Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction.

INTRODUCTION: Despite the high morbidity and mortality, the effective therapies for heart failure with preserved fraction (HFpEF) are limited as the poor understand of its pathophysiological basis. OBJECTIVE: This study was aimed to characterize the cellular heterogeneity and potential mechanisms of HFpEF at single-cell resolution. METHODS: An HFpEF mouse model was induced by a high-fat diet with N-nitro-L-arginine methyl ester. Cells from the hearts were subjected to single-cell sequencing. The key protein expression was measured with Immunohistochemistry and immunofluorescence staining. RESULTS: In HFpEF hearts, myocardial fibroblasts exhibited higher levels of fibrosis. Furthermore, an increased number of fibroblasts differentiated into high-metabolism and high-fibrosis phenotypes. The expression levels of genes encoding certain pro-angiogenic secreted proteins were decreased in the HFpEF group, as confirmed by bulk RNA sequencing. Additionally, the proportion of the endothelial cell (EC) lineages in the HFpEF group was significantly downregulated, with low angiogenesis and high apoptosis phenotypes observed in these EC lineages. Interestingly, the fibroblasts in the HFpEF heart might cross-link with the EC lineages via over-secretion of ANGPTL4, thus displaying an anti-angiogenic function. Immunohistochemistry and immunofluorescence staining then revealed the downregulation of vascular density and upregulation of ANGPTL4 expression in HFpEF hearts. Finally, we predicted ANGPTL4as a potential druggable target using DrugnomeAI. CONCLUSION: In conclusion, this study comprehensively characterized the angiogenesis impairment in HFpEF hearts at single-cell resolution and proposed that ANGPTL4 secretion by fibroblasts may be a potential mechanism underlying this angiogenic abnormality.

A Fully Automated Mini-Mental State Examination Assessment Model Using Computer Algorithms for Cognitive Screening.

Background: Rapidly growing healthcare demand associated with global population aging has spurred the development of new digital tools for the assessment of cognitive performance in older adults. Objective: To develop a fully automated Mini-Mental State Examination (MMSE) assessment model and validate the model's rating consistency. Methods: The Automated Assessment Model for MMSE (AAM-MMSE) was an about 10-min computerized cognitive screening tool containing the same questions as the traditional paper-based Chinese MMSE. The validity of the AAM-MMSE was assessed in term of the consistency between the AAM-MMSE rating and physician rating. Results: A total of 427 participants were recruited for this study. The average age of these participants was 60.6 years old (ranging from 19 to 104 years old). According to the intraclass correlation coefficient (ICC), the interrater reliability between physicians and the AAM-MMSE for the full MMSE scale AAM-MMSE was high [ICC (2,1)=0.952; with its 95% CI of (0.883,0.974)]. According to the weighted kappa coefficients results the interrater agreement level for audio-related items showed high, but for items "Reading and obey", "Three-stage command", and "Writing complete sentence" were slight to fair. The AAM-MMSE rating accuracy was 87%. A Bland-Altman plot showed that the bias between the two total scores was 1.48 points with the upper and lower limits of agreement equal to 6.23 points and -3.26 points. Conclusions: Our work offers a promising fully automated MMSE assessment system for cognitive screening with pretty good accuracy.

Prediction of survival of persons with advanced dementia using the advanced dementia prognostic tool: A 2-year prospective study.

BACKGROUND: In this prospective study, we evaluated the usefulness of the advanced dementia prognostic tool (ADEPT) for estimating the 2-year survival of persons with advanced dementia (AD) in China. METHODS: The study predicted the 2-year mortality of 115 persons with AD using the ADEPT score. RESULTS: In total, 115 persons with AD were included in the study. Of these persons, 48 died. The mean ADEPT score was 13.0. The AUROC for the prediction of the 2-year mortality rate using the ADEPT score was 0.62. The optimal threshold of the ADEPT score was 11.2, which had an AUROC of 0.63, specificity of 41.8, and sensitivity of 83.3. CONCLUSIONS: The ADEPT score based on a threshold of 11.2 may serve as a prognostic tool to determine the 2-year survival rate of persons with AD in Chongqing, China. However, further studies are needed to explore the nature of this relationship.

Natural Chlorogenic Acid Planted Nanohybrids with Steerable Hyperthermia for Osteosarcoma Suppression and Bone Regeneration.

Surgical resection is the most common approach for the treatment of osteosarcoma. However, two major complications, including residual tumor cells and large bone defects, often arise from the surgical resection of osteosarcoma. Discovering new strategies for programmatically solving the two above-mentioned puzzles has become a worldwide challenge. Herein, a novel one-step strategy is reported for natural phenolic acid planted nanohybrids with desired physicochemical properties and steerable photothermal effects for efficacious osteosarcoma suppression and bone healing. Nanohybrids are prepared based on the self-assembly of chlorogenic acid and gold nanorods through robust Au-catechol interface actions, featuring precise nanostructures, great water solubility, good stability, and adjustable hyperthermia generating capacity. As expected, on the one hand, these integrated nanohybrids can severely trigger apoptosis and suppress tumor growth with strong hyperthermia. On the other hand, with controllable mild NIR irradiation, the nanohybrids promote the expression of heat shock proteins and induce prominent osteogenic differentiation. This work initiates a brand-new strategy for assisting osteosarcoma surgical excision to resolve the blockage of residual tumor cells elimination and bone regeneration.

Impact of probiotics use on clinical outcomes of immune checkpoint inhibitors therapy in cancer patients.

BACKGROUND: Dysbiosis of the gut microbiota can lead to impaired therapeutic effect of immune checkpoint inhibitors (ICIs). This study aimed to investigate the use of probiotics on the clinical outcomes of cancer patients receiving ICIs therapy. METHOD: PubMed, EMBASE, and the Cochrane Library database were searched to retrieve relevant studies that exploring the relationship between probiotics and the efficacy of ICIs. The primary endpoints included overall survival (OS) and progression-free survival (PFS), evaluated by the hazard rations (HRs) with 95% confidence intervals (CI), and the secondary endpoint was objective response rate (ORR), evaluated by the odd ratio (OR) with a 95% CI. RESULTS: A total of five studies including 1031 patients were eligible for analysis. Our results indicated that the use of probiotics was associated with a superior OS (HR = 0.50, 95% CI: 0.30-0.85, p = 0.01) and PFS (HR = 0.51, 95% CI: 0.42-0.61, p < 0.01), but had no relationship with ORR (OR = 2.11, 95%CI: 0.51-8.65, p = 0.30) in non-small cell lung cancer (NSCLC) patients. CONCLUSIONS: Probiotics were positively correlated with OS and PFS in NSCLC patients administrated with ICIs, but had no relationship with ORR.

Comparison of the Suitability Between NRS2002 and MUST as the First-Step Screening Tool for GLIM Criteria in Hospitalized Patients With GIST.

Objective: The Global Leader Initiative on Malnutrition (GLIM) criteria have been recommended for malnutrition diagnosis recently, for which the first step is malnutrition risk screening with any validated tool. This study aims to investigate the incidence of malnutrition risk in gastrointestinal stromal tumor (GIST) inpatients and compare the suitability of Nutritional Risk Screening 2002 (NRS2002) and Malnutrition Universal Screening Tool (MUST) as the first-step screening tool for GLIM criteria. Methods: We retrospectively analyzed the clinical data of GIST inpatients in our hospital from January 2015 to December 2019. NRS2002 and MUST were used to screen malnutrition risk at the time of admission. The diagnostic consistency of these two tools with GLIM criteria for malnutrition was analyzed, and the predictive performance of both tools for the length of hospital stay and the occurrence of complications was also evaluated in surgical and non-surgical inpatients. Results: A total of 269 GIST inpatients were included in this study, of which 45.7 and 40.9% were at malnutrition risk determined by NRS2002 and MUST, respectively. In non-surgical inpatients, NRS2002 and MUST had similar diagnostic consistency with GLIM criteria in sensitivity (93.0 vs. 97.7%), specificity (81.1 vs. 81.1%), and Kappa value (K = 0.75 vs. 0.80), and high nutritional risk classified by NRS2002 and malnutrition identified by GLIM criteria were found to be associated with the length of hospital stay. In surgical inpatients, MUST had better diagnostic consistency with GLIM criteria in sensitivity (86.1 vs. 53.5%) and Kappa value (K = 0.61 vs. 0.30) than NRS2002, but no factors were found associated with the length of postoperative hospital stay or the occurrence of complications. Conclusion: The malnutrition risk is common in GIST inpatients. NRS2002 is more suitable than MUST for the first-step risk screening of the GLIM scheme in non-surgical inpatients, considering its better performance in screening malnutrition risk and predicting clinical outcomes. MUST was found to have good diagnostic consistency with GLIM criteria for malnutrition in both non-surgical and surgical GIST inpatients, and further studies need to be conducted to investigate its predictive performance on clinical outcomes.

Pharmacokinetics, distribution and excretion of inulin-type fructan CPA after oral or intravenous administration to mice.

The aim of this work has been to establish and validate a simple and efficient method to detect the concentration of inulin-type fructan CPA from the roots of Codonopsis pilosula (Franch.) Nannf. in biosamples, and then apply it to evaluate the pharmacokinetics behavior, distribution character in tissue and excretion in mice. In this work, fluorescein isothiocyanate (FITC) was used to label CPA. Then FCPA was intravenously and orally administered to mice at different doses. In both i.v and p.o administration, FCPA concentration slowly declined in the circulatory system with a much longer T1/2 and MRT. After p.o administration, the area under the time curve (AUC0-∞) was dose-dependently increased. Taken together, FCPA showed poor absorption and wide tissue distribution. These pharmacokinetic results yield helpful insights into the pharmacological actions of FCPA.

Shaoyao-Gancao Decoction Ameliorates the Inflammation State in Polycystic Ovary Syndrome Rats via Remodeling Gut Microbiota and Suppressing the TLR4/NF-κB Pathway.

Background: Emerging evidence suggests that gut microbiota plays a vital role in the occurrence of multiple endocrine disorders including polycystic ovary syndrome (PCOS). Shaoyao-Gancao Decoction (SGD), a classical Chinese prescription, has been widely used in the treatment of PCOS for decades. In previous studies, we found that SGD treatment could effectively reduce ovarian inflammation in PCOS rats. However, whether the anti-inflammation effect of SGD involves the regulation of the gut microbiota remains elusive. Methods: Letrozole-induced PCOS rat models were established, and the therapeutic effects of SGD were evaluated. Specifically, body weight, serum hormone concentrations, estrus phase and ovary histopathology were assessed. Then the structure of gut microbiota was determined by 16s rRNA sequencing. Additionally, the serum levels of pro-inflammatory cytokines and LPS were measured by ELISA kits. The key gene and protein expressions of TLR4/NF-κB signaling pathway were detected by quantitative real-time PCR and western blot. Results: SGD could effectively reduce body weight, regulate estrous cycles and ameliorate hyperandrogenism in PCOS rats. In addition, SGD treatment decreased releases of pro-inflammatory cytokines, enhanced the expressions of tight junction (occludin and claudin1), and then prevented a translocation of LPS into bloodstream. SGD could significantly reduce the ratio of Firmicutes to Bacteroidetes, decrease the abundance of LPS-producing pathogens Proteobateria and enrich the abundance of Butyricicoccus, Coprococcus, Akkermansia Blautia and Bacteroides in PCOS rats. Furthermore, SGD blunted the key gene and protein expressions of TLR4/NF-κB signaling pathway both in vivo and in LPS-induced RAW264.7 cells. Conclusion: SGD administration could ameliorate the inflammatory response in PCOS rats by remodeling gut microbiome structure, protecting gut barrier, and suppressing TLR4/NF-κB signaling pathway.

Windblown Sand-Induced Degradation of Glass Panels in Curtain Walls.

The windblown sand-induced degradation of glass panels influences the serviceability and safety of these panels. In this study, the degradation of glass panels subject to windblown sand with different impact velocities and impact angles was studied based on a sandblasting test simulating a sandstorm. After the glass panels were degraded by windblown sand, the surface morphology of the damaged glass panels was observed using scanning electron microscopy, and three damage modes were found: a cutting mode, smash mode, and plastic deformation mode. The mass loss, visible light transmittance, and effective area ratio values of the glass samples were then measured to evaluate the effects of the windblown sand on the panels. The results indicate that, at high abrasive feed rates, the relative mass loss of the glass samples decreases initially and then remains steady with increases in impact time, whereas it increases first and then decreases with an increase in impact angle such as that for ductile materials. Both visible light transmittance and effective area ratio decrease with increases in the impact time and velocities. There exists a positive linear relationship between the visible light transmittance and effective area ratio.

Immune-related adverse events: promising predictors for efficacy of immune checkpoint inhibitors.

PURPOSE: This study was designed to investigate the correlation between immune-related adverse events (irAEs) of immune checkpoint inhibitors (ICIs) and corresponding efficacy, and to explore the potential of predicting the efficacy of ICIs via irAEs. METHODS: Electronic databases including PubMed, Embase, Cochrane Library, CNKI and Wanfang were applied to search for relevant studies. The primary endpoint was overall survival (OS) or progression-free survival (PFS), and the secondary endpoint was objective response rate (ORR). Stratification analyses were conducted according to the type of irAEs and ICIs, region of studies and primary tumors. Furthermore, statistical analyses were realized by means of RevMan 5.3 software. RESULTS: Altogether, 40 studies with 8,641 participants were enrolled, among which the incidence of irAEs ranged from 15.34 to 85.23% and the major sites reached out to skin, endocrine organ, gastrointestinal tract, liver and lung. The ORR, OS and PFS in irAE group were significantly higher than those in non-irAE group as per pooled analyses and stratification analyses. Importantly, patients with irAEs in skin, endocrine organ or gastrointestinal tract rather than in liver and lung were found to obtain survival benefits (p < 0.05). CONCLUSION: IrAEs, especially in skin, endocrine organ or gastrointestinal tract, triggered by ICIs indicate significant survival benefits.

The impact of antibiotics on efficacy of immune checkpoint inhibitors in malignancies: A study based on 44 cohorts.

BACKGROUND: Pre-clinical and clinical data had revealed the gut microbiome plays a critical role in immune checkpoint inhibitors (ICIs) efficacy. This study was designed to investigate whether antibiotics (ATBs) affect the prognosis of malignancies treated with ICIs. METHODS: Electronic databases were searched to identify relevant trials that evaluated the impact of ATBs on ICIs efficacy. The primary endpoints were overall survival (OS) and progression-free survival (PFS) measured by HRs with corresponding 95%CIs. Subgroup analyses were performed based on cancer type, study design, ICIs agent, and time of ATBs administration. RESULTS: Totally, 12,492 individuals in the 44 cohorts were recruited. Pooled results showed that ATBs administration was significantly correlated with a worse objective remission rate (ORR) (OR = 0.61, 95%CI (0.42-0.90), P = 0.0128), PFS (HR = 1.18, 95%CI (1.11-1.25), P < 0.0001), and OS (HR = 1.20, 95%CI (1.15-1.25), P < 0.0001) in patients treated with ICIs. In subgroup analyses, patients treated with ICIs exposed to ATBs suffered an evidently worse ORR in arms of renal cell carcinoma (RCC) (OR = 0.30, 95%CI (0.14-0.67), P = 0.0034), multiple (OR = 0.44, 95%CI (0.27-0.73), P = 0.0016), and before ICIs initiation (OR = 0.47, 95%CI (0.32-0.71), P = 0.0003) without heterogeneity; experienced a worse PFS and OS in arms of non-small cell lung cancer, melanoma, RCC, urothelial carcinoma, multiple, prospective, retrospective, PD-(L)1 alone, PD-(L)1 plus CTLA-4, before ICIs initiation, before ICIs initiation and concurrent, and before or after ICIs within 1 month, while a better PFS and OS in concurrent with ICIs arm. CONCLUSIONS: ATBs administration was negatively associated with ORR, PFS and OS in malignancies treated with ICIs, while the time of ATBs exposure might impact ICIs efficacy.

The Neuropsychiatric Changes After COVID-19 Quarantine in Patients With Cognitive Impairment and Their Caregivers in Chongqing, China: A Cohort Study.

BACKGROUND: The follow-up study on neuropsychiatric changes after the lifting of coronavirus disease 2019 (COVID-19) quarantine in patients with cognitive impairment and their caregivers is still lacking, and relative information is needed to formulate more comprehensive healthcare prevention measures worldwide. AIMS: To provide data on the changes in neuropsychiatric performance after the lifting of COVID-19 quarantine in patients with cognitive disorders and their caregivers. METHODS: Two surveys in Chongqing, China were conducted via telephonic interview with 531 patients and their caregivers. The baseline survey was performed from February 11 to 23, 2020, and the follow-up was from October 24 to November 9, 2020. The data of neuropsychiatric symptoms (NPSs), sleep, nutrition, and chronic diseases of patients, as well as the burden of care, anxiety, and depression of caregivers were evaluated. RESULTS: Significant alleviation of NPSs after the lifting of COVID-19 quarantine was observed in patients with mild cognitive impairment (MCI) and dementia (both P < 0.05). Compared with baseline, the prevalence for NPSs of all participants dropped from 57.94 to 38.82%. Among NPS subdomains, apathy displayed the biggest decline at follow-up by 10.72%, followed by nighttime behavior by 8.65%. Mixed effect generalized estimation equation analysis showed significant amelioration in hallucination, depression, apathy, irritability, aberrant motor behavior, and nighttime behavior (all P < 0.05), with the most prominent changes in nighttime behavior and apathy. Among the patients with unsatisfactory control of chronic disease, the medication adherence rate dropped by approximately 30% after the lifting of quarantine. More importantly, around 13% increase of care burden was observed among the caregivers at follow-up, with both depression and anxiety rising by nearly 4%. CONCLUSION: The prolonged quarantine may exacerbate NPS in patients with memory disorders, while the care burden and mental stability of the caregivers after the pandemic should also be concerned.

Oridonin Attenuates TNBS-induced Post-inflammatory Irritable Bowel Syndrome via PXR/NF-κB Signaling.

To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1ß, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-κB activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-κB and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.

Shaoyao-Gancao Decoction Relieves Visceral Hyperalgesia in TNBS-Induced Postinflammatory Irritable Bowel Syndrome via Inactivating Transient Receptor Potential Vanilloid Type 1 and Reducing Serotonin Synthesis.

Postinflammatory irritable bowel syndrome (PI-IBS) is a common functional gastrointestinal disorder, which is characterized by abdominal pain, low-grade inflammation, and visceral hypersensitivity. Shaoyao-Gancao decoction (SGD) has been used to improve the clinical symptoms of abdominal spasmodic pain accompanying acute gastroenteritis, but the underlying therapeutic mechanism has not been fully elucidated. In the present study, a rat model of PI-IBS was established via rectal administration of TNBS. Rats were scored daily for 28 days using disease activity index (DAI). Abdominal withdrawal reflex (AWR) was used to measure the pain threshold. After SGD (6.25, 12.5, and 25 g/kg/d) treatment for 14 days, rat colonic tissue was collected for histopathological grading, enterochromaffin (EC) cell count, and 5-HT content measurement. RT-qPCR and western blot analyses were employed to detect the gene and protein level of tryptophan hydroxylase (TPH), serotonin reuptake transporter (SERT), and transient receptor potential vanilloid 1 (TRPV1). To further validate the effect of SGD on TRPV1, another experiment was performed in cells. The results revealed that visceral hyperalgesia, reflected by increased DAI, AWR, pathological injury score, 5-HT content, and EC cell count in PI-IBS rats, was significantly ameliorated by SGD. In cells, SGD markedly inhibited the expression and function of TRPV1. Moreover, the expression levels of TPH were also repressed by SGD. The findings of the present study indicated that the therapeutic effect of SGD on visceral hyperalgesia may be closely associated with the regulatory role of TRPV1 and 5-HT signaling pathways.

Fatal toxic effects related to EGFR tyrosine kinase inhibitors based on 53 cohorts with 9,569 participants.

BACKGROUND: To estimate the incidence and susceptible factors of fatal toxic effects related to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). METHODS: PubMed and Embase were thoroughly searched for clinical trials based on the following terms and corresponding Medical Subject Heading ones: "erlotinib", "gefitinib", "afatinib", "dacomitinib", "osimertinib", and "non-small-cell lung cancer (NSCLC)". A total of 53 eligible cohorts with 9,569 participants were collected. RESULTS: A total of 105 cases of fatal toxic effects related to EGFR-TKIs occurred in 53 cohorts. The overall incidence was 1.33% [95% confidence interval (CI): 1.08-1.63%]. The odds and incidence were apparently higher in Japanese group (compared with non-East Asian group) [2.72 vs. 1.30, P=0.015; odds ratio (OR): 2.26, 95% CI: 1.17-4.37, P=0.015], in first-line treatment group (compared with EGFR-TKI retreatment group) (1.54 vs. 0.69, P=0.028; OR: 2.41, 95% CI: 1.10-5.26, P=0.028), and in the trial phase II (compared with trial phase III) (1.82% vs. 1.11%, P=0.009; OR: 1.73, 95% CI: 1.15-2.62, P=0.009). Notably, the Japanese group was higher than non-East Asian group after controlling for the treatment-line and trial phase (OR: 2.16, 95% CI: 1.12-4.16, P=0.022). Interstitial lung disease (ILD) was predominant in 29 fatal causes followed by pneumonia, respiratory failure and diarrhea. CONCLUSIONS: The overall incidence of fatal toxic effects related to EGFR-TKIs was 1.33%, and the major fatal cause was ILD, followed by pneumonia, respiratory failure and diarrhea. The susceptible factor of fatal toxic effects related to EGFR-TKIs was the Japanese group. This study provided a capability for clinicians to predict and detect high-risk populations of fatal toxic effects.

Correction to: Predictive value of positron emission tomography for the prognosis of immune checkpoint inhibitors (ICIs) in malignant tumors.

The original version of this article unfortunately contained a mistake. The correct information is given in the following.

Predictive value of positron emission tomography for the prognosis of immune checkpoint inhibitors (ICIs) in malignant tumors.

PURPOSE: This study aimed at investigating the value of applying positron emission tomography (PET) to early predict the effect of immune checkpoint inhibitors (ICIs) in malignant tumors. METHODS: Electronic databases MEDLINE/PubMed, EMBASE, and Cochrane Library were searched to identify relevant trials. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The results were analyzed utilizing Stata 12.0 statistical software. Subgroup analyses were implemented based on primary tumors, study designs, continents, type of ICIs, evaluation index of PET, and evaluated PET timing. RESULTS: Fifteen studies incorporating 664 individuals were eligible. Compared with PET nonresponse group, PET response group displayed a significantly prolonged PFS (HR 0.27, 95% CI [0.16, 0.44]; P < 0.001) and OS (HR 0.56, 95% CI [0.48, 0.65]; P < 0.001). Analogical outcomes were obtained in subgroup analyses of PFS in non-small cell lung cancer, prospective, America, ipilimumab, nivolumab/pembrolizumab combined ipilimumab, PET Response Criteria in Solid Tumors (PERCIST), baseline PET and early PET timing arms without heterogeneity; so did OS in melanoma, retrospective, Europe, America, ipilimumab, nivolumab/pembrolizumab, PERCIST, baseline metabolic tissue volume, baseline standard uptake value, and baseline total lesion glycolysis, baseline PET timing, early PET timing and late PET timing arms. CONCLUSION: Our study demonstrated that PET was a promising approach to early predict the prognosis of ICIs for malignancies.

Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Outcome of Immune Checkpoint Inhibitors.

A meta-analysis of 14 studies (16 cohorts) incorporating 1751 participants was performed to evaluate the correlation between baseline neutrophil-to-lymphocyte ratio (NLR) and outcome of immune checkpoint inhibitors (ICI). The pooled hazard ratio (HR) suggested elevated pretreatment NLR was associated with poor OS (HR: 2.61, 95% confidence intervals (CI): 1.77-3.86, p < 0.00001) and PFS (HR: 1.74, 95% CI: 1.34-2.27, p < 0.0001). Stratified analyses on tumor types, ICI agents, the cutoff value of NLR and study regions exhibited the similar outcomes. This study demonstrated that elevated NLR was a predictor of poor OS and PFS for ICI.

Comparative pharmacokinetics and metabolites study of seven major bioactive components of Shaoyao-Gancao decoction in normal and polycystic ovary syndrome rats by ultra high pressure liquid chromatography with tandem mass spectrometry.

A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R2 ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome.

CDK4/6 Inhibitor Palbociclib Amplifies the Radiosensitivity to Nasopharyngeal Carcinoma Cells via Mediating Apoptosis and Suppressing DNA Damage Repair.

BACKGROUND: Radiotherapy is the primary approach for nasopharyngeal carcinoma (NPC). Although high survival rates can be obtained with radiation for early stage lesions, distant metastasis and local recurrence frequently occur. In this study, we pioneeringly investigated the antitumor activity and underlying mechanism of cyclin-dependent kinase 4/6 inhibitor (palbociclib) combined with radiation on NPC cells. METHODS: Evaluation of radiation enhancement with palbociclib was based on results from CCK8 and clonogenicity assays for cell proliferation, flow cytometry for apoptosis, ROS level and cell cycle and immunocytochemistry for DNA double-strand break repair. RESULTS: Palbociclib inhibited cellular growth of RB-proficient CNE-1 and CNE-2 via reducing RB phosphorylation and arresting cell cycle. Combination regimens of palbociclib plus radiation were significantly superior to palbociclib or radiation only through inhibiting cellular growth and inducing apoptosis. Moreover, the antitumor activity of both concurrent palbociclib plus radiation and radiation followed by palbociclib consistently preceded that of palbociclib followed by radiation. Meanwhile, the two preferable combination regimens possessed higher proportion of G2/M phase cells, evidently inhibited DNA double-strand break repair and eventually triggered tumor cell apoptosis. CONCLUSION: Our study demonstrated that palbociclib could provoke a strong antitumor activity as a potential adjuvant to radiation therapy for NPC harboring RB expression.