Miracle-dz/UniFAR-FTUs huggingface dataset:
ADAMTS1 Promotes Adhesion to Extracellular Matrix Proteins and Predicts Prognosis in Early Stage Breast Cancer Patients.

BACKGROUND/AIMS Despite, several studies demonstrating pro-metastatic effects of the metalloproteinase ADAMTS1 in breast cancer, its role in facilitating the metastatic cascade remains unclear. To date there have been limited studies that have examined the expression of ADAMTS1 in primary and metastatic breast cancer tissues. METHODS We assessed ADAMTS1 mRNA levels in publically available breast cancer sets and analysed ADAMTS1 protein levels by immunohistochemistry in breast tissue microarrays containing normal breast tissue (n=9), primary invasive ductal breast carcinomas (n=79) and metastatic lesions (n=58). To understand the underlying events influenced by ADAMTS1 and provide a mechanism by which tumors expressing this protease promote metastasis, we assessed the ability of PyMT/Adamts1+/+, PyMT/Adamts1+/- and PyMT/Adamts1-/- primary mammary cancer cells to adhere to matrigel and migrate or invade towards a chemoattractive environment. RESULTS High ADAMTS1 expression was associated with reduced disease-free survival, distant metastasis free-survival and overall survival in breast cancer patients with node negative disease. Although ADAMTS1 expression was reduced in primary breast cancers compared to normal tissue and not elevated in metastatic lesions, high ADAMTS1 immunostaining was associated with a higher number of positive lymph nodes (p=0.006) and the presence of distant metastasis (p=0.023). Depletion of Adamts1 in mammary cancer cells impeded their adhesion to a biological matrix substratum and diminished cell migration but not invasion. CONCLUSION The effects observed on cell adhesion and migration demonstrates a potential mechanism whereby ADAMTS1 promotes breast cancer metastasis.
Endosome and Golgi‐associated degradation (EGAD) of membrane proteins regulates sphingolipid metabolism

Cellular homeostasis requires the ubiquitin‐dependent degradation of membrane proteins. This was assumed to be mediated exclusively either by endoplasmic reticulum‐associated degradation (ERAD) or by endosomal sorting complexes required for transport (ESCRT)‐dependent lysosomal degradation. We identified in Saccharomyces cerevisiae an additional pathway that selectively extracts membrane proteins at Golgi and endosomes for degradation by cytosolic proteasomes. One endogenous substrate of this endosome and Golgi‐associated degradation pathway (EGAD) is the ER‐resident membrane protein Orm2, a negative regulator of sphingolipid biosynthesis. Orm2 degradation is initiated by phosphorylation, which triggers its ER export. Once on Golgi and endosomes, Orm2 is poly‐ubiquitinated by the membrane‐embedded “Defective in SREBP cleavage” (Dsc) ubiquitin ligase complex. Cdc48/VCP then extracts ubiquitinated Orm2 from membranes, which is tightly coupled to the proteasomal degradation of Orm2. Thereby, EGAD prevents the accumulation of Orm2 at the ER and in post‐ER compartments and promotes the controlled de‐repression of sphingolipid biosynthesis. Thus, the selective degradation of membrane proteins by EGAD contributes to proteostasis and lipid homeostasis in eukaryotic cells.
Associations between carcass weight uniformity and production measures on farm and at slaughter in commercial broiler flocks

ABSTRACT In poultry flocks, flock weight uniformity is often defined as the percent individuals within 10% of the mean body weight (BW) and the variability of this uniformity can be expressed as the CV of BW. Flock weight uniformity is a standardized and objective measured, and could potentially be used as a welfare indicator; however, little is known about the relationship between flock uniformity and other production measures on-farm or at slaughter. The aim of this study was to investigate the associations between carcass weight uniformity (CV of BW) and production measures on-farm and at slaughter in Norwegian commercial broiler flocks. A total of 45 randomly selected mixed-sex Ross 308 broiler flocks were visited prior to slaughter at 28 to 30 D of age (average slaughter age 30.6 D). All flocks were raised under similar farm management systems. The Welfare Quality protocol for broilers was used to assess different animal welfare indicators in each flock. All production data from the slaughterhouse were collected for each flock, including carcass weight uniformity (%), mortality (%), growth rate (g), feed conversion ratio (FCR), and rejected birds (%) in different rejection categories. Univariable and multivariable linear regression models were used to investigate the associations between flock weight uniformity and production and welfare measures. The results showed that flock uniformity varied from 11% to 18% between flocks within the same hybrid, similar management standards, and similar slaughter age (day 29 to 32). Poorer uniformity (i.e., high CV) was associated with increased first week mortality (P < 0.004, r = 1.48, increased total mortality (P < 0.013, r = 0.01), increased FCR (i.e., less efficient growth) (P < 0.024, r = 0.06), reduced growth rate (P < 0.0012, r = −0.01), and a reduced rejection rate at slaughter (P < 0.006, r = −0.01). The results show that flock uniformity varies across broiler flocks, and is associated with several production measures.
Are neonatal clinical practice guidelines truly evidence‐based? A case for incorporating family values and preferences

Neonatologists take pride in practicing state-of-the-art medicine to care for newborns, particularly sick or premature newborns. Neonatologist aim to combine state of the art medicine with the principles and practice of evidence-based medicine (EBM). Evidence-based medicine involves two fundamental principles: First, the use of the best available evidence to guide clinical decision-making, ideally based on the hierarchy of evidence and, when multiple studies are available, unbiased systematic reviews. This article is protected by copyright. All rights reserved.
Plant water content integrates hydraulics and carbon depletion to predict drought-induced seedling mortality.

Widespread drought-induced forest mortality (DIM) is expected to increase with climate change and drought and is expected to have major impacts on carbon and water cycles. For large scale assessment and management, it is critical to identify variables that integrate the physiological mechanisms of DIM and signal risk of DIM. We tested whether plant water content, a variable that can be remotely sensed at large scales, is a useful indicator of DIM risk at the population level. We subjected Pinus ponderosa seedlings to experimental drought using a point of no return experimental design. Periodically during the drought, independent sets of seedlings were sampled to measure physiological state (volumetric water content [VWC], percent loss of conductivity [PLC] and non-structural carbohydrates) and to estimate population-level probability of mortality through re-watering. We show that plant VWC is a good predictor of population-level DIM risk and exhibits a threshold-type response that distinguishes plants at no risk from those at increasing risk of mortality. We also show that plant VWC integrates the mechanisms involved in individual tree death: hydraulic failure (PLC), carbon depletion across organs, and their interaction. Our results are promising for landscape-level monitoring of DIM risk.
Effect of anti-mu-specific immunosuppression on Friend virus leukemia.

Evidence is presented that neonatally initiated immunosuppression of BALB/c mice with rabbit anti-µ antiserum renders them refractory to Friend virus leukemia. Mice so treated failed to develop typical leukemic leukocytosis, splenomegaly, or splenic foci upon injection of 2.2 LD50 doses of Friend leukemia virus. A brief regimen of anti-µ treatment in young adult mice was shown to depress moderately the immune response against sheep red blood cells but to have no discernible effect upon the development of Friend virus leukemia. Several possible explanations for these observations are discussed.
Allodepleted T‐cell immunotherapy after haploidentical haematopoietic stem cell transplantation without severe acute graft‐versus‐host disease (GVHD) in the absence of GVHD prophylaxis

Graft‐versus‐host disease (GVHD) is a major cause of transplant‐related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T‐cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose‐finding study, 19 adults (median age: 54 years) with high‐risk haematological malignancies were treated with T‐cell‐depleted human leucocyte antigen‐haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 × 104–5 × 106 CD3+ cells/kg (median 31 days post‐transplant). No patient received post‐transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long‐term follow ‐up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0·3–2 × 106 CD3+ cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse‐related mortality was 33% and overall survival was 67% in these patients.
Family history of cancer and risk of esophageal and gastric cancers in the United States

The worldwide rates for histology‐ and subsite‐specific types of esophageal and gastric cancer reveal strikingly divergent patterns. The contribution of environmental and genetic factors has been explored in several high‐incidence areas, but data on genetic influences are scarce for Western countries. Using data from a multicenter, population‐based, case‐control study on 1,143 cases and 695 controls in the United States, we evaluated whether a family history of digestive or other cancers was associated with an increased risk of esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261) or non‐cardia gastric adenocarcinoma (n = 368). After adjusting for other risk factors, individuals reporting a family history of digestive cancers experienced no increased risk of either type of esophageal cancer but they were prone to adenocarcinomas of the gastric cardia [odds ratio (OR) = 1.34, 95% confidence interval (CI) 0.91–1.97] and non‐cardia segments (OR =1.46, 95% CI 1.03–2.08). This familial tendency, particularly for non‐cardia gastric tumors, was largely explained by an association with family history of stomach cancer (OR = 2.52, 95% CI 1.50–4.23). In addition, family history of breast cancer was associated with increased risks of esophageal adenocarcinoma (OR = 1.74, 95% CI 1.07–2.83) and non‐cardia gastric adenocarcinoma (OR = 1.76, 95% CI 1.09–2.82). Also seen were non‐significant familial associations of esophageal squamous‐cell cancer with prostate cancer as well as non‐cardia gastric cancer with leukemia and brain tumors, though these relationships must be interpreted with caution. Our data point to the role of familial susceptibility to gastric cancer, but not to any form of esophageal cancer, in the United States. © 2001 Wiley‐Liss, Inc.
Long‐term results of surgical resection of lung metastases from soft tissue sarcoma: A single center experience

A single‐institution experience of pulmonary metastasectomy in soft tissue sarcoma (STS) was retrospectively reviewed. Our specific aim was to examine, whether the resection of pulmonary metastases could be curative. We also compared overall survival (OS) of patients after complete or incomplete pulmonary resection and nonsurgical treatment.
Room Design—A Phenomenological-Hermeneutical Study

Medical technology has progressed tremendously over the last few decades, but the same development cannot be seen in the design of these intensive care unit environments. Authors report results of a study of evidence-based room design, emphasizing the impact on conveying a caring attitude to patients. Ten nonparticipant observations were conducted in patient rooms with 2 different designs, followed by interviews. The data were analyzed using a phenomenological-hermeneutical approach. The results did not reveal that it was obvious that redesigned spaces resulted in a more caring attitude. The meanings of caring displayed during nursing activities were interpreted by interpreting gazes. Some of the nursing staff had an instrumental gaze, interpreted as caring with a task-orientated approach, while others communicated their caring with an attentive and attuned gaze, where the needs of the patients regulated the working shift. The study findings indicated that caring may not be perceived when nurses use a task-oriented approach. However, when nurses practice a person-centered approach, using an attentive and attuned gaze, caring is conveyed. Caring in intensive care contexts needs to be assisted by a supportive environment design that cultivates the caring approach.
Meta-analysis of BRCA1 and BRCA2 penetrance.

PURPOSE Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis. METHODS We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach. RESULTS Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years were as follows: breast cancer risk of 57% (95% CI, 47% to 66%) for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2 mutation carriers; and ovarian cancer risk of 40% (95% CI, 35% to 46%) for BRCA1 and 18% (95% CI, 13% to 23%) for BRCA2 mutation carriers. We also report the prospective risks of developing cancer for currently asymptomatic carriers. CONCLUSION This article provides a set of risk estimates for BRCA1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study.
Cav1.4α1 Subunits Can Form Slowly Inactivating Dihydropyridine-Sensitive L-Type Ca2+ Channels Lacking Ca2+-Dependent Inactivation

The neuronal L-type calcium channels (LTCCs) Cav1. 2α1 and Cav1. 3α1 are functionally distinct. Cav1. 3α1 activates at lower voltages and inactivates more slowly than Cav1. 2α1, making it suitable to support sustained L-type Ca2+ inward currents (ICa,L) and serve in pacemaker functions. We compared the biophysical and pharmacological properties of human retinal Cav1. 4α1 using the whole-cell patch-clamp technique after heterologous expression in tsA-201 cells with other L-type α1 subunits. Cav1. 4α1-mediated inward Ba2+ currents (IBa) required the coexpression of α2δ1 and β3 or β2a subunits and were detected in a lower proportion of transfected cells than Cav1. 3α1. IBa activated at more negative voltages (5% activation threshold; -39mV; 15 mm Ba2+) than Cav1. 2α1 and slightly more positive than Cav1. 3α1. Voltage-dependent inactivation of IBa was slower than for Cav1. 2α1 and Cav1. 3α1(∼50% inactivation after 5 sec; α2δ1 + β3 coexpression). Inactivation was not increased with Ca2+ as the charge carrier, indicating the absence of Ca2+-dependent inactivation. Cav1. 4α1 exhibited voltage-dependent, G-protein-independent facilitation by strong depolarizing pulses. The dihydropyridine (DHP)-antagonist isradipine blocked Cav1. 4α1 with ∼15-fold lower sensitivity than Cav1. 2α1 and in a voltage-dependent manner. Strong stimulation by the DHP BayK 8644 was found despite the substitution of an otherwise L-type channel-specific tyrosine residue in position 1414 (repeat IVS6) by a phenylalanine. Cav1. 4α1 + α2δ1 + β channel complexes can form LTCCs with intermediate DHP antagonist sensitivity lacking Ca2+-dependent inactivation. Their biophysical properties should enable them to contribute to sustained ICa,L at negative potentials, such as required for tonic neurotransmitter release in sensory cells and plateau potentials in spiking neurons.
Optical Coherence Tomography Angiography (OCT-A) in young choroideremia (CHM) patients

ABSTRACT Purpose: To study OCT-A findings in young patients affected with CHM Methods: Young patients affected with CHM and age-matched control subjects were consecutively enrolled at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence. All patients underwent a complete ophthalmic examination including best-corrected visual acuity (BCVA), fundus autofluorescence (FA), optical coherence tomography (SS-OCT) and 3 × 3 mm swept-source OCT angiography (SS-OCTA). Superficial capillary plexus (SCP), deep capillary plexus (DCP) and OCT-A choriocapillaris slabs (CC) were processed using Imagej software to identify vessel density (VD). Results: Seven patients affected with CHM (14 eyes) and 7 age – matched control subjects (14 eyes) were included in our study. Visual acuity was 20/20 in all subjects. The detected CRT was significantly lower in the control group (212 ± 8,01 µm) in comparison with the patients (234 ± 53,7 µm), p < 0.01. The CC VD was reduced compared to controls (p < 0.01). Quantitative analysis of the inner retinal vasculature disclosed a significant impairment of both SCP (P < 0.01) and DCP (p < 0.01) vessel density compared to the control group. The FAZ area of the patients was smaller than controls (p < 0.01). Conclusion: OCT-A examinations revealed early vascular abnormalities in both inner retinal layers and choriocapillaris. A reduced vascular flow was also detectable in the presence of a preserved macular RPE at the color fundus, FA, and OCT examinations. OCT-A is clinically useful for evaluating early involvement of the retinal and choriocapillaris vascular network in choroideremia.
Evidence for intermediates during unfolding and refolding of a two-domain protein, phage T4 lysozyme: equilibrium and kinetic studies.

Equilibrium and kinetic studies of the unfolding-refolding of phage T4 lysozyme induced by guanidine hydrochloride are reported. Tryptophan fluorescence and circular dichroism (CD) were used as observables. Several results indicated the existence of intermediates in the unfolded-folded transition, including (1) the noncoincidence of the transition observed by fluorescence and CD, (2) the asymmetry of the transition recorded by CD, and (3) triphasic kinetics, followed by both observables, accounting for the forward and reverse processes. Our data were inconsistent with an independent unfolding or refolding of each domain. They indicated the existence of residual structured regions particularly resistant to denaturant, which involved one or more of the three tryptophans located in the C-terminal domain. Kinetic analysis has made it possible to propose a minimum pathway corresponding to a sequential refolding, with dead-end species arising from an intermediate. We compared our data with the experimental results of Elwell and Schellman [Elwell, M. , & Schellman, J.A. (1975) Biochim. Biophys. Acta 386, 309-313] and the theoretical analysis of B. Maigret (unpublished results) and proposed that the C-terminal domain refolds first, after which the overall structure can be formed and stabilized.
Immunodiagnosis of active tuberculosis

ABSTRACT Introduction: There is an unmet clinical need for improved diagnostic tests for active tuberculosis (TB) to provide high sensitivity for all cases, accelerate time to diagnosis and ensure timely and appropriate treatment. Whilst the measurement of M.tb-specific immune responses is widely used for detecting infection in the absence of TB symptoms (i.e. latent TB infection), there is currently no role for immunodiagnostics in active TB disease. This is primarily due to insufficient sensitivity, and an inability to discriminate between active disease and controlled, latent TB infection. Areas covered: In this review, we focus on recent developments in the use of immune-based tests to provide a point of care test for the rule-in or rule-out of active TB. Expert opinion: Recent studies have demonstrated that second-generation IGRAs have the potential to rule-out active TB, particularly in low burden settings. Newer technological platforms, including systems serology and flow cytometry, offer the means to measure specific M.tb specific immune signatures which have been shown to have a high level of accuracy for active TB. However, it is now crucial that new and promising test undergo validation in clinically relevant cohorts which include the full spectrum of TB patients and differential diagnoses.
Elementary purinergic Ca2+ transients evoked by nerve stimulation in rat urinary bladder smooth muscle

The translation of nerve transmission to Ca2+ signals in urinary bladder smooth muscle (UBSM) is incompletely understood. Thus, we sought to characterize Ca2+ signals in strips of UBSM loaded with the Ca2+‐sensitive fluorescent dye, fluo‐4, using laser scanning confocal microscopy. Two types of Ca2+ signals occurred spontaneously and could be evoked with field stimulation: large, rapid, global Ca2+ transients termed ‘global Ca2+ flashes’, and much smaller, localized Ca2+ transients. Global Ca2+ flashes were inhibited by the L‐type voltage‐dependent Ca2+ channel (VDCC) inhibitor, diltiazem and with P2X receptor blockade. Simultaneous intracellular recordings and Ca2+ measurements indicated that these events are caused by Ca2+ influx through VDCCs during action potentials. Small, local Ca2+ transients occurred spontaneously, and their frequency could be elevated with field stimulation. Atropine, an inhibitor of muscarinic receptors, did not affect these local Ca2+ transients. However, the desensitizing P2X receptor agonist α,β‐methylene ATP, and the purinergic antagonist, suramin, effectively inhibited the local Ca2+ transients. The frequency of these ‘purinergic Ca2+ transients’ was increased about 7‐fold by a 10 s stimulus train (1 Hz). The amplitude, duration at one‐half amplitude and the spatial spread of the evoked purinergic Ca2+ transients were F/Fo= 2.4 ± 0.13, 111.7 ± 9.3 ms and 14.0 ± 1.0 μm2, respectively. Tetrodotoxin inhibited evoked purinergic Ca2+ transients, indicating that they were dependent on nerve fibre activation. Purinergic Ca2+ transients were not dependent on VDCC activity. Neither 2‐APB, an inhibitor of inositol 1,4,5‐triphosphate (Ins(1,4,5)P3) (IP3)‐induced Ca2+ release, nor ryanodine inhibited the purinergic Ca2+ transients. We have identified two novel Ca2+ signals in rat UBSM. Large, rapid, global Ca2+ flashes that represent Ca2+ influx through VDCCs during action potentials, and local, purinergic Ca2+ transients that represent Ca2+ entry through P2X receptors. Our results indicate that purinergic Ca2+ transients evoked by release of ATP from nerve varicosities are elementary signals in the process of nerve‐smooth muscle communication.