Miracle-dz/UniFAR-FTUs huggingface dataset:
ROS-Mediated Necroptosis Is Involved in Iron Overload-Induced Osteoblastic Cell Death

Excess iron has been reported to lead to osteoblastic cell damage, which is a crucial pathogenesis of iron overload-related osteoporosis. However, the cytotoxic mechanisms have not been fully documented. In the present study, we focused on whether necroptosis contributes to iron overload-induced osteoblastic cell death and related underlying mechanisms. Here, we showed that the cytotoxicity of iron overload in osteoblastic cells was mainly due to necrosis, as evidenced by the Hoechst 33258/PI staining, Annexin-V/PI staining, and transmission electronic microscopy. Furthermore, we revealed that iron overload-induced osteoblastic necrosis might be mediated via the RIPK1/RIPK3/MLKL necroptotic pathway. In addition, we also found that iron overload was able to trigger mitochondrial permeability transition pore (mPTP) opening, which is a critical downstream event in the execution of necroptosis. The key finding of our experiment was that iron overload-induced necroptotic cell death might depend on reactive oxygen species (ROS) generation, as N-acetylcysteine effectively rescued mPTP opening and necroptotic cell death. ROS induced by iron overload promote necroptosis via a positive feedback mechanism, as on the one hand N-acetylcysteine attenuates the upregulation of RIPK1 and RIPK3 and phosphorylation of RIPK1, RIPK3, and MLKL and on the other hand Nec-1, siRIPK1, or siRIPK3 reduced ROS generation. In summary, iron overload induced necroptosis of osteoblastic cells in vitro, which is mediated, at least in part, through the RIPK1/RIPK3/MLKL pathway. We also highlight the critical role of ROS in the regulation of iron overload-induced necroptosis in osteoblastic cells.
Benefits and Barriers to Increasing Regional Anesthesia in Resource-Limited Settings

Abstract Safe and accessible surgical and anesthetic care is critically limited for over half of the world’s population, particularly in Sub-Saharan African and Southeast Asian countries. Increasing the use of regional anesthesia in these areas has potential benefits regarding access, safety, and cost-effectiveness. Perioperative anesthesia-related mortality is significantly higher in resource-limited countries and every effort should be made to encourage the use of anesthetic techniques in these countries that are safest under the present conditions. Studies from Sub-Saharan Africa, although limited in number, have shown a lower risk of death with regional compared to general anesthesia. Regional anesthesia has the further benefit of decreasing the risk of COVID-19 spread to healthcare providers by avoiding the aerosol-generating procedures that occur during general anesthesia. Neuraxial regional anesthesia is relatively easy to teach and perform and is considered the anesthetic of choice for surgeries below the umbilicus in resource-limited settings due to its safety, efficacy, and low cost. Although regional anesthesia has multiple potential advantages, education and training of anesthetic providers in low-and-middle-income countries (LMIC) are a significant barrier to growth. Anesthesia professionals, especially in Sub-Saharan Africa, are often poorly supported and undervalued, and recruitment and retention of adequate numbers of trained practitioners are a continuing problem. Greater use of regional anesthesia could be one way to safely increase anesthesia access and simultaneously create value and enthusiasm for the field. Deficits in anesthesia infrastructure, equipment, and drugs also limit anesthesia capacity in low-and middle-income countries. Ultrasound-guided regional anesthesia may be helpful in improving access to safe and reliable anesthesia in low-resource countries as it continues to become more user-friendly, durable, and affordable.
Treatment trends in oral lichen planus and oral lichenoid lesions (Review)

Oral lichen planus (OLP) is a chronic inflammatory disease, associated with altered cell-mediated immunological function. It has long-term evolution, repeated exacerbations, sometimes painful and resistant to treatment, even all of these, OLP significantly affects patient's life quality. Not least, OLP is accompanied by an increased risk of malignant transformation. A wide spectrum of therapeutic options is available, but none are curative. In this review, 58 structured studies on the clinical symptomatology and treatment strategy of OLP were analyzed. The literature research was performed according to the criteria of the PRISMA system. This study summarizes current knowledge regarding management of OLP and oral lichenoid lesions, discusses the challenges of choosing an adequate treatment and, in attempt to improve the quality of patient life, trying to describe a therapeutic algorithm that takes into consideration the clinical features of the disease. Current OLP therapy aims at eliminating all mucosal-related lesions, reduce symptomatology and decrease the risk of oral cancer and include corticosteroids, immunomodulatory agents, retinoids, ultraviolet irradiation and/or laser therapy.
Upregulation of CFTR Protects against Palmitate-Induced Endothelial Dysfunction by Enhancing Autophagic Flux

Saturated free fatty acids (FFAs) elevate in metabolic symptom leading to endothelial dysfunction. Cystic fibrosis transmembrane regulator (CFTR) functionally expresses in endothelial cells. The role of CFTR in FFA-induced endothelial dysfunction remains unclear. This study is aimed at exploring the effects of CFTR on palmitate- (PA-) induced endothelial dysfunction and its underlying mechanisms. We found that PA-induced endothelial dysfunction is characterized by a decrease of cell viability, reduction of NO generation and mitochondrial membrane potential, impairment of the tube formation, but an increase of ROS generation and cell apoptosis. Simultaneously, PA decreased CFTR protein expression. CFTR agonist Forskolin upregulated CFTR protein expression and protected against PA-induced endothelial dysfunction, while CFTR knockdown exacerbated endothelial dysfunction induced by PA and blunted the protective effects of Forskolin. In addition, PA impaired autophagic flux, and autophagic flux inhibitors aggravated PA-induced endothelial apoptosis. CFTR upregulation significantly restored autophagic flux in PA-insulted endothelial cells, which was involved in increasing the protein expression of Atg16L, Atg12-Atg5 complex, cathepsin B, and cathepsin D. In contrast, CFTR knockdown significantly inhibited the effects of Forskolin on autophagic flux and the expression of the autophagy-regulated proteins. Our findings illustrate that CFTR upregulation protects against PA-induced endothelial dysfunction by improving autophagic flux and underlying mechanisms are involved in enhancing autophagic signaling mediated by the Atg16L-Atg12-Atg5 complex, cathepsin B, and cathepsin D. CFTR might serve as a novel drug target for endothelial protection in cardiovascular diseases with a characteristic of elevation of FFAs.
Gonadotropin Glycoforms Circulating in Women Using Progestins of the Levonorgestrel Family for Contraception

Abstract Context The progestins of the levonorgestrel family are 13-ethylgonane progestins, commonly used for contraception in women. One contraceptive effect of these progestins is inhibition of ovulation, which may be a result of changes in gonadotropin glycosylation patterns. Gonadotropin glycoforms differ in number of glycans and bioactivity: more bioactive low-N-glycosylated glycoforms, diglycosylated luteinizing hormone (LHdi) and triglycosylated follicle-stimulating hormone (FSHtri), and less bioactive fully N-glycosylated glycoforms, LHtri and FSHtetra. Objective Characterize the glycosylation patterns on the circulating gonadotropin glycoforms in women using 13-ethylgonane progestins for contraception. Design, Subjects, Main Outcome Measures Serum samples, collected from 92 healthy women using 13-ethylgonane progestins for contraception, were included. Forty women used progestin-only continuously and 52 used progestins combined with ethinylestradiol (EE) for 3 weeks followed by a hormone-free week. Concentration, sulfonation, and sialylation of each glycoform were determined and compared with follicular phase values of normal menstrual cycles. Results The progestin-only group had significantly increased serum levels, decreased sulfonation, and increased sialylation of LHdi. The LHdi/FSHtri ratio was increased. The progestin+EE group had significantly decreased gonadotropin glycoform concentrations and decreased sialylation of FSHtri. The progestin+EE effect on sialylation of FSHtri occurred later during the treatment cycle in contrast to the effect on FSHtri concentration. Conclusions The 2 different progestin treatments induced different effects on the glycan synthesis and concentrations of more bioactive low-glycosylated gonadotropins. Progestin-only treatment increased sialylation and decreased sulfonation of LHdi molecules, contributing to sustained higher levels of bioactive LHdi molecules. Progestin+EE treatment decreased sialylation of FSHtri, contributing to a shorter half-life and decreased levels of bioactive FSHtri.
Cetuximab-Coated Thermo-Sensitive Liposomes Loaded with Magnetic Nanoparticles and Doxorubicin for Targeted EGFR-Expressing Breast Cancer Combined Therapy

Background One major limitation of cancer chemotherapy is a failure to specifically target a tumor, potentially leading to side effects such as systemic cytotoxicity. In this case, we have generated a cancer cell-targeting nanoparticle-liposome drug delivery system that can be activated by near-infrared laser light to enable local photo-thermal therapy and the release of chemotherapeutic agents, which could achieve combined therapeutic efficiency. Methods To exploit the magnetic potential of iron oxide, we prepared and characterized citric acid-coated iron oxide magnetic nanoparticles (CMNPs) and encapsulated them into thermo-sensitive liposomes (TSLs). The chemotherapeutic drug, doxorubicin (DOX), was then loaded into the CMNP-TSLs, which were coated with an antibody against the epidermal growth factor receptor (EGFR), cetuximab (CET), to target EGFR-expressing breast cancer cells in vitro and in vivo studies in mouse model. Results The resulting CET-DOX-CMNP–TSLs were stable with an average diameter of approximately 120 nm. First, the uptake of TSLs into breast cancer cells increased by the addition of the CET coating. Next, the viability of breast cancer cells treated with CET-CMNP-TSLs and CET-DOX-CMNP-TSLs was reduced by the addition of photo-thermal therapy using near-infrared (NIR) laser irradiation. What is more, the viability of breast cancer cells treated with CMNP-TSLs plus NIR was reduced by the addition of DOX to the CMNP-TSLs. Finally, photo-thermal therapy studies on tumor-bearing mice subjected to NIR laser irradiation showed that treatment with CMNP-TSLs or CET-CMNP-TSLs led to an increase in tumor surface temperature to 44.7°C and 48.7°C, respectively, compared with saline-treated mice body temperature ie, 35.2°C. Further, the hemolysis study shows that these nanocarriers are safe for systemic delivery. Conclusion Our studies revealed that a combined therapy of photo-thermal therapy and targeted chemotherapy in thermo-sensitive nano-carriers represents a promising therapeutic strategy against breast cancer.
miR-425-5p Acts as a Molecular Marker and Promoted Proliferation, Migration by Targeting RNF11 in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and dangerous malignant tumors in China, which causes a large number of deaths every year. MicroRNAs (miRNAs) dysfunction contributes to the malignant progression of tumors. The aim of our study was to investigate the relationship between the biological role of miR-425-5p and malignant progression of HCC. Our results showed that miR-425-5p expression was significantly upregulated in HCC tissues and closely related to the poor prognosis of HCC patients. The knockdown of miR-425-5p inhibited cell proliferation and migration. Further, we identified RNF11 as the downstream target gene of miR-425-5p. In addition, the rescue experiments showed that the upregulation of RNF11 could rescue the inhibitory effect of miR-425-5p on HCC. In general, miR-425-5p as an oncogene promotes the malignant development of HCC via RNF11 and serves as a molecular target for predicting the prognosis of HCC patients.
Combination of Dabrafenib and Trametinib for the Treatment of Relapsed and Refractory Multiple Myeloma Harboring BRAF V600E Mutation

Multiple myeloma (MM) is an incurable plasma cell neoplasia characterized by relapsed and/or refractory (R/R) disease course, which poses a major therapeutic challenge. New therapies, including BRAF V600E mutation targeting, may become a new treatment option for R/R MM. In combination with mitogen-activated protein kinase inhibitors (MEKi), BRAF inhibitors (BRAFi) could provide better tailored clinical management, although experience in this field is lacking. To this date, there is only one case describing R/R MM treatment with BRAFi vemurafenib and MEKi cobimetinib. This is the first case presenting a R/R MM patient treated with BRAFi dabrafenib and MEKi trametinib.
Factors Associated with Episiotomy Practices in Bahirdar City, Ethiopia: A Cross-Sectional Study

Background Episiotomy is the surgical enlargement of the vaginal orifice during the last part of the second stage of labor or childbirth by an incision to the perineum. The World Health Organization advises the use of episiotomy on a restricted and selective basis. Indeed, the rate of episiotomy in developed countries is decreasing, but in developing countries, including Ethiopia, it still remains high. Therefore, this study tried to assess the proportion and factors associated with episiotomy among women who gave birth at Felege Hiwot Referral Hospital, Bahir Dar City, North West Ethiopia, 2017. Methods An institution-based cross-sectional study was conducted among 411 mothers from February to April 2017. Data were collected through face-to-face interviews and supported by observation using standard checklist with systematic random sampling technique. Data was entered by Epi Info and analyzed by SPSS version 23. The association between variables was analyzed using bivariable and multivariable logistic regression model. P-value <0.05 at 95% CI was considered to be statistically significant. Results The proportion of episiotomy was 41.1% with 95% CI (36.5%, 46.2%). Multivariable logistic regression showed that primiparity (AOR=6.026, 95% CI (3.542,10.253)), prolonged second stage of labor (AOR=4.612, 95% CI (2.247,9.465)), instrument delivery (AOR =3.933, 95% CI (1.526,10.141)), using oxytocin (AOR=2.608, 95% CI (1.431,4.751)), medical resident attendant (AOR =3.225, 95% CI (1.409,7.382)) and birth weight ≥4000 grams (AOR=5.127,95% Cl (1.106,23.772)) were significantly associated with episiotomy practice. Conclusion The proportion of episiotomy was high. Parity, using oxytocin, second-stage labor duration, instrument delivery, birth weight, and delivery attendant were statistically significant factors for episiotomy practice. Therefore, as per our findings, we suggest awareness creation, and the setting and use of new national guidelines, the practice of routine episiotomy should be abandoned, and selective and restrictive use of episiotomy is highly advised.
Examining the central effects of chronic stressful social isolation on rats

Stress-related disorders are extremely complex and current treatment strategies have limitations. The present study investigated alternative pathological mechanisms using a combination of multiple environmental approaches with biochemical and molecular tools. The aim of the present study was to evaluate blood-brain-barrier (BBB) integrity in socially manipulated animal housing conditions. Multiple environmentally-related models were employed in the current study. The main model proposed (chronically isolated rats) was biochemically validated using the level of peripheral corticosterone. The current study examined and compared the mRNA levels of certain inflammatory and BBB markers in the hippocampal tissue of chronically isolated rats, including claudin-5 (cldn5) and tight junction protein (tjp). Animals were divided into four groups: i) Standard housed rats (controls); ii) chronically isolated rats; iii) control rats treated with fluoxetine, which is a standard selective serotonin reuptake inhibitor; and iv) isolated rats treated with fluoxetine. To further examine the effect of environmental conditions on BBB markers, the current study assessed BBB markers in enriched environmental (EE) housing and short-term isolation conditions. The results demonstrated a significant increase in cldn5 and tjp levels in the chronically isolated group. Despite some anomalous results, alterations in mRNA levels were further confirmed in EE housing conditions compared with chronically isolated rats. This trend was also observed in rats subjected to short-term isolation compared with paired controls. Additionally, levels of IL-6, an inflammatory marker associated with neuroinflammation, were markedly increased in the isolated group. However, treatment with fluoxetine treatment reversed these effects. The results indicated that BBB integrity may be compromised in stress-related disorders, highlighting a need for further functional studies on the kinetics of BBB in stress-related models.
Plasma soluble PD-L1 and STAT3 predict the prognosis in diffuse large B cell lymphoma patients

Purpose: Diffuse large B cell lymphoma (DLBCL) is one of the most common B cell lymphomas, which displays heterogeneous pathologies. Programmed cell death 1/ programmed cell death ligand 1 (PD-1/PD-L1) plays an essential role in immunosuppression in multiple malignancies. Signal transducer and activator of transcription 3 (STAT3)-positive patients also have an independently inferior clinical outcome. However, there are no reports on the effect of plasma soluble PD-L1 (sPD-L1) combined with plasma STAT3 on the prognosis of DLBCL. In this study, we investigate the relationships between plasma sPD-L1 combined with STAT3 and clinical prognosis of DLBCL. Methods: Levels of plasma sPD-L1 and STAT3 were quantified using ELISA in eighty-seven DLBCL patients. Multiplexed immunofluorescence staining was performed to visualize the expression of PD-L1 in twenty-nine matched FFPE specimens from all patients. Results: The survival analysis revealed that the progression-free survival (PFS) and overall survival (OS) in high sPD-L1 level group were poorer than that in low sPD-L1 level group (PFS, P < 0.001; OS, P < 0.001). Similarly, the PFS and OS in high STAT3 level group were also poorer than that in low STAT3 level group. Multivariate cox regression analysis showed that both high sPD-L1 and high STAT3 levels were the independent prognostic factors negatively affecting survival. In addition, patients with DLBCL having high levels of both sPD-L1 and STAT3 had a worse outcome than those patients having any one high or low levels of both (P < 0.001). Conclusions: We therefore revealed that high levels of plasma sPD-L1 and STAT3 are associated with inferior outcome for DLBCL patients, suggesting that combined measurement of their levels in plasma may be a promising prognostic strategy for DLBCL patients.
Incidence and Risk Factors of Depressive Symptoms in Chinese College Students

Purpose Previous surveys have shown an increase in the prevalence of depression among college students. However, knowledge on the incidence and risk factors of depressive symptoms in Chinese college students is limited. The aim of the present study was to determine the two-year cumulative incidence of depressive symptoms in Chinese college freshmen and identified related psychosocial risk factors. Patients and Methods A prospective survey was used to examine the cumulative incidence and risk factors of depressive symptoms (as assessed by the Centre for Epidemiological Study-Depression Scale, CES-D) among undergraduate freshmen. Five times (baseline, 5, 12, 17, and 24 months later) of self-reported data were collected from the students. Results Of the initial 758 non-depressed respondents at baseline, 235 developed depressive symptoms (CES-D ≥ 16) during the follow-up period. The two-year cumulative incidence was estimated to be 42% and not significantly different between males and females (χ2=3.138, df =1, p=0.077). Logistic regression model showed that female gender (OR=0.43, 95% CI (0.28–0.64)), high level of self-esteem (OR=0.67, 95% CI (0.52–0.86)), and moderate exercise (OR=0.71, 95% CI (0.55–0.92)) reduced the onset of depressive symptoms; while high levels of baseline anxiety (OR=1.48, 95% CI (1.12–1.94)), Eysenck Personality Questionnaire-Neuroticism (OR=1.40, 95% CI (1.09–1.79)), concern over mistakes (OR=1.35,95% CI (1.07–1.71)), daytime sleepiness (OR=1.28, 95% CI (1.02–1.60)), mild exercise (OR=1.25, 95% CI (1.01–1.55)) increased the new onset of depressive symptoms. Conclusion The high two-year cumulative incidence indicates that depressive symptoms are an important mental problem in Chinese college students. The present findings on the risk factors of depressive symptoms in Chinese college students may be useful for the design of student health screening and intervention programs.
Plantain (Plantago lanceolata) reduces the environmental impact of farmed red deer (Cervus elaphus)1

Abstract The objective of this study was to evaluate the effect of plantain (Plantago lanceolata L.) on water dynamics and balance, as well as nitrogen (N) excretion by red deer (Cervus elaphus L.) as a potential forage tool to reduce negative environmental impacts. This experiment used a crossover design with red deer (n = 8) in metabolism crates to determine how fresh-cut herbage diets of either plantain or ryegrass (Lolium perenne L.) compared in terms of dry matter intake (DMI), diet digestibility, water dynamics, and N dynamics. Deer consuming plantain had greater water intake from herbage (P < 0.01) compared with ryegrass. Additionally, when fed plantain, deer had greater water excretion from urine (P < 0.01; 69.4%) and feces (P < 0.01; 29.4%) and, thus, total water excretion (P < 0.01; 61.7%) than when fed ryegrass. When consuming plantain, deer had greater DMI (P = 0.02; +11.2%) and fecal output (P < 0.01; +36.8%) and lower apparent dry matter digestibility (P = 0.03; −8.3%) compared with ryegrass. Plantain (15.9%) contained 30% less crude protein than ryegrass (22.8%) so that even with the greater DMI of plantain, plantain had lower (P < 0.01; −23%) N intake (g/d). Deer consuming plantain had lower urine N concentration (P < 0.01) than when consuming ryegrass. Additionally, deer consuming plantain had much less daily urine N (P < 0.01; −34.9%) excretions. Our results indicate deer fed plantain had greater DMI, ingested more water, and excreted more water than those consuming ryegrass, with lower urinary N (UN) concentration and lesser daily urine N excretion. Thus, we conclude that offering red deer plantain may reduce the environmental impact associated with UN output, such as nitrate leaching or N2O emissions to the atmosphere.