Efficacy comparison of fruquintinib, regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer.

BACKGROUND: Regorafenib (R) and fruquintinib (F) are the standard third-line regimens for colorectal cancer (CRC) according to the National Comprehensive Cancer Network guidelines, but both have limited efficacy. Several phase 2 trials have indicated that R or F combined with immune checkpoint inhibitors can reverse immunosuppression and achieve promising efficacy for microsatellite stable or proficient mismatch repair (MSS/pMMR) CRC. Due to the lack of studies comparing the efficacy between F, R, F plus programmed death-1 (PD-1) inhibitor, and R plus PD-1 inhibitors (RP), it is still unclear whether the combination therapy is more effective than monotherapy. AIM: To provide critical evidence for selecting the appropriate drugs for MSS/pMMR metastatic CRC (mCRC) patients in clinical practice. METHODS: A total of 2639 CRC patients were enrolled from January 2018 to September 2022 in our hospital, and 313 MSS/pMMR mCRC patients were finally included. RESULTS: A total of 313 eligible patients were divided into F (n = 70), R (n = 67), F plus PD-1 inhibitor (FP) (n = 95) and RP (n = 81) groups. The key clinical characteristics were well balanced among the groups. The median progression-free survival (PFS) of the F, R, FP, and RP groups was 3.5 months, 3.6 months, 4.9 months, and 3.0 months, respectively. The median overall survival (OS) was 14.6 months, 15.7 months, 16.7 months, and 14.1 months. The FP regimen had an improved disease control rate (DCR) (P = 0.044) and 6-month PFS (P = 0.014) and exhibited a better trend in PFS (P = 0.057) compared with F, and it was also significantly better in PFS than RP (P = 0.030). RP did not confer a significant survival benefit; instead, the R group had a trend toward greater benefit with OS (P = 0.080) compared with RP. No significant differences were observed between the R and F groups in PFS or OS (P > 0.05). CONCLUSION: FP is superior to F in achieving 6-month PFS and DCR, while RP is not better than R. FP has an improved PFS and 6-month PFS compared with RP, but F and R had similar clinical efficacy. Therefore, FP may be a highly promising strategy in the treatment of MSS/pMMR mCRC.

Effectiveness of risk-based caries management among Chinese preschool children: a randomized controlled single-blind trial.

BACKGROUND: Early childhood caries (ECC) remain a serious oral health problem on a global scale. Risk-based caries management (RBCM) implemented in some parts of the world has been effective in preventing ECC. However, there is a lack of prospective research on the application of RBCM among Chinese children, and little is known about its effectiveness. The purpose of this study was to evaluate the effectiveness of RBCM in preventing caries among children aged 3-5 years in Wanzhou District, Chongqing Municipality, China. METHODS: Three- to five-year-old children from four kindergartens in Wanzhou were randomly selected for baseline dental examination and caries risk assessment (CRA) and randomly assigned to the experimental group (EG) or the control group (CG) according to the kindergarten. The EG received caries prevention measures of different intensities based on the child's caries risk level. The CG received full-mouth fluoride twice a year according to standard prevention, regardless of their caries risk. One year later, another dental examination and CRA were conducted, to observe changes in the decayed, missing, and filled teeth (dmft) index and caries risk, and to analyze potential factors that may affect the incidence of new caries. RESULTS: Complete data were collected from 291 children (EG, N = 140, 84.8%; CG, N = 181, 83.4%). A total of 25.7% of the EG and 50.3% of the CG children developed new caries, with newly added dmft scores of 0.54 ± 1.12 and 1.32 ± 1.72, respectively (P < 0.05). Multivariate logistic regression indicated that children living in rural areas, assigned to the CG, and rated as high-risk at baseline were more likely to develop new caries (P < 0.05). The proportion of children with an increased caries risk in the EG was significantly lower than that in the CG (P < 0.05). CONCLUSIONS: RBCM effectively prevented new caries in 3- to 5-year-old Wanzhou children and reduced the proportion of children at increased risk of caries. It is an effective approach for preventing ECC. CLINICAL TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trials Register. The registration number was ChiCTR230067551 (11/01/2023).

Interpretable machine learning identifies metabolites associated with glomerular filtration rate in type 2 diabetes patients.

Objective: The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients. Methods: We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model. Results: For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1µmol/L, Cit higher than 26 µmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR. Conclusion: Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.

The EC50 of propofol with different doses of dexmedetomidine during gastrointestinal endoscopy: A double-blind, placebo-controlled trial.

PURPOSE: The goal of this study was to evaluate the dose-response relationship between dexmedetomidine and propofol in sedating patients and to determine the optimal dosage of dexmedetomidine during gastrointestinal endoscopy. METHODS: One hundred fifty patients were divided into 5 groups, each receiving a loading dose of dexmedetomidine (0.4, 0.6, 0.8, 1.0 µg/kg) or saline, with propofol for sedation. The median effective concentration (EC50) of propofol was calculated using the modified Dixon up-and-down approach. Adverse effects, vital signs, procedure, and recovery times were recorded. RESULTS: The EC50 of propofol in groups NS, D0.4, D0.6, D0.8, and D1.0 were 3.02, 2.44, 1.97, 1.85, and 1.83 µg/mL, respectively. Heart rate in the dexmedetomidine groups decreased more than the NS group (P < .001). The mean arterial pressure (MAP) in the NS group experienced a decline compared to groups D0.8 and D1.0 when the plasma concentration and effect-site concentration reached equilibrium. Additionally, the respiratory rate was found to be lower in groups NS, D0.4, D0.6, and D0.8 (P < .05). Recovery time in groups D0.8 and D1.0 was longer than the NS group (P < .05). Bruggemann comfort scales score was higher in group D1.0 (P < .05). No significant difference was found in the incidences of hypotension and bradycardia, and the dose of ephedrine and atropine. Respiratory depression was significantly reduced in groups D0.8 and D1.0 compared to the NS group. CONCLUSION: A single dose of 0.6 to 0.8 µg/kg of dexmedetomidine should be recommended in combination with propofol for gastrointestinal endoscopy. And the EC50 of propofol is 1.97 to 1.85 µg/mL.

A network meta-analysis evaluating the efficacy and safety of adjuvant therapy after nephrectomy in renal cell carcinoma.

BACKGROUND: In the past few years, there has been a continuous rise in the occurrence of renal cell carcinoma (RCC), with RCC recurrence becoming the primary factor behind fatalities. Despite numerous clinical trials, the impact of different medications on the long-term survival of patients with RCC after surgery remains uncertain. This network meta-analysis aimed to evaluate the impact of various medications on the survival and safety of drugs in individuals with RCC following nephrectomy. METHODS: We conducted a thorough search in various databases, including CNKI, WAN FANG DATA, VIP, Web of Science, Cochrane Library (CENTRAL), PubMed, Scopus, and Embase, for articles published prior to June 2, 2023. This meta-analysis incorporated randomized controlled trials (RCTs). RESULTS: The analysis included 17 studies with 14,298 participants. The findings from the disease-free survival (DFS) analysis indicated that pembrolizumab demonstrated efficacy in enhancing DFS among patients with RCC following nephrectomy when compared to the placebo group (HR = 0.83, 95%CI 0.70 to 0.99). None of the drugs included in the study significantly improved overall survival (OS) and recurrence-free survival (RFS) after nephrectomy. For adverse events (AEs), sorafenib, pazopanib, sunitinib, and nivolumab plus ipilimumab interventions showed a higher incidence of adverse events compared with placebo. CONCLUSION: The network meta-analysis yielded strong evidence indicating that pembrolizumab could potentially enhance DFS in patients with RCC following nephrectomy, surpassing the effectiveness of a placebo.

Mendelian randomization analysis reveals a protective association between genetically predicted systemic lupus erythematosus and renal cell carcinoma.

Observational studies have suggested that there may be a connection between systemic lupus erythematosus (SLE) and a higher likelihood of developing urological cancers, although the exact cause-effect relationship is still unclear. This study therefore investigated the causal relationship between SLE and urological cancers using the Mendelian randomization (MR) approach. Our primary MR analysis involved using the inverse variance weighted method, which employed an inverse-variance-weighted approach, to examine the causal relationship between SLE and urological conditions. In addition, we performed various sensitivity analyses, such as MR-Egger regression, tests for heterogeneity, and leave-one-out sensitivity tests, to assess the reliability of our results. The findings from our analysis using Two-Sample MR showed that genetically predicted SLE was linked to a reduced likelihood of developing renal cell carcinoma (RCC) (odds ratio = 0.9996, 95% confidence interval = 0.9993-0.9999, P value = .0159). These results suggest a possible protective impact of SLE against RCC. Nevertheless, no substantial correlation was detected between SLE and the likelihood of developing bladder cancer or prostate cancer. Collectively, these findings offer significant fresh perspectives on the possible correlation between SLE and genitourinary malignancies, specifically RCC, which will provide ideas and basis for the treatment of RCC.

Progress of Dispersants for Coal Water Slurry.

Dispersants, serving as an essential raw material in the formulation of coal water slurry, offer an economical and convenient solution for enhancing slurry concentration, thus stimulating significant interest in the development of novel and efficient dispersants. This paper intends to illuminate the evolution of dispersants by examining both the traditional and the newly conceived types and elaborating on their respective mechanisms of influence on slurry performance. Dispersants can be classified into anionic, cationic, amphoteric, and non-ionic types based on their dissociation properties. They can be produced by modifying either natural or synthetic products. The molecular structure of a dispersant allows for further categorization into one-dimensional, two-dimensional, or three-dimensional structure dispersants. This document succinctly outlines dispersants derived from natural products, three-dimensional structure dispersants, common anionic dispersants such as lignin and naphthalene, and amphoteric and non-ionic dispersants. Subsequently, the adsorption mechanism of dispersants, governed by either electrostatic attraction or functional group effects, is elucidated. The three mechanisms through which dispersants alter the surface properties of coal, namely the wetting dispersion effect, electrostatic repulsion effect, and steric hindrance effect, are also explained. The paper concludes with an exploration of the challenges and emerging trends in the domain of dispersants.

Revealing the mechanism of quinoa on type 2 diabetes based on intestinal flora and taste pathways.

To investigate the antidiabetic effects and mechanisms of quinoa on type 2 diabetes mellitus (T2DM) mice model. In this context, we induced the T2DM mice model with a high-fat diet (HFD) combined with streptozotocin (STZ), followed by treatment with a quinoa diet. To explore the impact of quinoa on the intestinal flora, we predicted and validated its potential mechanism of hypoglycemic effect through network pharmacology, molecular docking, western blot, and immunohistochemistry (IHC). We found that quinoa could significantly improve abnormal glucolipid metabolism in T2DM mice. Further analysis showed that quinoa contributed to the improvement of gut microbiota composition positively. Moreover, it could downregulate the expression of TAS1R3 and TRPM5 in the colon. A total of 72 active components were identified by network pharmacology. Among them, TAS1R3 and TRPM5 were successfully docked with the core components of quinoa. These findings confirm that quinoa may exert hypoglycemic effects through gut microbiota and the TAS1R3/TRPM5 taste signaling pathway.

Xiaozheng pill exerts an anti-mammary hyperplasia effect through Raf/ERK/ELK and HIF-1α/bFGF pathways.

Background and aim: The purpose of this study is to explore whether the Xiaozheng pill (XZP) has the effect of anti-hyperplasia of mammary glands (HMG) and to identify the related signaling pathways. Experimental procedure: We analyzed the effective chemical components of the XZP, as well as the key chemical components, key proteins, main biological processes, and pathways in the treatment of HMG; Secondly, the levels of Estradiol (E2), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Progesterone (P), Raf/ERK/ELK and HIF-1α/bFGF pathways related proteins were detected; Finally, the effect of XZP on metabolites was analyzed by metabolomics. Results and conclusion: In this study, we identified key targets and pathways for XZP therapy of HMG, including EGFR, VEGFA, ER, and Ras signaling pathways. Animal experiments show that XZP can reduce the levels of E2, LH, and FSH and increase the expression of P in HMG mice. XZP can restore the normal structure of breast tissue and reduce ERα, ERß, and PR expression in breast tissue. In addition, metabolomics results show that XZP also regulates HMG metabolites, including HIF-1α and metabolic pathways. The Western blot results showed that XZP intervention can reduce the protein expression of p-Raf1, Raf1, p-ERK1/2, ERK1/2, ELK, HIF-1α, and bFGF in the breast tissue of HMG mice. XZP may eliminate abnormal breast hyperplasia through inhibition of apoptosis and angiogenesis, which may be linked with the regulation of the Raf/ERK/ELK and HIF-1α/bFGF signaling pathways in HMG mice. These results suggest that XZP treatment may be beneficial for the management of HMG.

Moringa oleifera leaf supplementation relieves oxidative stress and regulates intestinal flora to ameliorate polycystic ovary syndrome in letrozole-induced rats.

This study investigated the effects of supplementation Moringa oleifera leaf (MOL) on relieving oxidative stress, anti-inflammation, changed the relative abundance of multiple intestinal flora and blood biochemical indices during letrozole-induced polycystic ovary syndrome (PCOS). Previous studies have shown that MOL has anti-inflammatory, anti-oxidation, insulin-sensitizing effects. However, whether MOL has beneficial effects on PCOS remains to be elucidated. In the current study, 10-week-old female Sprague-Dawley rats received letrozole to induce PCOS-like rats, and subsequently were treated with a MOL diet. Then, the body weight and estrus cycles were measured regularly in this period. Finally, the ovarian morphology, blood biochemical indices, anti-oxidative, intestinal flora, and anti-inflammation were observed at the end of the experiment. We found that MOL supplementation markedly decreased the body weight, significantly upregulated the expression of Sirt1, FoxO1, PGC-1α, IGF1, and substantially modulated the sex hormone level and improved insulin resistance, which may be associated with the relieves oxidative stress. Moreover, the supplementation of MOL changed the relative abundance of multiple intestinal flora, the relative abundance of Fusobacterium, Prevotella were decreased, and Blautia and Parabacteroides were increased. These results indicate that MOL is potentially a supplementary medication for the management of PCOS.

MMP9 and TYROBP affect the survival of circulating tumor cells in clear cell renal cell carcinoma by adapting to tumor immune microenvironment.

Circulating tumor cells (CTCs) play a key role in tumor metastasis. CTCs have altered gene expression and can survive in the bloodstream. Finding the key genes whose expression are altered in CTCs could help explain the mechanism of tumor metastasis. We searched for genes differentially expressed in CTCs by analyzing four CTCs and primary tumor gene expression datasets in the GEO database. Key genes of clear cell renal cell carcinoma (ccRCC) CTCs were identified. The correlation between key genes and the immune microenvironment of ccRCC was explored. Finally, the CTCs cell model of ccRCC was constructed by in vivo screening method, and the expression of key genes was detected at the cell and tissue levels. A total of 771 DEGs were obtained. Gene enrichment analysis showed that DEGs of CTCs were mainly involved in the regulation of the tumor immune process and tumor cell apoptosis. Finally, we found 2 key genes, MMP9 and TYROBP in ccRCC CTCs. The high expression of these 2 genes predicted a poor prognosis of ccRCC, and the expression levels of these 2 genes were significantly increased in CTCs and ccRCC tissues. Our study suggested that genetic alterations in CTCs contribute to the ability of CTCs to survive in the blood by adapting to the tumor microenvironment. MMP9 and TYROBP are potential therapeutic and prognostic targets for ccRCC.

SERPINE1 and its co-expressed genes are associated with the progression of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma(ccRCC) is a frequently occurring malignant tumor of the urinary system. Despite extensive research, the regulatory mechanisms underlying the pathogenesis and progression of ccRCC remain largely unknown. METHODS: We downloaded 5 ccRCC expression profiles from the Gene Expression Omnibus (GEO) database and obtained the list of differentially expressed genes (DEGs). Using String and Cytoscape tools, we determined the hub genes of ccRCC, and then analyzed their relationship with ccRCC patient survival. Ultimately, we identified SERPINE1 as a prognostic factor in ccRCC. Meanwhile, we confirmed the role of SERPINE1 in 786-O cells by cell transfection and in vitro experiments. RESULTS: Our analysis yielded a total of 258 differentially expressed genes, comprising 105 down-regulated genes and 153 up-regulated genes. Survival analysis of SERPINE1 expression in The Cancer Genome Atlas (TCGA) confirmed its association with the increase of tumor grade, lymph node metastasis, and tumor stage, as well as with shorter survival. Furthermore, we found that SERPINE1 expression levels were associated with CD8 + T cells, CD4 + T cells, B cells, macrophages, neutrophils, and dendritic cells. Cell experiments showed that knockdown SERPINE1 expression could inhibit the proliferation, migration and invasion of ccRCC cells. Among the co-expressed genes with the highest correlation, ITGA5, SLC2A3, SLC2A14, SHC1, CEBPB, and ADA were overexpressed and associated with shorter overall survival (OS) in ccRCC. CONCLUSIONS: In this study, we identified hub genes that are strongly related to ccRCC, and highlights the potential utility of overexpressed SERPINE1 and its co-expressed genes could be used as prognostic and diagnostic biomarkers in ccRCC.

Gut microbiota in heart failure and related interventions.

Heart failure (HF) is a sophisticated syndrome with structural or functional impairment of ventricular filling or ejection of blood, either causing symptoms and signs or being asymptomatic. HF is a major global health issue affecting about 64.3 million people worldwide. The gut microbiota refers to the complex ecosystem of microorganisms, mainly bacteria, in the gut. Studies have revealed that the gut microbiota is associated with many diseases ranging from neurodegenerative diseases to inflammatory bowel disease and cardiovascular diseases. The gut hypothesis of HF suggests that low cardiac output and systemic circulation congestion would cause insufficient intestinal perfusion, leading to ischemia and intestinal barrier dysfunction. The resulting bacterial translocation would contribute to inflammation. Recent studies have refined the hypothesis that changes of metabolites in the gut microbiota have a close relationship with HF. Thus, the gut microbiota has emerged as a potential therapeutic target for HF due to both its critical role in regulating host physiology and metabolism and its pivotal role in the development of HF. This review article aims to provide an overview of the current understanding of the gut microbiota's involvement in HF, including the introduction of the gut hypothesis of HF, its association with HF progression, the potential mechanisms involved mediated by the gut microbiota metabolites, and the impact of various interventions on the gut microbiota, including dietary interventions, probiotic therapy, fecal microbiota transplantation, antibiotics, and so on. While the gut hypothesis of HF is refined with up-to-date knowledge and the gut microbiota presents a promising target for HF therapy, further research is still needed to further understand the underlying mechanisms between gut microbiota and HF, the efficacy of these interventions, and contribute to the health of HF patients.

Sorafenib-Loaded Cu2-xSe Nanoparticles Boost Photothermal-Synergistic Targeted Therapy against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for the predominant form of liver malignancy and presents a leading cause of cancer-related death globally. Sorafenib (SOR), a first-line targeted drug for advanced HCC treatment, has a battery of untoward side effects. Photothermal therapy (PTT) has been utilized as an effective adjuvant in synergy with other approaches. However, little is known about the tumoricidal efficacy of combining SOR with PTT for HCC. Herein, a novel versatile nanoparticle, Cu2-xSe@SOR@PEG (CSP), that is based on a photothermal Cu2-xSe core and SOR for simultaneously reinforcing PTT and reducing the adverse effects of SOR was constructed. The synthesized CSP exhibited a remarkably enhanced therapeutic effect upon 808 nm laser irradiation via dampening HCC cell propagation and metastasis and propelling cell apoptosis. The intravenous administration of CSP substantially suppressed tumor growth in a xenograft tumor mouse model. It was noted that the CSP manifested low toxicity and excellent biocompatibility. Together, this work indicates a promising and versatile tool that is based on synergistic PTT and molecular-targeted therapy for HCC management.

Comprehensive analysis of the collagen family members as prognostic markers in clear cell renal cell carcinoma.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the common malignant tumors worldwide. There is still a lack of effective diagnostic and therapeutic targets for the recurrence and metastasis of ccRCC. In this study, we sought to identify effective diagnostic and therapeutic targets for ccRCC recurrence and metastasis. Methods: Gene Expression Omnibus (GEO) dataset was used to obtain differentially expressed genes (DEGs) between primary and metastasis ccRCC. We used The Cancer Genome Atlas (TCGA), GeneMANIA, cBioPortal, MethSurv, and TIMER to analyze the expression differences, mutation status, prognostic value, molecular function, and immune infiltration of hub genes in renal cell carcinoma (RCC). Results: We obtained a total of 35 different gene lists. Six collagen family members were identified as hub genes. The expression level of collagen family members was closely related to ccRCC. Moreover, differences in the expression levels of collagen family members were closely related to the stage and prognosis of ccRCC. Members of the collagen family were responsible for more than 15% of the genetic alterations in ccRCC and are involved in multiple signaling pathways. The expression level of collagen family members was closely related to the infiltration of tumor-associated immune cells. Univariate and multivariate Cox regression identified the prognosis-related genes: COL5A1. Conclusions: Our study implied that members of the collagen family may serve as a biomarker for ccRCC metastasis and prognosis.

Combined analysis of whole-exome sequencing and RNA sequencing in type 2 diabetes mellitus patients with thirst and fatigue.

BACKGROUND: The principal objective of this study was to gain a better understanding of the mechanisms of type 2 diabetes mellitus (T2DM) patients with fatigue (D-T2DM) through exome and transcriptome sequencing. METHODS: After whole-exome sequencing on peripheral blood of 6 D-T2DM patients, the consensus mutations were screen out and analyzed by a series of bioinformatics analyses. Then, we combined whole-exome sequencing and transcriptome sequencing results to find the important genes that changed at both the DNA and RNA levels. RESULTS: The results showed that a total of 265,393 mutation sites were found in D-T2DM patients compared with normal individuals, 235 of which were consensus mutations shared with D-T2DM patients. These genes significantly enriched in HIF-1 signaling pathway and sphingolipid signaling pathway. At the RNA level, a total of 375 genes were identified to be differentially expressed. After the DNA-RNA joint analysis, eight genes were screened that changed at both DNA and RNA levels. Among these genes, FUS and LMNA were related to carbohydrate metabolism, energy metabolism, and mitochondrial function. Subsequently, we predicted the herbs, including Qin Pi and Hei Zhi Ma, that might play a therapeutic role in D-T2DM through the SymMap database. CONCLUSION: These findings have significant implications for understanding the mechanisms of D-T2DM and provide potential targets for D-T2DM diagnosis and treatment.

Iridium Complex-Loaded Sorafenib Nanocomposites for Synergistic Chemo-photodynamic Therapy of Hepatocellular Carcinoma.

Although sorafenib, a multi-kinase inhibitor, has provided noteworthy benefits in patients with hepatocellular carcinoma (HCC), the inevitable side effects, narrow therapeutic window, and low bioavailability seriously affect its clinical application. To be clinically distinctive, innovative drugs must meet the needs of reaching tumor tissues and cause limited side effects to normal organs and tissues. Recently, photodynamic therapy, utilizing a combination of a photosensitizer and light irradiation, was selectively accumulated at the tumor site and taken up effectively via inducing apoptosis or necrosis of cancer cells. In this study, a nano-chemo-phototherapy drug was fabricated to compose an iridium-based photosensitizer combined with sorafenib (IPS) via a self-assembly process. Compared to the free iridium photosensitizer or sorafenib, the IPS exhibited significantly improved therapeutic efficacy against tumor cells because of the increased cellular uptake and the subsequent simultaneous release of sorafenib and generation of reactive oxygen species production upon 532 nm laser irradiation. To evaluate the effect of synergistic treatment, cytotoxicity detection, live/dead staining, cell proliferative and apoptotic assay, and Western blot were performed. The IPS exhibited sufficient biocompatibility by hemolysis and serum biochemical tests. Also, the results suggested that IPS significantly inhibited HCC cell proliferation and promoted cell apoptosis. More importantly, marked anti-tumor growth effects via inhibiting cell proliferation and promoting tumor cell death were observed in an orthotopic xenograft HCC model. Therefore, our newly proposed nanotheranostic agent for combined chemotherapeutic and photodynamic therapy notably improves the therapeutic effect of sorafenib and has the potential to be a new alternative option for HCC treatment.

Case Report: A Programmed Cell Death-1 Inhibitor-Related Abdominal Fibroinflammatory Reaction Affecting Multiple Organs in A Non-Small-Cell Lung Cancer Patient.

Immunotherapy utilizing programmed cell death-1 (PD-1)/PD-L1 inhibitors has been regarded as a rising hope for tumor patients, and their effects have been demonstrated in many clinical trials. However, immune-related adverse events also occur in patients and can sometimes have severe consequences. Pembrolizumab (Keytruda) is a humanized monoclonal anti-PD-1 antibody that has been approved by the US Food and Drug Administration for non-small-cell lung cancer. Here, we report a rare case of an abdominal fibroinflammatory reaction that affected multiple organs during anti-PD-1 immunotherapy using pembrolizumab in a non-small-cell lung cancer patient. The patient's case demonstrates that immunotherapy-related abdominal fibroinflammatory reactions need to be considered, especially for patients with a history of pre-existing conditions in the abdomen. Glucocorticoids may be useful as a treatment when a diagnosis is confirmed.

Naringenin regulates gut microbiota and SIRT1/ PGC-1ɑ signaling pathway in rats with letrozole-induced polycystic ovary syndrome.

PURPOSE: To evaluate the effect of naringenin on improving PCOS and explore the mechanism. METHODS: Firstly, we carried out differential gene expression analysis from transcriptome sequencing data of human oocyte to screen the KEGG pathway, then the PCOS-like rat model was induced by letrozole. They were randomly divided into four groups: Normal group (N), PCOS group (P), Diane-35 group (D), and Naringenin group (Nar). The changes of estrus cycle, body weight, ovarian function, serum hormone levels, glucose metabolism, along with the expression of SIRT1, PGC-1ɑ, claudin-1 and occludin of the ovary and colon were investigated. Furthermore, the composition of the gut microbiome of fecal was tested. RESULTS: By searching the KEGG pathway in target genes, we found that at least 15 KEGG pathways are significantly enriched in the ovarian function, such as AMPK signaling pathway, insulin secretion, and ovarian steroidogenesis. Interestingly, naringenin supplementation significantly reduced body weight, ameliorated hormone levels, improved insulin resistance, and mitigated pathological changes in ovarian tissue, up-regulated the expression of PGC-1ɑ, SIRT1, occludin and claudin-1 in colon. In addition, we also found that the abundance of Prevotella and Gemella was down-regulated, while the abundance of Butyricimonas, Lachnospira, Parabacteroides, Butyricicoccus, Streptococcus, Coprococcus was up-regulated. CONCLUSION: Our data suggest that naringenin exerts a treatment PCOS effect, which may be related to the modulation of the gut microbiota and SIRT1/PGC-1ɑ signaling pathway. Our research may provide a new perspective for the treatment of PCOS and related diseases.