Miracle-dz/UniFAR-FTUs huggingface dataset:
Norcantharidin overcomes vemurafenib resistance in melanoma by inhibiting pentose phosphate pathway and lipogenesis via downregulating the mTOR pathway

Melanoma is the most aggressive type of skin cancer with a high incidence and low survival rate. More than half of melanomas present the activating BRAF mutations, along which V600E mutant represents 70%–90%. Vemurafenib (Vem) is an FDA-approved small-molecule kinase inhibitor that selectively targets activated BRAF V600E and inhibits its activity. However, the majority of patients treated with Vem develop acquired resistance. Hence, this study aims to explore a new treatment strategy to overcome the Vem resistance. Here, we found that a potential anticancer drug norcantharidin (NCTD) displayed a more significant proliferation inhibitory effect against Vem-resistant melanoma cells (A375R) than the parental melanoma cells (A375), which promised to be a therapeutic agent against BRAF V600E-mutated and acquired Vem-resistant melanoma. The metabolomics analysis showed that NCTD could, especially reverse the upregulation of pentose phosphate pathway and lipogenesis resulting from the Vem resistance. In addition, the transcriptomic analysis showed a dramatical downregulation in genes related to lipid metabolism and mammalian target of the rapamycin (mTOR) signaling pathway in A375R cells, but not in A375 cells, upon NCTD treatment. Moreover, NCTD upregulated butyrophilin (BTN) family genes, which played important roles in modulating T-cell response. Consistently, we found that Vem resistance led to an obvious elevation of the p-mTOR expression, which could be remarkably reduced by NCTD treatment. Taken together, NCTD may serve as a promising therapeutic option to resolve the problem of Vem resistance and to improve patient outcomes by combining with immunomodulatory therapy.
Analysis of gene expression in monocytes of immunized pigs after infection with homologous or heterologous African swine fever virus

African swine fever is a deadly disease of pigs caused by the large DNA virus (ASFV). Despite intensive research, little is known about the molecular mechanisms of ASFV pathogenesis. Transcriptome analysis of host and viral genes in infected macrophages revealed changes in expression of genes involved in various biological processes, including immune response, inflammatory response and apoptosis. To understand the mechanisms of virus pathogenesis, we used transcriptome analysis to identify the differences in gene expression between peripheral blood monocytes (PBMCs) isolated from pigs immunized with attenuated Congo ASFV strain (KK262), and then infected in vitro with virulent homologous Congo strain (K49) or heterologous Mozambique strain (M78). We found that overexpression of IFN-γ was detected only in cells infected with M78, although the expression of interferon-stimulated genes was increased in both types of cells. In addition, up-regulation of pro-inflammatory cytokines and chemokines was found in PBMCs infected with the heterologous strain M78, in contrast to the cells infected with K49. These data may indicate the beginning of an early immune response in cells infected with a heterologous, but not homologous strain. Transcriptome analysis revealed down-regulation of genes involved in endocytosis and phagocytosis in cells infected with the K49 strain, but not in PBMCs infected with M78. On the contrary, we detected activation of endoplasmic reticulum stress response genes in cells infected with a homologous strain, but not in cells infected with a heterologous strain. This study is the first attempt to determine the differences in the response to ASF infection between homologous and heterologous strains at the cellular level. Our results showed that not only genes of the immune response, but also genes involved in endocytosis and cellular stress response may be important for the formation of cross-protective immunity. This data may be useful for vaccine development or testing of candidate vaccines.
Contribution of muscle satellite cells to sarcopenia

Sarcopenia, a disorder characterized by age-related muscle loss and reduced muscle strength, is associated with decreased individual independence and quality of life, as well as a high risk of death. Skeletal muscle houses a normally mitotically quiescent population of adult stem cells called muscle satellite cells (MuSCs) that are responsible for muscle maintenance, growth, repair, and regeneration throughout the life cycle. Patients with sarcopenia are often exhibit dysregulation of MuSCs homeostasis. In this review, we focus on the etiology, assessment, and treatment of sarcopenia. We also discuss phenotypic and regulatory mechanisms of MuSC quiescence, activation, and aging states, as well as the controversy between MuSC depletion and sarcopenia. Finally, we give a multi-dimensional treatment strategy for sarcopenia based on improving MuSC function.
An immediate postoperative response to therapy assessment can help avoid unnecessary RAI therapy

Background Radioiodine (RAI) therapy plays a vital role in the postoperative treatment of differentiated thyroid cancer (DTC) patients underwent total thyroidectomy (TT). However, even in the presence of capsular invasion and lymph node metastasis prognosis can be excellent and a postoperative RAI treatment might not be necessary for all patients. Therefore, this study explored the criteria for avoiding unnecessary RAI therapy in these patients. Method We applied response to therapy assessment immediately after surgery and prospectively recruited 179 excellent or indeterminate response DTC patients with capsular invasion and/or LNM who underwent TT without RAI therapy. During the follow-up, thyroglobulin (Tg), thyroglobulin antibody (TgAb) levels, and cervical ultrasonography were collected and analyzed. Disease-free survival (DFS) was calculated using the Kaplan-Meier method. In addition, response to therapy assessments was performed on patients during each follow-up. Results The mean follow-up period was 29.85 ± 17.44 months, and the 3- and 5-year DFS for all the patients was 99.3% in each. At the last follow-up, 165 (92.2%) patients had excellent responses, while 12 (6.7%) had an indeterminate response, and one (0.6%) each had biochemical and incomplete responses. No significant difference was observed in response to therapy between the subgroups of LNM and tumor invasion (P>0.05). For patients with capsular invasion and a number of metastatic lymph nodes ≤5 and >5, the proportions of recorded excellent responses were 95.9%, 91.0%, and 85.7%, respectively. Better responses were observed in females (excellent response: 95.5%, P=0.023), patients with stimulated Tg (s-Tg) ≤1ng/ml (excellent response: 100%, P<0.001), s-Tg ≤ 2ng/ml (excellent response: 98.4%, P<0.001), and excellent response for the immediate postoperative assessment (excellent response: 98.5%, P=0.004). Conclusions The current study suggested that the response to therapy assessment immediately applied postoperatively could help avoid unnecessary RAI therapy among DTC patients with capsular invasion and/or LNM. Moreover, excellent response patients and patients with indeterminate response and s-Tg ≤ 2ng/ml could be managed without RAI therapy.
Associations of hedonic and eudaimonic orientations with subjective experience and objective functioning in academic settings: The mediating roles of academic behavioral engagement and procrastination

The question of how the pursuit of happiness affects an individual’s actual well-being has received much scholarly attention in recent years. However, few studies have investigated the associations of happiness orientation with people’s subjective experience and objective functioning simultaneously. The current research examines the possibility that hedonic and eudaimonic orientations have different relationships with college students’ affective well-being and academic achievement, while taking into consideration the behavioral mechanism that underlies the process. We conducted online surveys to collect data including hedonic and eudaimonic orientations at the beginning of the semester and academic behavioral engagement, procrastination, and affective well-being at the end of the semester with a final sample of 566 Chinese undergraduate students. Their official grade point average for the semester was extracted from the university records system. The results confirmed that overall hedonic orientation was negatively associated with affective well-being and academic achievement, whereas eudaimonic orientation was positively associated with these outcomes. The study further found that both academic behavioral engagement and procrastination played mediating roles in the associations of happiness orientation with positive affect and academic achievement. However, only procrastination mediated the relationship between happiness orientation and negative affect. Theoretical and practical implications were discussed.
Immunogenicity and toxicity of AAV gene therapy

Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.
Transcriptomic changes in the large organs in lethal meningococcal shock are reflected in a porcine shock model

Background Fulminant meningococcal sepsis with shock and multiple organ failure is associated with a massive systemic inflammatory response involving solid organs. We have previously established a porcine model of the disease to study pathophysiologic and possible therapeutic strategies. Objective This study examined whether the organ specific gene expression profile in such a large animal model reflects the profile seen in patients with fulminant meningococcal sepsis. Patients and methods Data from gene expression profiles induced in organs from patients (n=5) and the porcine model (n=8) were imported into the Ingenuity pathway analysis (IPA) software for comparison analysis. The number of meningococci in the organs were quantified by real time-PCR. Results The all-over transcriptional activation between different organs revealed a striking concordance between the patients and the pigs regarding the pattern of transcriptional activation and activated pathways. Comparison analysis demonstrated similar pattern of upregulation of genes being associated with a large range of inflammatory biofunctions in the patients and the porcine model. Genes associated with biofunctions such as organismal death, morbidity and mortality were similarly downregulated in the patients and the porcine model. Comparison analysis of main predicted canonical pathways also demonstrated a high degree of similarity regarding up- and downregulation in both groups. Core analysis revealed different top-upstream regulators in the different organs in the patients. In the patients pro-inflammatory regulators were most activated in the lungs. In the other organs up-stream factors that regulate signaling pathways involved in development, growth, repair and homeostasis and triglyceride synthesis were most activated. In the porcine model, the top-upstream regulators were pro-inflammatory in all organs. The difference may reflect the shorter duration of the porcine experiment than the duration of the patient’s infection before death. Conclusion The inflammatory responses measured on the transcriptomic level in organs in patients with fulminant meningococcal sepsis is reproduced in the porcine model of the disease, although some differences may exist regarding the top-upregulated factors in individual organs. Thus, this large animal model reproduces important immunological features of meningococcal sepsis and can be a valuable tool in further investigations of inflammatory aspects and possible treatment options
Thresholds for vestibular and cutaneous perception and oculomotor response induced by galvanic vestibular stimulation

Objectives In this study, the specific threshold intensities and response characteristics of galvanic vestibular stimulation (GVS) on vestibular (conscious) and cutaneous (detrimental) perception as well as oculomotor nystagmus (reflex) were determined. Methods The threshold intensities for vestibular and cutaneous perception and oculomotor response induced by GVS were determined in 25 right-handed healthy subjects (32.6 ± 7.2 years of age; 56% female). The subjects were seated upright, and eye movements were recorded while a direct GVS current was applied with paradigms of cathode on the right and anode on the left (CRAL) and also cathode on the left and anode on the right (CLAR). Results Subjects experienced dizziness, sense of spinning, or fall tendency, which was more frequently directed to the cathode (76%) than the anode (24%, p < 0.001, chi-square one-variable test) at mean current greater than 0.98 ± 0.29 mA (mean vestibular threshold). The current also triggered a more frequent mild tingling sensation at the cathode (56%) than the anode (30%) or on both sides (14%; p = 0.001, chi-square one-variable test) when above the mean cutaneous threshold of 0.9 ± 0.29 mA. Above the mean oculomotor threshold of 1.61 ± 0.35 mA, combined horizontal and torsional nystagmus was more frequent toward the cathode (86%) than toward the anode (p < 0.001, chi-square one-variable test). The mean oculomotor threshold was significantly higher than both the vestibular (p < 0.001, Mann–Whitney U-test) and cutaneous (p < 0.001, Mann–Whitney U-test) thresholds, which were comparable (p = 0.317, Mann–Whitney U-test). There was no significant disparity in these specific thresholds between the two GVS paradigms. The vestibular threshold was significantly higher in males than in females [1 (0.5–1.25) mA vs. 0.75 (0.625–1.125) mA, Z = −2.241, p = 0.025, Mann–Whitney U-test]. However, the thresholds of cutaneous perception and oculomotor response did not differ by sex. Conclusion The findings indicate that thresholds for vestibular and somatosensory perception are lower than the oculomotor threshold. Therefore, a strategy to reduce GVS current intensity to the level of vestibular or somatosensory perception threshold could elicit beneficial vestibular effects while avoiding undesirable effects such as oculomotor consequences.
Integrating network pharmacology analysis and pharmacodynamic evaluation for exploring the active components and molecular mechanism of moutan seed coat extract to improve cognitive impairment

Paeonia suffruticosa (Moutan) is a traditional medicinal plant in China. Its seed coat is rich in resveratrol oligomer, especially suffruticosol B (SB). Previous studies had shown that the seed coat extracts of Paeonia suffruticosa (PSCE) had good cholinesterase inhibitory activity and neuroprotective effect, but the effective dose range was unknown, and the pharmacodynamic components and molecular mechanism of PSCE had not been discussed. The current study aimed to screen the pharmacodynamic components in PSCE and investigate the improvement effect of PSCE and the selected SB on scopolamine-induced cognitive dysfunction in mice and its mechanism. The results of high-throughput sequencing and bioinformatics analysis showed that suffruticosol B (SB) and trans-gnetin H (GH) might be the main active components of PSCE; PSCE might improve cognitive dysfunction through p53, HIF-1, MAPK, and PI3K-Akt signaling pathways, while SB and GH might improve cognitive dysfunction through HIF-1 signaling pathway. SB and GH had good molecular docking activity with the target of HIF-1 signaling pathway. The pharmacodynamic activities of PSCE and SB were further verified by behavioral experiments. PSCE and SB could improve the recognition ability of familiar and new objects and shorten the escape latency in the Morris Water Maze test (PSCE 120 mg∙kg-1, p < 0.05; SB 60 mg∙kg-1, p < 0.01); PSCE and SB could increase Ach and GSH levels, enhance the activities of ChAT, SOD and CAT, decrease the levels of IL-1β, IL-6, and TNF-α, and decrease the activity of AChE. In conclusion, the results indicated that PSCE might exert pharmacodynamic activity through multiple components, targets, and pathways, and SB and GH might be the main active components of PSCE. PSCE and SB might improve cognitive dysfunction by regulating cholinergic, antioxidant, and anti-inflammatory effects. These results indicated that PSCE and SB might be potential anti-AD drug candidates, providing a scientific basis for the development and utilization of Moutan bark.
TMAO as a potential biomarker and therapeutic target for chronic kidney disease: A review

The gut microbiota and its metabolites have become a hotspot of recent research. Trimethylamine N-oxide (TMAO) metabolized by the gut microbiota is closely related to many diseases such as cardiovascular disease, chronic kidney disease, type 2 diabetes, etc. Chronic kidney disease (CKD) is an important contributor to morbidity and mortality from non-communicable diseases. Recently, increasing focus has been put on the role of TMAO in the development and progress of chronic kidney disease. The level of TMAO in patients with chronic kidney disease is significantly increased, and a high level of TMAO deteriorates chronic kidney disease. This article describes the relationship between TMAO and chronic kidney disease and the research progress of drugs targeted TMAO, providing a reference for the development of anti-chronic kidney disease drugs targeted TMAO.
A meta-analysis of leadership and intrinsic motivation: Examining relative importance and moderators

This paper provides the first meta-analytic examination of the relationship between leadership and followers' intrinsic motivation. In particular, we examined 6 leadership variables (transformational, ethical, leader-member exchange, servant, empowering, and abusive supervision) using data from 50 independent samples and 21,873 participants. We found that transformational leadership, ethical leadership, leader-member exchange (LMX), servant leadership, and empowering leadership were positively related to intrinsic motivation, whereas abusive supervision was negatively linked to intrinsic motivation. Although these leadership styles were associated with intrinsic motivation, they varied considerably in their relative importance. Empowering, ethical, and servant leadership emerged as the more important contributors to intrinsic motivation than transformational leadership. LMX showed a similar contribution with transformational leadership to intrinsic motivation. Effectiveness of leadership styles in relation to intrinsic motivation varied by power distance, publication year, and journal quality. Drawing on our findings, we discuss the theoretical and practice implications.
Cost-effectiveness analysis of olaparib as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in china

Objective: The aim of this study was to investigate the cost-effectiveness of olaparib as the maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China. Methods: A Markov model was developed to simulate the clinical course of typical patients with ovarian cancer in the SOLO2 trial. The Weibull survival model was employed to fit the Kaplan–Meier progression-free survival and overall survival probabilities of the olaparib and placebo strategies, respectively. The clinical and direct costs data were derived from randomized clinical trials and published reports. Quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) were estimated over a 10-year lifetime horizon. Meanwhile, one-way and probabilistic sensitivity analyses were used to explore the impact of uncertainty on the model’s outcomes. Results: Overall, the incremental effectiveness and cost of olaparib versus placebo were 0.56 QALYs and $43,292.92, respectively, resulting in an ICER of $77,620.56/QALY, higher than the willingness-to-pay (WTP) threshold of China ($31,498.70/QALY). The results were sensitive to the cost of olaparib and utility of PFS. Scenario analyses suggested that when the cost of olaparib was reduced by 60%, ICER decreased to $30,611.52/QALY, lower than the WTP threshold of China. Conclusion: The findings from the present analysis suggest that olaparib with a 60% discount as maintenance therapy might be cost effective in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation in China.
Effective leaders(hip) in community-academic health partnership projects: An inductive, qualitative study

To deepen our understanding of how project leaders can lead effectively in different community-academic health partnerships (CAHPs), we conducted an inductive, qualitative study through semi-structured interviews (N = 32) and analyzed the data with Grounded Theory approaches. By presenting a process model illustrating the cycle of effective leaders(hip) in CAHP projects, we contribute to the literature on CAHP, leadership development, and complexity leadership theory in three ways. Firstly, the model depicts the strategies enabling leaders to navigate typical project challenges and perform leadership tasks effectively. Secondly, we distill four beneficial qualities (i.e., adopting a proactive attitude, having an open and adaptive mindset, relying on peer learning and support, and emphasizing self-growth and reflexivity) which CAHP project leaders require to develop themselves into effective leaders. Thirdly, we illustrate leaders' dynamic developmental logics and processes of effective leadership and their contributions to better project functioning in diverse CAHPs.