Late coronary artery injury following chemoradiotherapy for thymic carcinoma: a case report.

INTRODUCTION: Surgery remains the primary treatment modality for thymic carcinoma, with adjuvant radiotherapy being recommended to effectively mitigate local recurrence and metastasis rates subsequent to incomplete or complete resection. Chemoradiotherapy has the potential to induce coronary artery occlusion, thereby potentially impacting patients' long-term survival rates. The existing literature currently lacks comprehensive research on the lesion characteristics of coronary artery injury resulting from chemoradiotherapy. CASE PRESENTATION: The male patient, aged 55, was admitted to the hospital due to recurrent chest tightness and pain persisting for one week. Notably, the patient had previously undergone curative resection surgery for thymic carcinoma seven years ago. After the surgical procedure, the patient underwent a course of adjuvant chemotherapy comprising docetaxel and platinum. 11 months later, imaging examination diagnosed tumor recurrence, and concurrent chemoradiotherapy was administered at a total dose of 62 Gy/31F for planning gross target volume (PGTV) and 54 Gy/31F for planning target volume (PTV) with 2 cycles of paclitaxel and cisplatin. Re-admission of the patient occurred after a 7-year interval subsequent to the completion of concurrent chemoradiotherapy, leading to a subsequent diagnosis of acute non-ST segment elevation myocardial infarction. Following administration of antiplatelet, anticoagulant, and anti-myocardial ischemia therapy, coronary angiography revealed the presence of a bifurcation lesion at the distal end of the left main trunk. Intravascular ultrasound (IVUS) examination demonstrated significant negative remodeling of both the main trunk and its branches at the bifurcation site, characterized by minimal atherosclerotic plaque components. CONCLUSIONS: Chemoradiotherapy may induce damage to endothelial cells, resulting in an inflammatory response. Negative remodeling of blood vessels is likely to occur, primarily characterized by vasoconstriction but with less atherosclerotic plaque burden. Routine stent implantation in negatively remodeled areas may lead to vascular rupture, necessitating intravascular imaging examination.

Design of a Compact 2-6 GHz High-Efficiency and High-Gain GaN Power Amplifier.

In this paper, a novel wideband power amplifier (PA) operating in the 2-6 GHz frequency range is presented. The proposed PA design utilizes a combination technique consisting of a distributed equalization technique, multiplexing the power supply network and matching network technique, an LR dissipative structure, and an RC stability network technique to achieve significant bandwidth while maintaining superior gain flatness, high efficiency, high gain, and compact size. For verification, a three-stage PA using the combination technique is designed and implemented in a 0.25 µm GaN high-electron-mobility transistor (HEMT) process. The fabricated prototype demonstrates a saturated output power of 4 W, a power gain of 21 dB, a gain flatness of ±0.6 dB, a power-added efficiency of 39-46%, and a fractional bandwidth of 100% under the operating conditions of drain voltage 28 V (continuous wave) and gate voltage -2.6 V. Moreover, the chip occupies a compact size of only 2.51 mm × 1.97 mm.

The RNA sequencing results revealed the expression of different genes and signaling pathways during chemotherapy resistance in peripheral T-cell lymphoma.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is a subtype of non-Hodgkin's lymphoma that occurs primarily at extranodal sites and is commonly treated using chemotherapy and radiotherapy. PTCL is more malignant than other lymphoid tumors, resulting in a poor prognosis.The 5-year recurrence rate remains high, and there is a lack of standard treatment for patients with relapse-resistant disease. However, the molecular mechanisms underlying the resistance of peripheral T-cell lymphoma cells to chemotherapeutic drugs, as well as identifying strategies to overcome drug resistance remains unclear. In this study, we aimed to identify pivotal genes and signaling pathways associated with chemotherapy resistance in PTCL. METHODS: In this study, a total of 5 healthy controls and 7 clinical patients were enrolled; 4 patients were classified as chemotherapy sensitive, and 3 patients were classified as chemotherapy resistant. Peripheral blood samples were collected from each participant, and total RNA was extracted from the white blood cells. RNA sequencing was conducted on the Illumina HiSeq platform to obtain comprehensive gene expression profiles. Subsequently, the expression patterns of the DEGs associated with the most enriched signaling pathways, with a special focus on cancer-related genes, were validated using quantitative real-time polymerase chain reaction (qRT-PCR) in peripheral TCL patients. RESULTS: RNA sequencing (RNA-seq) analysis revealed 4063 differentially expressed genes (DEGs) in peripheral T-cell lymphoma specimens from patients with chemotherapy resistance, of which 1128 were upregulated and 2935 were downregulated. Subsequent quantitative gene expression analysis confirmed a differential expression pattern in all the libraries, with 9 downregulated genes and 10 upregulated genes validated through quantitative real-time PCR in 6 clinical specimens from patients with chemotherapy resistance. KEGG pathway analysis revealed significant alterations in several pathways, with 6 downregulated pathways and 9 upregulated pathways enriched in the DEGs. Notably, the TNF signaling pathway, which is extensively regulated, was among the pathways that exhibited significant changes. These findings suggest that DEGs and the TNF signaling pathway may play crucial roles in chemotherapy resistance in peripheral T-cell lymphoma. CONCLUSION: Our study revealed that the expression of specific genes, including TNFRSF1B, TRADD2, and MAP3K7, may play an important role in chemotherapy resistance in peripheral T-cell lymphoma. Moreover, we identified the downregulation of the TNF signaling pathway, a crucial pathway involved in cell survival, death, and differentiation, as a potential contributor to the development of chemotherapy resistance in peripheral T-cell lymphoma. These findings provide valuable insights into the molecular mechanisms underlying chemotherapy resistance and highlight potential targets for overcoming treatment resistance in this challenging disease.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

Tenapanor in Chinese ESRD patients with hyperphosphatemia on haemodialysis: a randomised, phase 3 trial.

Background: The efficacy and safety of tenapanor has not been confirmed in Chinese end-stage renal disease (ESRD) patients with hyperphosphatemia on haemodialysis (HD). Methods: This was a randomised, double blind, phase 3 trial conducted at 26 dialysis facilities in China (https://www.chictr.org.cn/index.aspx; CTR20202588). After a 3-week washout, adults with ESRD on HD with hyperphosphatemia were randomised (1:1) using an interactive web response system to oral tenapanor 30 mg twice a day or placebo for 4 weeks. The primary endpoint was the change in mean serum phosphorous level from baseline to the endpoint visit (day 29 or last serum phosphorus measurement). Efficacy was analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drug. Results: Between 5 March 2021 and 8 June 2022, 77 patients received tenapanor and 73 received placebo. Tenapanor treatment (n = 75) resulted in a significantly greater least squares (LS) mean reduction in serum phosphate at the endpoint visit versus placebo (n = 72): LS mean difference -1.17 mg/dl (95% CI -1.694 to -0.654, P < .001). More patients receiving tenapanor achieved a serum phosphorous level <5.5 mg/dl at the endpoint visit (44.6% versus 10.1%). The most common treatment-related adverse event was diarrhoea [tenapanor 28.6% (22/77), placebo 2.7% (2/73)], which was mostly mild and led to treatment discontinuation in two patients receiving tenapanor. Conclusions: Tenapanor significantly reduced the serum phosphorous level versus placebo in Chinese ESRD patients on HD and was generally well tolerated.

M6A demethylase ALKBH5 regulates FOXO1 mRNA stability and chemoresistance in triple-negative breast cancer.

Resistance to chemotherapy is the main reason for treatment failure and poor prognosis in patients with triple-negative breast cancer (TNBC). Although the association of RNA N6-methyladenosine (m6A) modifications with therapy resistance is noticed, its role in the development of therapeutic resistance in TNBC is not well documented. This study aimed to investigate the potential mechanisms underlying reactive oxygen species (ROS) regulation in doxorubicin (DOX)-resistant TNBC. Here, we found that DOX-resistant TNBC cells displayed low ROS levels because of increased expression of superoxide dismutase (SOD2), thus maintaining cancer stem cells (CSCs) characteristics and DOX resistance. FOXO1 is a master regulator that reduces cellular ROS in DOX-resistant TNBC cells, and knockdown of FOXO1 significantly increased ROS levels by inhibiting SOD2 expression. Moreover, the m6A demethylase ALKBH5 promoted m6A demethylation of FOXO1 mRNA and increased FOXO1 mRNA stability in DOX-resistant TNBC cells. The analysis of clinical samples revealed that the increased expression levels of ALKBH5, FOXO1, and SOD2 were significantly positively correlated with chemoresistance and poor prognosis in patients with TNBC. To our knowledge, this is the first study to highlight that ALKBH5-mediated FOXO1 mRNA demethylation contributes to CSCs characteristics and DOX resistance in TNBC cells. Furthermore, pharmacological targeting of FOXO1 profoundly restored the response of DOX-resistant TNBC cells, both in vitro and in vivo. In conclusion, we demonstrated a critical function of ALKBH5-mediated m6A demethylation of FOXO1 mRNA in restoring redox balance, which in turn promoting CSCs characteristics and DOX resistance in TNBC, and suggested that targeting the ALKBH5/FOXO1 axis has therapeutic potential for patients with TNBC refractory to chemotherapy.

The New Role of HNF1A-NAS1/miR-214/INHBA Signaling Axis in Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and one of the leading causes of death worldwide. Seriously threatens human life and health. Previous studies have identified that inhibin ßA (INHBA) could induce tumorgenesis and progression of CRC through the regulation of the TGF-ß/Smad signal axis. The abnormal expression of INHBA is related to the poor prognosis of patients. The aim of this study was to identify the molecular mechanism of HNF1A-AS1 and miR-214 regulating INHBA and carcinogenesis through bioinformatics combined with experiments. METHODS: The expression of HNF1A-AS1, miRNA-214-5p, INHBA in pan-cancer and CRC were investigated in the Cancer Genome Atlas (TCGA). The correlation between HNF1A-AS1 and immune-related genes or miRNAs was explored via the Gene Expression Profiling Interactive Analysis (GEPIA) and volcano plots, respectively. The association between HNF1A-AS1 and differentially expressed miRNAs was constructed by TargetScan. The miRDB, miRWalk, and TargetScan databases were utilized to predict the target genes of hsa-miR-214. The expression of INHBA in tissues and cell lines of CRC was examined by RT-qPCR and western blot assay. RESULTS: The INHBA and HNF1A-AS1 expressions were increased in Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) of the TCGA database. Hsa-miR-214 was relatively less expressed in CRC tissues compared with para-cancer tissues. The expression of HNF1A-AS1 was negatively correlated with hsa-miR-214. INHBA was one of the target genes of hsa-miR-214 based on miRDB, miRWalk, and TargetScan databases. The specific binding sites of INHBA-3'UTR and miR-214-5p were identified by starBase. The expression level of INHBA was positively correlated with the T stage of tumor and negatively correlated with overall survival (OS) and disease-free survival (DFS) in CRC patients. The results of RT-qPCR and western blot indicated that the expression of INHBA in tissues and cell lines in CRC was higher than those in para-carcinoma tissues and normal colon cell lines, respectively. CONCLUSIONS: These findings suggested that HNF1A-AS1 and miRNA-214-5p were key upstream non-coding RNAs of INHBA. The HNF1A-AS1/miR-214/INHBA signal axis plays a significant role in the tumorgenesis and progression of CRC. By interfering with HNF1A-AS1 and INHBA genes on HT29 and SW480 cells, it was found that HNF1A-AS1 and INHBA genes may be important target genes in CRC.

Effect of High-Fat Food on the Pharmacokinetic Profile and Safety of SAF-189s, an ALK/ROS1 Inhibitor, in Healthy Chinese Adults.

BACKGROUND AND OBJECTIVES: This study was conducted to investigate the effect of high-fat meals on the pharmacokinetics (PK) and safety profile of SAF-189s, a novel ALK/ROS1 inhibitor. METHODS: This was a single-center, phase I, open-label, crossover study in which healthy adults (≥18 years) were randomized (1:1) to two sequences of SAF-189s administration (fasted-fed or fed-fasted) separated by a 14-day washout. After a ≥10-h overnight fast, volunteers received SAF-189s 160 mg orally in a fasted state or 30 min after a high-fat, high-calorie meal. Similarity of pharmacokinetic parameters was concluded if the 90% CI for the geometric mean ratio (GMR) between the fed and fasted group fell within the predefined range of 0.80-1.25. RESULTS: In total, 24 subjects were enrolled and 23 completed the study. SAF-189s maximum plasma concentration (Cmax; GMR: 109.1% [90% CI 103.1-115.4]) was comparable under fed (high-fat meal, n = 24) versus fasted (n = 23) conditions, with no effect on area under the plasma concentration-time curve from time 0 to t (AUC0-t; GMR: 105.1% [90% CI 100.3-110.2]) and AUC from time 0 to infinity (AUC0-∞; GMR: 105.5% [90% CI, 100.6-110.6]). In both groups, the median time to maximum plasma concentration (tmax) was around 6 h and mean plasma half-life (t½) was around 35 h. Fed administration led to a lower incidence of treatment-emergent adverse events (TEAEs; 29.2% vs 54.2%), including gastrointestinal disorders (4.2% vs 41.7%) and headache (0.0% vs 12.5%), versus fasted administration. CONCLUSIONS: A high-fat meal had minimal effect on the pharmacokinetic profile of SAF-189s compared with a fasted state following a single dose of 160 mg. Administration with a high-fat meal led to a lower incidence of TEAEs.

Survival analysis of patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment of Yunnan in southwestern China: a real-world study.

Importance: Patients with EGFR mutations who have advanced-stage non-small cell lung cancer (NSCLC) already receive tyrosine kinase inhibitors (TKIs) as the standard first-line therapy. Notably, Yunnan is a regional high incidence area of lung cancer in the highlands with a high rate of rare EGFR mutations. Overall, lung cancer patients in Xuanwei may present a distinct subgroup globally. Recent studies suggested that the NSCLC cohort in Xuanwei harbored a significantly higher uncommon mutation rate. However, little was known about the clinicopathological features and treatment efficacy of EGFR-TKI in Yunnan NSCLC patients. Objective: This study aimed to investigate the clinical impact of histologic type on the survival outcomes of patients with stage IIIB and IV NSCLC receiving EGFR-TKI treatment of Yunnan in southwestern China. Methods: In this retrospective study, we enrolled advanced NSCLC patients (IIIB-IV) with EGFR mutations who were first diagnosed and treated at Yunnan Cancer hospital from January 2016 to December 2019. Sociodemographics, lifestyle, survival, and clinicopathological characteristics of the patients were collected. The Kaplan-Meier method was used to assess the OS and PFS of patients. An analysis of prognostic factors was conducted using Cox regression. Results: A total of 468 eligible patients were included. The median progression-free survival (PFS) and overall survival(OS) were 11.30(95% CI, 10.12-12.48) months and 30.30(95% CI, 26.24-34.36) months. Based on survival analysis among all the patients,females(HR=0.815;95% CI:0.671-0.989; P=0.017), Xuanwei origin (HR=0.776; 95% CI: 0.609-0.989; P=0.040), sample types(HR=0.780; 95% CI: 0.642-0.947; P=0.012) had a longer PFS. Multivariable analysis showed that only the sample type was an independent factor on median PFS with EGFR-TKI therapy. Patients less than 60 years old (HR=1.433; 95% CI:1.134-1.812, P=0.003)had better OS, but objectives with BMI≥24kg/m2(HR=0.653; 95% CI: 0.500-0.864; P=0.002), females(HR=0.776; 95% CI:0.613-0.982; P=0.035)and patients with tissue sample type (HR=0.760; 95% CI:0.600-.0961; P=0.022) had better OS. Notably, subgroup analysis of our study also found that PFS was significantly better in patients with G719X, L861Q, S768I, G719X+L861Q, and G719X+S768I in Xuanwei than classical mutation ones, including 19-Del and L858R (median 22.7 vs. 12.0 months, HR=0.523, P=0.010), while PFS was inferior in patients with rare mutations of EGFR in non-Xuanwei than the classical mutation ones (median 5.10 vs. 11.10 months, HR=1.760, P=0.015). Conclusion: NSCLC patients in Yunnan displayed a unique EGFR mutation profile, especially a higher prevalence of EGFR uncommon and compound mutations subtype. This study indicates prognostic factors of NSCLC treated with EGFR-TKI in Yunan and Xuanwei. This study will provide new clinical evidence for EGFR-TKI-targeted therapy in patients with rare EGFR mutations in China and worldwide. More researchs were needed for NSCLC EGFR-TKI therapy and medical insurance policy-making in Yunnan, Xuanwei area and uncommon especially.

Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China.

Background: Immune thrombocytopenia (ITP) is an autoimmune disorder with decreased platelet counts and increased bleeding risk. Objectives: To evaluate the efficacy and safety of avatrombopag, a second-generation oral thrombopoietin receptor agonist, for the treatment of Chinese patients with chronic primary ITP. Methods: This multicenter, randomized, double-blind, placebo-controlled phase 3 study (CTR20210431) consisted of a 6-week double-blind core treatment phase followed by a 20-week, open-label extension phase. Chinese adults with chronic primary ITP for at least 12 months and a platelet count <30 × 109/L were randomized (2:1) to receive avatrombopag (initial dose of 20 mg/day) or matched placebo. The primary endpoint was the proportion of subjects with a platelet count ≥50 × 109/L at week 6 of the core treatment phase in absence of rescue therapy. Results: In total, 74 patients were randomized (avatrombopag: N = 48; placebo: N = 26) between March 5, 2021, and August 6, 2021; all of whom entered the extension phase (72 received avatrombopag up to 26 weeks). At week 6 of the core study, the platelet response (≥50 x 109/L) rate was significantly higher in the avatrombopag group (77.1%; 95% CI, 62.7, 88.0) vs placebo (7.7%; 95% CI, 1.0, 25.1); the treatment difference was 69.4% (95% CI, 56.2, 86.3; P < .0001). During the 6-week core study, treatment-emergent adverse events were reported in 41 (85.4%) and 20 (76.9%) patients in the avatrombopag and placebo groups, respectively. The most common avatrombopag-related treatment-emergent adverse events were upper respiratory tract infection (14/48 [29.2%]), increased platelet count (13/48 [27.1%]) and headache (7/48 [14.6%]). Conclusion: Avatrombopag was efficacious and generally well tolerated in Chinese patients with chronic primary ITP, with comparable efficacy and safety to previous reports in Western patients.

[Review on the Long-term and Short-term Effects of Biochar Addition on Soil Greenhouse Gas Emissions].

Increasing concentrations of greenhouse gases in the atmosphere caused by human activities are the main cause of climate warming. Global warming is a severe challenge confronted by human society today. Reducing greenhouse gas emissions and increasing carbon sinks are the keys to addressing climate warming. Biochar addition is considered to be a promising way to reduce greenhouse gas emissions and increase carbon sinks, due to its unique physical, chemical, and biological properties. Therefore, it is of great significance to study the effects of biochar on soil greenhouse gas emissions to mitigate the greenhouse effect and achieve "carbon neutrality." The long-term and short-term effects of biochar on soil greenhouse gas emissions and their influencing mechanism were reviewed. It was found that the effects of biochar on soil greenhouse gas emissions varied with the types of biochar feedstock, pyrolysis temperature, application ratio, and soil and vegetable types. In addition, due to the different aging times and modes and cultivation methods, the mitigation effect of aged biochar on soil greenhouse gas could be enhanced or weakened or even disappeared. Further, based on the deficiencies of the previous research, the direction and focus of future research on the effects of biochar on soil greenhouse gas emissions were analyzed and prospected. It was proposed to strengthen simultaneous research on the effects of biochar on CO2, N2O, and CH4 emissions; reducing greenhouse gas emissions and carbon sequestration; different aging modes and cultivation methods of biochar; and revealing the influencing mechanism at the process level, through exploring the effects of biochar on soil carbon and nitrogen dynamics and tracing the source of greenhouse gases using 13C and 15N tracer technology.

Chitosan/copper sulfide nanoparticles (CS/CuSNPs) hybrid fibers with improved mechanical and photo-thermal conversion properties via tuning CuSNPs' morphological structures.

Conventional textiles are inadequate for maintaining warmth in extremely cold conditions. Therefore, the development of photo-thermal fibers for personal thermal management textiles has emerged as an urgent need. Herein, novel chitosan/copper sulfide nanoparticles (CS/CuSNPs) hybrid fibers with photo-thermal function were fabricated successfully. Significantly, our study demonstrated that the tensile and photo-thermal conversation properties of the CS/CuSNPs hybrid fibers could be effectively regulated by altering the CuSNPs` morphological structures. Compared with other CuSNPs (tube-like, sphere-like, and flower-like), the plate-like CuSNPs with smooth surfaces and uniform nanometer size played a significant role by scattering incident light in the fibers as a secondary light source for CuSNPs absorbance. Thus, under IR light irradiation at a power density of 1.0 W/cm2, the surface temperature of CS/0.1 wt% plate-like CuSNPs hybrid fibers sharply increased by 27.6 °C, which was more than 4 times of the pure CS fibers. And the breaking strength and initial modulus of CS/0.1 wt% plate-like CuSNPs hybrid fibers increased by more than 18.37 and 6.88 % compared with the nascent CS fibers. This study develops a novel and effective strategy to tune the photo-thermal and tensile properties of CS hybrid fibers without incorporating more content or additives.

Safety and Pharmacokinetics of PSD502 in Healthy Chinese Male and Female Volunteers: Two Randomized, Double-Blind, Placebo-Controlled, Phase I Trials.

BACKGROUND AND OBJECTIVE: PSD502 is a metered-dose spray for premature ejaculation. The two trials aimed to evaluate the safety and pharmacokinetics of PSD502 in healthy Chinese male and female individuals. METHODS: Two phase I, randomized, double-blind, placebo-controlled trials were conducted in men (Trial 1) and women (Trial 2). The participants were randomized 3:1 to receive PSD502 (7.5 mg of lidocaine and 2.5 mg of prilocaine per spray) or a placebo. For male individuals, a single dose (three sprays) once daily was applied to the glans penis for 21 days except for nine sprays (three doses) on days 7 and 14, 4 h apart for each dose. For female individuals, two sprays were applied to the vagina and one to the cervix once daily for 7 days. The primary endpoint was safety. Pharmacokinetics analysis was also performed. RESULTS: Twenty-four male and 24 female individuals were recruited. Treatment-emergent adverse events occurred in 38.9% (7/18) of male individuals and 66.7% (12/18) of female individuals in the PSD502 group, respectively. Both trials reported 50.0% (3/6) treatment-emergent adverse events for the placebo. No grade ≥ 3 treatment-emergent adverse events, serious adverse events, or treatment-emergent adverse events leading to early withdrawal or discontinuation occurred. After consecutive applications, lidocaine and prilocaine cleared rapidly in both trials. Plasma concentrations exhibited high inter-individual variability. The maximum plasma concentrations of active ingredients were far below the anticipated minimum toxic concentrations. The area under the plasma concentration-time curve of metabolites were ≤ 20% of the parent drugs. No clinically significant accumulations were observed in the two trials. CONCLUSIONS: PSD502 was well tolerated and showed low plasma concentrations in healthy Chinese male and female individuals.

Sodium alginate/chitosan-coated TiO2NPs hybrid fiber with photocatalytic self-cleaning property, UV resistance and enhanced tensile strength.

SA/CS-coated TiO2NPs hybrid fibers with photocatalytic self-cleaning properties, UV resistance and enhanced tensile strength were successfully prepared by adding CS-coated TiO2NPs to SA matrix. The FTIR and TEM results demonstrate the successful preparation of CS-coated TiO2NPs core-shell structured composite particles. SEM and Tyndall effect results showed that the core-shell particles were uniformly dispersed in the SA matrix. When the content of Core-shell particles increased from 0.1 to 0.3 wt%, the tensile strength of SA/CS-coated TiO2NPs hybrid fibers increased from 26.89 to 64.45 % compared with SA/TiO2NPs hybrid fibers. The SA/CS-coated TiO2NPs hybrid fiber (0.3 wt%) exhibits excellent photocatalytic degradation performance, achieving a 90 % degradation rate for the RhB solution. And the fibers also exhibit outstanding photocatalytic degradation performance towards various dyes and stains commonly encountered in daily life, including methyl orange, malachite green, Congo red, coffee and mulberry juice. The UV transmittance of the SA/CS-coated TiO2NPs hybrid fibers decreased significantly from 90 % to 75 % with the increase in core-shell particle addition, and correspondingly, the UV absorption capacity increased. The SA/CS-coated TiO2NPs hybrid fibers prepared lay the groundwork for potential applications in various fields, including textiles, automotive engineering, electronics and medicine.

Unique profile on the progress free survival and overall survival in patients with advanced non-small cell lung cancer in the Qujing area, Southwest China.

Background: China's southwestern region, Qujing, harbors a high incidence of non-small cell lung cancer (NSCLC) and related mortality. This study was designed to reveal the impact of an immune-related prognostic signature (IRPS) on advanced NSCLC in the Qujing. Methods: Tissue specimens from an independent cohort of 37 patients with advanced NSCLC were retrospectively evaluated to determine the relationship between the IRPS estimated by next-generation sequencing (NGS) and clinical outcome. To compare the IRPS in tissue and the clinical outcomes between Qujing and non-Qujing populations, we analyzed datasets of 23 patients with advanced NSCLC from The Cancer Genome Atlas (TCGA) database. In addition, an independent cohort (n=111) of blood specimens was retrospectively analyzed to determine the relationship between the IRPS and clinical outcome. Finally, we evaluated the utility of the blood IRPS in classifying 24 patients with advanced NSCLC who might benefit from immunotherapy. Results: In cohort 1, the Qujing population with tTMB-H (≥ 10 mutations/Mb) or KRAS mutations had shorter progression-free survival (PFS) (hazard ratio [HR] 0.37, 0.14 to 0.97, P = 0.04; HR 0.23, 0.08 to 0.66, P < 0.01) and overall survival (OS) (HR 0.05, 0.01 to 0.35, P < 0.01; HR 0.22, 0.07 to 0.66, P < 0.01). In cohort 2 of the Qujing population, bTMB-H (≥ 6 mutations per Mb) and KRAS mutations were related to PFS (HR 0.59, 0.36 to 0.99, P = 0.04; HR 0.50, 0.26 to 0.98, P = 0.04) and OS (HR 0.58, 0.35 to 0.96, P = 0.03; HR 0.48, 0.25 to 0.93, P = 0.03). Notably, the Qujing population with bTMB-H had superior PFS (HR 0.32, 0.09 to 1.09, P = 0.01), OS (HR 0.33, 0.10 to 1.13, P < 0.01) and objective response rates (ORRs) (83.3% vs. 14.3% vs. 20.0%, P <0.01) to immunotherapy than other populations. Conclusions: These findings show that tTMB, bTMB and KRAS mutations appear to be independent validated IRPSs that predict the clinical outcomes of Qujing populations with advanced NSCLC and that bTMB may be used as a reliable IRPS to predict the clinical benefit from anti-PD-1 therapies among populations from Qujing with advanced NSCLC.

Single Posterior Surgery Versus Combined Posterior-Anterior Surgery for Lumbar Tuberculosis Patients.

OBJECTIVE: Posterior approach of debridement, interbody graft, and instrumentation, and combined posterior-anterior approach of posterior instrumentation and anterior debridement and interbody graft are two essential surgeries for the surgical treatment of spinal tuberculosis (TB), and, until now, which one should be chosen is still controversial. This study aimed to compare the therapeutic efficacy between the single posterior surgery and combined posterior-anterior surgery for lumbar tuberculosis (LTB) patients to elucidate the role of debridement and the effects that result from posterior structure resection. METHODS: One hundred and nineteen LTB patients managed with single posterior debridement, interbody graft, and instrumentation surgery (Group P, 73 cases), or combined posterior-anterior surgery of posterior instrumentation and anterior debridement and interbody graft (Group P-A, 46 cases) from January 2008 to December 2016 were retrospectively analyzed. Different indexes were compared between the two groups to evaluate the curative effect and explore the role of debridement and the effects that result from posterior structure resection: operation time, blood loss, visual analog scale (VAS), Japanese Orthopaedic Association (JOA), Erythrocyte Sedimentation Rate (ESR), C-reactive Protein (CRP), surgical complication type and rate, spinopelvic sagittal parameters (local kyphosis [LK], pelvic incidence [PI] and pelvic tilt [PT], lumbar lordosis [LL], and sacral slope [SS]), drainage retention duration, hospital stay, time of abscess disappearance, time of activity recovery, and time of bone graft fusion by t-test or χ2 test. RESULTS: The follow-up period ranged from 24 to 60 months. No significant variations were detected between the two groups for age, sex ratio, BMI, disease duration, indication, and the preoperative values of VAS, JOA, ESR, CRP, and LK (p > 0.05). The VAS, JOA, ESR, and CRP significantly improved in both groups after the operation (p < 0.05), along with the LK and LL (p < 0.05). Meanwhile, the SS, PI, and PT showed minor improvement after the operation (p > 0.05). Compared to the P-A group, the P group had shorter operation time and less blood loss and hospital stay (p < 0.05). However, both groups presented similar VAS, JOA, ESR, CRP, and LK improvements (p > 0.05). Additionally, the surgical complication type and rate, postoperative spinopelvic sagittal parameters, and bone graft fusion time did not differ between the two groups (p > 0.05). On the other hand, the patients in the P-A group had a shorter time of abscess disappearance and activity recovery (p < 0.05) but a similar time of drainage retention (p > 0.05) compared to the P group. CONCLUSION: Both single posterior and combined posterior-anterior surgeries presented a good therapeutic effect for LTB patients with a low surgical complication rate and good quality of LK correction and LL reconstruction and maintenance. Moreover, single posterior surgery was less traumatic than combined posterior-anterior surgery but with slower TB lesion healing and activity recovery. Compared to debridement, stability seems to be more vital for STB healing, posterior structure resection does not affect the effect of spinopelvic realignment.

Greenhouse Gas Emissions from Soils Amended with Cornstalk Biochar at Different Addition Ratios.

Biochar addition has been recommended as a potential strategy for mitigating climate change. However, the number of studies simultaneously investigating the effects of biochar addition on CO2, N2O and CH4 emissions and sequentially global warming potential (GWP) is limited, especially concerning its effect on native soil organic carbon (SOC) mineralization. An incubation experiment was conducted to investigate soil physicochemical properties, CO2, N2O and CH4 emissions and GWP in the treatments with 0% (CK), 1% (BC1) and 4% (BC4) cornstalk biochar additions, and clarify the priming effect of biochar on native SOC mineralization by the 13C tracer technique. Generally, biochar addition increased soil pH, cation exchange capacity, SOC and total nitrogen, but decreased NH4+-N and NO3--N. Compared with CK, BC1 and BC4 significantly reduced CO2 emissions by 20.7% and 28.0%, and reduced N2O emissions by 25.6% and 95.4%, respectively. However, BC1 significantly reduced CH4 emission by 43.6%, and BC4 increased CH4 emission by 19.3%. BC1 and BC4 significantly reduced the GWP by 20.8% and 29.3%, but there was no significant difference between them. Biochar addition had a negative priming effect on native SOC mineralization, which was the reason for the CO2 emission reduction. The negative priming effect of biochar was attributed to the physical protection of native SOC by promoting microaggregate formation and preferentially using soluble organic carbon in biochar. The N2O emission decrease was rooted in the reduction of nitrification and denitrification substrates by promoting the microbial assimilation of inorganic nitrogen. The inconsistency of CH4 emissions was attributed to the different relative contributions of CH4 production and oxidation under different biochar addition ratios. Our study suggests that 1% should be a more reasonable biochar addition ratio for mitigating greenhouse gas emissions in sandy loam, and emphasizes that it is necessary to furtherly investigate nitrogen primary transformation rates and the relative contributions of CH4 production and oxidation by the 15N and 13C technique, which is helpful for comprehensively understanding the effect mechanisms of biochar addition on greenhouse gas emissions.

Exosomal transfer of miR-195-5p restrains lung adenocarcinoma progression.

Exosome is an important way for tumor cells to communicate with other cells and plays an important role in tumor progression. Previous studies revealed that miR-195-5p acts as a tumor suppressor in lung cancer. However, the role and molecular mechanism of exosomal transferred miR-195-5p in lung adenocarcinoma (LAC) remains unknown. Here, we found that miR-195-5p expression in circulating exosomes of LAC patients was lower than that of healthy controls. Meanwhile, the expression of exosomal miR-195-5p from normal bronchial epithelial cell line BEAS-2B cells was significantly higher than that of lung cancer cell lines. The exosome labeling assay confirmed that BEAS-2B cells-derived exosomes could be captured by lung cancer cells. Furthermore, exosomal miR-195-5p derived from BEAS-2B cells remarkably inhibited the proliferation, migration, invasion of lung cancer cells, and tumor growth in vivo. In addition, exosomal miR-195-5p from BEAS-2B cells also suppressed the tube-forming ability of vascular endothelial cells. Moreover, we verified that miR-195-5p decreased apelin (APLN) expression to inactivate the Wnt signaling pathway, thereby inhibiting tumor invasiveness and angiogenesis. In conclusion, our research shows that exosomal miR-195-5p from normal bronchial epithelial cells hinders the progression of LAC, suggesting that regulation of exosomal miR-195-5p provides a novel strategy for LAC treatment.

Chitosan grafting coumarin-3-carboxylic acid fluorescent fiber with enhanced strength prepared by in-situ wet-spinning.

Chitosan grafting coumarin-3-carboxylic acid (CS-g-CCA) fiber with fluorescent function and enhanced tensile strength was successfully prepared by in-situ wet-spinning. FTIR and NMR results demonstrate that CCA is successfully grafted onto the CS molecule chains. As the grafting rate increases from 4.2 to 15.8 %, the spinning solution viscosity increases from 22 to 54 Pa·s. SEM observations show that the CS and CS-g-CCA fiber surfaces and cross-sections exhibit homogeneity and smoothness. Likewise, as the drawing ratio increases from 1.0 to 1.4, 2D WAXS patterns illustrate the molecular chain oriented significantly along the drawing direction. The CS-g-CCA fiber (the grafting rate of 15.8 %) exhibits a maximum breaking strength of 1.06 cn/dtex, increasing by 20 % more than the CS fiber. Meanwhile, it has a peak fluorescence intensity of around 480 nm. In addition, the continuous preparation process simplifies the technological route and improves the preparation efficiency of CS-g-CCA fiber. As-prepared CS-g-CCA fiber with enhanced tensile strength and elevated fluorescence efficiency lays the foundation for potential application in fluorescent probes, anti-counterfeiting, and biomedicine fields.

Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis.

Purpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib's treatment response and outcome were also explored. Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.