We performed a Bayesian network meta-analysis to indirectly compare the relative efficacy and safety of the latest JAK inhibitors for moderate-to-severe alopecia areata (AA). 13 trials totaling 3,613 ...patients were included. Two low-dose groups of oral formulations (ritlecitinib 10mg and ivarmacitinib 2mg) and two topical formulations (delgocitinib ointment and ruxolitinib cream) appeared to be relatively ineffective against moderate-to-severe AA. Ranking analysis suggested that brepocitinib 30mg has the best relative effect in reducing the SALT score (sucra = 0.9831), and demonstrated comparable efficacy to deuruxolitinib 12mg (sucra = 0.9245), followed by deuruxolitinib 8mg (sucra = 0.7736). Regarding the SALT
response, brepocitinib 30mg ranked highest (sucra = 0.9567), followed by ritlecitinib 50mg (sucra = 0.8689) and deuruxolitinib 12mg (sucra = 0.7690). For achieving the SALT
response, deuruxolitinib 12mg had the highest probability (sucra = 0.9761), followed by deuruxolitinib 8mg (sucra = 0.8678) and brepocitinib 30mg (sucra = 0.8448). Deuruxolitinib 12mg might be the most effective therapy for patients with severe AA (sucra = 0.9395), followed by ritlecitinib 50mg (sucra = 0.8753) and deuruxolitinib 8mg (sucra = 0.8070). Deuruxolitinib 12mg/8mg demonstrated notable efficacy for moderate-to-severe AA, and is expected to be a new treatment option for AA. It was worth noting that deuruxolitinib exhibit a greater likelihood of causing adverse events in comparison to other JAK inhibitors. Ritlecitinib 50mg seemed to exhibit fewer adverse effects in the high-dose groups of oral JAK inhibitors and might be an optimal choice to balance safety and efficacy. The majority of JAK inhibitors exhibited acceptable short-term safety profiles. To enhance the applicability and accuracy of our research, further head-to-head trials with longer follow-up periods are needed.
identifier CRD42022368012.
Triple negative (TN, tumors that do not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2)) and HER2-overexpressing (H2E, ER−/HER2+) tumors ...are two particularly aggressive subtypes of breast cancer. There is a lack of knowledge regarding the etiologies of these cancers and in particular how anthropometric factors are related to risk. We conducted a population-based case–case study consisting of 2659 women aged 20–69 years diagnosed with invasive breast cancer from 2004 to 2012. Four case groups defined based on joint ER/PR/HER2 status were included: TN, H2E, luminal A (ER+/HER2−), and luminal B (ER+/HER2+). Polytomous logistic regression was used to estimate odds ratios (ORs) and associated 95 % confidence intervals (CIs) where luminal A patients served as the reference group. Obese premenopausal women body mass index (BMI) ≥30 kg/m
2
had an 82 % (95 % CI 1.32–2.51) increased risk of TN breast cancer compared to women whose BMI <25 kg/m
2
, and those in the highest weight quartile (quartiles were categorized based on the distribution among luminal A patients) had a 79 % (95 % CI 1.23–2.64) increased risk of TN disease compared to those in the lowest quartile. Among postmenopausal women obesity was associated with reduced risks of both TN (OR = 0.74, 95 % CI 0.54–1.00) and H2E (OR = 0.47, 95 % CI 0.32–0.69) cancers. Our results suggest obesity has divergent impacts on risk of aggressive subtypes of breast cancer in premenopausal versus postmenopausal women, which may contribute to the higher incidence rates of TN cancers observed among younger African American and Hispanic women.
Sickle cell disease (SCD) is a type of hemoglobinopathy due to an autosomal recessive genetic defect, causing significant red cell sickling, multi‐organ damage and long‐term severe morbidities. Due ...to its complicated care and the impact on quality of life, a curative treatment for SCD is highly desirable. In recent years, gene therapy is emerging as a curative option for SCD, where autologous haematopoietic stem cells are collected from SCD patients and genetically modified ex vivo to reduce its sickling tendency before reinfusion. Although still largely investigational, a limited number of gene therapy options have been recently granted approval for SCD patients. Published data are still currently limited, but early studies have so far demonstrated the intended outcomes of less vaso‐occlusive crisis and haemolysis. Nonetheless, despite its curative potential, larger clinical trials and longer follow‐up period are still necessary to evaluate the safety of this treatment option, especially the risk of unintended genetic modifications. Furthermore, SCD patients frequently have limited access to specialty care; hence, the issues of affordability and accessibility to SCD gene therapy must also be addressed for it to benefit the appropriate patient population.
This paper presented the analysis on the influence of the pinch point temperature difference (PPTD) and the evaporation temperature on the performance of organic Rankine cycle (ORC) in recovering the ...low temperature waste heat of the flue gas. Both the net power output and the heat transfer area of the evaporator and condenser were evaluated for dry and isentropic working fluids. When the heat and cold source conditions were given, the maximum net power output and the heat transfer area were obtained. The results show that some organic working fluids cannot reach the maximum net power output to avoid the low temperature corrosion. With the increase of the PPTD of the evaporator at a given total temperature difference, the total heat transfer area decreases first and then increases, while the corresponding cost-effective performance (ratio of the net power output to total heat transfer area) displays almost the opposite variation tendency. The PPTD of the evaporator for the optimization cost-effective performance is approximately the same for different organic working fluids. Meanwhile, the isentropic working fluids show better cost-effective performance than dry working fluids.
► Variation law of the heat transfer area with the pinch point temperature difference in evaporator and condenser. ► Optimization of performance of the ORC system based on pinch point temperature difference and evaporation temperature. ► Evaluation for the different organic working fluids at a given external condition.
The present study used metabolomics, transcriptomics, protein analysis by immunoblots, chemical inhibition and gene knockout mice to determine the effects of celastrol on cholestasis and its ...mechanisms. Samples from patients were used to validate our findings, and the data supported the conclusions that celastrol protected against cholestatic liver injury through modulation of the SIRT1 and FXR.
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Highlights
•1. Celastrol alleviated cholestatic liver injury.•2. Celastrol inhibited the decrease of SIRT1 induced by deoxycholic acid.•3. SIRT1-FXR signaling pathway mediated the effect of celastrol.
Celastrol, derived from the roots of the Tripterygium Wilfordi, shows a striking effect on obesity. In the present study, the role of celastrol in cholestasis was investigated using metabolomics and transcriptomics. Celastrol treatment significantly alleviated cholestatic liver injury in mice induced by α-naphthyl isothiocyanate (ANIT) and thioacetamide (TAA). Celastrol was found to activate sirtuin 1 (SIRT1), increase farnesoid X receptor (FXR) signaling and inhibit nuclear factor-kappa B and P53 signaling. The protective role of celastrol in cholestatic liver injury was diminished in mice on co-administration of SIRT1 inhibitors. Further, the effects of celastrol on cholestatic liver injury were dramatically decreased in Fxr-null mice, suggesting that the SIRT1-FXR signaling pathway mediates the protective effects of celastrol. These observations demonstrated a novel role for celastrol in protecting against cholestatic liver injury through modulation of the SIRT1 and FXR.
As a stem cell of alveolar epithelium, the physiological status of alveolar epithelium type II cells (AECII) after hyperoxia exposure is closely related to the occurrence of hyperoxia-induced lung ...injury and the restoration of normal morphological function of damaged alveolar epithelium. However, the relevant mechanisms involved are not very clear. Therefore, this study aimed to explore the effect of calcitonin gene-related peptide (CGRP) on AECII exposed to hyperoxia and its potential mechanisms. The AECII viability was detected using MTT assay. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected by spectrophotometry. The transdifferentiation capacity of AECII was evaluated by flow cytometry. The expression levels of Notch1, Hes, HERP, and AECII markers were detected using immunohistochemistry and/or RT-qPCR or immunofluorescence. ELISA was used for the determination of inflammatory markers. The results showed that CGRP significantly promoted cell viability, and markedly suppressed hyperoxia-induced transdifferentiation of AECII; these biological alterations were coincided with decreased MDA level, increased SOD activity, and activated Notch signaling pathway (upregulated expression levels of Notch1, Hes, and HERP). Notably, the in vitro effects of CGRP on Notch signaling pathway were further investigated in animal model, and the HE staining results showed that CGRP reduced in vivo oxidative injury and inflammation in hyperoxia-treated AECII through the promotion of structural and functional regeneration, accompanied by elevated Notch1 expression and activated Notch signaling cascade as shown by immunohistochemistry and QPCR, respectively. Immunohistochemistry of APQ-5 and SPC indicated that CGRP reversed the transdifferentiation of AECIIs in vivo. Our current results were consistent across both in vitro and in vivo settings, and provide a new direction for the prevention and treatment of bronchopulmonary dysplasia (BPD).
Astragali Radix
(
A. Radix
) is the dried root of
Astragalus membranaceus var. mongholicus
(Bge) Hsiao or
Astragalus membranaceus
(Fisch.) Bge., belonging to the family Leguminosae, which is mainly ...distributed in China.
A. Radix
has been consumed as a tonic in China for more than 2000 years because of its medicinal effects of invigorating the spleen and replenishing qi. Currently, more than 400 natural compounds have been isolated and identified from
A. Radix
, mainly including saponins, flavonoids, phenylpropanoids, alkaloids, and others. Modern pharmacological studies have shown that
A. Radix
has anti-tumor, anti-inflammatory, immunomodulatory, anti-atherosclerotic, cardioprotective, anti-hypertensive, and anti-aging effects. It has been clinically used in the treatment of tumors, cardiovascular diseases, and cerebrovascular complications associated with diabetes with few side effects and high safety. This paper reviewed the progress of research on its chemical constituents, pharmacological effects, clinical applications, developing applications, and toxicology, which provides a basis for the better development and utilization of
A. Radix
.
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