Miracle-dz/UniFAR-FTUs huggingface dataset:
Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population

There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26±2y), healthy elderly (HEld) (n=15, 79±7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36±7y) and ESRD elderly (EnEld) (n=31, 65±3y) prior to Ktx regarding their naïve, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4+ memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required. (ClinicalTrials.gov number: NTC01631058).
A prospective multicenter observational study evaluating the risk of periendoscopic events in patients using anticoagulants: the Osaka GIANT Study

Abstract Background and study aims An increasing number of patients have been using anticoagulants including anti-vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs); however, in patients using anticoagulants, limited data are available with regard to the risks of gastrointestinal bleeding and thromboembolic events during the peri-endoscopic period. We aimed to evaluate the peri-endoscopic bleeding and thrombotic risks in patients administered VKAs or DOACs. Patients and methods Consecutive patients using anticoagulants who underwent endoscopic biopsy, mucosal resection, or submucosal dissection were prospectively enrolled across 11 hospitals. The primary outcome assessed was difference in incidence of post-procedural gastrointestinal bleeding in patients using VKAs and DOACs. Duration of hospitalization and peri-procedural thromboembolic events were also compared. Results We enrolled 174 patients using VKAs and 37 using DOACs. In total, 16 patients using VKA were excluded from the analysis because of cancellation of endoscopic procedures and contraindications to the use of DOACs; 128 (81 %) patients using VKAs and 17 (46 %) using DOACs received heparin-bridging therapy (HB). The rate of post-procedural gastrointestinal bleeding in DOAC users was similar to that in VKA users (16.2 % vs. 16.4 %, P = 1.000). Duration of hospitalization was significantly longer in patients using VKAs than in those using DOACs (median 15 vs. 7 days, P < 0.0001). Myocardial infarction occurred during pre-endoscopic HB in one patient using VKAs. Conclusion DOAC administration showed similar post-procedural gastrointestinal bleeding risk to VKA administration in patients undergoing endoscopic procedures, but it shortened the hospital stay.
Chronic Kidney Disease Is Linked to Carotid Nodular Calcification, An Unstable Plaque Not Correlated to Inflammation

The incidence and the different type of carotid calcifications, nodular and non-nodular, and their role in the acute cerebrovascular disease has not yet been defined. Various studies have correlated the presence of specific risk factors, in particular the chronic kidney disease, with the presence of calcification, but not with the type of calcification. Since it is likely that carotid nodular calcifications rather than those with non-nodular aspect may represent a plaque at high risk of rupture, the purpose of our study was to evaluate the role of nodular calcification in the pathogenesis of cerebrovascular syndromes and their possible correlation with specific risk factors. A total of 168 carotid plaques from symptomatic and asymptomatic patients submitted to endarterectomy, whom complete clinical and laboratory assessment of major cardiovascular risk factors was available, were studied. In 21 endarterectomies (5 from symptomatic and 16 from asymptomatic patients) an eruptive calcified nodule, consisting of calcified plates associated to a small amount of fibrous tissue without extracellular lipids and inflammatory cells, was found protruding into the lumen. Nodular calcifications were significantly observed in patients affected by chronic kidney disease (with GFR<60 ml / min / 1.73 m2), with a normal lipidic and glycemic profile. On the contrary, non-nodular calcification, mainly correlated to diabetes, were stable lesions. Results of our study suggest that the mechanisms and the clinical significance of carotid atherosclerotic calcification may be different. The nodular calcification could represent a type of unstable plaque, significantly related to chronic kidney disease, without inflammation, morphologically different from the classical vulnerable plaques.
Elevated Inflammatory Status and Increased Risk of Chronic Disease in Chronological Aging: Inflamm-aging or Inflamm-inactivity?

Age-associated hyper-inflammation or “inflamm-aging” has been linked to the development of chronic diseases and characterized as an unavoidable aspect of aging. However, the inflamm-aging model does not adequately address the potential anti-inflammatory effects of exercise training and the potential for exercise to ameliorate several age-related diseases. In this brief review, we introduce a new paradigm—inflamm-inactivity—that describes a potent counter-measure to age-associated inflammatory illness.
Inadequate steroid injection after esophageal ESD might cause mural necrosis

Abstract Background and study aims Locoregional triamcinolone acetonide (TAC) injection is increasingly used for prevention of stricture after extensive endoscopic submucosal dissection (ESD) for superficial esophageal neoplasia. However, the safety of intramural TAC injection has not been elucidated. The aim of this study was to assess the clinical courses and histopathological changes after TAC injection into the muscle layer in a porcine model. Methods Three pigs were subjected to ESD under general anesthesia. Two artificial 30-mm lesions were created at the oral and anal ends of the esophagus in each pig. TAC was injected into the muscle layer of the artificial oral ulcers (TAC group) and saline was injected into the muscle layer of the artificial anal ulcers (control group). Endoscopic, macroscopic, and histopathological evaluations were performed. Results The artificial ulcers remained open at sacrifice on day 28 post-ESD in the three ulcers injected with TAC. Esophageal wall perforation and abscess spreading to the mediastinum were observed in two of the three ulcers in the TAC group. The abscesses involved the lungs, bronchi, and aortic adventitia. Severe inflammatory cell infiltration in the muscularis propria layer and significant muscularis propria degradation were observed in all three ulcers in the TAC group. Conclusions This study suggests that TAC may cause deep mural damage when it is injected into the muscularis propria. Care should be taken not to inject TAC into the muscle layer when it is used to prevent post-ESD stricture formation.
Carbon dioxide versus room air for colonoscopy in deeply sedated pediatric patients: a randomized controlled trial

Abstract Background and study aims Use of carbon dioxide (CO2) instead of room air (RA) during colonoscopy in adults revealed significantly less flatulence and abdominal pain in several studies. The objectives of this study were to investigate the effects of CO2 usage on post-interventional pain, abdominal discomfort, abdominal girth, pCO2 levels, and narcotic requirement in deeply sedated pediatric patients. Patients and methods A total of 97 children and adolescents aged 4 years to 17 years undergoing colonoscopy were randomized to RA or CO2 in a prospective, randomized, controlled trial. Age-appropriate pain scales assessed abdominal pain as primary outcome. In addition, abdominal girth, abdominal bloating, transcutaneous pCO2, narcotic requirement to achieve deeply sedation, and post-procedural analgesic demand was analyzed in 73 patients. Results Overall, significantly fewer patients reported bloating in the CO2 group (P = 0.0012). However, we observed only a trend to lower post-interventional pain (P = 0.15) and a lower pain score. There was no significant difference in transcutaneous pCO2 level and no adverse events occurred. Although there was no difference in the dosage of propofol and midazolam, we observed a significant increased necessity for use of synthetic opioids in the RA group to achieve optimal examination conditions (P = 0.023). Conclusions The benefits using CO2 in colonoscopy of deeply sedated children predominate. In particular, CO2 insufflation may allow a less painful post-interventional time and it significantly reduces abdominal bloating. Moreover, with CO2, significantly less additional opioids were used. Thus, CO2 insufflation can be considered as safe in deeply sedated patients as there was no relevant pulmonary CO2 retention observed. (DRKS00013914)
Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies

Human malignancies are often the result of overexpressed and constitutively active receptor and non-receptor tyrosine kinases, which ultimately lead to the mediation of key tumor-driven pathways. Several tyrosine kinases (ie, EGFR, FGFR, PDGFR, VEGFR), are aberrantly activated in most common tumors, including leukemia, glioblastoma, gastrointestinal stromal tumors, non-small-cell lung cancer, and head and neck cancers. Iclusig™ (ponatinib, previously known as AP24534) is an orally active multi-tyrosine kinase inhibitor and is currently approved by the US Food and Drug Administration for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, specifically targeting the BCR-ABL gene mutation, T315I. Due to ponatinib’s unique multi-targeted characteristics, further studies have demonstrated its ability to target other important tyrosine kinases (FGFR, PDGFR, SRC, RET, KIT, and FLT1) in other human malignancies. This review focuses on the available data of ponatinib and its molecular targets for treatment in various cancers, with a discussion on the broader potential of this agent in other cancer indications.
A haplotype of the phosphodiesterase 4D (PDE4D) gene is associated with myocardial infarction and with cardiometabolic parameters: the GEA study

The phosphodiesterase family is involved in a wide spectrum of diseases, including ischemic stroke. However, few studies have analyzed the relationship between phosphodiesterase 4D (PDE4D) and myocardial infarction (MI). Therefore, the aim of this research was to evaluate the association of the PDE4D gene polymorphisms with MI, and with cardiometabolic parameters in the Mexican population. Six polymorphisms (rs2910829, rs1423246, rs966221, rs4502776, rs13172481, and rs6869495) were genotyped in 1023 MI patients and 1105 healthy controls. A similar distribution of the six polymorphisms was observed in both studied groups. However, after evaluating the linkage disequilibrium, we detected a risk haplotype for MI (AGAGAA; OR = 1.148; P = 0.025). In addition, the polymorphisms were associated with the presence of some clinical and metabolic parameters (central obesity, hypertriglyceridemia, Aspartate transaminase >p75, Lipoprotein (a) >30 mg/dL, TAT >p75, fatty liver, and vitamin D <30 ng/dL) in healthy controls. The results suggest that in the Mexican population, a PDE4D haplotype is associated with increased risk of developing MI, and that PDE4D polymorphisms are independently associated with the presence of cardiometabolic parameters.
Clinical characteristics, treatment outcomes and potential novel therapeutic options for patients with neuroendocrine carcinoma of the prostate

Background Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited. Methods Retrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017. Results Of 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years. Conclusions EP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.
Comprehensive characterization of the adult ND4 Swiss Webster mouse retina: Using discovery-based mass spectrometry to decipher the total proteome and phosphoproteome

Purpose Diverse groups of proteins play integral roles in both the physiology and pathophysiology of the retina. However, thorough proteomic analyses of retinas of experimental species are currently unavailable. The purpose of the present paper is providing the field with a comprehensive proteomic characterization of the retina of a commonly used laboratory mouse using a discovery-based mass spectrometry (MS) approach. Methods Retinas from eight male and eight female 30-week-old outbred ND4 Swiss Webster mice were harvested and immediately processed for MS analysis on a Thermo Fisher (TF) Fusion Orbitrap MS. The retinal proteome and phosphoproteome were identified and subsequently analyzed using Proteome Discoverer 2.2 and Panther-GeneGo. SEQUEST-HT scoring was used for analysis, and the reference protein FASTA database was from Mus musculus. Specifically, three technical repeats were performed for each biological sample. For characterization, only high-scoring peptides were considered, with a false discovery rate (FDR) of <1%. Downstream bioinformatic analysis used Ingenuity Pathway Analysis (IPA; Qiagen). Results Using Proteome Discoverer 2.2, 4,767 different proteins were identified and segregated into 26 major protein classes, 9 functional molecular classes, and 12 categories of biological processes. The five largest protein classes included the following: nucleic acid binding (17%), hydrolases (13%), enzyme modulators (10%), transferases (9%), and oxidoreductases (6%). “Binding” and “catalytic” proteins contributed to 81% of the molecular function class at 37% and 42%, respectively. “Cellular processing” and “metabolic processes” contributed the most to biologic activity, at 31% and 26%, respectively. Phosphopeptide enrichment yielded the identification of 610 additional unique proteins that were not originally identified. The two datasets combined produced an adult mouse retinal proteome consisting of 5,377 unique proteins. Overall, 41% of the retinal proteome was phosphorylated. The overwhelming diversity of retinal protein functionality was reflected through further analyses revealing 2,086 unique pathway hits across 241 different pathways (TF). A core analysis summary report was performed in IPA (Qiagen) to analyze the top signaling networks, protein–protein interaction (PPI) enrichments, and canonical pathways. Conclusions Using this high-throughput technique, we have further deciphered and updated the diverse proteome of the mouse retina, including the phosphoproteome, thereby providing the most comprehensive proteomic profile for this tissue known to date. These findings, and the bioinformatic analyses we also provided, establish a platform for future studies, facilitating the elucidation of the relevance of these proteins to the molecular and cellular pathologies that underlie retinal function and disease.
EULAR ‘points to consider’ for the conduction of workforce requirement studies in rheumatology

Objective Current methods used for forecasting workforce requirements in rheumatology are disparate, as are the parameters incorporated into workforce projection studies. The objective of these European League Against Rheumatism (EULAR points to consider (PTC) is to guide future workforce studies in adult rheumatology in order to produce valid and reliable manpower estimates. Methods The EULAR Standardised Operating Procedures were followed. A multidisciplinary task force with experts including patients with rheumatic diseases from 11 EULAR countries and the USA was assembled. A systematic literature review (SLR) was conducted to retrieve workforce models in rheumatology and other medical fields. PTC were based on expert opinion informed by the SLR, followed by group discussions with consensus obtained through informal voting. The level of agreement with the PTC was voted anonymously. Results A total of 10 PTC were formulated. The task force recommends models integrating supply (=workforce available in rheumatology), demand (=health services requested by the population) and need (=health services that are considered appropriate to serve the population). In general, projections of workforce requirements should consider all factors relevant for current and future workload in rheumatology inside and outside of direct patient care. Forecasts of workforce supply should consider demography and attrition of rheumatologists, as well as the effects of new developments in healthcare. Predictions of future need/demand should take demographic, sociocultural and epidemiological development of the population into account. Conclusion These EULAR-endorsed PTC will provide guidance on the methodology and the parameters to be applied in future national and international workforce requirement studies in rheumatology.
Bortezomib sensitizes multiple myeloma to NK cells via ER-stress-induced suppression of HLA-E and upregulation of DR5

ABSTRACT Although the proteasome inhibitor bortezomib has significantly improved the survival of patients with multiple myeloma (MM), the disease remains fatal as most patients eventually develop progressive disease. Recent data indicate that MM cells can evade bortezomib-induced cell death by undergoing autophagy as a consequence of endoplasmatic reticulum (ER)-stress induced by proteasome inhibition. Here we show that bortezomib sensitizes MM cells to NK cell killing via two distinct mechanisms: a) upregulation of the TRAIL death receptor DR5 on the surface of MM cells and b) ER-stress induced reduction of cell surface HLA-E. The latter mechanism is completely novel and was found to be exclusively controlled by the inhibitory receptor NKG2A, with NKG2A single-positive (NKG2ASP) NK cells developing a selective augmentation in tumor killing as a consequence of bortezomib-induced loss of HLA-E on the non-apoptotic MM cells. In contrast, the expression of classical HLA class I molecules remained unchanged following bortezomib exposure, diminishing the augmentation of MM killing by NK cells expressing KIR. Further, we found that feeder cell-based ex vivo expansion of NK cells increased both NK cell TRAIL surface expression and the percentage of NKG2ASP NK cells compared to unexpanded controls, substantially augmenting their capacity to kill bortezomib-treated MM cells. Based on these findings, we hypothesize that infusion of ex vivo expanded NK cells following treatment with bortezomib could eradicate MM cells that would normally evade killing through proteasome inhibition alone, potentially improving long-term survival among MM patients.
Age-related aqueous humor (AH) and lens epithelial cell/capsule protein carbonylation and AH protein concentration in cataract patients who have pseudoexfoliative diseases

Purpose The aim of this study is to investigate the age-correlation of oxidative stress (OS, assessed by the accumulative OS damage marker protein carbonyls) in aqueous humour (AH; together with protein concentration) and lens epithelial cells plus capsule (LECs/capsule) in patients with cataract (CAT), and also suffering from pseudoexfoliation syndrome (PEX), primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). Methods AH samples from 78 male/female patients (21, 20, 19 and 18 with CAT, PEX, PXG, and POAG, respectively), and LECs/capsule samples from 104 male/female patients (34, 32, 18, and 20 with CAT, PEX, PXG and POAG, respectively) were collected during phacoemulsification CAT surgery. Average protein carbonyl concentrations were measured in patients grouped in 5-year age intervals (ranging from 56-60 to 86-90). The non-overlapping age ranges and numbers of the tested subjects did not allow comparative follow up studies for the tested diseases. Results There is an age-dependent increase of protein carbonyls in AH (nmol mg-1 protein and ml-1), and in the order CAT<PXG=~POAG<PEX and CAT<PEX=~POAG<PXG respectively. Moreover, protein concentration in AH accumulates in the order CAT<PEX<POAG<PXG but is not age-related. An age-dependent increase of protein carbonyls (nmol mg-1 protein) is also observed in LECs/capsule, and in the order CAT<PEX=~POAG<PXG. Conclusions The present study shows for the first time an age-increased OS-induced protein damage (protein carbonyl formation) in the AH and LECs/capsule of CAT patients with PEX, POAG or PXG. The slow rate of change of protein carbonyls strongly suggests a long-term implication of OS in ocular disease pathogenesis. Additionally, protein concentration levels in the AH of CAT patients increase independently of age, and in same as with protein carbonyls increasing order levels for CAT<POAG<PXG in AH and LECs/capsule. This may suggest a protein cross-diffusion taking place between AH and LECs/capsule, most likely originating from PEX deposition and/or necrotic/apoptotic LECs/capsule. Moreover, the findings of the present study establish the use of protein carbonyls (together with a methodology for their more accurate quantification, which overcomes serious unreliability problems of past methods) as an age accumulative marker of OS damage, for future studies that investigate long-term OS involvement in pseudoexfoliative ocular disorders.