Miracle-dz/UniFAR-FTUs huggingface dataset:
Ampullary Large-Cell Neuroendocrine Carcinoma, a Diagnostic Challenge of a Rare Aggressive Neoplasm: A Case Report and Literature Review

Ampullary large-cell neuroendocrine carcinomas (LCNECs) are extremely rare, and available data are limited on case reports. They present with jaundice, non-specific abdominal pain, or weight loss, imitating adenocarcinoma. Their incidence increases due to the improved diagnostic techniques. However, preoperative diagnosis remains challenging. We report the case of a 70-year-old man with a history of metabolic syndrome, cholecystectomy, and right hemicolectomy, presenting with jaundice. Laboratory results showed increased liver biochemistry indicators and elevated CA 19-9. Esophagogastroduodenoscopy revealed an ulcerative tumor on the ampulla of Vater, and the biopsy revealed neuroendocrine carcinoma. Although computed tomography (CT) detected enlarged regional lymph nodes, the positron emission tomography (PET) showed a hyperactive lesion only in this area. Pylorus-preserving pancreatoduodenectomy with R0 resection was performed. Pathologic evaluation of the 3.1 × 1.9 cm tumor revealed an LCNEC with immunohistochemical positivity at Synaptophysin, EMA, CD56, and cytokeratin CK8/18. The Ki-67 index was 45%. Two out of the nine dissected lymph nodes were occupied by the neoplasm. The patient was discharged home free of symptoms, and adjuvant chemotherapy with carboplatin + etoposide was initiated. A comprehensive review of the reported cases showed that the preoperative biopsy result was different from the final diagnosis in few cases, regarding the subtypes. Conventional radiology cannot identify small masses, and other methods, such as endoscopy, magnetic resonance cholangiopancreatography (MRCP), and FDG-PET scan, might aid the diagnosis. Diagnosis is based on histology and immunohistochemical markers of the surgical specimens. The treatment of choice is pancreatoduodenectomy, followed by adjuvant chemotherapy. However, recurrence is frequent, and the prognosis remains poor.
Development of Fermented Shrimp Shell Product with Hypoglycemic and Hypolipidemic Effects on Diabetic Rats

In 2020, approximately 9.3 billion tons of crustaceans were consumed, and 45–48% of shrimp shell (SS) by-products were discarded as waste. In this study, the SS of Litopenaeus vannamei was fermented by Lactobacillus plantarum LV33204, Stenotrophomonas maltophilia LV2122 (strong proteolytic activity), and Aeromonas dhakensis LV1111 (chitin-degrading activity), and the optimal fermentation conditions of liquid-fermented SS was established. Contents of total peptide, astaxanthin, and total phenolic content of the fermented SS were significantly higher than that of unfermented SS. In the presence of fermented SS, glucose uptake and insulin resistance of TNF-α-stimulated FL83B hepatocytes were markedly improved. Furthermore, daily oral supplement of fermented SS to streptozotocin (STZ)/nicotinamide (NA)-induced diabetic rats for 7 weeks significantly reduced plasma glucose and insulin resistance. Meanwhile, ingestion of fermented SS might enhance hepatic catabolism of glucose by increasing hexokinase and glucose-6-phosphate dehydrogenase activity and decreasing glucose-6-phosphatase activity. In addition, the fermented SS downregulated plasma total cholesterol (TG), triglycerides (TCs), low-density lipoprotein cholesterol (LDL-C), liver TG, and TC and lipid peroxidation levels in diabetic rats. In conclusion, a biorefinery process for waste SS was established through mixed strain fermentation. The in vitro and in vivo data reveal that the fermented SS is a promising functional food for the management of diabetic hyperglycemia and hyperlipidemia.
Sex and Care: The Evolutionary Psychological Explanations for Sex Differences in Formal Care Occupations

Men and women exhibit clear differences in occupational choices. The present article elucidates sex differences in terms of formal care occupational choices and care styles based on evolutionary psychological perspectives. Broadly (1) the motivation to attain social status drives male preference for occupations that signals prestige and the desire to form interpersonal affiliation underlies female preference for occupations that involve psychosocial care for people in need; (2) ancestral sex roles leading to sexually differentiated cognitive and behavioral phenotypic profiles underlie present day sex differences in care styles where men are things-oriented, focusing on disease management while women are people-oriented, focusing on psychosocial management. The implications for healthcare and social care are discussed and recommendations for future studies are presented.
Spillovers and contagion between BRIC and G7 markets: New evidence from time-frequency analysis

We examine the time-frequency spillovers, contagion, and pairwise interrelations between the BRIC index and its constituents, and between BRIC and G7 economies. The extent of interdependencies between market blocs and their constituents needs to be ascertained in the time-frequency domain for efficient asset allocation and portfolio management. Accordingly, the Baruník and Křehlík spillover index is employed with daily data between 11th December 2015 and 28th May 2021. We find the overall and net spillovers between BRIC and G7 to be significant in the short-term, with France, Germany, and the UK transmitting the greatest shocks to BRIC markets. We find no significant evidence of any sporadic volatilities for the studied markets in the COVID-19 period across all frequencies. However, we reveal contagious spillovers between the BRIC and G7 economies across all time scales in 2017 and 2019, which respectively reflect the persistent effect of Brexit and the US-China trade tension. Our findings divulge that in the short-term (mid-to-long-term), France and the UK (Canada and the US), are the sources of contagion between the BRIC and G7 markets. From the net-pairwise spillovers, we report high connectedness between the BRIC index and its members. BRIC countries are found to be transmitters of net-pairwise spillovers to the G7 markets excluding Japan. We recommend portfolio diversification using BRIC and G7 stocks in the intermediate-to-long-term horizon, where spillovers are less concentrated. Additionally, since individual markets are impacted by their unique shocks, investors should pay close attention to these shocks when distributing assets. In the interim, policy-makers and governments across the globe should ensure effective liberalisation of their economies to encourage international trade flows to boost portfolio diversification.
Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure

Heart failure (HF) is an acute or chronic clinical syndrome that results in a decrease in cardiac output and an increase in intracardiac pressure at rest or upon exertion. The pathophysiology of HF is heterogeneous and results from an initial harmful event in the heart that promotes neurohormonal changes such as autonomic dysfunction and activation of the renin-angiotensin-aldosterone system, endothelial dysfunction, and inflammation. Cardiac remodeling occurs, which is associated with degradation and disorganized synthesis of extracellular matrix (ECM) components that are controlled by ECM metalloproteinases (MMPs). MMP-2 is part of this group of proteases, which are classified as gelatinases and are constituents of the heart. MMP-2 is considered a biomarker of patients with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). The role of MMP-2 in the development of cardiac injury and dysfunction has clearly been demonstrated in animal models of cardiac ischemia, transgenic models that overexpress MMP-2, and knockout models for this protease. New research to minimize cardiac structural and functional alterations using non-selective and selective inhibitors for MMP-2 demonstrates that this protease could be used as a possible pharmacological target in the treatment of HF.
Neutrophil Elastase Increases Vascular Permeability and Leukocyte Transmigration in Cultured Endothelial Cells and Obese Mice

Neutrophil elastase (NE) plays a pivotal role in inflammation. However, the mechanism underlying NE-mediated inflammation in obesity remains unclear. Here, we report that NE activates protease-activated receptor-2 (PAR2), stimulates actin filament (F-actin) formation, decreases intercellular junction molecule VE-cadherin expression, and increases the permeability of human arterial endothelial cells (hECs). NE also prompts degradation of VE-cadherin and its binding proteins p120- and β-catenins via MG132-sensitive proteasomes. NE stimulates phosphorylation of myosin light-chain (MLC) and its regulator myosin phosphatase target subunit-1 (MYPT1), a target of Rho kinase (ROCK). Inhibitors of PAR2 and ROCK prohibit NE-induced F-actin formation, MLC phosphorylation, and VE-cadherin reduction in hECs, and impede monocyte transmigration through hEC monolayer pretreated with either neutrophils or NE. Further, administration of an NE inhibitor GW311616A significantly attenuates vascular leakage, leukocyte infiltration, and the expression of proinflammatory cytokines in the white adipose tissue from high-fat diet (HFD)-induced obese mice. Likewise, NE-deficient mice are resistant to HFD-induced vascular leakage in the heart. Together, NE regulates actomyosin cytoskeleton activity and VE-cadherin expression by activating PAR2 signaling in the endothelial cells, leading to increased vascular permeability and leukocyte extravasation. Hence, inhibition of NE is a potential approach to mitigate vascular injury and leukocyte infiltration in obesity-related systemic inflammation.
STING mediates neuroinflammatory response by activating NLRP3‐related pyroptosis in severe traumatic brain injury

Long‐term neurological deficits after severe traumatic brain injury (TBI), including cognitive dysfunction and emotional impairments, can significantly impair rehabilitation. Glial activation induced by inflammatory response is involved in the neurological deficits post‐TBI. This study aimed to investigate the role of the stimulator of interferon genes (STING)–nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing‐3 (NLRP3) signaling in a rodent model of severe TBI. Severe TBI models were established using weight‐drop plus blood loss reinfusion model. Selective STING agonist ADU‐S100 or antagonist C‐176 was given as a single dose after modeling. Further, NLRP3 inhibitor MCC950 or activator nigericin, or caspase‐1 inhibitor VX765, was given as an intracerebroventricular injection 30 min before modeling. After that, a novel object recognition test, open field test, force swimming test, western blot, and immunofluorescence assays were used to assess behavioral and pathological changes in severe TBI. Administration of C‐176 alleviated TBI‐induced cognitive dysfunction and emotional impairments, neuronal loss, and inflammatory activation of glia cells. However, the administration of STING agonist ADU‐S100 exacerbated TBI‐induced behavioral and pathological changes. In addition, STING activation exacerbated pyroptosis‐associated neuroinflammation via promoting glial activation, as evidenced by increased cleaved caspase‐1 and GSDMD N‐terminal expression. In contrast, the administration of C‐176 showed anti‐pyroptotic effects. The neuroprotective effects of C‐176 were partially reversed by the NLRP3 activator, nigericin. Collectively, glial STING is responsible for neuroinflammation post‐TBI. However, pharmacologic inhibition of STING led to a remarkable improvement of neuroinflammation partly through suppressing NLRP3 signaling. The STING–NLRP3 signaling is a potential therapeutic target in TBI‐induced neurological dysfunction.
Role of corneal radius of curvature in early identification of fundus tessellation in children with low myopia

Aim To assess the role of the corneal radius of curvature (CR) in the identification of fundus tessellation in children with low myopia. Methods In the cross-sectional study, students aged 9–12 years from 24 primary schools in Shanghai were enrolled by cluster sampling. Participants underwent measurements including cycloplegic refraction and axial length. Fundus images and choroidal thickness were obtained by swept-source optical coherence tomography. Fundus tessellation was classified into four grades according to fundus photographs. Results A total of 1127 children with low myopia (spherical equivalence (SE) >−3.00 dioptre (D) but ≤−0.50 D) were included, with a mean age of 10.29±0.60 years and a mean SE of −1.44±0.69 D. Fundus tessellation was found in 591 (52.4%) cases (grade 1: 428, 38.0%; grade 2: 128, 11.4%; grade 3: 35, 3.1%). Choroidal thickness decreased as fundus tessellation grade increased (p trend <0.001). According to regression analysis, higher fundus tessellation grade was independently associated with larger CR (OR, 7.499; 95% CI 2.279 to 24.675, p=0.001). For those with CR >7.9 mm, along with CR, degree and proportion of fundus tessellation increased sharply. Conclusion Fundus tessellation existed in more than half of children with low myopia. Preliminary fundus photography conducted in children with low myopia with large CR would be necessary and beneficial to the early management of myopic fundus changes. Trial registration number NCT02980445.
Recombinant human chorionic gonadotropin induces signaling pathways towards cancer prevention in the breast of BRCA1/2 mutation carriers

Background Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. Methods We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. Results We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/β-catenin signaling, MYC, HMGA1, and HOTAIR, whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. Conclusion Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.
2022 Consensus statement on the management of familial hypercholesterolemia in Korea

Familial hypercholesterolemia (FH) is the most common monogenic disorder. Due to the marked elevation of cardiovascular risk, the early detection, diagnosis, and proper management of this disorder are critical. Herein, the 2022 Korean guidance on this disease is presented. Clinical features include severely elevated low-density lipoprotein cholesterol (LDL-C) levels, tendon xanthomas, and premature coronary artery disease. Clinical diagnostic criteria include clinical findings, family history, or pathogenic mutations in the LDLR, APOB, or PCSK9. Proper suspicion of individuals with typical characteristics is essential for screening. Cascade screening is known to be the most efficient diagnostic approach. Early initiation of lipid-lowering therapy and the control of other risk factors are important. The first-line pharmacological treatment is statins, followed by ezetimibe, and PCSK9 inhibitors as required. The ideal treatment targets are 50% reduction and < 70 or < 55 mg/dL (in the presence of vascular disease) of LDL-C, although less strict targets are frequently used. Homozygous FH is characterized by untreated LDL-C > 500 mg/dL, xanthoma since childhood, and family history. In children, the diagnosis is made with criteria, including items largely similar to those of adults. In women, lipid-lowering agents need to be discontinued before conception.
COMPARATIVE EFFECTIVENESS OF ROBOT-ASSISTED TRAINING VERSUS ENHANCED UPPER EXTREMITY THERAPY ON UPPER AND LOWER EXTREMITY FOR STROKE SURVIVORS: A MULTICENTRE RANDOMIZED CONTROLLED TRIAL

Objective Robot-assisted neuro-rehabilitation therapy plays a central role in upper extremity recovery of stroke. However, the efficacy of robotic training on the upper extremity is not yet well defined, and little attention has been devoted to its potential effect on the lower extremity. The aim of this study was to compare the efficacy of robot-assisted training and therapist-mediated enhanced upper extremity therapy on the upper and lower extremities. Methods A randomized clinical trial involving 172 stroke survivors was conducted in China. All participants received either robot-assisted training or enhanced upper extremity therapy for 3 weeks. Fugl-Meyer assessment upper extremity subscale (FMA-UE), Fugl-Meyer assessment lower extremity subscale (FMA-LE), and Modified Barthel Index were administered at baseline, mid-treatment (1 week after treatment start), and post-treatment. Results Participants in the robot-assisted training group showed a significant improvement in the hemiplegia extremity, which was non-inferior to the enhanced upper extremity therapy group in FMA-UE (p < 0.05), while suggesting greater motor recovery of lower extremity in FMA-LE (p < 0.05) compared with the enhanced upper extremity therapy group. A marked increase in Modified Barthel Index was observed within groups; however, no significant difference was found between groups. Conclusion Robot-assisted training is non-inferior but not better in reducing impairment of the upper extremity and appears to be superior in reducing impairment of the lower extremity compared with enhanced upper extremity therapy for stroke survivors. LAY ABSTRACT Although post-stroke robot-assisted training of the upper extremity has been widely studied, its efficacy is not yet well defined, and its effects on the lower extremity are unknown. This study aimed to evaluate the effects of upper extremity robot-assisted training on the upper and lower extremities in stroke survivors. Robot-assisted training is non-inferior in improving the function of the upper extremity and superior in improving the function of the lower extremity compared with enhanced upper extremity therapy. Robot-assisted training can be used for functional recovery of the upper and lower extremities in stroke survivors.
Screening for Gestational Diabetes Mellitus and Pregnancy Outcomes: Results from a Multicentric Study in Tajikistan

Abstract The prevalence of gestational diabetes parallels the prevalence of type 2 diabetes mellitus and is associated with adverse pregnancy outcomes. However, these data are not available for many parts of the world. We assessed the prevalence of gestational diabetes and pregnancy outcomes in Tajikistan. This cohort study included 2438 consecutively recruited representative pregnant women from 8 locations in two cities in Tajikistan, in whom an oral glucose tolerance test (75 g, fasting, 1 h, 2 h) was performed during gestational weeks 24–28. Women with known diabetes and twin pregnancies were excluded. Associations between glucose tolerance test results and pregnancy outcomes were examined. According to the WHO 2013 thresholds, 32.4% of women qualified as having gestational diabetes, the vast majority (29.7%) based on an elevated fasting glucose level (5.1–5.6 mmol/L), while only 2.8% had elevated 1- or 2-hour values or met more than one threshold. Women with only elevated fasting glucose (impaired gestational fasting glycemia) had no evidence of adverse pregnancy outcomes, while those with elevated 1- and/or 2-hour values (impaired gestational glucose tolerance) had more pregnancy complications (infection of urinary tract 1.8 vs. 8.8% p<0.001; preeclampsia 0.7 vs. 10.3% p<0.001) and emergency cesarean sections (4.4 vs. 13.2% p=0.002). Neonates from pregnancies with impaired gestational glucose tolerance had lower APGARs, lower birth weights, lower 30 min glucose levels, and a lower probability of being discharged alive (all p<0.05). In conclusion, the formal prevalence of gestational diabetes is high in Tajikistan; however, this does not translate into adverse pregnancy outcomes for women with impaired gestational fasting glycemia.
Annual Review Of Nuclear And Particle Science

The contents of this review reflect some of the shifts of emphasis that are occurring among the fields of astrophysics, nuclear physics, and elementary particle physics. Particle physics has made great advances in the unification of the fundamental forces of nature. Discussions and planning for a next big step in accelerator-colliders are presented. The technology of superconducting magnet systems as well as the fundamental physical principles of particle accelerators are discussed. Also presented are: high-resolution electronic particle detectors; nuclear physics changes such as pion interactions within nuclei; discussion of future relativistic heavy-ion colliders; the role of rotational degrees of freedom in heavy-ion collisions at low and moderate energies; hyperon beta decays; and the analysis of materials via nuclear reaction techniques. Neutrinos, their interactions and possible masses, have an important bearing on cosmology and the matter density of the universe in addition to their inherent interest in the microscopic world and this is also examined.
Paroxetine Increases δ Opioid Responsiveness in Sensory Neurons

Abstract There are currently no Food and Drug Administration (FDA)-approved δ-opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and nonhuman primates compared with traditional μ-opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in noninflammatory pain patients (Stein et al., 1989). It was recently identified that G-protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in noninflamed nociceptors (Brackley et al., 2016, 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor (SSRI) and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine’s effects on GRK2 in vivo are limited to peripheral tissues in the male rat. The effects of paroxetine on DOR competence are notably antagonized by GRK2 overexpression. This is the first study to suggest that paroxetine induces peripheral DOR analgesic competence through a GRK2-dependent mechanism, improving analgesic efficacy in noninflamed tissue. Because paroxetine targets the protein that governs peripheral opioid receptor responsiveness, and does so in the absence of inflammation, we propose that paroxetine may be suitable as a co-therapy with peripherally-restrictive doses of opioids to improve analgesic efficacy in noninflammatory pain conditions.