Miracle-dz/UniFAR-FTUs huggingface dataset:
Sickle cell disease: progress towards combination drug therapy

Dr. John Herrick described the first clinical case of sickle cell anaemia (SCA) in the United States in 1910. Subsequently, four decades later, Ingram and colleagues characterized the A to T substitution in DNA producing the GAG to GTG codon and replacement of glutamic acid with valine in the sixth position of the βS‐globin chain. The establishment of Comprehensive Sickle Cell Centers in the United States in the 1970s was an important milestone in the development of treatment strategies and describing the natural history of sickle cell disease (SCD) comprised of genotypes including homozygous haemoglobin SS (HbSS), HbSβ0thalassaemia, HbSC and HbSβ+thalassaemia, among others. Early drug studies demonstrating effective treatments of HbSS and HbSβ0thalassaemia, stimulated clinical trials to develop disease‐specific therapies to induce fetal haemoglobin due to its ability to block HbS polymerization. Subsequently, hydroxycarbamide proved efficacious in adults with SCA and was Food and Drug Administration (FDA)‐approved in 1998. After two decades of hydroxycarbamide use for SCD, there continues to be limited clinical acceptance of this chemotherapy drug, providing the impetus for investigators and pharmaceutical companies to develop non‐chemotherapy agents. Investigative efforts to determine the role of events downstream of deoxy‐HbS polymerization, such as endothelial cell activation, cellular adhesion, chronic inflammation, intravascular haemolysis and nitric oxide scavenging, have expanded drug targets which reverse the pathophysiology of SCD. After two decades of slow progress in the field, since 2018 three new drugs were FDA‐approved for SCA, but research efforts to develop treatments continue. Currently over 30 treatment intervention trials are in progress to investigate a wide range of agents acting by complementary mechanisms, providing the rationale for ushering in the age of effective and safe combination drug therapy for SCD. Parallel efforts to develop curative therapies using haematopoietic stem cell transplant and gene therapy provide individuals with SCD multiple treatment options. We will discuss progress made towards drug development and potential combination drug therapy for SCD with the standard of care hydroxycarbamide.
Integrating Lung Parenchyma Segmentation and Nodule Detection With Deep Multi-Task Learning

Lung parenchyma segmentation is valuable for improving the performance of lung nodule detection in computed tomography (CT) images. Traditionally, the two tasks are performed separately. This paper proposes a deep multi-task learning (MTL) approach to integrate these tasks for better lung nodule detection. Three new ideas lead to our proposed approach. First, lung parenchyma segmentation is used as the attention module and is combined with nodule detection in a single deep network. Second, lung nodule detection is performed in an anchor-free manner by dividing it into two subtasks, nodule center identification and nodule size regression. Third, a novel pyramid dilated convolution block (PDCB) is proposed to utilize the advantage of dilated convolution and tackle its gridding problem for better lung parenchyma segmentation. Based on these ideas, we design our end-to-end deep network architecture and corresponding MTL method to achieve lung parenchyma segmentation and nodule detection simultaneously. We evaluate the proposed approach on the commonly used Lung Nodule Analysis 2016 (LUNA16) dataset. The experimental results show the value of our contributions and demonstrate that our approach can yield significant improvements compared with state-of-the-art counterparts.
Reference intervals for selected haematological and biochemical parameters among apparently healthy adults in different eco-geographical zones in Ghana

Background Due to the influence of gender, race/genetics, age, lifestyle habits and geography on the references intervals (RIs), the Clinical and Laboratory Standards Institute (CLSI) recommends the determination of population-specific RIs. Ghana continues to depend on pre-established RIs from other countries which poses the risk of misdiagnoses and wrong treatment. This study presents the haemato-biochemical RIs from four eco-geographical zones in Ghana. Methods In this population-based cross-sectional study, a total of 1227 randomly selected healthy voluntary blood donors from the four eco-geographic zones (Coastal Savannah, Rain Forest, Savannah and Transitional) were enrolled and screened. Based on the CLSI Guidance Document C28A2992, the data of eligible participants were used to non-parametrically determine the RIs for the haemato-biochemical parameters at the 2.5th and 97.5th percentiles. Comparison of analytes by gender was done by Wilcoxon rank sum test and eco-geographic differences were assessed using the Kruskal-Wallis with the Dunn post hoc multiple comparison tests. Results There were statistically significant differences in most of the haematological parameters (RBC, Hb, HCT, MCV, PLT, WBC; p-values <0.0001 and MCH; p-value = 0.007), and biochemical analytes (Urea, Cr, Trig, HDL-C, AST, ALT, ALP, GGT, BID, BIT, Prot-T and Albumin; p-values <0.0001) based on gender. Significant inter eco-geographic (intra-population) variations and substantial differences between the established RI and the RIs accompanying the analyzers used were also observed. Conclusion This study reports significant inter-sex and inter-geographical differences in haemato-biochemical RIs in Ghana as well as differences in RIs with both the RIs accompanying the analyzers and those of other countries. Determining RIs representative of populations and including them in the report systems of laboratories to ensure effective and efficient healthcare service delivery is thus recommended.
Global metabolomic analysis of blood from mice infected with Brucella abortus

To better understanding Brucella abortus infection, serum metabolites of B. abortus-infected and -uninfected mice were analyzed and twenty-one metabolites were tentatively identified at 3 and 14 days post-infection (d.p.i.). Level of most lysophosphatidylcholines (LPCs) was found to increase in infected mice at 3 d.p.i. , while it was decreased at 14 d.p.i. as compared to uninfected mice. In contrast, acylcarnitines were initially reduced at 3 d.p.i then elevated after two-weeks of infection, while hydroxysanthine was increased at 14 d.p.i. in infected mice. Our findings suggest that the significant changes in LPCs and other identified metabolites may serve as potential biomarkers in acute phase of B. abortus infection.
Kv4.3 Channel Dysfunction Contributes to Trigeminal Neuropathic Pain Manifested with Orofacial Cold Hypersensitivity in Rats

Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K+ currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K+ channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain. SIGNIFICANCE STATEMENT Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K+ channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.
Quercetin ameliorates cytotoxic effects of zinc oxide nanoparticles on sertoli cells by enhancing autophagy and suppressing oxidative stress

Previous studies have demonstrated the toxic impacts of zinc oxide nanoparticles (ZO‐NPs) on male reproductive cells. The effect of quercetin (QCT) on ZO‐NPs‐induced mouse Sertoli cell (TM4 cell line) toxicity and its underlying mechanisms were investigated in this study. The TM4 cells were exposed to ZO‐NPs or QCT in different groups for 24 hr. The TM4 cells pre‐treated with 3MA (3‐Methyladenine, an autophagy inhibitor) to evaluate the autophagy role of QCT and ZO‐NPs in the TM4 cells. ZO‐NPs significantly reduced the viability percentage of the TM4 cells. The apoptosis percentage and Bax/Bcl‐2 ratio of the ZO‐NPs group were significantly increased, while the expression of autophagy‐related genes was considerably downregulated. ZO‐NPs also induced oxidative stress in the TM4 cells through increasing malondialdehyde contents and reactive oxygen species levels (ROS) and reducing antioxidant factors including superoxide dismutase, catalase, glutathione and glutathione peroxidase. In QCT + ZO‐NPs group, these events were considerably reversed. 3MA could significantly decrease the cell viability of TM4 cells exposed to the QCT and ZO‐NPs in comparison with the untreated 3MA groups. According to these results, the protective effects of QCT on ZO‐NPs‐exposed TM4 cells are related to inducing autophagy, prevention apoptosis and suppressing oxidative stress.
A study protocol for a feasibility trial of telephone‐delivered Adherence Therapy for adults with type 2 diabetes

Adherence therapy is a candidate intervention to improve medication adherence and clinical outcomes in patients with type 2 diabetes. The feasibility of conducting a trial of adherence therapy in this population has not been established. The objective of this study is therefore to test the feasibility of conducting a randomized controlled trial of adherence therapy in a Middle Eastern context.
TL1A: A New Potential Target in the Treatment of Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. In the last years, the development of biological agents targeting cytokines and receptors involved in IBD pathogenesis, has led to better outcomes and has improved the course of the disease. Despite their effectiveness, drugs such as tumor necrosis factor (TNF) inhibitors, anti-Interleukin-12/23 and anti-integrins, do not induce response in about one-third of patients and 40% of patients lose response over time, therefore more efficient therapies are required. Recent studies showed that TL1A (Tumor necrosis factor-like cytokine 1A) acts as a regulator of mucosal immunity and participates in immunological pathways, involved in the IBD pathogenesis. In this review article we analyze the role of TL1A as a new potential target therapy in IBD patients.
Cooperative self-assembly of squaraine dyes

A novel, highly soluble squaraine dye was synthesised in organic solvents by condensation of squaric acid with an appropriately functionalised donor unit and the aggregation behaviour of this squaraine in organic solvents was investigated in detail by concentration- and temperature-dependent UV/vis spectroscopy. The absorption band of this squaraine dye exhibits a hypsochromic shift of more than 100 nm upon aggregation, indicating a H-type excitonic coupling in aggregates. Our detailed studies reveal a cooperative aggregation process with K2 = 4.87 ± 0.13 × 104 M−1 for the dimerization and an elongation constant of K = 4.87 ± 0.13 × 105 M−1 according to the K2/K model. The thermodynamics of this process were investigated by applying Meijer's model of nucleation–elongation growth, which provided an elongation temperature of Te = 311 K with a molecular enthalpy release of he = −97 kJ mol−1 and a nucleus size of about two. Furthermore, the structural features of the aggregates were elucidated by AFM and spectroscopic methods, revealing the formation of extended supramolecular fibres.
A Novel Amperometric Urea Sensor

In a previous paper', an amperometric ammonia sensor based on an ammonium-ion selective PVCnitrobenzene-dibenzo-l 8-crown-6 (DB18C6) gel electrode has been reported. The electrode was covered with a gas-permeable Teflon membrane, with an internal-solution layer being sandwitched between the electrode and the membrane. In this study, an amperometric urea sensor was fabricated by immobilizing urease on the gas-permeable membrane surface of the amperometric ammonia sensor. ' Urea enzyme sensors based on potentiometric detection of ammonium ion2'3, ammonia gas4-6, carbon dioxide' and pH-changes have been reported. An amperometric urea enzyme sensor based on the pH dependence of electrochemical oxidation of hydrazine has also been reported.9"0 To the authors' knowledge, however, no sensor based on direct, amperometric detection of ammonium ion, as described in this paper, has yet been reported.
Effects of cooling or warming of the distal upper limb on skin vascular conductance and brachial artery shear profiles during cycling exercise

ABSTRACT The relative influence of skin vascular conductance in glabrous (G; palm) and non-glabrous (NG; dorsal and forearm) regions to upstream brachial artery-shear stress (BA-SS) profile are unknown. This study aimed to elucidate the effects of G and/or NG skin vascular conductance (VC), which were modulated by warming or cooling manipulation, on BA-shear rate (SR, an estimate of SS) during cycling exercise. Seven healthy subjects performed 60-min exercise. Between 20 and 50 min of the exercise, the NG+G or G skin region were warmed to 42°C or cooled to 15°C using a water bath. Throughout the protocol, diameter and blood velocity in BA and skin VCs in forearm and palm were measured. All measurements showed that a steady-state response was reached after 20 min of exercise. Subsequently, during cooling manipulation, forearm VC was significantly decreased, and the concomitant BA-SR profile was revealed (primarily characterized by decreased antegrade SR and increased retrograde SR) in the NG+G. Such changes were not observed in G alone. During warming manipulation, forearm VC and mean BA-SR significantly increased only in the NG+G. In conclusion, vascular response in NG skin possibly plays a major role in the modulation of BA-SS profile during cycling exercise.
Prevalence of Borrelia burgdorferi and Anaplasma phagocytophilum in Ixodid Ticks from Southeastern Ukraine

Objectives: Tick-borne diseases have emerged as an increasing medical problem in the world. Being the most prevalent ixodid ticks in Europe, Ixodes ricinus and Dermacentor reticulatus are responsible for transmission of numerous zoonotic pathogens (e.g., human granulocytic anaplasmosis and Lyme borreliosis). Despite their public health significance, studies on the prevalence of tick-borne agents are scare for Eastern Europe. The objective of this study was to examine the prevalence of Anaplasma phagocytophilum, Ehrlichia chaffeensis, and Borrelia burgdorferi sensu lato (B. burgdorferi s. l.) in ixodid ticks from Southeastern Ukraine. Methods: Over a 5-year period (2014–2018), 358 questing and 389 engorged ixodid ticks were collected from Southeastern Ukraine (Zaporizhzhya region). The ticks were identified as Dermacentor marginatus, D. reticulatus, I. ricinus, and Rhipicephalus rossicus. Nucleic acid samples extracted from tick pools were subjected to RT-PCR analyses for A. phagocytophilum, E. chaffeensis, and B. burgdorferi s. l. Results: The examined ixodid ticks tested negative for the aforementioned pathogens with the exception of I. ricinus ticks. For questing I. ricinus ticks, minimum infection rates of A. phagocytophilum and B. burgdorferi s. l. were, respectively, 4.2–7.7% and 8.6–12.7%. Conclusions: These findings will be valuable for medical and veterinary practitioners when risks associated with tick-borne diseases are assessed for southeastern regions of Ukraine.
Identification of Celastrol As a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A).

OBJECTIVE Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. CONCLUSIONS These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA.
A review of nanocarrier-mediated drug delivery systems for posterior segment eye disease: challenges analysis and recent advances

Abstract Posterior segment eye disease is a leading cause of irreversible vision impairment and blindness. As the unique organ for vision, eyes are protected by various protective barriers. The existence of physiological barriers and elimination mechanisms makes it challenging to treat the posterior segment eye diseases. To achieve efficient drug delivery to the posterior segment of eyes, different drug delivery systems have been proposed. Due to their abilities to enhance ocular tissue permeability, make controlled drug release and target retina, nanocarriers, such as lipid nanoparticles, liposomes and polymeric nanomicelles, have been widely studied for posterior segment drug delivery. However, clinical applications of nanocarrier mediated drug delivery systems as non-invasive ocular drops is still not ready. The delivery of nanocarrier-mediated drug for posterior segment disease still faces the choice of being more effective or more invasive for long-term treatment. Therefore, it is necessary to have a clear understanding of the barriers and the routes of ocular drug delivery while developing the delivery systems. In this review, types of ocular barriers and drug administration routes are categorised in a more intuitive way. Recent advances in nanocarrier mediated drug delivery systems with focus on posterior segment are reviewed with illustrative examples.
An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications

ABSTRACT Introduction Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of gluten. While presenting many similarities with other autoimmune diseases, celiac disease is unique in that the external trigger, gluten, and the genetic background necessary for disease development (HLA DQ2/DQ8) are well described. The prevalence of celiac disease is dramatically increasing over the years and new epidemiologic data show changes regarding age of onset and symptoms. A better understanding of CD-pathogenesis is fundamental to highlight the reasons of this rise of celiac diagnoses. Areas covered In this review we describe CD-pathogenesis by dissecting all the components necessary to lose tolerance to gluten (ingestion of gluten, genetic predisposition, loss of barrier function and immune response). Additionally, we also highlight the role that microbiome plays in celiac disease as well as new proposed therapies and experimental tools. Expert opinion Prevalence of autoimmune diseases is increasing around the world. As a result, modern society is strongly impacted by a social and economic burden. Given the unique characteristics of celiac disease, a better understanding of its pathogenesis and the factors that contribute to it may shed light on other autoimmune diseases for which external trigger and genetic background are not known.
Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype ( IDH wt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research. A recent small randomized phase III trial examined the benefit of an intensified lomustine-TMZ regimen for newly diagnosed MGMT promoter methylated glioblastoma. When combined with radiotherapy, median OS increased from 31.4 months with standard TMZ to 48.1 months with lomustine-TMZ. 144 Since the sample size was small (~70 patients in each arm), the survival curves separated late (after 2–3 y), and in univariate analysis the effect was small, the role of this regimen remains unclear. 172 Hematologic toxicity was greater in the lomustine-TMZ arm, and fewer patients were able to complete all 6 cycles of adjuvant treatment. 144