bluuebunny/crossref_metadata_2025_split huggingface dataset:
The predictive and prognostic role of metabolic and volume-based parameters of positron emission tomography/computed tomography as non-invasive dynamic biological markers in early breast cancer treated with preoperative systemic therapy
Authors: Inno Alessandro , Peri Marta , Turazza Monica , Bogina Giuseppe , Modena Alessandra , Massocco Alberto , Pezzella Modestino , Valerio Matteo , Mazzola Rosario , Olivari Laura , Severi Fabrizia , Foti Giovanni , Mazzi Cristina , Marchetti Fabiana , Lunardi Gianluigi , Salgarello Matteo , Russo Antonio , Gori Stefania 
Published: January 2023

IntroductionThe role of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in early breast cancer treated with preoperative systemic therapy (PST) is not yet established in clinical practice. PET parameters have aroused great interest in the recent years, as non-invasive dynamic biological markers for predicting response to PST.MethodsIn this retrospective study, we included 141 patients with stage II-III breast cancer who underwent surgery after PST. Using ROC analysis, we set optimal cutoff of FDG-PET/CT parameters predictive for pathological complete response (pCR). We investigated the correlation between FDG-PET/CT parameters and pCR, median disease-free survival (DFS), and median overall survival (mOS).ResultsAt multivariable analysis, baseline SUVmax (high vs low: OR 9.00, CI 1.85 – 61.9, p=0.012) and Delta SUVmax (high vs low: OR 9.64, CI 1.84, 69.2, p=0.012) were significantly associated with pCR rates. Interestingly, we found that a combined analysis of the metabolic parameter Delta SUVmax with the volume-based parameter Delta MTV, may help to identify patients with pCR, especially in the subgroup of hormone receptor positive breast cancer. Delta SUVmax was also an independent predictive marker for both mDFS (high vs low: HR 0.17, 95%CI 0.05-0.58, p=0.004) and mOS (high vs. low: HR 0.19, 95%CI 0.04-0.95, p=0.029).DiscussionOur results suggest that Delta SUVmax may predict survival of early BC patients treated with PST.
Exploring the immunomodulatory effects and mechanisms of Xinjiang fermented camel milk-derived bioactive peptides based on network pharmacology and molecular docking
Authors: Wang Yuxing , Liang Zhuangzhuang , Shen Fang , Zhou Wenting , Manaer Tabusi , Jiaerken Didaier , Nabi Xinhua 
Published: January 2023

Purpose: Fermented camel milk from Xinjiang is rich in probiotics and has immunomodulatory effects as an important source of bioactive peptides. However, it is not clear whether it is the probiotic or the bioactive peptide that acts. The present study aimed to extract and identify bioactive peptides from fermented camel milk in Xinjiang and investigate their immunomodulatory effects and mechanisms based on network pharmacology and molecular docking.Methods: Four probiotic bacteria were used to ferment the fresh camel milk and the bioactive peptides were extracted and isolated by ultrafiltration and column chromatography. Network pharmacology predicts targets and pathways of action. GeneCards and OMIM-GENE-MAP database were used in order to search disease target genes and screen common target genes. Then we used STRING web to construct a protein-protein interaction (PPI) interaction network of the common target protein. The key targets were analyzed by GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis through the David database. The "drug (bioactive peptide)-disease-targets-pathway" network was established and molecular docking was used for prediction.Results: Two fractions were obtained by UV spectrophotometer; whey acidic protein, α-lactalbumin, and peptidoglycan recognition protein 1 were the main protein-like components of Xinjiang fermented camel milk-derived bioactive peptides. The repeat sequence of peptidoglycan recognition protein 1 was selected and then seven bioactive peptides were obtained. Bioactive peptides had 222 gene targets, anti-inflammatory diseases had 2598 gene targets, and immune regulation had 866 gene targets, the intersection of which was 66 in common gene targets. Gene ontology and KEGG analysis reveals that bioactive peptides mainly play a vital role in the signaling pathways of lipid and atherosclerosis, pathways in cancer. The molecular docking results showed that the seven bioactive peptides bound well to the top four scoring proteins.Conclusion: The immunomodulatory and anti-inflammatory effects and mechanisms of Xinjiang fermented camel milk-derived bioactive peptides were initially investigated by network pharmacology and molecular docking, providing a scientific basis for future studies.
Systems and in vitro pharmacology profiling of diosgenin against breast cancer
Authors: Khanal Pukar , Patil Vishal S. , Bhandare Vishwambhar V. , Patil Priyanka P. , Patil B. M. , Dwivedi Prarambh S. R. , Bhattacharya Kunal , Harish Darasaguppe R. , Roy Subarna 
Published: January 2023

Aim: The purpose of this study was to establish a mode of action for diosgenin against breast cancer employing a range of system biology tools and to corroborate its results with experimental facts.Methodology: The diosgenin-regulated domains implicated in breast cancer were enriched in the Kyoto Encyclopedia of Genes and Genomes database to establish diosgenin-protein(s)-pathway(s) associations. Later, molecular docking and the lead complexes were considered for molecular dynamics simulations, MMPBSA, principal component, and dynamics cross-correlation matrix analysis using GROMACS v2021. Furthermore, survival analysis was carried out for the diosgenin-regulated proteins that were anticipated to be involved in breast cancer. For gene expression analyses, the top three targets with the highest binding affinity for diosgenin and tumor expression were examined. Furthermore, the effect of diosgenin on cell proliferation, cytotoxicity, and the partial Warburg effect was tested to validate the computational findings using functional outputs of the lead targets.Results: The protein-protein interaction had 57 edges, an average node degree of 5.43, and a p-value of 3.83e-14. Furthermore, enrichment analysis showed 36 KEGG pathways, 12 cellular components, 27 molecular functions, and 307 biological processes. In network analysis, three hub proteins were notably modulated: IGF1R, MDM2, and SRC, diosgenin with the highest binding affinity with IGF1R (binding energy −8.6 kcal/mol). Furthermore, during the 150 ns molecular dynamics (MD) projection run, diosgenin exhibited robust intermolecular interactions and had the least free binding energy with IGF1R (−35.143 kcal/mol) compared to MDM2 (−34.619 kcal/mol), and SRC (-17.944 kcal/mol). Diosgenin exhibited the highest cytotoxicity against MCF7 cell lines (IC50 12.05 ± 1.33) µg/ml. Furthermore, in H2O2-induced oxidative stress, the inhibitory constant (IC50 7.68 ± 0.51) µg/ml of diosgenin was lowest in MCF7 cell lines. However, the reversal of the Warburg effect by diosgenin seemed to be maximum in non-cancer Vero cell lines (EC50 15.27 ± 0.95) µg/ml compared to the rest. Furthermore, diosgenin inhibited cell proliferation in SKBR3 cell lines more though.Conclusion: The current study demonstrated that diosgenin impacts a series of signaling pathways, involved in the advancement of breast cancer, including FoxO, PI3K-Akt, p53, Ras, and MAPK signaling. Additionally, diosgenin established a persistent diosgenin-protein complex and had a significant binding affinity towards IGF1R, MDM2, and SRC. It is possible that this slowed down cell growth, countered the Warburg phenomenon, and showed the cytotoxicity towards breast cancer cells.
Efficacy and safety of Keluoxin capsule in combination with Western medicine for diabetic kidney disease: A systematic review and meta-analysis
Authors: Zhang Wenhua , Zhou Jingxin , Wang Churan , Wang Xu , Zhang Shuwen , Jia Weiyu , Jiang Yijia , Lin Lan , Gong Yanbing 
Published: January 2023

Objective: Keluoxin capsule (KLXC) has been widely used in diabetic kidney disease (DKD), but its efficacy and safety have not yet been clarified. A systematic review and meta-analysis were performed to assess the efficacy and safety of KLXC for DKD.Methods: The randomized control trials (RCTs) included KLXC searched from seven major English and Chinese databases up until 3 June 2022. The methodological quality and risk of bias were assessed by version 2 of the Cochrane risk-of-bias tool (RoB 2) for the RCTs from the Cochrane Handbook. The analyses were conducted by RevMan 5.4 and Stata 17.0.Results: A total of 20 trials with 1,500 participants were identified. The meta-analysis showed that KLXC combined with Western medicine was superior to the use of Western medicine alone for DKD which included improvements in the estimated glomerular filtration rate (eGFR) [MD = 3.04, 95% CI (0.30, 5.78), p = 0.03], reduction in microalbuminuria (mALB) [MD = −25.83, 95% CI (−41.20, −10.47), p = 0.001], urinary albumin excretion rate (UAER) [SMD = −0.97, 95% CI (−1.50, −0.44), p = 0.0003], 24-h urine protein (24hUpro) [SMD = −1.31, 95% CI (−1.82, −0.80), p &lt; 0.00001], serum creatinine (Scr) [MD = −11.39, 95% CI (−18.76, −4.02), p = 0.002], blood urea nitrogen (BUN) [MD = −1.28, 95% CI (−1.67, −0.88), p &lt; 0.00001], fasting blood glucose (FBG) [MD = −0.51, 95% CI (−0.90, −0.11), p = 0.01], total cholesterol (TC) [MD = −1.04, 95% CI (−1.40, −0.68), p &lt; 0.00001], triglycerides (TG) [MD = −0.36, 95% CI (−0.50, −0.23), p &lt; 0.00001], and low-density lipoprotein cholesterol (LDL) [MD = −0.39, 95% CI (−0.71, −0.07), p = 0.02]. Results showed no statistically significant difference in glycated hemoglobin (HbA1c) (p = 0.14) or adverse events (p = 0.81) between the two groups.Conclusion: The combination of KLXC and Western medicine had a positive effect on DKD. However, due to the high clinical heterogeneity and low quality of included studies, further standardized, large-scale, rigorously designed RCTs for DKD in the definitive stage are still necessary to achieve more accurate results.Systematic Review Registration:https://inplasy.com/inplasy-2021-11-0067/, identifier INPLASY 2021110067.
Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway
Authors: Niu Ting , Wei Zhiying , Fu Jiao , Chen Shu , Wang Ru , Wang Yuya , Zheng Ruihe 
Published: January 2023

Introduction: Venlafaxine is one of the most commonly used anti-depressant and antineoplastic drug. Previous studies have predicted venlafaxine as an anti-cancer compound, but the therapeutic effects of venlafaxine in melanoma have not yet been demonstrated. Nur77 is an orphan nuclear receptor that highly expressed in melanoma cells and can interact with Bcl-2 to convert Bcl-2 from an antiapoptotic to a pro-apoptotic protein.Method: We examined the effects of venlafaxine in MV3 cells in vitro and MV3 xenograft tumor in nude mice. Western-blot, PCR, TUNEL assay and immunofluorescence were used to reveal the growth of melanoma cells.Results: Here, our data revealed that venlafaxine could reduce the growth, and induce apoptosis of melanoma cells through a Nur77-dependent way. Our results also showed that treatment with venlafaxine (20 mg/kg, i.p.) potently inhibited the growth of melanoma cells in nude mice. Mechanistically, venlafaxine activated JNK1/2 signaling, induced Nur77 expressions and mitochondrial localization, thereby promoting apoptosis of melanoma cells. Knockdown of Nur77 and JNK1/2, or inhibition of JNK1/2 signaling with its inhibitor SP600125 attenuated the anti-cancer effects of venlafaxine.Conclusion: In summary, our results suggested venlafaxine as a potential therapy for melanoma.
Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India
Authors: Resendiz-Galvan Juan Eduardo , Arora Prerna R. , Abdelwahab Mahmoud Tareq , Udwadia Zarir F. , Rodrigues Camilla , Gupta Amita , Denti Paolo , Ashavaid Tester F. , Tornheim Jeffrey A. 
Published: January 2023

Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either dose-adjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300 mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21–35), weight 55.0 kg (IQR 45.6–65.8), and fat-free mass 38.7 kg (IQR 32.7–46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81 L/h. Simulations predicted that treatment with 300 mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA &gt;90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%). These data suggest potential benefit to individualized dosing taking host and microbial characteristics into account to improve the likelihood of treatment efficacy while minimizing risk of toxicity from linezolid for the treatment of MDR-TB. Further prospective evaluation in different clinical settings is urgently needed to inform safety and efficacy of these lower doses.
Bear bile powder ameliorates type 2 diabetes via modulation of metabolic profiles, gut microbiota, and metabolites
Authors: Chen Xing-Ling , Cai Ke , Zhang Wen , Su Shu-Lan , Zhao Li-Hui , Qiu Li-Ping , Duan Jin-Ao 
Published: January 2023

Introduction: Bear bile powder (BBP) is widely used in the clinic and has a hypoglycemic effect, but its mechanism is not clear.Methods: In this study, type 2 diabetes mellitus (T2DM) rats induced by a high-sugar and high-fat diet combined with streptozotocin were given BBP, and biochemical indexes, pathological sections, metabonomics, intestinal microbiota (IM) and short-chain fatty acids (SCFAs) were determined.Results: The results showed that BBP could reduce blood glucose, relieve inflammation, insulin resistance, and lipid metabolism disorder, and alleviate tissue damage of the liver, spleen, kidney, and pancreas in T2DM rats. It is worth noting that BBP can reverse the changes in blood and urine metabolites in T2DM rats, which are mainly related to tryptophan metabolism, pentose and glucuronate interconversions, starch and sucrose metabolism, and glycerophospholipid metabolism. In addition, BBP restored IM disorder in T2DM rats, decreased the abundance of Allobaculum, Blautia, Dubosiella, and Anaerostipes, enriched the abundance of Lactobacillus, Romboutsia, UCG-005, and norank_f__Eggerthellaceae, and increased the concentration of SCFAs in intestinal contents.Discussion: These findings suggest that BBP may improve T2DM by regulating multiple metabolic pathways, IM composition, and SCFAs levels.
Cost-effectiveness of fuzuloparib compared to routine surveillance, niraparib and olaparib for maintenance treatment of patients with germline BRCA1/2 mutation and platinum-sensitive recurrent ovarian carcinoma in China
Authors: Nie Jing , Wu Huina , Sun Lei , Ding Yanjiao , Luan Yepeng , Wu Jiyong 
Published: January 2023

Background: Maintenance therapy with the poly (ADP-ribose) polymerase inhibitors (PARPis) for platinum-sensitive recurrent ovarian carcinoma (OC) have proven to be effective compared with placebo. We aimed to evaluate the cost-effectiveness (CE) of maintenance fuzuloparib compared to routine surveillance (RS), niraparib and olaparib for platinum-sensitive recurrent OC from the Chinese healthcare systems.Method: A partitioned survival model with three-state (progression-free, progressed, death) was constructed utilizing TreeAge Pro 2011 software to evaluate the economic value of fuzuloparib, niraparib and olaparib maintenance treatment for platinum-sensitive recurrent OC based on the clinical data derived from FZOCUS-2, ENGOT-OV16/NOVA and ENGOT-Ov21/SOLO2. Transition probabilities were estimated from the reported survival probabilities in those trials. Cost and health preference data were derived from the literature. The quality-adjusted life-years (QALYs) and lifetime costs were measured for this analysis. A 5 years horizon and 5%/year discount rates were used. One-way analysis, and probabilistic sensitivity analysis (PSA) were performed to explore the model uncertainties.Results: Total cost of fuzuloparib, niraparib and olaparib were $31628.10, $48183.48 and $54605.54, whereas they had an incremental cost-utility ratio of $31992.69, $32216.08 and $23359.26 per additional progression-free survival (PFS) QALYs gained compared with RS, relatively. Model showed that maintenance fuzuloparib achieved at least an 85.5% probability of CE at the threshold of $37654.50/QALY. One-way sensitivity analysis revealed that the results were sensitive to the PFS and the price of medicines.Conclusion: Fuzuloparib was less cost-effective for patients with germline BRCA1/2 mutation and platinum-sensitive recurrent OC compared to olaparib, but was superior to niraparib from the Chinese healthcare systems perspective.
High-flux positron generation via the ultra-intense laser irradiating density-modulated plasmas
Authors: Liu Jian-Xun , Gao Ting , Wang Xu , Jin Hong-Bin , Deng Wei-Qiang , Liu Tai-Yang , Yu Tong-Pu 
Published: January 2023

To investigate plasma density during the Breit–Wheeler positron generation, a comparative study of four plasma targets is performed via the PIC (particle-in-cell) code EPOCH. When an ultra-intense laser (2.8×1023 Wcm−2) is incident, more positrons with high energy are generated in the increasing density plasmas. The positron yield is already 1.5×108 with a cutoff energy of 2 GeV at t=37T0. It is demonstrated that increasing density plasmas will enhance gamma photon radiation and positron generation. In increasing density plasmas, under-dense plasmas favor electron acceleration, and over-dense plasmas will induce laser reflection. Cross sections of the Compton back-scattering and the BW positron generation are both increased via high-energy electrons colliding with the reflected laser. In addition, increasing the laser intensity will directly enhance positron generation. This investigation will further facilitate high-flux positron generation and application.
Menstrual phase influences cerebrovascular responsiveness in females but may not affect sex differences
Authors: Skinner Bethany D. , Weaver Samuel R. C. , Lucas Samuel J. E. , Lucas Rebekah A. I. 
Published: January 2023

Background and aims: Sex differences in the rate and occurrence of cerebrovascular diseases (e.g., stroke) indicate a role for female sex hormones (i.e., oestrogen and progesterone) in cerebrovascular function and regulation. However, it remains unclear how cerebrovascular function differs between the sexes, and between distinct phases of the menstrual cycle. This study aimed to compare cerebrovascular-CO2 responsiveness in 1) females during the early follicular (EF), ovulatory (O) and mid-luteal (ML) phases of their menstrual cycle; and 2) males compared to females during phases of lower oestrogen (EF) and higher oestrogen (O).Methods: Eleven females (25 ± 5 years) complete experimental sessions in the EF (n = 11), O (n = 9) and ML (n = 11) phases of the menstrual cycle. Nine males (22 ± 3 years) completed two experimental sessions, approximately 2 weeks apart for comparison to females. Middle and posterior cerebral artery velocity (MCAv, PCAv) was measured at rest, during two stages of hypercapnia (2% and 5% CO2 inhalation) and hypocapnia (voluntary hyperventilation to an end-tidal CO2 of 30 and 24 mmHg). The linear slope of the cerebral blood velocity response to changes in end-tidal CO2 was calculated to measure cerebrovascular-CO2 responsiveness..Results: In females, MCAv-CO2 responsiveness to hypocapnia was lower during EF (−.78 ± .45 cm/s/mmHg) when compared to the O phase (−1.17 ± .52 cm/s/mmHg; p &lt; .05) and the ML phase (−1.30 ± .82; p &lt; .05). MCAv-CO2 responsiveness to hypercapnia and hypo-to-hypercapnia, and PCAv-CO2 responsiveness across the CO2 range were similar between menstrual phases (p ≥ .20). MCAv-CO2 responsiveness to hypo-to hypercapnia was greater in females compared to males (3.12 ± .91 cm/s/mmHg vs. 2.31 ± .46 cm/s/mmHg; p = .03), irrespective of menstrual phase (EF or O).Conclusion: Females during O and ML phases have an enhanced vasoconstrictive capacity of the MCA compared to the EF phase. Additionally, biological sex differences can influence cerebrovascular-CO2 responsiveness, dependent on the insonated vessel.
Sex differences in stretch-induced hypertrophy, maximal strength and flexibility gains
Authors: Warneke Konstantin , Zech Astrid , Wagner Carl-Maximilian , Konrad Andreas , Nakamura Masatoshi , Keiner Michael , Schoenfeld Brad J. , Behm David George 
Published: January 2023

Introduction: If the aim is to increase maximal strength (MSt) and muscle mass, resistance training (RT) is primarily used to achieve these outcomes. However, research indicates that long-duration stretching sessions of up to 2 h per day can also provide sufficient stimuli to induce muscle growth. In RT literature, sex-related differences in adaptations are widely discussed, however, there is a lack of evidence addressing the sex-related effects on MSt and muscle thickness (MTh) of longer duration stretch training. Therefore, this study aimed to investigate the effects of 6 weeks of daily (1 h) unilateral static stretch training of the plantar flexors using a calf-muscle stretching device.Methods: Fifty-five healthy (m = 28, f = 27), active participants joined the study. MSt and range of motion (ROM) were measured with extended and flexed knee joint, and MTh was investigated in the medial and lateral heads of the gastrocnemius.Results: Statistically significant increases in MSt of 6%–15% (p &lt; .001–.049, d = 0.45–1.09), ROM of 6%–21% (p &lt; .001–.037, d = 0.47–1.38) and MTh of 4%–14% (p &lt; .001–.005, d = 0.46–0.72) from pre-to post-test were observed, considering both sexes and both legs. Furthermore, there was a significant higher increase in MSt, MTh and ROM in male participants. In both groups, participants showed more pronounced adaptations in MSt and ROM with an extended knee joint as well as MTh in the medial head of the gastrocnemius (p &lt; .001–.047). Results for relative MSt increases showed a similar result (p &lt; .001–.036, d = 0.48–1.03).Discussion: Results are in accordance with previous studies pointing out significant increases of MSt, MTh and ROM due to long duration static stretch training. Both sexes showed significant increases in listed parameters however, male participants showed superior increases.