Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of c-FLIPL and c-FLIPS as critical regulators of death receptor-induced apoptosis in pancreatic cancer cells

Background Evasion of apoptosis is a hallmark of pancreatic cancer. However, the underlying mechanisms are still only partly understood and may involve antiapoptotic proteins such as c-FLIP. Here, the role of c-FLIP in the regulation of death receptor-mediated apoptosis in pancreatic cancer was investigated. Methods Expression of c-FLIPL and c-FLIPS was analysed in primary pancreatic carcinoma samples, pancreatic carcinoma cell lines and primary tumour cells together with its function as a regulator of death receptor-induced apoptosis by knockdown and overexpression studies and through modulation by chemotherapeutics. Results c-FLIP is expressed in pancreatic intraepithelial neoplasm (PanIN) lesions and in pancreatic ductal adenocarcinomas, whereas normal pancreatic ducts were consistently negative for c-FLIP. Simultaneous downregulation of c-FLIPL and c-FLIPS as well as individual knockdown of either isoform by RNA interference significantly enhances TRAIL (tumour necrosis factor-related apoptosis-inducing ligand)- and CD95-induced caspase activation and caspase-dependent apoptosis. Also, pretreatment with chemotherapeutic drugs—that is, 5-fluorouracil (5-FU), cisplatin or gemcitabine—downregulates c-FLIP and renders cells sensitive to death receptor-triggered apoptosis. Similarly, primary cultured pancreatic cancer cells are primed for TRAIL-induced apoptosis by pre-exposure to 5-FU or cisplatin. Mechanistic studies revealed that 5-FU-mediated suppression of c-FLIP results in increased TRAIL-induced recruitment and activation of caspase-8 at the death-inducing signalling complex (DISC), leading to caspase-3 activation and caspase-dependent cell death. Overexpression of c-FLIPL rescues cells from 5-FU- or cisplatin-mediated sensitisation for TRAIL-induced apoptosis, indicating that c-FLIP suppression is a key event in this chemotherapy-mediated sensitisation to TRAIL. Further, concomitant neutralisation of c-FLIP and XIAP acts in concert to potentiate TRAIL-induced apoptosis. Conclusions Both the long and the short isoform of the antiapoptotic protein c-FLIP are critical regulators of death receptor-induced apoptosis in pancreatic carcinoma cells and are suppressed by chemotherapeutics. Targeting either c-FLIPL or c-FLIPS is sufficient to promote death receptor-induced apoptosis in pancreatic carcinoma cells. These findings have important implications for the design of TRAIL-based combination protocols in pancreatic cancer.
Recognition and management of drug-induced cytopenias: the example of idiosyncratic drug-induced thrombocytopenia

Background: Several hundred drugs, toxins and herbs have been reported to cause blood abnormalities, and drugs account for 20 – 40% of all instances of cytopenias. Objective: In the present paper, we report and discuss the recognition and management of moderate to severe idiosyncratic drug-induced thrombocytopenia. Methods: A bibliographic search was performed on the PubMed database of the US National Library of Medicine for articles published from January 1990 to November 2008. Results/conclusions: Moderate to severe idiosyncratic drug-induced thrombocytopenia (platelet count < 100 × 109/l) is a relatively rare and potentially serious disorder. The origin may be myelosuppression or peripheral, owing to either the consumption of platelets or their immune-mediated destruction. The most common molecules responsible are heparins, quinidine, sulfonamides and gold salts. Clinically, the most classical symptom is a typical pattern of bleeding of variable intensity depending on the severity of thrombocytopenia and the molecule involved. Immune-mediated thrombocytopenia induced by heparin (type II) is more often associated with thrombotic events. The diagnosis is based on medical history and a set of clinical criteria, which also specify the level of imputability. Although the role of serological tests is not well established, they seem particularly valuable in some situations in which differential diagnosis is difficult or in type II heparin-induced thrombocytopenia. The treatment includes discontinuation of the suspected drug, and symptomatic measures that depend on the severity of clinical symptoms.
Retrospective analysis of 95 patients with large vessel vasculitis: a single center experience

Although Takayasu arteritis (TAK) and giant cell arteritis (GCA) have been considered as distinct disease entities, similarities of these diseases have been recently reported. However, little data is available regarding this issue in Japanese patients with TAK and GCA. In addition, the classification criteria for TAK established in 1990 by the American College of Rheumatology (ACR) have been criticized due to the age restriction for disease onset (≤ 40 years). Thus, we aimed to compare the clinical characteristics of Japanese patients with TAK and those with GCA and to clarify whether clinical differences existed between patients with early‐onset (≤ 40 years) and late‐onset (> 40 years) TAK.
Wet deposition of fission-product isotopes to North America from the Fukushima Dai-ichi incident, March 2011.

Using the infrastructure of the National Atmospheric Deposition Program (NADP), numerous measurements of radionuclide wet deposition over North America were made for 167 NADP sites before and after the Fukushima Dai-ichi Nuclear Power Station incident of March 12, 2011. For the period from March 8 through April 5, 2011, wet-only precipitation samples were collected by NADP and analyzed for fission-product isotopes within whole-water and filterable solid samples by the United States Geological Survey using gamma spectrometry. Variable amounts of (131)I, (134)Cs, or (137)Cs were measured at approximately 21% of sampled NADP sites distributed widely across the contiguous United States and Alaska. Calculated 1- to 2-week individual radionuclide deposition fluxes ranged from 0.47 to 5100 Becquerels per square meter during the sampling period. Wet deposition activity was small compared to measured activity already present in U.S. soil. NADP networks responded to this complex disaster, and provided scientifically valid measurements that are comparable and complementary to other networks in North America and Europe.
Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango?

The birth of Hepatology as a defined clinical discipline coincides with the introduction of Menghini's needle in the late 1950s.1 In those days, very little was known about the aetiology of liver disease and in the majority of patients diagnosis was mainly based on the morphological examination of liver specimens obtained with a biopsy. Features such as necrosis, inflammation and fibrosis were not precisely categorised, and the final label was merely descriptive—that is, chronic persistent, chronic active hepatitis and cirrhosis. In these terms, liver biopsy was the only available diagnostic means, and truly represented a gold standard. The introduction of the so-called ‘one second needle biopsy of the liver’ was characterised since the beginning by a significant cooperative effort between the clinician and the pathologist. Clinical hepatologists were trained in liver pathology and this led to the foundation of the main academic schools of Hepatology in Europe and the USA. The introduction of scoring systems represented a step forward in the use of liver biopsy. This introduction implied the necessity for more precision in the evaluation of liver biopsy specimens that was beyond the description and, in many instances, the opinion of the pathologist. Overall, the introduction of scoring systems was supposed to facilitate the comparison between samples and the communication of the results according to a global agreement. However, this obvious advantage, once analysed by statistical studies, started to be criticised in term of reproducibility, intraobserver and interobserver agreement, etc. For these and other reasons (sampling error, lack of standards, etc.), the value of liver biopsy as gold standard started to become questionable for clinicians. These issues started to be quite evident when liver biopsy was used to assess the extent of disease progression in terms of fibrotic transformation of the liver tissue, and even more when the …
Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease

Objective External fistulas represent a disabling manifestation of Crohn's disease with a difficult curability and a high relapse rate despite a large therapeutic armamentarium. Stem cell therapy is a novel and promising approach for treatment of chronic inflammatory conditions. We therefore investigated the feasibility, safety and efficacy of serial intrafistular injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in the treatment of fistulising Crohn's disease. Patients and methods We enrolled 12 consecutive outpatients (eight males, median age 32 years) refractory to or unsuitable for current available therapies. MSCs were isolated from bone marrow and expanded ex vivo to be used for both therapeutic and experimental purposes. Ten patients (two refused) received intrafistular MSC injections (median 4) scheduled every 4 weeks, and were monitored by surgical, MRI and endoscopic evaluation for 12 months afterwards. The feasibility of obtaining at least 50×106 MSCs from each patient, the appearance of adverse events, and the efficacy in terms of fistula healing and reduction of both Crohn's disease and perianal disease activity indexes were evaluated. In addition, the percentage of both mucosal and circulating regulatory T cells expressing FoxP3, and the ability of MSCs to influence mucosal T cell apoptosis were investigated. Results MSC expansion was successful in all cases; sustained complete closure (seven cases) or incomplete closure (three cases) of fistula tracks with a parallel reduction of Crohn's disease and perianal disease activity indexes (p<0.01 for both), and rectal mucosal healing were induced by treatment without any adverse effects. The percentage of mucosal and circulating regulatory T cells significantly increased during the treatment and remained stable until the end of follow up (p<0.0001 and p<0.01, respectively). Furthermore, MSCs have been proven to affect mucosal T cell apoptotic rate. Conclusions Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohn's disease.
Venetoclax and obinutuzumab in chronic lymphocytic leukemia.

To the editor: In chronic lymphocytic leukemia (CLL), the median age at diagnosis is 72 years, and most patients requiring therapy have coexisting medical conditions. Venetoclax is a potent BH3-mimetic compound that selectively antagonizes BCL-2 and has shown efficacy as monotherapy and with
Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn's disease: results of a phase I study

Background and aim Mesenchymal stromal cells (MSCs) are pluripotent cells that have immunosuppressive effects both in vitro and in experimental colitis. Promising results of MSC therapy have been obtained in patients with severe graft versus host disease of the gut. Our objective was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory Crohn's disease. Patients and intervention 10 adult patients with refractory Crohn's disease (eight females and two males) underwent bone marrow aspiration under local anaesthesia. Bone marrow MSCs were isolated and expanded ex vivo. MSCs were tested for phenotype and functionality in vitro. 9 patients received two doses of 1–2×106 cells/kg body weight, intravenously, 7 days apart. During follow-up, possible side effects and changes in patients' Crohn's disease activity index (CDAI) scores were monitored. Colonoscopies were performed at weeks 0 and 6, and mucosal inflammation was assessed by using the Crohn's disease endoscopic index of severity. Results MSCs isolated from patients with Crohn's disease showed similar morphology, phenotype and growth potential compared to MSCs from healthy donors. Importantly, immunomodulatory capacity was intact, as Crohn's disease MSCs significantly reduced peripheral blood mononuclear cell proliferation in vitro. MSC infusion was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. Baseline median CDAI was 326 (224–378). Three patients showed clinical response (CDAI decrease ≥70 from baseline) 6 weeks post-treatment; conversely three patients required surgery due to disease worsening. Conclusions Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory Crohn's disease. No serious adverse events were detected during bone marrow harvesting and administration.
Difficulties at work experienced by patients with inflammatory bowel disease (IBD) and factors relevant to work motivation and depression

This research examined the experiences in the workplace, and factors relevant to work motivation and depression, of patients in Japan with Inflammatory Bowel Disease (IBD), with the goal of clarifying the best way to support their work and mental health. Initial interview results achieved with 19 IBD patients, guided the development of an anonymous questionnaire which was distributed to 3,794 patients by mail. Valid responses were obtained from 2,009 patients. We analyzed the results with a focus on patients currently in a job. IBD patients with a job experienced 5 categories of typical difficulties in their day-to-day work life, and which had high degree of burden. The severity of difficulties was greater in patients who had retired within the past year, than it was in patients currently in work. In particular, difficulties that influenced patients' performance at work and in their careers, and the association between work that affected the physical condition and health care behavior of patients and the lack of work-related sensitive considerations' were strongly correlated or had a tendency to be correlated with the patients' work motivation and depression ; this applied to patients with ulcerative colitis (UC) or Crohn's disease (CD). Difficulties were associated with greater depression, while number of social support network (SSN) and post-traumatic growth (PTG) were associated with greater work-motivation or lower depression in both types of IBD patients. These results indicated the importance of the improvement of mental health of IBD patients in Japan, along with the reduction or elimination of difficulties at work, with particular attention to SSN and PTG.
Job stress related to glyco‐lipid allostatic load, adiponectin and visfatin

Job stress has been associated with an increased risk for glyco-lipid metabolic dysfunction, which can lead to coronary artery disease, diabetes and other adverse health outcomes. We undertook a cross-sectional study to evaluate the relationship between job stress and glyco-lipid metabolic change in healthy industrial employees in China. Volunteers (n = 504) were investigated during the routine annual health examination period between June and August 2006. Job stress was assessed by the 22-item Job Content Questionnaire (JCQ), which included three dimensions: job control, job demand and social support. Glyco-lipid metabolic status was determined by the glyco-lipid allostatic load based on the allostasis paradigm and the concept of allostatic load. There were 11 parameters comprising the glyco-lipid allostatic load: body mass index (BMI); waist to hip ratio (WHR); high-density lipoprotein (HDL); low-density lipoprotein (LDL); total cholesterol (TC); triglyceride (TG); glycosylated haemoglobin (HbA1C); homeostasis model assessment-insulin resistance (HOMA-IR); HOMA-β-cell function; plasma concentrations of adiponectin; and visfatin. Score points were given for values in the high-risk quartile (0–11). Multivariate analysis of variance (MANOVA) revealed that BMI, WHR, TG, adiponectin, visfatin and glyco-lipid allostatic load were significantly different between high and low job stress groups after being adjusted for demographic characteristics and health-related behaviour. Plasma adiponectin levels were negatively correlated with BMI, WHR, HbA1C, TG, IR and visfatin, and positively correlated with HDL. Plasma concentration of visfatin was positively correlated with BMI, WHR, TC and IR. Multiple stepwise linear regression analysis indicated that job control was significantly related to glyco-lipid allostatic load, plasma adiponectin concentration and plasma visfatin concentration after controlling for demographic characteristics and health-related behaviour. In conclusion, we found association between job stress, job control and the glyco-lipid metabolism summary score. Plasma adiponectin and visfatin concentrations related with job stress and job control. Copyright © 2007 John Wiley & Sons, Ltd.
Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer

Objective Non-steroidal anti-inflammatory drug (NSAID) use decreases both the incidence of colorectal cancer and recurrence of adenomas among patients with prior colorectal neoplasia. However, few studies have investigated the association between NSAID use and colorectal cancer-specific survival. The role of prediagnostic NSAID use was therefore examined in relation to colorectal cancer-specific survival among cases from the Seattle Colon Cancer Family Registry (Seattle Colon CFR). Methods This was a follow-up study that included incident cases of colorectal cancer from the Seattle Colon CFR. Cases were aged 20–74, diagnosed from 1997 to 2002, and were identified using the population-based Puget Sound SEER registry. Detailed information on history of NSAID use, including type, recency and duration, was collected through an interviewer-administered questionnaire. Follow-up for mortality was completed through linkages to the National Death Index. The main outcome measure was death due to colorectal cancer after diagnosis. Cox proportional hazards regression was used to investigate the relationship between prediagnostic NSAID use and colorectal cancer-specific mortality among cases. Results NSAID use prior to colorectal cancer diagnosis was associated with an ∼20% lower rate of colorectal cancer mortality after diagnosis compared with never use (HR 0.79; 95% CI 0.65 to 0.97). This relationship appeared to be duration dependent, with longer reported use prior to diagnosis associated with lower rates of colorectal cancer mortality among cases. The most pronounced reductions in mortality were observed among cases diagnosed with proximal disease (HR 0.55; 95% CI 0.37 to 0.82), whereas no association was observed between NSAID use prior to diagnosis and colorectal cancer-specific mortality among cases diagnosed with distal or rectal disease. Conclusions The findings suggest that regular use of NSAIDs prior to diagnosis is associated with improved colorectal cancer survival, particularly among cases diagnosed with proximal disease and in longer term NSAID users.
Client Satisfaction with Transportation and Handyman/Chore Services in a Pilot Shared Cost-Service Coordination Program

Abstract This descriptive study investigates the validity and reliability of two new instruments to measure client satisfaction with transportation (TSM) and handyman/chore (HSM) services and determines the degree to which clients were satisfied with the transportation and handyman chore services that they received in a pilot cost share program. Reliability testing indicated that both the TSM and the HSM had high internal consistency with respective Chronbach's Alphas of . 73 and . 77. Validity testing with the TSM (r =.52, p < .01) and the HSM (r =.30, p =.05) also yielded significant positive correlations with their criterion measures. Thus, there is some evidence that the TSM and the HSM are methodologically sound instruments that can be used to evaluate client satisfaction with transportation and handyman chore services.
Unaffected reaction level in tuberculin skin test by long‐term therapy with tumor necrosis factor inhibitors for rheumatoid arthritis

The tuberculin skin test (TST) is used to diagnose tuberculosis; however, the influence of tumor necrosis factor (TNF) inhibitors on the test is unclear. This study investigated whether therapy with TNF inhibitors suppresses the TST reaction due to immunosuppression or whether the TST reaction increases due to reactivation of latent Mycobacterium tuberculosis infection.
Identifying the primary site of origin of MRI brain metastases from lung and breast cancer following a 2D radiomics approach

Detection of brain metastases in patients with undiagnosed primary cancer is unusual but still an existing phenomenon. In these cases, identifying the cancer site of origin is non-feasible by visual examination of magnetic resonance (MR) images. Recently, radiomics has been proposed to analyze differences among classes of visually imperceptible imaging characteristics. In this study we analyzed 46 T1-weighted MR images of brain metastases from 29 patients: 29 of lung and 17 of breast origin. A total of 43 radiomics texture features were extracted from the metastatic lesions. Support vector machine (SVM) and k-nearest neighbors (k-NN) classifiers were implemented to evaluate the classification performance. The influence of gray-level quantization for computation of texture features was also examined. The best classification (AUC = 0.953 ± 0.061), evaluated with nested cross-validation, was obtained using the SVM classifier with two texture features derived from the 16 gray-level quantization co-occurrence matrix.
Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response

Background and methods In advanced liver damage, hepatic regeneration can occur through proliferation of a resident hepatic progenitor cell (HPC) population. HPCs are located within a designated niche in close association with myofibroblasts and bone marrow (BM) derived macrophages. Extra-cellular matrix (ECM) laminin invariably surrounds HPCs, but the functional requirement of this matrix-cell association is untested in vivo. Using the collagen Iα1(r/r) mouse (r/r), which produces mutated collagen I resistant to matrix metalloproteinase degradation and has an exaggerated fibrotic response to liver injury, we test the relationship between collagen degradation, laminin deposition, and the HPC response. Results Chronic fibrotic carbon tetrachloride (CCl4) injury can induce a florid HPC response associated with dense laminin deposition. In the recovery phase after chronic CCl4 injury, r/r mice have a markedly attenuated HPC response compared to wild-types, together with persistence of collagen I and failure to deposit ECM laminin. Similar results were found in r/r mice given the choline-deficient ethionine supplemented diet, another model of the HPC response. In cross-over sex-mismatched BM transplantation (BMT) experiments between r/r mice and wild-types, the blunted HPC response of r/r mice was not rescued by wild-type BMT and likewise not conferred on to wild-type recipients by r/r BMT, demonstrating that the attenuated HPC response in r/r mice is a property intrinsic to the liver. Conclusion Failure of ECM remodelling after chronic fibrotic liver injury hinders the ability of the liver to activate HPCs. Laminin-progenitor cell interactions within the HPC niche are a critical for HPC mediated regeneration.
Origins of myelodysplastic syndromes after aplastic anemia.

To the editor: The course of aplastic anemia (AA) is often complicated by the development of clonal disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and secondary myelodysplastic syndromes (sMDS). [1][1][⇓][2][⇓][3][⇓][4]-[5][5] Identification of patients at risk for development of