Blautia coccoides and its metabolic products enhance the efficacy of bladder cancer immunotherapy by promoting CD8+ T cell infiltration.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have emerged as a novel and effective treatment strategy, yet their effectiveness is limited to a subset of patients. The gut microbiota, recognized as a promising anticancer adjuvant, is being increasingly suggested to augment the efficacy of ICIs. Despite this, the causal link between the gut microbiota and the success of immunotherapy is not well understood. This gap in knowledge has driven us to identify beneficial microbiota and explore the underlying molecular mechanisms. METHODS: Through 16S rDNA sequencing, we identified distinct gut microbiota in patients undergoing treatment with ICIs. Following this, we assessed the impact of probiotics on anti-PD-1 therapy in bladder cancer using mouse models, employing a multi-omics strategy. Subsequently, we uncovered the mechanisms through which Blautia-produced metabolites enhance antitumor immunity, utilizing untargeted metabolomics and a range of molecular biology techniques. RESULTS: In our research, the LEfSe analysis revealed a significant enrichment of the Blautia genus in the gut microbiota of patients who responded to immunotherapy. We discovered that the external addition of Blautia coccoides hampers tumor growth in a bladder cancer mouse model by enhancing the infiltration of CD8+ T cells within the tumor microenvironment (TME). Further investigations through untargeted metabolomics and molecular biology experiments showed that oral administration of Blautia coccoides elevated trigonelline levels. This, in turn, suppresses the ß-catenin expression both in vitro and in vivo, thereby augmenting the cancer-killing activity of CD8+ T cells. CONCLUSIONS: This research provided valuable insights into enhancing the efficacy of PD-1 inhibitors in clinical settings. It was suggested that applying Blautia coccoides and its metabolic product, trigonelline, could serve as a synergistic treatment method with PD-1 inhibitors in clinical applications.

Gut microbiota Parabacteroides distasonis enchances the efficacy of immunotherapy for bladder cancer by activating anti-tumor immune responses.

OBJECTIVE: Bladder cancer(BCa) was a disease that seriously affects patients' quality of life and prognosis. To address this issue, many researches suggested that the gut microbiota modulated tumor response to treatment; however, this had not been well-characterized in bladder cancer. In this study, our objective was to determine whether the diversity and composition of the gut microbiota or the density of specific bacterial genera influence the prognosis of patients with bladder cancer. METHODS: We collected fecal samples from a total of 50 bladder cancer patients and 22 matched non-cancer individuals for 16S rDNA sequencing to investigate the distribution of Parabacteroides in these two groups. Further we conducted follow-up with cancer patients to access the impact of different genera of microorganisms on patients survival. We conducted a Fecal Microbiota Transplantation (FMT) and mono-colonization experiment with Parabacteroides distasonis to explore its potential enhancement of the efficacy of anti-PD-1 immunotherapy in MB49 tumor-bearing mice. Immunohistochemistry, transcriptomics and molecular experiment analyses were employed to uncover the underlying mechanisms. RESULTS: The 16S rDNA showed that abundance of the genus Parabacteroides was elevated in the non-cancer control group compared to bladder cancer group. The results of tumor growth curves showed that a combination therapy of P. distasonis and ICIs treatment significantly delayed tumor growth and increased the intratumoral densities of both CD4+T and CD8+T cells. The results of transcriptome analysis demonstrated that the pathways associated with antitumoral immune response were remarkably upregulated in the P. distasonis gavage group. CONCLUSION: P. distasonis delivery combined with α-PD-1 mAb could be a new strategy to enhance the effect of anti-PD-1 immunotherapy. This effect might be achieved by activating immune and antitumor related pathways.

Association between Cerebrovascular Risk Factors and Collateral Compensation in Chronic Symptomatic Intracranial Vertebrobasilar Stenosis.

INTRODUCTION: The level of collateral compensation plays a pivotal role in chronic symptomatic intracranial vertebrobasilar stenosis (IVBS). This study aimed to evaluate the association between cerebrovascular risk factors and collateral compensation in chronic symptomatic IVBS. METHODS: This single-center cross-sectional study retrospectively reviewed 238 patients with angiographically demonstrated IVBS and divided them into good collateral compensation (GCC) group (collateral grade: 3-4, n = 110) and poor collateral compensation (PCC) group (collateral grade: 0-2, n = 128). The demographic information, laboratory tests, and clinical data of the two groups were compared and assessed using univariate logistic regression. Multivariate logistic regression was employed to analyze the independent related factors of collateral compensation. RESULTS: Hyperlipidemia, high-density lipoprotein (HDL), and fasting blood glucose (FBG) were significantly different between the two groups. Multivariate logistic regression analysis revealed that HDL (odds ratio [OR]: 1.134, 95% confidence interval [CI]: 1.081-1.190), FBG (OR: 0.945, 95% CI: 0.925-0.964), and hyperlipidemia (OR: 0.261, 95% CI: 0.129-0.527) were statistically independent related factors of collateral compensation. The receiver-operating characteristic (ROC) analysis provided cutoff values of 34 mg/dL and 135 mg/dL for HDL and FBG associated with GCC and PCC. CONCLUSION: Higher HDL levels are associated with higher incidence of GCC, whereas higher FBG levels and hyperlipidemia are associated with higher incidence of PCC.

Bypass Surgery to Treat Giant Cavernous Carotid Artery Aneurysms.

BACKGROUND: With the development of bypass technique, more and more complex aneurysms can be treated with bypass surgery. The goal of this study is to evaluate the efficacy and safety of bypass in patients with giant cavernous carotid aneurysms (GCCAs). To further discuss the treatment of asymptomatic GCCAs. METHODS: The authors retrospectively reviewed our experience of the internal carotid artery (ICA) ligation/constriction combined with high/low-flow bypass surgery in the treatment of GCCAs. RESULTS: Among the entire cohort, 4 patients underwent ICA ligation combined with high-flow bypass, 7 patients underwent ICA ligation/constriction combined with low-flow bypass. The postoperative symptom improvement: of 9 patients with preoperative ophthalmoplegia, the symptom resolved in 2 patients, improved in 7 patients, of 7 patients with preoperative pain, the symptom resolved in 2 patients, improved in 4 patients and was unchanged in 1 patient. The results of following-up were measured using the modified Rankin scale (mRS). During the follow-up, there were 9 patients with mRS score 0 to 1, 1 patient with mRS score 2, and 1 patient with mRS score 3. The long-term graft patency rate was 100%. All patients had no recurrence of intracranial aneurysm. CONCLUSIONS: Bypass surgery is a safe and effective method to treat GCCAs. Because of the risk of GCCAs and the improvement of bypass surgery technology, active surgical strategies should be adopted for asymptomatic or mild symptomatic GCCAs.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

Spatiotemporal variation reconstruction of total phosphorus in the Great Lakes since 2002 using remote sensing and deep neural network.

Total phosphorus (TP) is non-optically active, thus TP concentration (CTP) estimation using remote sensing still exists grand challenge. This study developed a deep neural network model (DNN) for CTP estimation with synchronous in-situ measurements and MODIS-derived remote sensing reflectance (Rrs) (N = 3916). Using DNN, the annual and intra-annual CTP spatial distributions of the Great Lakes since 2002 were reconstructed. Then, the reconstructions were correlated to nine potential factors, e.g., Chlorophyll-a, snowmelt, and cropland, to explain seasonal and long-term CTP variations. The results showed that DNN reliably estimated CTP from MODIS Rrs, with R2, mean absolute error (MAE), root mean squared error (RMSE), mean absolute percentage error (MAPE), and root mean squared logarithmic error (RMSLE) of 0.83, 1.05 µg/L, 2.95 µg/L, 9.92%, and 0.13 on the test set. The near-surface CTP in the Great Lakes decreased significantly (p < 0.05) during 2002 - 2022, primarily attributed to cropland reduction, coupled with improvements in basin natural ecosystems. The sensitivity analysis verified the model robustness when confronted with input feature changes < 35%. This result along with the marginal difference between CTP derived from two sensors (R2 = 0.76, MAE = 2.12 µg/L, RMSE = 2.51 µg/L, MAPE = 11.52%, RMSLE = 0.24) suggested the model transferability from MODIS to VIIRS. This transformation facilitated optimal usage of MODIS-related archive and enhanced the continuity of CTP estimation at moderate resolution. This study presents a practical method for spatiotemporal reconstruction of CTP using remote sensing, and contributes to better understandings of driving factors behind CTP variations in the Great Lakes.

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/ß­catenin signaling.

Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote the gut microbiota homeostasis; however, its role in renoprotection remains unknown. The present study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8­week 2% NaCl­feeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, The medium and high doses of PLR significantly alleviated CKD­associated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and downregulating the canonical Wnt/ß­catenin pathway. Furthermore, PLR rescued the gut microbiota dysbiosis and protected against high salt­induced gut barrier dysfunction. Enrichment of Akkermansia and Bifidobacterium was found after PLR intervention, the relative abundances of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was, at least partially, exerted through gut microbiota reestablishment and downregulation of the Wnt/ß­catenin pathway. The present study provided evidence for a new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.

Akkermansia muciniphila Metabolite Inosine Inhibits Castration Resistance in Prostate Cancer.

Prostate cancer (PCa) is initially sensitive to androgen deprivation therapy (ADT) but ultimately develops resistance and progresses to castration-resistant prostate cancer (CRPC) with a poor prognosis. This study indicated that some PCa patients and mice were more sensitive to ADT and entered CRPC later, which was related to the gut microbiota, especially the enrichment of Akkermansia muciniphila (AKK). Untargeted metabolomics analysis found that serum inosine level was upregulated in the treatment-sensitive group and significantly correlated with AKK. Furthermore, we revealed that intestinal permeability and serum lipopolysaccharide (LPS) levels increased in treatment-resistant mice. LPS stimulated the upregulation of p-NF-κB p65 and AR in tumors. Supplementing AKK metabolite inosine could alleviate intestinal barrier damage and reduce serum LPS level, ultimately inhibiting castration resistance via the LPS/NF-κB/AR axis. Finally, we constructed a predictive model for CRPC combining gut microbiota and clinical information (AUC = 0.729). This study revealed the potential mechanism of gut microbiota on CRPC and provided potential therapeutic targets and prognostic indicators.

Differential effects of climatic and non-climatic factors on the distribution of vegetation phenology trends on the Tibetan plateau.

The study of vegetation phenology changes is important because it is a sensitive indicator of climate change, affecting the exchange of carbon, energy and water fluxes between the land and the atmosphere. Previous studies have focused on the effects of climatic factors among environmental factors on vegetation phenology, thus the effects of non-climatic factors among environmental factors have not been well quantified. This study endeavors to scrutinize the spatiotemporal inconsistency in the start-of-season (SOS) and the end-of-season (EOS) on the Tibetan Plateau (TP) and to quantify the effects of environmental factors on phenology. To this end, the Moderate-resolution Imaging Spectroradiomater (MODIS) Normalized Difference Vegetation Index (NDVI) data from 2001 to 2018 and four common used methods were employed to extract SOS and EOS, and the site data was used to select the most appropriate phenology results. The Geodetector model was used to assess and measure the explanatory power of different environmental factors. The research results indicate that temperature exerts a more substantial impact on phenology than precipitation on TP. non-climatic factors such as longitude, latitude, and elevation are more influential in determining the distribution of phenological trends than climatic factors. Among these non-climatic factors, latitude has the most prominent effect on the trends of SOS. Furthermore, non-climatic factors exhibit a stronger effect on SOS, whereas EOS is more susceptible to climatic factors and less influenced by non-climatic factors. These discoveries bear great significance in comprehending the intricate outcomes of regional changes on vegetation phenology and enhancing phenology models.

Clinical Grading System, Surgical Outcomes and Prognostic Analysis of Cranial Base Chordomas.

OBJECTIVE: Cranial base chordomas are rare, but their treatment is challenging. Tumor recurrence is still common despite improvements in microsurgical techniques and postoperative radiotherapy. We retrospectively analyzed the course of treatment, overall survival, and recurrence/progression of chordomas over the past 10 years. METHODS: We retrospectively reviewed 50 patients who underwent surgery at Tianjin Huanhu Hospital between 2010 and 2020 and were pathologically diagnosed with chordomas. Tumor resection was performed within the maximum safe range in all patients; the extent of resection was evaluated by imaging; and the incidence of complications, recurrence or progression, and overall survival were assessed. RESULTS: Fifty patients were divided into the low-risk group (LRG) and high-risk group (HRG) based on the cranial chordoma grading system (CCGS). The Karnofsky Performance Scale scores and gross total resection rate of the LRG were significantly higher than those of the HRG (p<0.05). The incidence of complications and mortality in the LRG were lower than those of HRG. The analysis of cumulative survival and cumulative recurrence free survival/progression free survival (RFS/PFS) showed no statistical differences in the extent of resection for survival, recurrence, or progression. Univariate and multivariate analyses showed that Ki-67 was significantly associated with tumor recurrence and was an independent hazard factor (p=0.02). CONCLUSION: The CCGS can help neurosurgeons anticipate surgical outcomes. Pathological results are important in evaluating the possibility of tumor recurrence, and postoperative radiotherapy improves overall survival and RFS/PFS.

Surgical Strategy for Skull Base Chordomas : Transnasal Midline Approach or Transcranial Lateral Approach.

OBJECTIVE: The clinical management paradigm of skull base chordomas is still challenging. Surgical resection plays an important role of affecting the prognosis. Endonasal endoscopic approach (EEA) has gradually become the preferred surgical approach in most cases, but traditional transcranial surgery cannot be completely replaced. This study presents a comparison of the results of the two surgical strategies and a summary of the treatment algorithms for skull base chordomas. METHODS: We retrospectively analyzed the surgical outcomes and follow-up data of 48 patients with skull base chordomas diagnosed pathologically who received transnasal midline approaches (TMA) and transcranial lateral approaches (TLA) from 2010 to 2020. RESULTS: Among the 48 patients, 36 cases were adopted TMA and 12 cases were performed with TLA. In terms of gross total resection (GTR) rate, 27.8% in TMA and 16.7% in TLA and with EEA alone it was increased to 38.9%, while 29.7% in primary surgery. In TMA, the cerebrospinal fluid (CSF) leak remains the most common complication (13 cases, 36.1%), other main complications included death, cranial nerve palsy, hypopituitarism, all the comparisons were no statistical significance. The Karnofsky Performance Scale scores in TMA were all better than those in TLA at different time, and the overall survival (OS) and recurrence free survival/progression free survival was just the reverse. CONCLUSION: The EEA for skull base chordomas resection has improved the GTR rate, but transcranial approach is still an alternative approach. It is necessary to select an appropriate surgical approach based on the location and the pattern of tumor growth in order to obtain the best surgical outcomes.

Unraveling the impact of Lactobacillus spp. and other urinary microorganisms on the efficacy of mirabegron in female patients with overactive bladder.

Objective: Overactive bladder (OAB) is a disease that seriously affects patients' quality of life and mental health. To address this issue, more and more researchers are examining the relationship between OAB treatment and urinary microecology. In this study, we sought to determine whether differences in treatment efficacy were related to microbiome diversity and composition as well as the abundance of specific genera. Machine learning algorithms were used to construct predictive models for urine microbiota-based treatment of OAB. Methods: Urine samples were obtained from 64 adult female OAB patients for 16S rRNA gene sequencing. Patients' overactive bladder symptom scores (OABSS) were collected before and after mirabegron treatment and patients were divided into effective and ineffective groups. The relationship between the relative abundance of certain genera and OABSS were analyzed. Three machine learning algorithms, including random forest (RF), supporting vector machine (SVM) and eXtreme gradient boosting (XGBoost) were utilized to predict the therapeutic effect of mirabegron based on the relative abundance of certain genera in OAB patients' urine microbiome. Results: The species composition of the two groups differed. For one, the relative abundance of Lactobacillus was significantly higher in the effective group than in the ineffective group. In addition, the relative abundance of Gardnerella and Prevotella in the effective group was significantly lower than in the ineffective group. Alpha-diversity and beta-diversity differed significantly between the two groups. LEfSe analysis revealed that Lactobacillus abundance increased while Prevotella and Gardnerella abundance decreased in the effective group. The Lactobacillus abundance ROC curve had high predictive accuracy. The OABSS after treatment was negatively correlated with the abundance of Lactobacillus, whereas the relationship between OABSS and Prevotella and Gardnerella showed the opposite trend. In addition, RF, SVM and XGBoost models demonstrated high predictive ability to assess the effect of mirabegron in OAB patients in the test cohort. Conclusions: The results of this study indicate that urinary microbiota might influence the efficacy of mirabegron, and that Lactobacillus might be a potential marker for evaluating the therapeutic efficacy of mirabegron in OAB patients.

Mapping the occurrence and spatial distribution of noxious weed species with multisource data in degraded grasslands in the Three-River Headwaters Region, China.

The invasion of noxious weed species has long been associated with the degradation of alpine grasslands ecosystems. However, traditional in situ-based methods for surveying noxious weed species are generally time consuming and inefficient over large-scale areas. This paper investigates the possibility of applying multisource data to map the occurrence and spatial distribution of noxious weed species in degraded alpine grasslands in the Three-River Headwaters Region, China. Sentinel-2 image-related vegetation indices (VIs), field sample data and environmental variables were integrated to build a noxious weed species detection model based on the maximum entropy (MaxEnt) species modeling framework. The modeling results suggest that based on both training and testing AUC (area under the receiver operating characteristic (ROC) curve) values higher than 0.82, the VI-only variable model, the environmental-only variable model and the combined environmental and VI variables model, all yielded good simulation results. The spatial distributions of noxious weed species mapped by the VI-only variable model and the combined environmental and VI variable model were more concentrated, while the VI-only variable model yielded more scattered results. This analysis also explains why noxious weed species are mainly distributed in the low-elevation flat riverine zone in the study area. The model combining Sentinel-2 imagery-related VIs, environmental variables and in situ sample data proposed in this study can successfully map the occurrence and spatial distributions of noxious weed species. The method and results of this research can be used to help monitor noxious weed species invasions and better manage grassland ecosystems.

The combination of db-cAMP and ChABC with poly(propylene carbonate) microfibers promote axonal regenerative sprouting and functional recovery after spinal cord hemisection injury.

This study describes the use of poly(propylene carbonate) (PPC) electrospun microfibres impregnated with a combination of dibutyryl cyclic adenosine monophosphate (db-cAMP) and chondroitinase ABC (ChABC) in the treatment of right-side hemisected spinal cord injury (SCI). Release of db-cAMP and/or ChABC from the microfibres was assessed in vitro using high-performance liquid chromatography (HPLC). Drug-impregnated microfibres were implanted into the hemisected thoracic spinal cord of rats, and treatment was evaluated using functional recovery examinations and immunohistochemistry. Our results demonstrated that the microfibres containing db-cAMP and/or ChABC displayed a stable and prolonged release of each agent. Sustained delivery of db-cAMP and/or ChABC was found to promote axonal regenerative sprouting, functional recovery, and reduced glial scar formation when compared to untreated control animals. The combination of both db-cAMP and ChABC was determined to be more effective than using either drug alone in the treatment of SCI. These findings demonstrate the feasibility of using PPC electrospun microfibres for multi-drug combination therapy in SCI.

Local in vitro delivery of rapamycin from electrospun PEO/PDLLA nanofibers for glioblastoma treatment.

Rapamycin, a mammalian target of rapamycin inhibitor and anti-proliferative agent, is used to treat glioma and other malignancies, but its effectiveness is limited by the fact that it cannot be delivered in a targeted manner to the site of the tumor. To address this issue, we fabricated a mesh via electrospinning using two biodegradable materials, poly(lactic acid) (PLA) and polyethylene oxide (PEO) as a carrier for rapamycin delivery to the tumor. Nanofiber diameter decreased with increasing PLA concentration in the mixed solution. Scanning electron microscopy analysis revealed the smooth and uniform surface morphology of hybrid fibers. Fourier transform infrared spectroscopy analysis demonstrated that rapamycin was encapsulated in the polymer solution; encapsulation efficiency was high and stable over the range of drug concentrations from 0.5-2wt%. A correlation was observed between sustained release of the drug in vitro and cytotoxicity in cultured glioma cells. These results indicate that the PEO/poly(d,l-lactic acid) nanofiber mesh can be used as a targeted delivery system for rapamycin that can limit side effects and prevent locoregional recurrence following surgical resection of glioma.

Anti-Neoplastic Cytotoxicity of SN-38-Loaded PCL/Gelatin Electrospun Composite Nanofiber Scaffolds against Human Glioblastoma Cells In Vitro.

Electrospun poly(ε-caprolactone) (PCL)/gelatin (GT) scaffolds were developed to provide controlled release of 7-ethyl-10-hydroxy camptothecin (SN-38). Acetic acid was introduced to improve the miscibility of PCL and GT to produce a homogeneous nanofiber membrane mixture. The effect of SN-38 content in binary mixtures on processability, fiber morphology, water sorption, swelling, and drug release was investigated. Electrospun PCL/GT blend nonwoven fibers showed fiber surface roughness, decreased PCL crystallinity, and increased swelling with increasing drug content of 1, 2, and 4 wt %. Additionally, increasing the SN-38 concentration reduced the degradation rate of the GT. Furthermore, we hypothesize the existence of a drug content saturation point in the monoaxial fiber to explain the different drug release patterns of PG2 compared with those of PG1 and PG4. The matrix also showed good biodegradation and anti-tumor function. Our results demonstrate that SN-38-loaded PCL/GT fibers can be obtained by electrospinning. The SN-38-loaded fibers merit further evaluation as a means to potentially prevent locoregional recurrence following surgical tumor resection.