Miracle-dz/UniFAR-FTUs huggingface dataset:
Neutrophil-to-Lymphocyte Ratio as a Prognostic Biomarker for Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

There is increasing evidence to suggest that the neutrophil-to-lymphocyte ratio (NLR) is related to the prognosis of patients with renal cell carcinoma (RCC) treated with immune checkpoint inhibitors (ICIs). However, these findings are inconsistent. The present study was performed with the aim of exploring the utility of NLR in patients with RCC treated with ICIs. For this purpose, a comprehensive search of PubMed, Web of Science, and Embase was performed to find studies evaluating the prognostic value of NLR. The overall survival (OS) and progression-free survival (PFS) were the assessed clinical outcomes. All statistical analysis was performed using Stata version 12.0 software. The combined hazard ratios (HRs) and 95% confidence intervals (CIs) of NLR for OS and PFS were calculated using the random-effect models. Heterogeneity was evaluated based on the I 2 value and Cochran’s Q test. Egger’s and Begg’s tests were applied to precisely assess the publication bias. The “trim and fill” method was adopted to perform the sensitivity analysis to determine whether the results were stable. In total, 12 studies encompassing 1,275 patients were included in the final analysis. The results revealed that a high NLR at baseline or pre-therapy was associated with a poor OS (HR, 2.23; 95% CI, 1.84–2.70; p < 0.001) and PFS (HR, 1.78; 95% CI, 1.72–2.09; p < 0.001). During the course of treatment, a decrease in the NLR was associated with a significantly longer OS (HR, 0.34; 95% CI, 0.20–0.56; p < 0.001) and PFS (HR, 0.44; 95% CI, 0.30–0.63; p < 0.001) compared to an increase in NLR. As a preliminary screening of other risk factors, age, sex, race, and IMDC risk may have a certain prognostic value for RCC treated with ICIs. People over 70 years old had better OS compared to people younger than 70 (HR, 0.65; 95% CI, 0.48–0.89). Non-Caucasians treated with immunotherapy had a worse OS (HR, 8.67; 95% CI, 2.87–26.2) and PFS (HR, 2.65; 95% CI, 1.28–5.48) than Caucasians. Males had a worse OS than females (HR, 1.48; 95% CI, 1.14–1.93). Compared with the IMDC favorable risk group, the OS of the IMDC poor risk group was worse (HR, 2.59; 95% CI, 1.56–4.32). There was no significant publication bias or heterogeneity observed in the present study. On the whole, the present study demonstrated that an elevated NLR is associated with an adverse OS and PFS in patients with RCC treated with ICIs. The NLR may thus be used as a readily available prognostic biomarker for these patients. Age, sex, race, and IMDC risk may have potential predictive value for the prognosis of RCC treated with ICIs. However, further investigations are warranted to validate these results.
Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan. Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks. Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively. Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.
Uncovering the Sex-Specific Endocrine Responses to Reproduction and Parental Care

Hormones mediate physiological and behavioral changes in adults as they transition into reproduction. In this study, we characterize the circulating levels of five key hormones involved in reproduction in rock doves (Columba livia): corticosterone, progesterone, estradiol, testosterone, and prolactin using univariate and multivariate approaches. We show similar patterns as previous studies in the overall patterns in circulating levels of these hormones, i.e., testosterone (males) and estradiol (females) high during nest-building or egg-laying, prolactin increasing at mid-incubation and peaking at hatching (both sexes), and elevated corticosterone levels in later incubation and early nestling development. In our investigation of hormone co-variation, we find a strong correlation between prolactin and corticosterone across sampling stages and similarities in earlier (early to mid-incubation) compared to later (late incubation to nestling d9) sampling stages in males and females. Finally, we utilized experimental manipulations to simulate nest loss or altered caregiving lengths to test whether external cues, internal timing, or a combination of these factors contributed most to hormone variation. Following nest loss, we found that both males and females responded to the external cue. Males generally responded quickly following nest loss by increasing circulating testosterone, but this response was muted when nest loss occurred early in reproduction. Similar treatment type, e.g., removal of eggs, clustered similarly in hormone space. These results suggest internal drivers limited male response early in reproduction to nest loss. In contrast, circulating levels of these hormones in females either did not change or decreased following nest manipulation suggesting responsiveness to external drivers, but unlike males, this result suggests that reproductive processes were decreasing.
Circulating CTRP7 Is a Potential Predictor for Metabolic Syndrome

Background Previous animal studies have revealed that CTRP7 is related to energy metabolism. However, little is known regarding the relationship between CTRP7 and metabolic diseases in humans. Hence, this study was designed to explore the association between CTRP7 and MetS through a cross-sectional study and multiple intervention studies. Methods A total of 624 individuals were enrolled in this study. The levels of CTRP7 and APN were determined by ELISA kit. HEC, OGTT and lipid infusion were performed in heathy individuals to investigate the association of CTRP7 and glucose, insulin and FFA. Bioinformatics analysis was then undertaken to identify genes and signaling pathways associated with CTRP7. The relationship between CTRP7 with MetS components was also evaluated. Results In MetS patients, serum CTRP7 concentrations were significantly higher than in healthy controls, and was positively correlated with WC, BP, FBG, 2h-BG and TG, but negatively correlated with HDL-C and APN. Multivariate logistic regression analysis uncovered that CTRP7 was strongly correlated with the occurrence of MetS. In addition, circulating levels of CTRP7 in patients with two or more MetS components were higher than those with one MetS component. In the intervention studies, OGTTs resulted in a significant reduction in serum CTRP7 concentration. However, the increase in insulin levels caused by EHC and the increase of FFA caused by lipid-infusion led to the significant increase of serum CTRP7 concentration. Meanwhile, bioinformatics analysis revealed that CTRP7 was strongly associated with metabolism-related genes and signal pathways, which further illustrate the association of CTRP7 with whole-body metabolism. Conclusions Serum CTRP7 is increased in MetS patients, which may be a biomarker related to metabolic diseases. Clinical Trial Registration Number ChiCTR2000032878
Machine Learning Algorithms to Distinguish Myocardial Perfusion SPECT Polar Maps

Myocardial perfusion imaging (MPI) plays an important role in patients with suspected and documented coronary artery disease (CAD). Machine Learning (ML) algorithms have been developed for many medical applications with excellent performance. This study used ML algorithms to discern normal and abnormal gated Single Photon Emission Computed Tomography (SPECT) images. We analyzed one thousand and seven polar maps from a database of patients referred to a university hospital for clinically indicated MPI between January 2016 and December 2018. These studies were reported and evaluated by two different expert readers. The image features were extracted from a specific type of polar map segmentation based on horizontal and vertical slices. A senior expert reading was the comparator (gold standard). We used cross-validation to divide the dataset into training and testing subsets, using data augmentation in the training set, and evaluated 04 ML models. All models had accuracy >90% and area under the receiver operating characteristics curve (AUC) >0.80 except for Adaptive Boosting (AUC = 0.77), while all precision and sensitivity obtained were >96 and 92%, respectively. Random Forest had the best performance (AUC: 0.853; accuracy: 0,938; precision: 0.968; sensitivity: 0.963). ML algorithms performed very well in image classification. These models were capable of distinguishing polar maps remarkably into normal and abnormal.
N2O–Assisted Siphon Foaming of Modified Galactoglucomannans With Cellulose Nanofibers

Foaming of most bio-based polymers is challenged by low pore formation and foam stability. At the same time, the developing utilization of bio-based materials for the circular economy is placing new demands for easily processable, low-density materials from renewable raw materials. In this work, we investigate cellulose nanofiber (CNF) foams in which foaming is facilitated with wood-based hemicelluloses, galactoglucomannans (GGMs). Interfacial activity of the GGM is modulated via modification of the molecule’s amphiphilicity, where the surface tension is decreased from approximately 70 to 30 mN m−1 for unmodified and modified GGM, respectively. The chemical modification of GGMs by substitution with butyl glycidyl ether increased the molecule’s hydrophobicity and interaction with the nanocellulose component. The highest specific foam volume using 1 wt% CNF was achieved when modified GGM was added (3.1 ml g−1), compared to unmodified GGM with CNF (2.1 ml g−1). An amount of 96 and 98% of the GGM and GGM-BGE foams were lost after 15 min of foaming while the GGM and GGM-BGE with cellulose nanofibers lost only 33 and 28% of the foam respectively. In the case of GGM-BGE, the foam stability increased with increasing nanofiber concentration. This suggests that the altered hydrophobicity facilitated increased foam formation when the additive was incorporated in the CNF suspension and foamed with nitrous oxide (N2O). Thus, the hydrophobic character of the modified GGM was a necessity for foam formation and stability while the CNFs were needed for generating a self-standing foam structure.
Combination Therapy With Rapamycin and Low Dose Imatinib in Pulmonary Hypertension

Rationale: Enhanced proliferation and distal migration of human pulmonary arterial smooth muscle cells (hPASMCs) both contribute to the progressive increases in pulmonary vascular remodeling and resistance in pulmonary arterial hypertension (PAH). Our previous studies revealed that Rictor deletion, to disrupt mTOR Complex 2 (mTORC2), over longer periods result in a paradoxical rise in platelet-derived growth factor receptor (PDGFR) expression in PASMCs. Thus, the purpose of this study was to evaluate the role of combination therapy targeting both mTOR signaling with PDGFR inhibition to attenuate the development and progression of PAH. Methods and Results: Immunoblotting analyses revealed that short-term exposure to rapamycin (6h) significantly reduced phosphorylation of p70S6K (mTORC1-specific) in hPASMCs but had no effect on the phosphorylation of AKT (p-AKT S473, considered mTORC2-specific). In contrast, longer rapamycin exposure (>24 h), resulted in differential AKT (T308) and AKT (S473) phosphorylation with increases in phosphorylation of AKT at T308 and decreased phosphorylation at S473. Phosphorylation of both PDGFRα and PDGFRβ was increased in hPASMCs after treatment with rapamycin for 48 and 72 h. Based on co-immunoprecipitation studies, longer exposure to rapamycin (24–72 h) significantly inhibited the binding of mTOR to Rictor, mechanistically suggesting mTORC2 inhibition by rapamycin. Combined exposure of rapamycin with the PDGFR inhibitor, imatinib significantly reduced the proliferation and migration of hPASMCs compared to either agent alone. Pre-clinical studies validated increased therapeutic efficacy of rapamycin combined with imatinib in attenuating PAH over either drug alone. Specifically, combination therapy further attenuated the development of monocrotaline (MCT)- or Hypoxia/Sugen-induced pulmonary hypertension (PH) in rats as demonstrated by further reductions in the Fulton index, right ventricular systolic pressure (RVSP), pulmonary vascular wall thickness and vessel muscularization, and decreased proliferating cell nuclear antigen (PCNA) staining in PASMCs. Conclusion: Prolonged rapamycin treatment activates PDGFR signaling, in part, via mTORC2 inhibition. Combination therapy with rapamycin and imatinib may be a more effective strategy for the treatment of PAH.
Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints

Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.
NMR Studies of Tau Protein in Tauopathies

Tauopathies, including Alzheimer’s disease (AD), are the most troublesome of all age-related chronic conditions, as there are no well-established disease-modifying therapies for their prevention and treatment. Spatio-temporal distribution of tau protein pathology correlates with cognitive decline and severity of the disease, therefore, tau protein has become an appealing target for therapy. Current knowledge of the pathological effects and significance of specific species in the tau aggregation pathway is incomplete although more and more structural and mechanistic insights are being gained using biophysical techniques. Here, we review the application of NMR to structural studies of various tau forms that appear in its aggregation process, focusing on results obtained from solid-state NMR. Furthermore, we discuss implications from these studies and their prospective contribution to the development of new tauopathy therapies.
Serum Neurofilament Light Chain Levels and Myelin Oligodendrocyte Glycoprotein Antibodies in Pediatric Acquired Demyelinating Syndromes

Introduction: The relationship between serum neurofilament light chain (sNfL) and myelin oligodendrocyte glycoprotein antibody (MOG-Ab) status has not been yet investigated in children with the acquired demyelinating syndrome (ADS). Objective and Methods: The sNfL levels and MOG-Abs were measured by ultrasensitive single-molecule array and cell-based assay in a cohort of 37 children with ADS and negativity for serum anti-aquaporin 4 (AQP4) antibodies. The sNfL levels were compared in MOG-Ab+/MOG-Ab– and in two subgroups MOG-Ab+ with/without encephalopathy. Results: About 40% ADS resulted in MOG-Ab+. MOG-Ab+ were younger at sampling (median = 9.8; range = 2.17–17.5 vs. 14.7/9–17; p = 0.002) with lower frequency of cerebrospinal fluid oligoclonal bands positivity (27% vs. 70%; p = 0.013) compared to MOG-Ab–. About 53% of MOG-Ab+ presented encephalopathy at onset, 1/22 of MOG-Ab– (p = 0.0006). Higher sNfL levels (p = 0.0001) were found in MOG-Ab+ (median/range = 11.11/6.8–1,129) and MOG-Ab– (median/range = 11.6/4.3–788) compared to age-matched controls (median/range = 2.98/1–4.53), without significant difference. MOG-Ab+ with encephalopathy resulted significantly younger at sampling (median/range: 4.5/2.17–11.17 vs. 14.16/9.8–17.5; p = 0.004), had higher sNfL levels (median/range:75.24/9.1–1,129 vs. 10.22/6.83–50.53; p = 0.04), and showed a trend for higher MOG-Ab titer (0.28/0.04–0.69 vs. 0.05/0.04–0.28; p = 0.1) in comparison to those without encephalopathy. Discussion: We confirmed high sNfL levels in pediatric ADS independently from the MOG-Ab status. Encephalopathy at onset is associated more frequently with MOG Ab+ children with higher sNfL levels and MOG titer. These findings suggest a role of acute demyelination in association with axonal damage in the pathogenesis of encephalopathy in pediatric ADS.
Identifying the Effect of Ursolic Acid Against Triple-Negative Breast Cancer: Coupling Network Pharmacology With Experiments Verification

Triple negative breast cancer (TNBC) is a subtype of breast cancer with complex heterogeneity, high invasiveness, and long-term poor prognosis. With the development of molecular pathology and molecular genetics, the gene map of TNBC with distinctive biological characteristics has been outlined more clearly. Natural plant extracts such as paclitaxel, vinblastine, colchicine etc., have occupied an important position in the treatment of hormone-independent breast cancer. Ursolic acid (UA), a triterpenoid acid compound derived from apple, pear, loquat leaves, etc., has been reported to be effective in a variety of cancer treatments, but there are few reports on the treatment of TNBC. This study performed comprehensive bioinformatics analysis and in vitro experiments to identify the effect of UA on TNBC treatment and its potential molecular mechanism. Our results showed that UA could not only reduce the proliferation, migration, and invasion in MDA-MB-231 and MDA-MB-468 cell lines with a dose-dependent manner but also induce cell cycle arrest and apoptosis. Meanwhile, we collected the gene expression data GSE45827 and GSE65194 from GEO for comparison between TNBC and normal cell type and obtained 724 DEGs. Subsequently, PLK1 and CCNB1 related to TNBC were screened as the key targets via topological analysis and molecular docking, and gene set enrichment analysis identified the key pathway as the p53 signaling pathway. In addition, quantitative real-time PCR and western blot verified the key genes were PLK1 and CCNB1. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. These findings provide strong evidence for UA intervention in TNBC via multi-target therapy.
The Versatile Gasdermin Family: Their Function and Roles in Diseases

The gasdermin (GSDM) family, a novel group of structure-related proteins, consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME/DNFA5, and PVJK/GSDMF. GSDMs possess a C-terminal repressor domain, cytotoxic N-terminal domain, and flexible linker domain (except for GSDMF). The GSDM-NT domain can be cleaved and released to form large oligomeric pores in the membrane that facilitate pyroptosis. The emerging roles of GSDMs include the regulation of various physiological and pathological processes, such as cell differentiation, coagulation, inflammation, and tumorigenesis. Here, we introduce the basic structure, activation, and expression patterns of GSDMs, summarize their biological and pathological functions, and explore their regulatory mechanisms in health and disease. This review provides a reference for the development of GSDM-targeted drugs to treat various inflammatory and tissue damage-related conditions.
Physiological and Transcriptomic Analyses Revealed the Implications of Abscisic Acid in Mediating the Rate-Limiting Step for Photosynthetic Carbon Dioxide Utilisation in Response to Vapour Pressure Deficit in Solanum Lycopersicum (Tomato)

The atmospheric vapour pressure deficit (VPD) has been demonstrated to be a significant environmental factor inducing plant water stress and affecting plant photosynthetic productivity. Despite this, the rate-limiting step for photosynthesis under varying VPD is still unclear. In the present study, tomato plants were cultivated under two contrasting VPD levels: high VPD (3–5 kPa) and low VPD (0.5–1.5 kPa). The effect of long-term acclimation on the short-term rapid VPD response was examined across VPD ranging from 0.5 to 4.5 kPa. Quantitative photosynthetic limitation analysis across the VPD range was performed by combining gas exchange and chlorophyll fluorescence. The potential role of abscisic acid (ABA) in mediating photosynthetic carbon dioxide (CO2) uptake across a series of VPD was evaluated by physiological and transcriptomic analyses. The rate-limiting step for photosynthetic CO2 utilisation varied with VPD elevation in tomato plants. Under low VPD conditions, stomatal and mesophyll conductance was sufficiently high for CO2 transport. With VPD elevation, plant water stress was gradually pronounced and triggered rapid ABA biosynthesis. The contribution of stomatal and mesophyll limitation to photosynthesis gradually increased with an increase in the VPD. Consequently, the low CO2 availability inside chloroplasts substantially constrained photosynthesis under high VPD conditions. The foliar ABA content was negatively correlated with stomatal and mesophyll conductance for CO2 diffusion. Transcriptomic and physiological analyses revealed that ABA was potentially involved in mediating water transport and photosynthetic CO2 uptake in response to VPD variation. The present study provided new insights into the underlying mechanism of photosynthetic depression under high VPD stress.