Miracle-dz/UniFAR-FTUs huggingface dataset:
Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.
Molecular Epizootiology of Toxoplasma gondii and Cryptosporidium parvum in the Eastern Oyster (Crassostrea virginica) from Maine (USA)

Shellfish are known as a potential source of Toxoplasma gondii (responsible for toxoplasmosis), and Cryptosporidium parvum, which is one of the major causes of gastroenteritis in the world. Here we performed a comprehensive qPCR-based monthly survey for T. gondii and C. parvum during 2016 and 2017 in oysters (Crassostrea virginica) (n = 1440) from all six sites along the coast of Maine (USA). Pooled samples (mantle, gills, and rectum) from individual oysters were used for DNA extraction and qPCR. Our study resulted in detections of qPCR positives oysters for T. gondii and C. parvum at each of the six sites sampled (in 31% and 10% of total oysters, respectively). The prevalence of T. gondii was low in 2016, and in September 2017 several sites peaked in prevalence with 100% of the samples testing positive. The prevalence of C. parvum was very low except in one estuarine location (Jack’s Point) in June 2016 (58%), and in October of 2016, when both prevalence and density of C. parvum at most of the sampling sites were among the highest values detected. Statistical analysis of environmental data did not identify clear drivers of retention, but there were some notable statistically significant patterns including current direction and nitrate along with the T. gondii prevalence. The major C. parvum retention event (in October 2016) corresponded with the month of highest dissolved oxygen measurements as well as a shift in the current direction revealed by nearby instrumentation. This study may guide future research to locate any contributing parasite reservoirs and evaluate the potential risk to human consumption.
Intestinal resection rates in Crohn’s disease decline across two different epidemiological areas: a consistent observation not merely due to introduction of anti-TNFα

With great interest we have read the manuscript written by Murthy et al , published in Gut in June 2019, on the influence of anti-tumour necrosis factor alpha (TNFα) therapy introduction on the rate of hospitalisation and intestinal resection rates in IBD.1 Despite the difference in the source of data between both studies (Canada: health administrative data and the Netherlands: nationwide pathology database), a declining rate of intestinal resections in Crohn’s disease has been confirmed in Canada, at equal rates as the decline that has been observed in the Netherlands.2 The authors used an advanced statistical method to …
Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value Peff) has been widely used to determine the rate and extent of the drug’s intestinal absorption (Fabs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting Fabs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal Peff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.
Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors

ABSTRACT Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (<10 min). Calcium-induced actin assembly is INF2 dependent and Arp2/3 complex independent, whereas depolarization-induced actin assembly is Arp2/3 complex dependent and INF2 independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as ‘clouds’ around depolarized mitochondria. We have previously shown that calcium-induced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1 (also known as DNM1L). In contrast, depolarization-induced actin is temporally associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent on the protease OMA1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics. This article has an associated First Person interview with the first author of the paper. Highlighted Article: Mitochondrial depolarization induces Arp2/3 complex-dependent actin clouds that restrain OMA1-induced mitochondrial shape changes. A distinct actin network stimulates calcium-induced mitochondrial fission.
The Effect of Low and High Dose Deoxynivalenol on Intestinal Morphology, Distribution, and Expression of Inflammatory Cytokines of Weaning Rabbits

Deoxynivalenol (DON) is a potential pathogenic factor to humans and animals, and intestinal tract is the primary target organ of DON. Data concerning the effects of DON on rabbits are scarce, especially for weaning rabbits. In this study, 45 weaning rabbits (35 d) were randomly and equally assigned into three groups. Group A was fed basic diet, while groups B and C were added DON at 0.5 mg/kg BW/d and 1.5 mg/kg BW/d, respectively, based on the basic diet. The experiment lasted for 24 days and the intestinal morphology, expression, and distribution of several cytokines in intestinal segments have been examined. The results indicated that ADG decreased while F/G increased significantly compared with the control group after DON added at 1.5 mg/kg BW/d. Some of the morphometric parameters (villi length, crypt depth, and goblet cells density) changed after DON was added. Meanwhile, the concentration as well as the expression levels of relative protein and mRNA of IL-1β, IL-2, IL-6, and IL-8 increased significantly. The immunohistochemistry results illustrated that the quantity and distribution of positive cells of inflammatory cytokines were changed after DON was added. In conclusion, the addition of DON damaged the intestinal morphology and changed the distribution and expression of inflammatory cytokines. The toxic effect depended on the dosage of DON.
Prenatal Testosterone Exposure Alters GABAergic Synaptic Inputs to GnRH and KNDy Neurons in a Sheep Model of Polycystic Ovarian Syndrome.

Prenatal testosterone (T) treated female sheep display reproductive deficits similar to women with polycystic ovary syndrome (PCOS), including an increase in luteinizing hormone (LH) pulse frequency due to actions of the central gonadotropin-releasing hormone (GnRH) pulse generator. Here we used multiple-label immunocytochemistry to investigate the possibility of changes in the GABA neurotransmitter system at two key components of the GnRH pulse generator in prenatal T sheep: Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus, and GnRH neurons in the preoptic area (POA) and medial basal hypothalamus (MBH). We observed a significant decrease and increase, respectively, in the number of GABAergic synapses onto POA and MBH GnRH neurons in prenatal T ewes; in addition, there was a significant increase in the number of GABAergic inputs onto KNDy neurons. To determine the actions of GABA upon GnRH and KNDy neurons, we examined co-localization with the chloride transporters, NKCC1 and KCC2, which indicate stimulatory or inhibitory activation of neurons by GABA, respectively. The majority of GnRH neurons in both POA and MBH co-localized NKCC1 transporters while none contained the KCC2 transporter. A majority of KNDy neurons co-localized either NKCC1 or KCC2, and 28% of the KNDy population contained NKCC1 alone. Therefore, we suggest that, as in the mouse, GABA in the sheep is stimulatory to GnRH neurons, as well as to a subset of KNDy neurons. Increased numbers of stimulatory GABAergic inputs to both MBH GnRH and KNDy neurons in prenatal T animals may contribute to alterations in steroid feedback control and increased GnRH/LH pulse frequency seen in this animal model of PCOS.
Spatial memory shapes migration and its benefits: evidence from a large herbivore.

From fine-scale foraging to broad-scale migration, animal movement is shaped by the distribution of resources. There is mounting evidence, however, that learning and memory also guide movement. Although migratory mammals commonly track resource waves, how resource tracking and memory guide long-distance migration has not been reconciled. We examined these hypotheses using movement data from four populations of migratory mule deer (n = 91). Spatial memory had an extraordinary influence on migration, affecting movement 2-28 times more strongly than tracking spring green-up or autumn snow depth. Importantly, with only an ability to track resources, simulated deer were unable to recreate empirical migratory routes. In contrast, simulated deer with memory of empirical routes used those routes and obtained higher foraging benefits. For migratory terrestrial mammals, spatial memory provides knowledge of where seasonal ranges and migratory routes exist, whereas resource tracking determines when to beneficially move within those areas.
Bilateral simultaneous acute anterior interosseous neuropathy after treatment with rituximab

Anterior interosseous nerve (AIN) neuropathy can be caused by a fracture or crush injury resulting in compression of the nerve. It can also occur as a transient neuritis. The etiology is not yet understood. Damage to this nerve affects the patient's ability to flex the distal phalanx of the thumb and index and middle fingers. The nerve carries no cutaneous sensory fibres. Rituximab is a chimeric monoclonal antibody that acts against CD20 antigen in B-lymphocytes to suppress an immune response. It is used to treat some hematological malignancies and autoimmune conditions such as myasthenia gravis. It has not been previously reported to cause isolated AIN damage. Infusion reactions occur in 77% of patients with nonHodgkin lymphoma during their first exposure to rituximab, with symptoms including fever, angioedema, hypotension, bronchospasm, and rash.
Association between birth weight and childhood cardiovascular disease risk factors in West Virginia

Abstract The reported associations between birth weight and childhood cardiovascular disease (CVD) risk factors have been inconsistent. In this study, we investigated the relationship between birth weight and CVD risk factors at 11 years of age. This study used longitudinally linked data from three cross-sectional datasets (N = 22,136) in West Virginia; analysis was restricted to children born full-term (N = 19,583). The outcome variables included resting blood pressure [systolic blood pressure (SBP), diastolic blood pressure (DBP)] and lipid profile [total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL, and triglycerides (TG)]. Multiple regression analyses were performed, adjusting for child’s body mass index (BMI), sociodemographics, and lifestyle characteristics. Unadjusted analyses showed a statistically significant association between birth weight and SBP, DBP, HDL, and TG. When adjusted for the child’s BMI, the association between birth weight and HDL [b = 0.14 (95% CI: 0.11, 0.18) mg/dl per 1000 g increase] and between birth weight and TG [b = –0.007 (–0.008, –0.005) mg/dl per 1000 g increase] remained statistically significant. In the fully adjusted model, low birth weight was associated with higher LDL, non-HDL, and TGs, and lower HDL levels. The child’s current BMI at 11 years of age partially (for HDL, non-HDL, and TG) and fully mediated (for SBP and DBP) the relationship between birth weight and select CVD risk factors. While effects were modest, these risk factors may persist and amplify with age, leading to potentially unfavorable consequences in later adulthood.
β-Estradiol Protects Against Acidosis-Mediated and Ischemic Neuronal Injury by Promoting ASIC1a (Acid-Sensing Ion Channel 1a) Protein Degradation.

Background and Purpose- Sex differences in the incidence and outcome of stroke have been well documented. The severity of stroke in women is, in general, significantly lower than that in men, which is mediated, at least in part, by the protective effects of β-estradiol. However, the detailed mechanisms underlying the neuroprotection by β-estradiol are still elusive. Recent studies have demonstrated that activation of ASIC1a (acid-sensing ion channel 1a) by tissue acidosis, a common feature of brain ischemia, plays an important role in ischemic brain injury. In the present study, we assessed the effects of β-estradiol on acidosis-mediated and ischemic neuronal injury both in vitro and in vivo and explored the involvement of ASIC1a and underlying mechanism. Methods- Cultured neurons and NS20Y cells were subjected to acidosis-mediated injury in vitro. Cell viability and cytotoxicity were measured by methylthiazolyldiphenyl-tetrazolium bromide and lactate dehydrogenase assays, respectively. Transient (60 minutes) focal ischemia in mice was induced by suture occlusion of the middle cerebral artery in vivo. ASIC currents were recorded using whole-cell patch-clamp technique while intracellular Ca2+ concentration was measured with fluorescence imaging using Fura-2. ASIC1a expression was detected by Western blotting and quantitative real-time polymerase chain reaction. Results- Treatment of neuronal cells with β-estradiol decreased acidosis-induced cytotoxicity. ASIC currents and acid-induced elevation of intracellular Ca2+ were all attenuated by β-estradiol treatment. In addition, we showed that β-estradiol treatment reduced ASIC1a protein expression, which was mediated by increased protein degradation, and that estrogen receptor α was involved. Finally, we showed that the level of ASIC1a protein expression in brain tissues and the degree of neuroprotection by ASIC1a blockade were lower in female mice, which could be attenuated by ovariectomy. Conclusions- β-estradiol can protect neurons against acidosis-mediated neurotoxicity and ischemic brain injury by suppressing ASIC1a protein expression and channel function.
Atherosclerosis in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) are at an increased risk of premature mortality, mainly from cardiovascular causes. The association between CKD on hemodialysis and accelerated atherosclerosis was described >40 years ago. However, more recently, it has been suggested that the increase in atherosclerosis risk is actually observed in early CKD stages, remaining stable thereafter. In this regard, interventions targeting the pathogenesis of atherosclerosis, such as statins, successful in the general population, have failed to benefit patients with very advanced CKD. This raises the issue of the relative contribution of atherosclerosis versus other forms of cardiovascular injury such as arteriosclerosis or myocardial injury to the increased cardiovascular risk in CKD. In this review, the pathophysiogical contributors to atherosclerosis in CKD that are shared with the general population, or specific to CKD, are discussed. The NEFRONA study prospectively assessed the prevalence and progression of subclinical atherosclerosis (plaque in vascular ultrasound), confirming an increased prevalence of atherosclerosis in patients with moderate CKD. However, the adjusted odds ratio for subclinical atherosclerosis increased with CKD stage, suggesting a contribution of CKD itself to subclinical atherosclerosis. Progression of atherosclerosis was closely related to CKD progression as well as to the baseline presence of atheroma plaque, and to higher phosphate, uric acid, and ferritin and lower 25(OH) vitamin D levels. These insights may help design future clinical trials of stratified personalized medicine targeting atherosclerosis in patients with CKD. Future primary prevention trials should enroll patients with evidence of subclinical atherosclerosis and should provide a comprehensive control of all known risk factors in addition to testing any additional intervention or placebo.
Remote photonic sensing of cerebral hemodynamic changes via temporal spatial analysis of acoustic vibrations

A novel photonic method for remote monitoring of task‐related hemodynamic changes in human brain activation is presented. Physiological processes associated with neural activity, such as nano‐vibrations due to blood flow and tissue oxygenation in the brain, are detected by remote sensing of nano‐acoustic vibrations using temporal spatial analysis of defocused self‐interference random patterns. Temporal nanometric changes of the speckle pattern due to visual task‐induced hemodynamic responses were tracked by this method. Reversing visual checkerboard stimulation alternated with rest epochs, and responsive signals were identified in occipital lobe using near‐infrared spectroscopy. Temporal vibrations associated with these hemodynamic response functions were observed using three different approaches: (a) single spot illumination at active and control areas simultaneously, (b) subspots cross‐correlation‐based analysis, and (c) multiwavelength measurement using a magnitude‐squared wavelet coherence function. Findings show remote sensing of task‐specific neural activity in the human brain.
Current advances in BCG-unresponsive non-muscle invasive bladder cancer

ABSTRACT Introduction: The current first line therapy for high grade (HG) non-muscle invasive bladder cancer (NMIBC) is intravesical Bacillus Calmette–Guerin (BCG). Patients who recur or progress despite BCG are recommended to undergo radical cystectomy or participate in clinical trials. There is an urgent need for alternative therapies in the BCG-unresponsive NMIBC realm. Areas covered: We queried clinicaltrials.gov and pubmed.gov for current and recently completed early clinical trials pertaining to investigational agents used for the treatment of BCG-unresponsive NMIBC. These included intravesical chemotherapy, immunotherapy, vaccines, gene therapy, viruses, and agents used with novel drug delivery methods. In this article, we discuss the treatment guidelines for non-muscle invasive bladder cancer and therapeutic approaches under investigation in clinical trials. Expert opinion: The FDA is currently allowing single-arm studies as a pathway for approval in BCG-refractory patients with CIS. Although many agents are currently undergoing testing, none have been approved since Valrubicin. Hopefully, we will identify therapies sufficiently effective and durable to achieve FDA approval. Other considerations in this realm include the use of biomarkers in NMIBC to identify patients who will most likely respond to specific interventions. In addition, as systemic agents such as checkpoint inhibitors, are studied further, a multidisciplinary approach may be needed to treat this subset of patients
Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy

Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.