Miracle-dz/UniFAR-FTUs huggingface dataset:
Body fatness at an early age and risk of colorectal cancer

While there is convincing evidence that excess body fatness in adulthood is positively associated with colorectal cancer risk, the association between body fatness at an early age (≤30 years) and the risk of colorectal cancer has been equivocal. The present meta‐analysis was performed to clarify this association. PubMed and Web of Science databases were searched for relevant studies that investigated this association. The risk estimates from each study were transformed into a continuous variable for each 5 kg/m2 increase in body mass index (BMI). A random effects model was used to calculate the summary relative risks (RRs) with 95% confidence intervals (CIs). A total of 15 observational studies (13 cohort studies and two case‐control studies) were included in this meta‐analysis. Each 5 kg/m2 increase in BMI was significantly associated with a 13% (RR 1.13, 95% CI 1.08, 1.19), 17% (RR 1.17, 95% CI 1.09, 1.25) and 8% (RR 1.08, 95% CI 1.04, 1.11) higher risk of colorectal cancer overall, in men, and in women, respectively. Substantial heterogeneity was observed across studies. Based on the anatomic subsite, each 5 kg/m2 increase in BMI was significantly associated with a 14% (RR 1.14, 95% CI 1.07, 1.22) higher risk of colon cancer, whereas no association (RR 1.03, 95% CI 0.95, 1.13) was observed with rectal cancer. In summary, body fatness at an early age may affect colon cancer risk later in life. Prevention of overweight and obesity in young individuals should be emphasized to prevent early‐onset colon cancer attributed to excess body fatness.
Clinicopathologic characteristics and outcomes of transformed diffuse large B‐cell lymphoma in hepatitis C virus‐infected patients

Hepatitis C virus (HCV) causes a chronic but curable infection associated with the development of marginal zone lymphoma (MZL) and diffuse large B‐cell lymphoma (DLBCL). Preliminary data have shown frequent transformation of indolent lymphoma to DLBCL in HCV‐infected patients. To compare their clinicopathologic characteristics and oncologic outcomes, we reviewed the medical records and pathology reports of HCV‐infected and uninfected patients with DLBCL that transformed from indolent lymphoma seen at The University of Texas MD Anderson Cancer Center (June 2004 to May 2015). To identify predictors of DLBCL relapse, patients with relapse after first‐line chemotherapy were compared with those without it using univariate and logistic regression analyses. Compared with the uninfected patients (n = 63), HCV‐infected patients (n = 21) were younger (median age =54 years [interquartile range= 49–62 years] vs. 62 years [53–66 years]; p = 0.01) and more often had advanced DLBCL (Ann Arbor stage 3–4; 95% vs. 76%; p = 0.05). Immunophenotypically, more HCV‐infected than uninfected patients had CD10‐negative B cells (76% vs. 43%; p = 0.008), CD5‐positive B cells (39% vs. 7%; p = 0.004) and activated B‐cell phenotypes (57% vs. 31%; p = 0.07). Comparison of the patients who had relapse after first‐line chemotherapy (n = 42) and those who did not (n = 40) revealed that having CD5‐positive B cells was the only factor associated with DLBCL relapse in multivariate analysis (odds ratio= 10.7; p = 0.02). HCV‐infected patients with transformed DLBCL have unique clinicopathologic characteristics that make their lymphoma difficult to treat, potentially leading to unfavorable outcome. The impact of HCV eradication should be explored in such patients.
Species‐specific role of gene‐adjacent retroelements in human and mouse gastric carcinogenesis

Helicobacter pylori (HP) infection promotes the recruitment of bone marrow stem cells into chronic gastritis lesions. Some of these marrow stem cells can differentiate into gastric epithelial cells and neoplastic cells. We propose that HP‐associated methylation could stabilize trans‐differentiation of marrow‐derived stem cells and that an unstable methylation status is associated with a risk of gastric cancer. Pathobiologic behavior of experimental mouse gastric cancer is mild compared to invasive and metastatic human gastric cancer. Differences in epigenetic stabilization of adult cell phenotypes between humans and mice could provide a foundation to explore the development of invasive and metastatic gastric cancer. Retroelements are highly repetitive sequences that play an essential role in the generation of species diversity. In this review, we analyzed retroelements adjacent to human and mouse housekeeping genes and proposed a possible epigenetic mechanism for HP‐associated carcinogenesis.
Dietary patterns and risk of recurrence and progression in non‐muscle‐invasive bladder cancer

The association of dietary factors with urinary bladder cancer prognosis has scarcely been investigated, and results of studies conducted to date are inconsistent. We investigated whether empirically derived dietary patterns are associated with risks of recurrence and progression in non‐muscle‐invasive bladder cancer (NMIBC) patients. Data from 595 newly diagnosed NMIBC patients from an ongoing prospective cohort study were used to derive dietary patterns using exploratory factor analysis. Factor scores were calculated and then categorized in sex‐specific tertiles. Multivariable‐adjusted proportional hazards regression models were used to estimate hazard ratios and 95% confidence intervals for the associations between tertiles of adherence to the dietary patterns and risks of recurrence and progression. We identified four dietary patterns: “fruits and vegetables,” “Western,” “low‐fat,” and “Tex‐Mex. ” Patients in the highest tertile of adherence to the Western pattern experienced a 1.48 times higher risk of recurrence (95% CI 1.06–2.06) compared to patients in the lowest tertile. No statistically significant associations of a Western diet with risk of progression or of the other dietary patterns with risk of recurrence and progression were found. Overall, we found that adherence to a Western diet was associated with a higher risk of recurrence but further studies are needed to confirm our findings.
Eurogin roadmap 2017: Triage strategies for the management of HPV‐positive women in cervical screening programs

Cervical cancer screening will rely, increasingly, on HPV testing as a primary screen. The requirement for triage tests which can delineate clinically significant infection is thus prescient. In this EUROGIN 2017 roadmap, justification behind the most evidenced triages is outlined, as are challenges for implementation. Cytology is the triage with the most follow‐up data; the existence of an HR‐HPV‐positive, cytology‐negative group presents a challenge and retesting intervals for this group (and choice of retest) require careful consideration. Furthermore, cytology relies on subjective skills and while adjunctive dual‐staining with p16/Ki67 can mitigate inter‐operator/‐site disparities, clinician‐taken samples are required. Comparatively, genotyping and methylation markers are objective and are applicable to self‐taken samples, offering logistical advantages including in low and middle income settings. However, genotyping may have diminishing returns in immunised populations and type(s) included must balance absolute risk for disease to avoid low specificity. While viral and cellular methylation markers show promise, more prospective data are needed in addition to refinements in automation. Looking forward, systems that detect multiple targets concurrently such as next generation sequencing platforms will inform the development of triage tools. Additionally, multistep triage strategies may be beneficial provided they do not create complex, unmanageable pathways. Inevitably, the balance of risk to cost(s) will be key in decision making, although defining an acceptable risk will likely differ between settings. Finally, given the significant changes to cervical screening and the variety of triage strategies, appropriate education of both health care providers and the public is essential.
Recapitulating the clinical scenario of BRCA‐associated pancreatic cancer in pre‐clinical models

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA‐associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient‐derived xenograft (PDX) models from metastatic lesions of germline BRCA‐mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA‐mutated PDXs and classified by whole‐genome sequencing to stable‐genome or homologous recombination deficient (HRD)‐genome. The sensitivity to DNA‐damaging agents was evaluated in vivo in three BRCA‐associated PDAC PDXs models: (1) HRD‐genome naïve to treatments; (2) stable‐genome naïve to treatment; (3) HRD‐genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD‐genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA‐associated PDX thus reflecting the wide clinical spectrum. An HRD‐genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD‐genome PDXs generated from a patient that had acquired resistance nor stable‐genome PDXs.
Increase in virulence of Sporothrix brasiliensis over five years in a patient with chronic disseminated sporotrichosis

Abstract The metropolitan region of Rio de Janeiro is hyperendemic for cat-associated sporotrichosis. This study aimed to assess the virulence of serial Sporothrix isolates from a 61-year-old male patient with chronic, destructive disseminated sporotrichosis. Five Sporothrix isolates were cultured from skin exudates and bone samples over a 5-year period, and all were molecularly identified as Sporothrix brasiliensis. The final isolate was significantly more virulent in Galleria mellonella larvae compared to earlier isolates. We conclude that S. brasiliensis has the capacity to increase in virulence in vivo. This finding is significant to clinicians caring for individuals with S. brasiliensis disease and it suggests that further studies are needed to identify the mechanisms underlying pathogenicity enhancement during chronic disease.
Clinical Trials with an Adaptive Choice of Hypotheses

In a clinical trial with an adaptive interim analysis it is possible to modify not only the design, but even the hypothesis(es) of interest, in a formally correct manner. Two examples of clinical trials are described where modifications of hypotheses are based on substantial scientific reasons. Generally, it is emphasized that the danger of manipulation caused by flexible designs must be controlled by very restrictive guidelines.
Human Health Risk Assessment of a Civilian-Accessible Active Firing Range

ABSTRACT The Korean Federation of Teachers Association, the Korea Ministry of Education, Science and Technology, and the Korea Ministry of National Defense (KMND) concluded a memorandum of understanding (MOU) on opening military sites to elementary, middle, and high school students to strengthen national security consciousness. According to the MOU, the KMND decided to open an active firing range; however, due to the ongoing firing activity, site contamination by toxic energetic materials (EMs) was suspected. To identify whether opening the firing range might pose a human health threat to the students and their teachers visiting the site, we conducted a risk assessment to evaluate potential risk. The risk assessment results revealed that both cancer risk and non-cancer risk were negligible. The potential cancer risk was in the range of 1.9 × 10–11 and 1.4 × 10–10, and the potential non-cancer hazard index was in the range of 2.3 × 10–6 and 4.9 × 10–6.
The Cek1‑mediated MAP kinase pathway regulates exposure of α‑1,2 and β‑1,2‑mannosides in the cell wall of Candida albicans modulating immune recognition

ABSTRACT The Cek1 MAP kinase (MAPK) mediates vegetative growth and cell wall biogenesis in the fungal pathogen Candida albicans. Alterations in the fungal cell wall caused by a defective Cek1‑mediated signaling pathway leads to increased β‑1,3‑glucan exposure influencing dectin‑1 fungal recognition by immune cells. We show here that cek1 cells also display an increased exposure of α‑1,2 and β‑1,2‑mannosides (α‑M and β‑M), a phenotype shared by strains defective in the activating MAPKK Hst7, suggesting a general defect in cell wall assembly. cek1 cells display walls with loosely bound material as revealed by transmission electron microscopy and are sensitive to tunicamycin, an inhibitor of N‑glycosylation. Transcriptomal analysis of tunicamycin treated cells revealed a differential pattern between cek1 and wild type cells which involved mainly cell wall and stress related genes. Mapping α‑M and β‑M epitopes in the mannoproteins of different cell wall fractions (CWMP) revealed an important shift in the molecular weight of the mannan derived from mutants defective in this MAPK pathway. We have also assessed the role of galectin‑3, a member of a β‑galactoside‑binding protein family shown to bind to and kill C. albicans through β‑M recognition, in the infection caused by cek1 mutants. Increased binding of cek1 to murine macrophages was shown to be partially blocked by lactose. Galectin-3−/− mice showed increased resistance to fungal infection, although galectin-3 did not account for the reduced virulence of cek1 mutants in a mouse model of systemic infection. All these data support a role for the Cek1‑mediated pathway in fungal cell wall maintenance, virulence and antifungal discovery.
Feasibility of implementing the Adolescent Community Reinforcement Approach in school settings for adolescents with substance use disorders

Nationally, approximately 10% of adolescents in need of treatment for a substance use (SU) disorder receive treatment. School-based treatment may provide an important opportunity to reduce the treatment gap by facilitating access to services. While some school-based SU treatment exists, little is known about whether newer, evidence-based treatments (e.g. Adolescent Community Reinforcement Approach [A-CRA]) can be well implemented in schools. The objectives of this study were to compare adolescents receiving A-CRA services in school-based versus clinic-based settings in regard to (1) intake characteristics, (2) treatment implementation quality, and (3) clinical outcomes. Results suggest that A-CRA in school-based settings was more likely to reach girls and youth with shorter SU histories; A-CRA was well implemented within school-based settings and the school-based group had equivalent or better outcomes than the clinic-based group.
Interdisciplinarity: History, Theory, and Practice

Medicine has evolved from the undertaking of the individual practitioner to a state in which many disciplines become involved in administering both diagnostic and treatment services. It has become a standard of care in hospital and clinic-based practice to utilize a multidisciplinary approach to medical care. Multidisciplinary modes of practice, however, do not ensure that participants interact cooperatively, or with the exclusive purpose of patient benefit. The usual mode of interaction within medical academic and clinical environments promotes individualism, protectionism, and some degree of isolation, not infrequently to the detriment of patient care. The stated purpose of this book is to provide a synthesis of theories and methodologies that promote a growing permeability of boundaries and that allow for intellectual accommodation. Health care professionals have been turning to interdisciplinary intervention approaches for several reasons, but the most compelling in medicine is the need to solve problems that are beyond the
Progress in HPV vaccination in low‐ and lower‐middle‐income countries

The past 10 years have seen remarkable progress in the global scale‐up of human papillomavirus (HPV) vaccinations. Forty‐three low‐ and lower‐middle‐income countries (LLMICs) have gained experience in delivering this vaccine to young adolescent girls through pilot programs, demonstration programs, and national introductions and most of these have occurred in the last 4 years. The experience of Senegal is summarized as an illustrative country case study. Publication of numerous delivery experiences and lessons learned has demonstrated the acceptability and feasibility of HPV vaccinations in LLMICs. Four areas require dedicated action to overcome remaining challenges to national scaling‐up: maintaining momentum politically, planning successfully, securing financing, and fostering sustainability. Advances in policy, programming, and science may help accelerate reaching 30 million girls in LLMICs with HPV vaccine by 2020.
Diverted recycling—Shigella subversion of Rabs

ABSTRACT Small GTPases of the Rab protein family control intracellular vesicular trafficking to allow their communication and maintenance. It is a common strategy for intracellular bacteria to exploit these pathways to shape their respective niches for survival. The subversion of Rabs for the generation of an intracellular environment favoring the pathogen has been described almost exclusively for intracellular bacteria that reside within bacterial containing vacuoles (BCVs). However, less is known about Rab subversion for bacteria that rupture the BCV to reach the host cytoplasm. Here, we provide recent examples of Rab targeting by both groups of intracellular bacteria with a special focus on Shigella, the causative agent of bacillary dysentery. Shigella recruits Rab11, the hallmark of the perinuclear recycling compartment to in situ formed macropinosomes at the entry foci via the bacterial effector IpgD. This leads to efficient BCV rupture and cytosolic escape. We discuss the concept of diverted recycling through host Rab GTPases that emerges as a novel pathogen strategy.
Normal epithelial cells trigger EphA2-dependent RasV12 cell repulsion at the single cell level

ABSTRACT Epithelial cells expressing oncogenic Ras (RasV12) are detected by normal neighbors and are often extruded from tissues. We recently demonstrated that differential EphA2 signaling drives the segregation of mutant cells from normal monolayers via cell repulsion and increased RasV12 cell contractility. EphA2 signaling on RasV12 cells is triggered by ephrin-A ligands presented by normal cells. Here, we show that normal epithelial cells trigger the repulsion and enhanced contractility of Ras-transformed epithelial cells at the single cell level. We also reveal that ephrin-A ligands expressed on RasV12 cells are not required to drive RasV12 cell segregation following interaction with normal cells. Thus, normal-RasV12 cell-cell interaction triggers EphA2 forward signaling in RasV12 cells to drive repulsion and segregation of the transformed cells.
Rab proteins as major determinants of the Golgi complex structure

ABSTRACT GTP-ases of the Rab family (about 70 in human) are key regulators of intracellular transport and membrane trafficking in eukaryotic cells. Remarkably, almost one third associate with membranes of the Golgi complex and TGN (trans-Golgi network). Through interactions with a variety of effectors that include molecular motors, tethering complexes, scaffolding proteins and lipid kinases, they play an important role in maintaining Golgi architecture.
From bench to bedside: translating new research from genetics and neuroimaging into treatment development for early‐onset schizophrenia

Objective: Children and adolescents with schizophrenia share a similar pattern of phenomenological, genetic and cognitive abnormalities to adults with schizophrenia. However, an early‐onset of schizophrenia (EOS) (prior to 18 years of age) is associated with a higher frequency of risk indicators associated with schizophrenia (e.g. developmental delays and familial spectrum disorders) and a worse long‐term outcome. This overview examines recent research on the neurobiological alterations, possible causes, developmental trajectory and treatment of EOS and attempts to identify gaps in the field.
Review of the operational definition for first‐episode psychosis

Aim: Given the growing interest in the study of first‐episode psychosis, clinical and research programmes would benefit from a conceptual clarification of how to operationalize ‘first‐episode psychosis’. We review the variety of definitions in use and discuss their relative merits with respect to both clinical (e.g. early treatment) and research (e.g. obtaining meaningfully homogeneous populations) agendas.
Early primary care follow-up after ED and hospital discharge – does it affect readmissions?

ABSTRACT Objectives: After hospitalization, timely discharge follow-up has been linked to reduced readmissions in the heart failure population, but data from general inpatients has been mixed. The objective of this study was to determine if there was an association between completed follow-up appointments within 14 days of hospital discharge and 30-day readmission amongst primary care patients at an urban academic medical center. Index discharges included both inpatient and emergency room settings. A secondary objective was to identify patient factors associated with completed follow-up appointments within 14 days. Methods: We conducted a retrospective review of primary care patients at an urban academic medical center who were discharged from either the emergency department (ED) or inpatient services at the Weill Cornell Medical Center/New York Presbyterian Hospital from 1 January 2014-31 December 2014. Cox proportional hazard models were used to identify the relationship between follow-up in primary care within 14 days and readmission within 30 days. Logistic regression was used to evaluate the association of patient factors with 14-day follow-up. Results: Among 9,662 inpatient and ED discharges, multivariable analysis (adjusting for age, gender, race/ethnicity, insurance, number of diagnoses on problem list, length of stay, and discharge service) showed that follow-up with primary care within 14 days was not associated with a lower hazard of readmission within 30 days (HR = 0.78; 95% CI 0.56–1.09). A higher number of diagnoses on the problem list was associated with greater odds of follow-up for both inpatient and emergency department discharges (inpatient: HR = 1.03, 95% CI 1.02–1.04; ED: HR = 1.02, 95% CI 1.00–1.04). For inpatient discharges, each additional day in length of stay was associated with 3% lower odds of follow-up (HR = 0.97, 95% CI 0.96–0.99). Conclusion: Early follow-up within 14 days after discharge from general inpatient services was associated with a trend toward lower hazard of 30-day readmission though this finding was not significant. Future studies should focus on identifying additional cohorts of patients in which readmission is reduced by early follow-up, so that access to primary care appointments is not compromised.