhancing the QUAlity and Transparency Of health Research network; www.equator-network.org) endorsed by many journals, the methodological quality of medical publications still remains low.3 Editors and reviewers may not have expert knowledge of statistics, and worse, could remain unconvinced about the importance of solid methodology in medical research.4 Thus, …
Integrative analyses of TEDDY Omics data reveal lipid metabolism abnormalities, increased intracellular ROS and heightened inflammation prior to autoimmunity for type 1 diabetes
Authors: Leandro Balzano-Nogueira, Ricardo Ramirez, Tatyana Zamkovaya, Jordan Dailey, Alexandria N. Ardissone, Srikar Chamala, Joan Serrano-Quílez, Teresa Rubio, Michael J. Haller, Patrick Concannon, Mark A. Atkinson, Desmond A. Schatz, Eric W. Triplett, Ana Conesa
Journal: Genome biology (2021)

The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective birth cohort designed to study type 1 diabetes (T1D) by following children with high genetic risk. An integrative multi-omics approach was used to evaluate islet autoimmunity etiology, identify disease biomarkers, and understand progression over time.