C8-ceramide modulates microglia BDNF expression to alleviate postoperative cognition dysfunction via PKCδ/NF-κB signaling pathway.

Postoperative cognitive dysfunction (POCD) is a kind of serious postoperative complication in surgery with general anesthesia and it may affect patients' normal lives. Activated microglia are thought to be one of the key factors in the regulation of POCD process. Once activated, resident microglia change their phenotype and secrete kinds of cytokines to regulate inflammatory response in tissues. Among these secretory factors, brain-derived neurotrophic factor (BDNF) is considered to be able to inhibit inflammation response and protect nervous system. Therefore, the enhancement of BDNF expression derived from resident microglia is suggested to be potential treatment for POCD. In our study, we focused on the role of C8-ceramide (a kind of interventional drug) and assessed its regulatory effect on improving the expression of BDNF secreted from microglia to treat POCD. According to the results of our study, we observed that C8-ceramide stimulated primary microglia to up-regulate the expression of BDNF mRNA after being treated with lipopolysaccharide (LPS) in vitro. We proved that C8-ceramide had ability to effectively improve POCD of mice after being accepted carotid artery exposure and their abnormal behavior recovered better than that of mice from the surgery group. Furthermore, we also demonstrated that C8-ceramide enhanced the cognitive function of mice via the PKCδ/NF-κB signaling pathway. In general, our study has confirmed a potential molecular mechanism that led to the occurrence of POCD caused by surgery and provided a new clinical strategy to treat POCD.

Comparison of the Biomechanical Properties between Healthy and Whole Human and Porcine Stomachs.

Gastric cancer poses a societal and economic burden, prompting an exploration into the development of materials suitable for gastric reconstruction. However, there is a dearth of studies on the mechanical properties of porcine and human stomachs. Therefore, this study was conducted to elucidate their mechanical properties, focusing on interspecies correlations. Stress relaxation and tensile tests assessed the hyperelastic and viscoelastic characteristics of porcine and human stomachs. The thickness, stress-strain curve, elastic modulus, and stress relaxation were assessed. Porcine stomachs were significantly thicker than human stomachs. The stiffness contrast between porcine and human stomachs was evident. Porcine stomachs demonstrated varying elastic modulus values, with the highest in the longitudinal mucosa layer of the corpus and the lowest in the longitudinal intact layer of the fundus. In human stomachs, the elastic modulus of the longitudinal muscular layer of the antrum was the highest, whereas that of the circumferential muscularis layer of the corpus was the lowest. The degree of stress relaxation was higher in human stomachs than in porcine stomachs. This study comprehensively elucidated the differences between porcine and human stomachs attributable to variations across different regions and tissue layers, providing essential biomechanical support for subsequent studies in this field.

Evolutionary analysis of SLC10 family members and insights into function and expression regulation of lamprey NTCP.

The Na ( +)-taurocholate cotransporting polypeptide (NTCP) is a member of the solute carrier family 10 (SLC10), which consists of 7 members (SLC10a1-SLC10a7). NTCP is a transporter localized to the basolateral membrane of hepatocytes and is primarily responsible for the absorption of bile acids. Although mammalian NTCP has been extensively studied, little is known about the lamprey NTCP (L-NTCP). Here we show that L-NTCP follows the biological evolutionary history of vertebrates, with conserved domain, motif, and similar tertiary structure to higher vertebrates. L-NTCP is localized to the cell surface of lamprey primary hepatocytes by immunofluorescence analysis. HepG2 cells overexpressing L-NTCP also showed the distribution of L-NTCP on the cell surface. The expression profile of L-NTCP showed that the expression of NTCP is highest in lamprey liver tissue. L-NTCP also has the ability to transport bile acids, consistent with its higher vertebrate orthologs. Finally, using a farnesoid X receptor (FXR) antagonist, RT-qPCR and flow cytometry results showed that L-NTCP is negatively regulated by the nuclear receptor FXR. This study is important for understanding the adaptive mechanisms of bile acid metabolism after lamprey biliary atresia based on understanding the origin, evolution, expression profile, biological function, and expression regulation of L-NTCP.

Nuclear mutagenesis and adaptive evolution improved photoautotrophic growth of Euglena gracilis with flue-gas CO2 fixation.

To effectively improve biomass growth and flue-gas CO2 fixation of microalgae, acid-tolerant Euglena gracilis was modified with cobalt-60 γ-ray irradiation and polyethylene glycol (PEG) adaptive screening to obtain the mutant strain M800. The biomass dry weight and maximum CO2 fixation rate of M800 were both 1.47 times higher than that of wild strain, which was attributed to a substantial increase in key carbon fixation enzyme RuBisCO activity and photosynthetic pigment content. The high charge separation quantum efficiency in PSII reaction center, efficient light utilization and energy regulation that favors light conversion, were the underlying drivers of efficient photosynthetic carbon fixation in M800. M800 had stronger antioxidant capacity in sufficient high-carbon environment, alleviating lipid peroxidation damage. After adding 1 mM PEG, biomass dry weight of M800 reached 2.31 g/L, which was 79.1 % higher than that of wild strain. Cell proliferation of M800 was promoted, the apoptosis and necrosis rates decreased.

Mortality risk after COVID-19 vaccination: A self-controlled case series study.

BACKGROUND: Although previous studies found no-increased mortality risk after COVID-19 vaccination, residual confounding bias might have impacted the findings. Using a modified self-controlled case series (SCCS) design, we assessed the risk of non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes after primary series COVID-19 vaccination. METHODS: We analyzed all deaths between December 14, 2020, and August 11, 2021, among individuals from eight Vaccine Safety Datalink sites. Demographic characteristics of deaths in recipients of COVID-19 vaccines and unvaccinated individuals were reported. We conducted SCCS analyses by vaccine type and death outcomes and reported relative incidences (RI). The observation period for death spanned from the dates of emergency use authorization to the end of the study period (August 11, 2021) without censoring the observation period upon death. We pre-specified a primary risk interval of 28-day and a secondary risk interval of 14-day after each vaccination dose. Adjusting for seasonality in mortality analyses is crucial because death rates vary over time. Deaths among unvaccinated individuals were included in SCCS analyses to account for seasonality by incorporating calendar month in the models. RESULTS: For Pfizer-BioNTech (BNT162b2), RIs of non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes were below 1 and 95 % confidence intervals (CIs) excluded 1 across both doses and both risk intervals. For Moderna (mRNA-1273), RI point estimates of all outcomes were below 1, although the 95 % CIs of two RI estimates included 1: cardiac-related (RI = 0.78, 95 % CI, 0.58-1.04) and non-COVID-19 cardiac-related mortality (RI = 0.80, 95 % CI, 0.60-1.08) 14 days after the second dose in individuals without pre-existing cancer and heart disease. For Janssen (Ad26.COV2.S), RIs of four cardiac-related death outcomes ranged from 0.94 to 0.98 for the 14-day risk interval, and 0.68 to 0.72 for the 28-day risk interval and 95 % CIs included 1. CONCLUSION: Using a modified SCCS design and adjusting for temporal trends, no-increased risk was found for non-COVID-19 mortality, all-cause mortality, and four cardiac-related death outcomes among recipients of the three COVID-19 vaccines used in the US.

Latent Tuberculosis Infection Testing Practices in a Large US Integrated Healthcare System.

BACKGROUND: Tuberculosis (TB) is a public health threat, with >80% of active TB in the United States occurring due to reactivation of latent TB infection (LTBI). We may be underscreening those with high risk for LTBI and overtesting those at lower risk. A better understanding of gaps in current LTBI testing practices in relation to LTBI test positivity is needed. METHODS: This study, conducted between 1 January 2008 and 31 December 2019 at Kaiser Permanente Southern California, included individuals aged ≥18 years without a history of active TB. We examined factors associated with LTBI testing and LTBI positivity. RESULTS: Among 3 816 884 adults (52% female, 37% White, 37% Hispanic, mean age 43.5 years [standard deviation, 16.1]), 706 367 (19%) were tested for LTBI, among whom 60 393 (9%) had ≥1 positive result. Among 1 211 971 individuals who met ≥1 screening criteria for LTBI, 210 025 (17%) were tested for LTBI. Factors associated with higher adjusted odds of testing positive included male sex (1.32; 95% confidence interval, 1.30-1.35), Asian/Pacific Islander (2.78, 2.68-2.88), current smoking (1.24, 1.20-1.28), diabetes (1.13, 1.09-1.16), hepatitis B (1.45, 1.34-1.57), hepatitis C (1.54, 1.44-1.66), and birth in a country with an elevated TB rate (3.40, 3.31-3.49). Despite being risk factors for testing positive for LTBI, none of these factors were associated with higher odds of LTBI testing. CONCLUSIONS: Current LTBI testing practices may be missing individuals at high risk of LTBI. Additional work is needed to refine and implement screening guidelines that appropriately target testing for those at highest risk for LTBI.

In-silico evaluation of Bismurrayaquinone-A phytochemical as a potential multifunctional inhibitor targeting dihydrofolate reductase: implications for anticancer and antibacterial drug development.

Dihydrofolate reductase (DHFR) has gained significant attention in drug development, primarily due to marked distinctions in its active site among different species. DHFR plays a crucial role in both DNA and amino acid metabolism by facilitating the transfer of monocarbon residues through tetrahydrofolate, which is vital for nucleotide and amino acid synthesis. This considers its potential as a promising target for therapeutic interventions. In this study, our focus was on conducting a virtual screening of phytoconstituents from the IMPPAT2.0 database to identify potential inhibitors of DHFR. The initial criterion involved assessing the binding energy of molecules against DHFR and we screened top 20 compounds ranging energy -13.5 to -11.4 (kcal/Mol) while Pemetrexed disodium bound with less energy -10.2 (kcal/Mol), followed by an analysis of their interactions to identify more effective hits. We prioritized IMPHY007679 (Bismurrayaquinone-A), which displayed a high binding affinity and crucial interaction with DHFR. We also evaluated the drug-like properties and biological activity of IMPHY007679. Furthermore, MD simulation was done, RMSD, RMSF, Rg, SASA, PCA and FEL explore the time-evolution impact of IMPHY007679 comparing it with a reference drug, Pemetrexed disodium. Collectively, our findings suggest that IMPHY007679 recommend further investigation in both in vitro and in vivo settings for its potential in developing anticancer and antibacterial therapies. This compound holds promise as a valuable candidate for advancing drug research and treatment strategies.Communicated by Ramaswamy H. Sarma.

Radioactive iodine therapy for follicular thyroid cancer: a 15 years follow-up study of Chinese patients.

PURPOSE: To identify long-term predictors of distant metastases (DM) and the overall survival (OS) of follicular thyroid cancer (FTC) patients who underwent radioactive iodine (RAI) therapy. And to expand the knowledge about the clinical course and experience of RAI treatment for FTC. MATERIALS: A total of 117 FTC patients who underwent RAI therapy at our institution from 2005 to 2020 were retrospectively studied. Patient characteristics, serum stimulating thyroglobulin (sTg) and thyroglobulin antibody levels, treatment process and follow-up data were collected until 26 April 2022. RESULTS: A total of 16 patients (13.7%) were lost to follow-up. A total of 23 (19.7%) patients with DM died and all FTC without DM were still alive. DM was seen in 58.4% (59/101) of patients. The most common location for metastatic lesions was the lung. Then was bone. The mean survival time of FTC with RAI was 156 months [95% confidence interval (CI): 142-171]. Five-year and 10-year cumulative survival rates of them were 88.8% and 67.4%, respectively. As for patients with DM were 80.4% and 41.3%, respectively. Age at diagnosis [odds ratio (OR) = 1.080, P  = 0.009], RAI therapy sessions (OR = 2.959, P  = 0.001) and sTg level (OR = 1.006, P  = 0.002) were predictive of DM occurrence in FTC with RAI. In the group of FTC with DM, survival analysis showed that males were more likely to have a lower OS than females ( P  = 0.039). CONCLUSION: Age, number of RAI therapy sessions, and sTg level were predictive of the occurrence of DM in FTC patients with RAI. Sex would influence the OS of FTC patients with DM.

Efficacy and Safety of Mazdutide in Chinese Patients With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.

S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury.

Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the S-nitrosylation of PXR (SNO-PXR) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for S-nitrosylation (SNO) modification. In hepatocytes, SNO suppressed both agonist-induced (rifampicin and SR12813) and constitutively active PXR (VP-PXR, a human PXR fused to the minimal transactivator domain of the herpes virus transcription factor VP16) activations. Furthermore, in acetaminophen-overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-/- mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of SNO-PXR. In conclusion, PXR is posttranslationally modified by SNO in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention.

Glycerol-3-Phosphate Acyltransferase GPAT9 Enhanced Seed Oil Accumulation and Eukaryotic Galactolipid Synthesis in Brassica napus.

Glycerol-3-phosphate acyltransferase GPAT9 catalyzes the first acylation of glycerol-3-phosphate (G3P), a committed step of glycerolipid synthesis in Arabidopsis. The role of GPAT9 in Brassica napus remains to be elucidated. Here, we identified four orthologs of GPAT9 and found that BnaGPAT9 encoded by BnaC01T0014600WE is a predominant isoform and promotes seed oil accumulation and eukaryotic galactolipid synthesis in Brassica napus. BnaGPAT9 is highly expressed in developing seeds and is localized in the endoplasmic reticulum (ER). Ectopic expression of BnaGPAT9 in E. coli and siliques of Brassica napus enhanced phosphatidic acid (PA) production. Overexpression of BnaGPAT9 enhanced seed oil accumulation resulting from increased 18:2-fatty acid. Lipid profiling in developing seeds showed that overexpression of BnaGPAT9 led to decreased phosphatidylcholine (PC) and a corresponding increase in phosphatidylethanolamine (PE), implying that BnaGPAT9 promotes PC flux to storage triacylglycerol (TAG). Furthermore, overexpression of BnaGPAT9 also enhanced eukaryotic galactolipids including monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG), with increased 36:6-MGDG and 36:6-DGDG, and decreased 34:6-MGDG in developing seeds. Collectively, these results suggest that ER-localized BnaGPAT9 promotes PA production, thereby enhancing seed oil accumulation and eukaryotic galactolipid biosynthesis in Brassica napus.

Metal organic framework-derived transition metal-doped CoSx nanocage for enhanced visible light-assisted methanol electrocatalytic oxidation.

Designing noble metal-free anode catalysts for visible light-assisted direct methanol fuel cells still remains a significant challenge. In this study, combining the photocatalytic and electrocatalytic properties of CoSx, a visible light-assisted methanol electrocatalytic oxidation strategy was provided. Doping engineering was employed to adjust the electronic structure of CoSx and improve their photoassisted methanol electrocatalytic oxidation activity. Using ZIF-67 as precursor, transition metal-doped CoSx (M-CoSx, M = Zn, Cu, Ni, and Cd) nanocage was synthesized by cation exchange and L-cysteine-controlled etching. Cd doping not only widens the light adsorption to the visible region but also enhances the separation efficiency of photogenerated electron-hole pairs. The electrochemical and photochemical results indicated that the strong oxidative photogenerated hole, OH˙, and O2˙- are beneficial for methanol electrocatalytic oxidation. The synergistic electrocatalytic and photocatalytic effect will be a practical strategy for improving the methanol electrocatalytic oxidation activity of noble metal-free semiconductor catalysts.

Diet Is Associated with Frailty in Lung Cancer: A Possible Role of Gut Microbiota.

This study investigated the associations between diet and frailty in lung cancer patients and the potential role of the gut microbiota involved. We assessed dietary intake and frailty status in 231 lung cancer patients by 3-day, 24-h dietary recalls and Fried frailty criteria, respectively, and collected 50 fecal samples for next-generation sequencing. A total of 75 (32.5%) patients were frail, which might be related to significantly lower intake of energy, protein, carbohydrate, dietary fiber, niacin, leucine, some minerals, and a poorer dietary quality as indicated by the Chinese Healthy Eating Index (p < 0.05). Among these, carbohydrate (OR = 0.98; 95% CI 0.96-0.99; p = 0.010), calcium (OR = 0.99; 95% CI 0.99-1.00; p = 0.025), and selenium (OR = 1.03; 95% CI 1.00-1.06; p = 0.022) were all significantly associated with frailty. A multivariate logistic regression analysis showed that the mean risk of frailty was 0.94 times lower (95% CI 0.90-0.99; p = 0.009) among participants with higher CHEI scores. Additionally, the frail patients demonstrated significantly lower gut microbiota ß diversity (p = 0.001) and higher relative abundance of Actinobacteriota (p = 0.033). Frailty in lung cancer patients might be associated with insufficient nutrients intake and a poor dietary quality through gut microbiota regulation.

Development of a continuously perfused ex vivo kidney training model for laparoscopic partial nephrectomy: validity and efficiency.

BACKGROUND: Suture hemostasis is essential for laparoscopic partial nephrectomy (LPN). This study aimed to develop, validate, and test the efficacy of a continuously perfused training model (CPTM) in LPN with high-level simulated bleeding. MATERIALS AND METHODS: The CPTM was constructed using fresh porcine kidneys with renal arteries continuously perfused with red-dyed liquid gelatin. Twenty-nine participants with expert, intermediate, or novice laparoscopic experience levels were recruited. The expert and intermediate participants evaluated the CPTM, and the novice participants were randomly assigned to one of two groups to complete training on a CPTM or dry box training model (DBTM). Messick's framework criteria were utilized to assess the validity and training efficacy of the model. The data were analyzed using the Mann-Whitney U , Kruskal-Wallis, and Friedman tests. A value of P< 0.05 was considered statistically significant. RESULTS: Positive comments were provided by all experts and intermediates for the Content . The Relationships with other variables demonstrated significant differences among novices, intermediates, and experts in all metrics ( P< 0.05). The Consequences showed that the CPTM helped novices acquire LPN skills. The training efficacy was significantly better than that of the DBTM ( P< 0.05). There were no significant differences between the final performances of the novices and the initial performances of the experts ( P >0.05). Synthesizing all metrics, the LPN skills learned using CPTMs were significantly improved in the 12th round of training. CONCLUSION: The CPTM offered a high-level simulation of bleeding with realistic tissue texture for acquiring LPN skills. Training of no fewer than 12 rounds is recommended for a novice's LPN training on the CPTM.

A General Protocol for Synthesizing Thiolated Folate Derivatives.

Folic acid (FA) has shown great potential in the fields of targeted drug delivery and disease diagnosis due to its highly tumor-targeting nature, biocompatibility, and low cost. However, FA is generally introduced in targeted drug delivery systems through macromolecular linkage via complex synthetic processes, resulting in lower yields and high costs. In this work, we report a general protocol for synthesizing thiolated folate derivatives. The small molecule thiolated folate (TFa) was first synthesized with a purity higher than 98.20%. First, S-S-containing diol was synthesized with a purity higher than 99.44 through a newly developed green oxidation protocol, which was carried out in water with no catalyst. Then, folic acid was modified using the diol through esterification, and TFa was finally synthesized by breaking the disulfide bond. Further, the synthesized TFa was utilized to modify silver nanoparticles. The results showed that TFa could be easily bonded to metal particles. The protocol could be extended to the synthesis of a series of thiolated derivatives of folate, such as mercaptohexyl folate, mercaptoundecyl folate, etc., which would greatly benefit the biological applications of FA.

Identification and validation of a novel prognostic circadian rhythm-related gene signature for stomach adenocarcinoma.

Circadian rhythm genes were reported to be strongly associated with the development and prognosis of circadian rhythm disorders related to stomach adenocarcinoma (STAD), which is one of the most prevalent cancers. This study aimed to identify a circadian rhythm-related gene signature that could help predict STAD outcome. Using bioinformatics analysis approaches, 105 genes were examined in 350 patients with STAD. Overall, six hub-type circadian rhythm-associated genes (GNA11, PER1, SOX14, EZH2, MAGED1, and NR1D1) were identified using univariate and multivariate Cox regression analyses. These genes were then used to build a genetic predictive model, which was further validated using a publicly available dataset (GSE26899). Overall, genes associated with the circadian rhythm were found to be substantially correlated with the characteristics of the STAD patients (grade, sex, and M stage). In addition, the circadian rhythm-related gene signature was significantly associated with the MAPK and Notch signaling pathways, which are known risk factors for poorer STAD outcome. Taken together, these findings suggest that the herein proposed prognostic model based on six circadian rhythm-associated genes may have predictive value and potential application for clinical decision-making and for personalized treatment of STAD.

Cellular immunotherapy combined with platinum-based chemotherapy prolongs survival for non-small cell lung cancer patients.

Platinum-based chemotherapy is the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients without a driver gene mutation, but its efficacy is still modest. Through a potential synergistic effect, autologous cellular immunotherapy (CIT) composed of cytokine-induced killer (CIK), natural killer (NK), and T cells might enhance it. NK cells exhibited in vitro cytotoxicity toward lung cancer cells (A549 cells) following platinum therapy. Using flow cytometry, the expression of MICA, MICB, DR4, DR5, CD112, and CD155 on lung cancer cells was assessed. In this retrospective cohort study, there were included 102 previously untreated stage IIIB/IV NSCLC patients ineligible for tyrosine kinase inhibitor (TKI) target therapy who received either chemotherapy alone (n=75) or combination therapy (n=27). The cytotoxicity of NK cells for A549 cells was increased obviously and a time-dependent enhancement of this effect was also observed. After platinum therapy, the levels of MICA, MICB, DR4, DR5, CD112, and CD155 on the surface of A549 cells were increased. In the combination group, the median PFS was 8.3 months, compared to 5.5 months in the control group (p=0.042); the median overall survival was 18.00 months, compared to 13.67 months in the combined group (p=0.003). The combination group had no obvious immune-related adverse effects. The combination of NK cells with platinum showed synergistic anticancer effects. Combining the two strategies increased survival with minor adverse effects. Incorporating CIT into conventional chemotherapy regimens may improve NSCLC treatment. However, additional evidence will require multicenter randomized controlled trials.

In vivo detection demonstrates circulating tumor cell reduction instead of baseline number has prognostic value in bladder cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: Previous studies have suggested the potential prognostic value of circulating tumor cells (CTCs) in bladder cancer (BC) patients. This study aims to validate the prognostic value of in vivo detection of CTCs in muscle invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC). METHODS: A total of 107 MIBC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as baseline, and those who received neoadjuvant chemotherapy (NAC) had a second detection after NAC and before radical cystectomy. CTCs dynamic change after NAC was analyzed. Prognostic value of in vivo CTCs detection was investigated. RESULTS: Among 68 patients who received NAC, 45 patients (66%) had a CTC reduction after NAC. CTC reduction instead of baseline CTC positivity was a key prognostic factor for better progression free survival (PFS) among all MIBC patients receiving NAC in Kaplan-Meier analysis (P < 0.01) and in both crude (HR 6.14, 95%CI 1.63-23.21) and adjusted regression model (HR 6.76, 95% CI 1.59-28.88). The AUC was 0.85. CONCLUSION: Our study demonstrated the prognostic value of in vivo detection of CTCs. The dynamic change of CTCs count may help evaluate the efficacy of NAC.

Efficacy and safety of tafolecimab in Chinese patients with heterozygous familial hypercholesterolemia: a randomized, double-blind, placebo-controlled phase 3 trial (CREDIT-2).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is largely underdiagnosed and undertreated in China where few patients achieved recommended target levels of low density lipoprotein cholesterol (LDL-C). We conducted the first randomized, placebo-controlled clinical trial in Chinese patients with HeFH to assess the efficacy and safety of tafolecimab, a novel fully human proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody. METHODS: Patients diagnosed with HeFH by Simon Broome criteria and on a stable lipid-lowering therapy for at least 4 weeks were randomized 2:2:1:1 to receive subcutaneous tafolecimab 150 mg every 2 weeks (Q2W), tafolecimab 450 mg every 4 weeks (Q4W), placebo Q2W or placebo Q4W in the 12-week double-blind treatment period. After that, participants received open-label tafolecimab 150 mg Q2W or 450 mg Q4W for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C levels. Secondary endpoints included proportion of participants achieving ≥50% LDL-C reductions and proportion of participants with LDL-C <1.8 mmol/L at week 12 and 24, the change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and lipoprotein(a) levels, as well as the change from baseline to week 24 in lipid levels. RESULTS: In total, 149 participants were randomized and 148 received at least one dose of the study treatment. At week 12, tafolecimab treatment induced significant reductions in LDL-C levels (treatment difference versus placebo [on-treatment estimand]: -57.4% [97.5% CI, -69.2 to -45.5] for 150 mg Q2W; -61.9% [-73.4 to -50.4] for 450 mg Q4W; both P <0.0001). At both dose regimens, significantly more participants treated with tafolecimab achieved ≥50% LDL-C reductions or LDL-C <1.8 mmol/L at week 12 as compared with corresponding placebo groups (all P <0.0001). Meanwhile, non-HDL-C, apolipoprotein B and lipoprotein(a) levels were significantly reduced in the tafolecimab groups at week 12. The lipid-lowering effects of tafolecimab were maintained till week 24. During the double-blind treatment period, the most commonly-reported adverse events in the tafolecimab groups included upper respiratory tract infection, increased blood creatine phosphokinase, increased alanine aminotransferase, increased aspartate aminotransferase and hypertension. CONCLUSIONS: Tafolecimab administered either 150 mg Q2W or 450 mg Q4W yielded significant and persistent reductions in LDL-C levels and showed a favorable safety profile in Chinese patients with HeFH. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04179669.

In vivo detection of circulating tumor cells predicts high-risk features in patients with bladder cancer.

Previous studies have suggested the potential diagnostic value of circulating tumor cells (CTCs). This study aims to validate the efficacy of in vivo detection of CTCs in bladder cancer (BC) patients. A total of 216 BC patients were enrolled in this study. All patients had one in vivo detection of CTCs before initial treatment as a baseline parameter. The results of CTCs were associated with different clinicopathological features including molecular subtypes. PD-L1 expression on CTCs was also assessed and compared with its expression on tumors. CTC positive was defined as > 2 CTCs detected. Among all 216 patients, 49 (23%) were detected as CTC positive (> 2 CTCs) at baseline. Positive detection of CTCs was associated with multiple high-risk clinicopathological features including the multiplicity of the tumor (P = 0.02), tumor size (P < 0.01), tumor stage (P < 0.01), tumor grade (P < 0.01) and tumor PD-L1 expression (P = 0.01). The expression of PD-L1 on tumor and CTCs were not coordinated. Only 55% (74/134) matched the same status of PD-L1 expression on tumor and CTCs, along with 56 CTC (+) Tissue (-) and 4 CTC (-) Tissue (+) (P < 0.01). Our study has demonstrated the efficacy of in vivo detection of CTCs. The positive detection of CTCs is associated with multiple clinicopathological features. PD-L1 expression on CTCs has the potential to be a supplementary biomarker for immunotherapy.