Case report: A clinical report of photodynamic neoadjuvant combined with fluorescent laparoscopic localization robotic surgery for the treatment of patients with advanced colorectal cancer combined with obstruction.

The incidence of colorectal cancer is relatively high in our country, with the majority of patients being diagnosed at an advanced stage. For individuals with advanced-stage colorectal cancer, conversion or neoadjuvant therapy is frequently necessitated to facilitate surgical intervention and achieve a curative effect. And about 10% to 30% of colon cancer patients are complicated with intestinal obstruction. Surgical intervention remains the primary treatment for managing intestinal obstructions, albeit with a considerable risk of perioperative mortality and an increased likelihood of postoperative complications. PDT, as a neoadjuvant treatment for colon cancer, can shrink the local tumor and relieve obstruction, and is effective in colon cancer combined with obstruction. Robotic surgery has the advantages of high stability and low trauma, and compared with laparoscopic colon cancer surgery, robotic surgery can achieve better results. Fluorescent laparoscopic clarifies the location and size of the tumor lesion, allowing for greater precision when removing colon cancer lesions in robotic surgery. Therefore, in the treatment of colon cancer, PDT can offer an opportunity for surgery after relieving obstruction in patients with obstructive colon cancer. Additionally, when combined with fluorescent laparoscopic robotic colon cancer surgery, it provides a novel treatment approach for patients with obstructive colon cancer. Preoperative photodynamic neoadjuvant therapy combined with robotic colon cancer surgery has not yet been reported. Here, we report a case of colon cancer with obstruction, preoperative TNM stage was T4N1, and the lesion had caused intestinal stenosis. After four sessions of PDT, the patient's intestinal lumen was unobstructed and the lesion had regressed. After evaluation, fluorescent laparoscopic localization and visualization of lymph nodes combined with robotic colon cancer resection were performed. Postoperative pathology showed that the patient's tumor regression grade was grade 1. The patient's tumor was completely resected with good resection effect. No tumor invasion was found on both sides of the resection margin, and the patient did not relapse after surgery.

Accelerated clinical response achieved by combining short-term tumor-directed photodynamic therapy with immunotherapy-based systemic therapies in synchronous colorectal cancer with MSI-H and POLE mutation: a case report.

Genetic sequencing has revolutionized immunotherapy in colorectal cancer (CRC). Recent clinical trials have revealed a positive response to immunotherapy-based systemic therapies in CRC patient subgroups with microsatellite instability (MSI)-High or DNA polymerase epsilon (POLE) mutation. However, the unsatisfactory response rates was the major limitation in real-world practice of the precision immunotherapy in CRC. Adding photodynamic therapy (PDT) to systemic immunotherapy has showed synergetic anti-tumor effect by modulating tumor microenvironment, while the eligible patient's subgroups which would benefit from this combination remained equivocal. Here we reported a synchronous colorectal cancer patient with MSI-High and POLE mutation who had accelerated response in less than 2 cycles (42 days) of immunotherapy-based systemic therapies after tumor-directed PDT and has remained progression-free by far. This case enlightened the synergetic effect of PDT in immunotherapy-treated CRC patients, with the MSI and POLE-mutation status as predictors of survival benefits.

Association of depressive symptoms with cardiovascular events and plasma BNP: A prospective cohort study of the elderly Chinese population.

OBJECTIVE: To estimate the prevalence of depressive symptoms and to evaluate the associations of mild and significant depressive symptoms with cardiovascular events and plasma BNP levels (which are surrogate endpoints for cardiovascular events) among older adults in a population-based study. METHODS: A population-based prospective study of 1,432 elderly people (aged 70-84 years and without cardiovascular disease) was conducted, and the median duration of follow-up for participants with outcomes was 18 weeks. Depressive symptoms were assessed with the 15-item Geriatric Depression Scale (GDS-15). The hazard ratios (HRs) for the time to events and time to death were calculated using the Cox regression analysis. Multiple linear regression models and Spearman rank correlations were used to examine the association of depressive symptoms with Log BNP values. RESULTS: The prevalence of mild (GDS-15 scores ≥ 6) and significant (GDS-15 scores ≥ 10) depressive symptoms were 7.3% and 2.0% at baseline, respectively. Older adults with significant depressive symptoms exhibited increased risks of time to death (HR: 12.56; 95% CI: 3.58-43.99) and composite cardiovascular endpoints (HR: 3.46; 95% CI: 1.19-3.75). Significant depressive symptoms were associated with Log BNP levels (ß=0.56, P = 0.02). Depressive symptom scores were also associated with Log BNP levels (rs=0.21, P = 0.04) in the older adults with depressive symptoms. CONCLUSIONS: Significant depressive symptoms were associated with a higher risk of cardiovascular events and higher BNP levels in the elderly.

Predictive impact of sarcopenia in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: A retrospective study.

Background: Sarcopenia, characterised by an ongoing loss of skeletal muscle mass and reduced strength and function, is frequently observed in patients with non-small cell lung cancer (NSCLC). However, the relationship between sarcopenia and the prognosis of NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear. This aimed to assess whether sarcopenia is an independent prognostic factor for survival in patients with advanced NSCLC receiving ICIs. Methods: For this retrospective cohort study, we analysed the medical records of patients attending our hospital aged 18-75 years who were newly diagnosed with stage IIIB to stage IV NSCLC, and who had received ICIs as first- or second-line therapy between May 2019 and April 2022. The skeletal muscle index (SMI) was calculated from computed tomography (CT) images and relevant clinical characteristics within 4 weeks of initiating treatment and used to diagnose sarcopenia status. The Kaplan-Meier method and log-rank test were used to calculate and compare patients' progression-free survival (PFS). Cox proportional hazard regression was used to examine the associations between sarcopenia and survival outcomes. The chi-square test was used to compare treatment response outcomes, such as the objective response rate (ORR), disease control rate (DCR), and immunotherapy-related adverse events (irAEs), between individuals with and without sarcopenia. Additionally, the Student's t-test was utilised to compare SMI values between patients by their objective response (OR) and disease control (DC). Finally, the Mann-Whitney U test was used to compare nutritional and inflammatory indicators between the sarcopenia groups. Results: The study enrolled 70 patients, of whom 34 (48.6%) were diagnosed with sarcopenia. The median PFS of patients with and without sarcopenia was 7.5 vs. 13.4 months, respectively (p = 0.006). The proportional hazards regression analysis showed sarcopenia to be an independent prognostic factor for shorter PFS (hazard ratio (HR): 0.504, 95% CI: 0.265-0.962, p = 0.038). Using chi square tests, we found significant differences in the ORR (20.59% vs. 58.33%, p = 0.001) and occurrence of any irAEs (44.1% vs. 22.2%, p = 0.028) between the sarcopenia and the non-sarcopenia groups, respectively. The Student's t-test showed a significant difference in SMI between the ORR group and the non-ORR group (49.99 ± 7.00 vs. 42.98 ± 2.18 cm2/m2, p = 0.0015). While the sarcopenia group were with significantly a lower CD4+/CD8+ ratios and a higher C-reactive protein (CRP) level (p = 0.026, p = 0.011, respectively). Conclusions: This study found that sarcopenia is a significant predictor of a poor prognosis for patients with advanced NSCLC receiving ICIs. Multiple inflammatory and immune functions related to prognosis also differ by sarcopenia status.

Metabolic reprogramming of glycolysis favors cartilage progenitor cells rejuvenation.

Osteoarthritis (OA), the leading cause of disability in the elderly, still lacks effective treatment due to the unelucidated mechanisms of pathogenesis and progression. In cartilage, although the solo cell type of chondrocytes is resident, cartilage progenitor cells (CPCs) are identified. Chondrocytes in cartilage mainly utilize glycolysis because of the low oxygen tension. Until now, whether the metabolic pathway changes are associated with OA initiation or progression, as well as the biology of CPCs, remains fully clarified. By reviewing relevant literature from previous functional studies, we further mined recently published mouse and human chondrocytes single-cell RNA-sequencing datasets to explore gene expression profiles shift in OA initiation or during OA progression, regarding metabolism. In this review, we demonstrated that chondrocytes' metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) in OA initiation or during OA progression. Genes that related to OXPHOS, electron transport, mitochondrial translation, and mitochondrial respiratory chain complex assembly were upregulated in chondrocytes of injured cartilage or during OA progression. In addition, compared to OXPHOS, glycolysis facilitates CPC expansion and chondrogenic potential. The collated information suggests a potential therapeutic for OA through metabolic reprogramming of glycolysis to interrupt OA pathology and favor CPCs rejuvenation to restore healthy cartilage.

[Effect of Wnt/ß-catenin signaling pathway in neural differentiation of human bone marrow mesenchymal stem cells].

Objective: To explore the effect of basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and the combination of bFGF and EGF in the neural differentiation of human bone marrow mesenchymal stem cells (hBMSCs), and the role of Wnt/ß-catenin signaling pathway in this process. Methods: The identified 4th-generation hBMSCs were divided into five groups according to different induction conditions, namely control group (group A), EGF induction group (group B), bFGF induction group (group C), EGF and bFGF combined induction group (group D), and EGF, bFGF, and Dickkopf-related protein 1 (DKK-1) combined induction group (group E). After 7 days of continuous induction, the cell morphology was observed by inverted fluorescence phase contrast microscopy, levels of genes that were related to neural cells [Nestin, neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP-2), and glial fibrillary acidic protein (GFAP)] and key components of the Wnt/ß-catenin signaling pathway (ß-catenin and Cyclin D1) were detected by RT-PCR, and the levels of proteins that were related to neural cells (Nestin and GFAP) as well as genes that were involved in Wnt/ß-catenin signaling pathway [ß-catenin, phosphorylation ß-catenin (P-ß-catenin), Cytoplasmic ß-catenin, and Nuclear ß-catenin] were explored by cellular immunofluorescence staining and Western blot. Results: When compared to groups A and B, the typical neuro-like cell changes were observed in groups C-E, and most obviously in group D. RT-PCR showed that the relative expressions of Nestin, NSE, and MAP-2 genes in groups C-E, the relative expressions of GFAP gene in groups D and E, the relative expression of NSE gene in group B, the relative expressions of ß-catenin gene in groups C and D, and the relative expressions of Cyclin D1 gene in groups B-D significantly increased when compared with group A ( P<0.05). Compared with group E, the relative expressions of Nestin, NSE, MAP-2, GFAP, ß-catenin, and CyclinD1 genes significantly increased in group D ( P<0.05); compared with group C, the relative expression of Nestin gene in group D significantly decreased ( P<0.05), while NSE, MAP-2, and GFAP genes significantly increased ( P<0.05). The cellular immunofluorescence staining showed that the ratio of NSE- and GFAP-positive cells significantly increased in groups C-E than in group A, in group D than in groups C and E ( P<0.05). Western blot assay showed that the relative expression of NSE protein was significantly higher in groups C and D than in group A and in group D than in groups C and E ( P<0.05). In addition, the relative expression of GFAP protein was significantly higher in groups C-E than in group A and in group D than in group E ( P<0.05). Besides, the relative expressions of ß-catenin, Cytoplasmic ß-catenin, Nuclear ß-catenin, and the ratio of Nuclear ß-catenin to Cytoplasmic ß-catenin were significantly higher in groups C and D than in group A and in group D than in group E ( P<0.05), whereas the relative expression of P-ß-catenin protein was significantly lower in groups C and D than in group A and in group D than in group E ( P<0.05). Conclusion: Different from EGF, bFGF can induce neural differentiation of hBMSCs. In addition, EGF can enhance the hBMSCs neural differentiation of bFGF, while the Wnt/ß-catenin signaling pathway may play a positive regulatory role in these processes.

Lipid Nanoparticles-Based Therapy in Liver Metastasis Management: From Tumor Cell-Directed Strategy to Liver Microenvironment-Directed Strategy.

Metastasis to the liver, as one of the most frequent metastatic patterns, was associated with poor prognosis. Major drawbacks of conventional therapies in liver metastasis were the lack of metastatic-targeting ability, predominant systemic toxicities and incapability of tumor microenvironment modulations. Lipid nanoparticles-based strategies like galactosylated, lyso-thermosensitive or active-targeting chemotherapeutics liposomes have been explored in liver metastasis management. This review aimed to summarize the state-of-art lipid nanoparticles-based therapies in liver metastasis management. Clinical and translational studies on the lipid nanoparticles in treating liver metastasis were searched up to April, 2023 from online databases. This review focused not only on the updates in drug-encapsulated lipid nanoparticles directly targeting metastatic cancer cells in treating liver metastasis, but more importantly on research frontiers in drug-loading lipid nanoparticles targeting nonparenchymal liver tumor microenvironment components in treating liver metastasis, which showed promise for future clinical oncological practice.

Risk factors and prognosis of early neurological deterioration in patients with posterior circulation cerebral infarction.

BACKGROUND: The incidence, risk factors, and pathogenesis of early neurological deterioration (END) in posterior circulation stroke are still unclear. In this study, we aimed to determine the risk factors and prognosis of END in patients with acute posterior circulation cerebral infarction. METHODS: Acute posterior circulation ischemic stroke patients who had completed neuroimaging within 72 h of onset were selected from a prospective registry study Demographic characteristics, physiological data, medical history, laboratory data, in-hospital evaluation, neurological severity and TOAST classification, treatment, and the modified Rankin Scale (mRS) score of patients were assessed. Early neurological deterioration was defined as an increase of 2 points in the National Institutes of Health Stroke Scale score between the baseline and 72 h evaluation. Favorable and poor outcomes were defined as mRSs of 02 and≥ 3, respectively, at 3 months. The incidence and risk factors were evaluated by univariate and multivariate regression analysis (step-back method). RESULTS: The analysis included 455 subjects with an acute posterior circulation non-cardiac ischemic stroke, 330 (72.53 %) of them male, with an average age of 63.12 ( ± 10.14) years and with 47 (10.33 %) having END. The results of univariate and multivariate logistic regression analysis showed that BATMAN scores ≥ 5 (OR: 0.1, 95 % CI: 0.02-0.53, P < 0.01), large artery atherosclerosis (OR: 11.55, 95 % CI: 4.18-31.93, P < 0.01), vascular stenosis > 50 % (OR: 2.44, 95 % CI: 1.1-5.42, P = 0.029), reperfusion therapy (OR: 4.21, 95 % CI: 1.66-10.64, P < 0.01), and the distribution of pontine lesions (OR: 5.66, 95 % CI: 2.39-13.44, P < 0.01) were significantly associated with END. Patients with END had a lower rate of favorable outcomes at discharge and long-term follow-up (P < 0.001), regardless of whether they received reperfusion therapy. CONCLUSION: The lesion distribution of the pons, the progression of temporo-occipital lobe lesions, and large arterial atherosclerosis are independent risk factors of END that might predict a poor short- and long-term prognosis.

Case report: Significant response to PD-L1 inhibitor after resistance to PD-1 inhibitor in an advanced alpha-fetoprotein-positive gastric cancer.

Alpha-fetoprotein-positive gastric cancer (AFPGC) is a type of gastric cancer with a high degree of malignancy. The disease is more common in the elderly, with a high prevalence in males and generally atypical clinical manifestations. For advanced patients, the current treatment options are limited and, to date, few cases of advanced AFPGC have been treated successfully with conventional chemotherapy. With the development of molecular biology and immunology, tumor immunotherapy offers more therapeutic options to patients with advanced gastric cancer. This study describes a case of advanced gastric cancer in a young woman with a high blood alpha-fetoprotein (AFP) level (>54,000 ng/mL). The patient showed initial promising results when programmed cell death-1 (PD-1) inhibitor treatment was combined with chemotherapy after systemic chemotherapy failed. When the disease progressed again after 129 days, adjustment of the treatment regimen to Atezolizumab in combination with Irinotecan and Surufatinib capsules achieved partial remission (PR). There were no immune-related pneumonia, myocarditis, or other adverse effects observed. The patient currently has an overall survival of more than 14 months. This case demonstrated that switching from PD-1 inhibitor to programmed cell death-Ligand 1 (PD-L1) inhibitor therapy may overcome potential resistance. It providing a reference for immunotherapy of patients with AFP-positive advanced gastric cancer.

Identification of the OA-related metabolism-related genes, corresponding transcription factors, relevant pathways, and specific bioactive small molecules.

Metabolic alteration of articular cartilage is associated with the pathogenesis of Osteoarthritis (OA). This study aims to identify the metabolism-related genes, corresponding transcription factors (TFs), and relevant pathways. Overall, RNA sequencing profiles of articular cartilage were collected from the GEO database. Metabolism-related genes and OA-related hallmarks were collected from the MSigDB v7.1. Differential expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and Gene Set Variation Analysis (GSVA) were conducted to identify pathways or hallmarks that were related to the pathogenesis of OA. The Pearson correlation analysis was used to establish the regulatory network among transcription factors, metabolism-related genes, and hallmarks. To further confirm the regulation of the identified transcription factors, Chromatin Immunoprecipitation-sequencing (ChIP-seq) was conducted, and single-cell sequencing was used to locate the cell clusters. Connectivity Map (CM) analysis were also conducted to identify the potential specific bioactive small molecules targeting the metabolic alteration of osteoarthritis. scTPA database was used to detect activated signaling pathways. Collectively, a total of 74 and 38 differentially expressed metabolism-related genes and TFs were retrieved. Skeletal system development, extracellular matrix, and cell adhesion molecule binding were important pathways in GO analysis. Human papillomavirus infection, PI3K-Akt signaling pathway, and Human T-cell leukemia virus 1 infection were the top 3 pathways in KEGG. 7 and 12 hallmarks were down- and up-regulated in GSVA, respectively. Ten bioactive small molecules may be potential treatments of OA by regulating the metabolism of articular cartilage. ChIP-seq analysis showed high relativity between transcription factors and their target genes. Furthermore, single-cell sequencing confirms the high expression of identified transcription factors in chondrocytes. To conclude, we established a comprehensive network integrated with transcription factors, metabolism-related genes, and hallmarks.

Association Study of Mitochondrial DNA Haplogroup D and C5178A Polymorphisms with Chronic Kidney Disease.

Objective: To explore the associations of common mitochondrial DNA polymorphisms with chronic kidney disease (CKD). Methods: Data from 286 longevous individuals aged 95 years or older from the longevity arm from the Rugao Longevity and Ageing Study (RuLAS) were used. Twenty-eight common haplogroups defined by 33 single nucleotide polymorphisms were genotyped using SNaPshot minisequencing reaction assays. The creatinine-based estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: The prevalence of CKD was 23.6% among the longevous participants aged 95 years and older. The D haplogroup (67.37 ± 14.72 vs. 70.65 ± 11.07, p = 0.045), the D5 haplogroup (60.86 ± 18.36 vs. 70.34 ± 11.53, p = 0.002), and the 5178A allele (67.23 ± 14.48 vs. 70.75 ± 11.10, p = 0.029) were associated with lower eGFR levels compared with noncarriers. The D5 haplogroup (13.8% vs. 3.6%, p = 0.005) was significantly higher, while D haplogroup (35.4% vs. 24%, p = 0.067) and the 5178A allele (36.9% vs. 24.9%, p = 0.056) were borderline significantly higher in CKD individuals than those without CKD. Further, after adjusting for multiple covariates, the D haplogroup, the D5 haplogroup, and the 5178A allele were associated with increased odds of CKD with odds ratios of 1.93 (95% confidence interval [CI]: 1.00-3.72, p = 0.050), 4.76 (95% CI: 1.49-15.22, p = 0.009) and 2.04 (95% CI: 1.05-3.96, p = 0.035), respectively. Conclusions: The D and D5 haplogroups, as well as the 5178A allele are associated with decreased eGFR levels and an increased risk of CKD in a longevous population.

Long non-coding RNA MCM3AP-AS1 protects chondrocytes ATDC5 and CHON-001 from IL-1ß-induced inflammation via regulating miR-138-5p/SIRT1.

Osteoarthritis (OA) is a chronic inflammatory joint disease. Increased apoptosis of chondrocytes contributes to cartilage degradation in OA pathogenesis. The function of lncRNA MCM3AP-AS1 in regulating the viability of chondrocytes still awaits further elaboration. In this work, MCM3AP-AS1, miR-138-5p and SIRT1 mRNA expression levels in OA and normal cartilage tissues were detected by qRT-PCR. Besides, chondrocyte cell lines, CHON-001 and ATDC5 induced by interleukin-1ß (IL-1ß) were used to initiate the inflammatory response environment of OA. CCK-8 assay was used to examine the cell multiplication; meanwhile, transwell assay was utilized to detect migration. Western blot was adopted to determine SIRT1 expression in chondrocyte. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate inflammatory factor levels. In addition, the binding sites between MCM3AP-AS1 and miR-138-5p, miR-138-5p and 3'UTR of SIRT1 were validated by dual-luciferase reporter assay, RIP assay or RNA pull-down assay. It was found that MCM3AP-AS1 was declined in OA cartilage tissues, positively interrelated with SIRT1 expression while negatively correlated with miR-138-5p. MCM3AP-AS1 up-regulation enhanced the viability and migration of CHON-001 and ATDC5 cells while restraining the apoptosis and inflammatory response. Additionally, miR-138-5p overexpression counteracted the effects on chondrocytes caused by MCM3AP-AS1 overexpression. MCM3AP-AS1 could adsorb miR-138-5p, and SIRT1 was verified as a target of miR-138-5p, and SIRT1 could be up-regulated by overexpression of MCM3AP-AS1 indirectly. In conclusion, MCM3AP-AS1 has the potential to be the 'ceRNA' to regulate miR-138-5p and SIRT1 in chondrocytes, and to participate in the pathogenesis of OA.

Molecular profiling of Chinese R-CHOP treated DLBCL patients: Identifying a high-risk subgroup.

Diffuse large B-cell lymphoma (DLBCL) is a clinically aggressive and heterogenous disease. Although most patients can be cured by immunochemotherapy, 30% to 40% patient will ultimately develop relapsed or refractory disease. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. We performed capture-based targeted sequencing on baseline samples of 105 DLBCL patients using a panel consisting of 112 lymphoma-related genes. Subsequently, 81 treatment-naïve patients with measurable disease and followed for over 1 year were included for survival analysis. Collectively, the most commonly seen mutations included IGH fusion (69%), PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (87.0% vs 50.0%, P = .009). For those with TP53 disruptive mutations, 91.7% patients were in the primary refractory group. Interestingly, BCL-2 somatic hypermutation was only seen in patients without primary refractory disease (P = .014). In multivariate analysis, BCL-2 amplification (hazard ratio [HR] = 2.94, P = .022), B2M mutation (HR = 2.99, P = .017) and TP53 mutation (HR = 3.19, P < .001) were independently associated with shorter time to progression (TTP). Furthermore, TP53 mutations was correlated with worse overall survival (P = .049). Next, we investigated mutation landscape in patients with wild-type (WT) TP53 (n = 58) and found that patients harboring MYD88 L265P had significantly inferior TTP than those with WT or non-265P (P = .046). Our study reveals the mutation spectrum of treatment-naive Chinese DLBCL patients. It also confirms the clinical significance of TP53 mutations and indicates the prognostic value of MYD88 L265P in TP53 WT patients.

Metronomic paclitaxel improves the efficacy of PD-1 monoclonal antibodies in breast cancer by transforming the tumor immune microenvironment.

The clinical efficacy of PD-1/PD-L1 monoclonal antibodies (mAbs) in triple-negative breast cancer (TNBC) is unsatisfactory. Immunotherapy combined with chemotherapy shows good therapeutic potential. Preclinical and clinical studies have shown that metronomic chemotherapy may stimulate anticancer immune responses. We aimed to verify whether metronomic paclitaxel (PTX, TAX) treatment can improve the efficacy of a PD-1 mAb in a TNBC mouse model and to explore the potential mechanism. After constructing the TNBC mouse model and treating with PD-1 mAb, metronomic PTX chemotherapy or combined therapy, the differences in the efficacy of each treatment group were compared and analyzed. Our findings suggested that the combination of metronomic PTX chemotherapy and PD-1 mAb produces a potent antitumor effect. Further experiments demonstrated that metronomic PTX chemotherapy changed the immune cell population in tumor tissues. These data suggest that metronomic PTX improves the efficacy of the PD-1 mAb in TNBC by transforming the tumor immune microenvironment, and these results provide strong evidence for the use of this treatment in TNBC patients in the future.

Vanillin derivative VND3207 activates DNA-PKcs conferring protection against radiation-induced intestinal epithelial cells injury in vitro and in vivo.

Vanillin is a natural compound endowed with antioxidant and anti-mutagenic properties. We previously identified the vanillin derivative VND3207 with strong radio-protective and antioxidant effects and found that VND3207 confers survival benefit and protection against radiation-induced intestinal injury (RIII) in mice. We also observed that VND3207 treatment enhanced the expression level of the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) in human lymphoblastoid cells with or without γ-irradiation. DNA-PKcs is a critical component of DNA double strand break repair pathway and also regulates mitotic progression by stabilizing spindle formation and preventing mitotic catastrophe in response to DNA damage. In the present study, we found that VND3207 protected intestinal epithelial cells in vitro against ionizing radiation by promoting cell proliferation and inhibiting cell apoptosis. In addition, VND3207 promoted DNA-PKcs activity by increasing autophosphorylation at S2056 site. Consistent with this, VND3207 significantly decreased the number of γH2AX foci and mitotic catastrophe after radiation. DNA-PKcs deficiency abolished these VND3207 radio-protective effects, indicating that DNA-PKcs activation is essential for VND3207 activity. In conclusion, VND3207 promoted intestinal repair following radiation injury by regulating the DNA-PKcs pathway.

Depressive symptoms are associated with incident frailty in a Chinese population: the Rugao Longevity and Aging Study.

BACKGROUND AND AIMS: This study aimed at investigating whether depression symptoms are associated with prevalent and incident physical frailty in Chinese older population. METHODS: We analyzed data of 1168 older Chinese adults aged 70 and above in the aging arm of the Rugao Longevity and Aging Study (RuLAS). Depressive symptoms (Geriatric Depression Scale ≥ 6) were assessed by the Geriatric Depression Scale. Frailty was defined using Fried phenotype criteria at baseline and 3-year survey. RESULTS: At baseline, 8.9% of the participants had depression symptoms. The prevalence of pre-frailty and frailty were 34.5% and 5.9%, respectively. The percentages of depressive symptoms increase from robust (5.3%) to pre-frail (11.2%), and then to frail (31.9%) groups. After adjustments of multiple covariates, depressive symptoms were associated with both prevalent pre-frailty (OR = 1.75, 95% CI 1.08-2.84) and prevalent frailty (OR = 5.64, 95% CI 2.85-11.14) at baseline. At 3-year survey, 9.3% participants reported the development of frailty. After multiple adjustments, depressive symptoms were associated with a 2.79-fold (95% CI 1.09-7.10) increased risk of 3-year incident frailty. CONCLUSION: Depressive symptoms are associated with prevalent and incident frailty in Chinese older population. Together with the observations of the European populations, depressive symptoms may be a candidate risk factor of frailty.

Frailty index is associated with increased risk of elevated BNP in an elderly population: the Rugao Longevity and Ageing Study.

BACKGROUND AND AIMS: To explore whether frailty, defined by frailty index (FI), is associated with the risk of elevated B-type natriuretic peptide (BNP), a surrogate endpoint of cardiovascular events. METHODS: Data of 1382 community-dwelling elders who had no documented cardiovascular diseases aged 70-84 years from the ageing arm of the Rugao Longevity and Ageing Study was used. Traditional risk factor index (TI) was constructed using eight established cardiovascular-related risk factors. FI was constructed using 36 health deficits. Elevated BNP was defined as BNP ≥ 100pg/mL. Cardiovascular events include incident major cardiovascular events and cardiovascular death. RESULTS: During a 3-year follow-up period, 97 participants had cardiovascular events. TI was not associated with the risk of elevated BNP, but was associated with cardiovascular events (HR = 1.16, 95% CI 1.01-1.34). Frailty index was not only associated with cardiovascular events (HR = 1.32, 95% CI 1.06-1.64), but also associated with elevated BNP with an OR of 1.22 (95% CI 1.02-1.47) for each 0.1 increment. Further, both frailty (OR = 1.93, 95% CI 1.67-3.17) and pre-frailty (OR = 1.54, 95% CI 1.06-2.25) were associated with increased risk of elevated BNP. CONCLUSION: FI is associated with increased risks of both cardiovascular events and surrogated endpoint of cardiovascular disease-elevated BNP. Frailty may be a non-traditional risk factor of cardiovascular diseases and frailty index may be a measurement for early identifying high risk elderly individuals of cardiovascular abnormities.

Oral administration of hydroxylated-graphene quantum dots induces intestinal injury accompanying the loss of intestinal stem cells and proliferative progenitor cells.

Graphene quantum dots (GQDs) have gained significant attention in various biomedical applications. The physicochemical properties of these nanoparticles, including toxic effects, are largely determined by their surface modifications. Previous studies have demonstrated high in vitro cytotoxicity of the hydroxylated GQDs (OH-GQDs). The focus of this study was on the intestinal toxicity of OH-GQDs. Briefly, C57BL/6J mice were given daily oral gavage of 0.05, 0.5 or 5 mg/kg OH-GQD for 7 days, and the indices of intestinal damage were evaluated. Higher doses of the OH-GQDs caused significant intestinal injuries, such as enhanced intestinal permeability, shortened villi and crypt loss. The number of Lgr5+ intestinal stem cells also decreased dramatically upon OH-GQDs exposure, which also inhibited the Ki67+ proliferative progenitor cells. In addition, an increased number of crypt cells harboring the oxidized DNA base 8-OHdG and γH2AX foci were also detected in the intestines of OH-GQD-treated mice. Mechanistically, the OH-GQDs up-regulated both total and phosphorylated p53. Consistent with this, the average number of TUNEL+ and cleaved caspase-3+ apoptotic intestinal epithelial cells were significantly increased after OH-GQDs treatment. Finally, a 3-dimensional organoid culture was established using isolated crypts, and OH-GQDs treatment significantly reduced the size of the surviving intestinal organoids. Taken together, the intestinal toxicity of the OH-GQDs should be taken into account during biomedical applications.

The vanillin derivative VND3207 protects intestine against radiation injury by modulating p53/NOXA signaling pathway and restoring the balance of gut microbiota.

The intestine is a highly radiosensitive tissue that is susceptible to structural and functional damage due to systemic as well as localized radiation exposure. Unfortunately, no effective prophylactic or therapeutic agents are available at present to manage radiation-induced intestinal injuries. We observed that the vanillin derivative VND3207 improved the survival of lethally irradiated mice by promoting intestinal regeneration and increasing the number of surviving crypts. Pre-treatment with VND3207 significantly increased the number of Lgr5+ intestinal stem cells (ISCs) and their daughter cells, the transient Ki67+ proliferating cells. Mechanistically, VND3207 decreased oxidative DNA damage and lipid peroxidation and maintained endogenous antioxidant status by increasing the level of superoxide dismutase and total antioxidant capacity. In addition, VND3207 maintained appropriate levels of activated p53 that triggered cell cycle arrest but were not sufficient to induce NOXA-mediated apoptosis, thus ensuring DNA damage repair in the irradiated small intestinal crypt cells. Furthermore, VND3207 treatment restores the intestinal bacterial flora structures altered by TBI exposure. In conclusion, VND3207 promoted intestinal repair following radiation injury by reducing reactive oxygen species-induced DNA damage and modulating appropriate levels of activated p53 in intestinal epithelial cells.