Unveiling Novel Double-Negative Prostate Cancer Subtypes Through Single-Cell RNA Sequencing Analysis.

Recent advancements in single-cell RNA sequencing (scRNAseq) have facilitated the discovery of previously unrecognized subtypes within prostate cancer (PCa), offering new insights into disease heterogeneity and progression. In this study, we integrated scRNAseq data from multiple studies, comprising both publicly available cohorts and data generated by our research team, and established the HuPSA (Human Prostate Single cell Atlas) and the MoPSA (Mouse Prostate Single cell Atlas) datasets. Through comprehensive analysis, we identified two novel double-negative PCa populations: KRT7 cells characterized by elevated KRT7 expression, and progenitor-like cells marked by SOX2 and FOXA2 expression, distinct from NEPCa, and displaying stem/progenitor features. Furthermore, HuPSA-based deconvolution allowed for the re-classification of human PCa specimens, validating the presence of these novel subtypes. Leveraging these findings, we developed a user-friendly web application, "HuPSA-MoPSA" (https://pcatools.shinyapps.io/HuPSA-MoPSA/), for visualizing gene expression across all newly-established datasets. Our study provides comprehensive tools for PCa research and uncovers novel cancer subtypes that can inform clinical diagnosis and treatment strategies.

Adaptation process of decellularized vascular grafts as hemodialysis access in vivo.

Arteriovenous grafts (AVGs) have emerged as the preferred option for constructing hemodialysis access in numerous patients. Clinical trials have demonstrated that decellularized vascular graft exhibits superior patency and excellent biocompatibility compared to polymer materials; however, it still faces challenges such as intimal hyperplasia and luminal dilation. The absence of suitable animal models hinders our ability to describe and explain the pathological phenomena above and in vivo adaptation process of decellularized vascular graft at the molecular level. In this study, we first collected clinical samples from patients who underwent the construction of dialysis access using allogeneic decellularized vascular graft, and evaluated their histological features and immune cell infiltration status 5 years post-transplantation. Prior to the surgery, we assessed the patency and intimal hyperplasia of the decellularized vascular graft using non-invasive ultrasound. Subsequently, in order to investigate the in vivo adaptation of decellularized vascular grafts in an animal model, we attempted to construct an AVG model using decellularized vascular grafts in a small animal model. We employed a physical-chemical-biological approach to decellularize the rat carotid artery, and histological evaluation demonstrated the successful removal of cellular and antigenic components while preserving extracellular matrix constituents such as elastic fibers and collagen fibers. Based on these results, we designed and constructed the first allogeneic decellularized rat carotid artery AVG model, which exhibited excellent patency and closely resembled clinical characteristics. Using this animal model, we provided a preliminary description of the histological features and partial immune cell infiltration in decellularized vascular grafts at various time points, including Day 7, Day 21, Day 42, and up to one-year post-implantation. These findings establish a foundation for further investigation into the in vivo adaptation process of decellularized vascular grafts in small animal model.

Targeting CXCR4/CXCL12 axis via [177Lu]Lu-DOTAGA.(SA.FAPi)2 with CXCR4 antagonist in triple-negative breast cancer.

PURPOSE: Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS: Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS: CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION: The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.

The expression of PKM1 and PKM2 in developing, benign, and cancerous prostatic tissues.

Background: Neuroendocrine prostate cancer (NEPCa) is the most aggressive type of prostate cancer (PCa). However, energy metabolism, one of the hallmarks of cancer, in NEPCa has not been well studied. Pyruvate kinase M (PKM), which catalyzes the final step of glycolysis, has two main splicing isoforms, PKM1 and PKM2. The expression pattern of PKM1 and PKM2 in NEPCa remains unknown. Methods: In this study, we used immunohistochemistry, immunofluorescence staining, and bioinformatics analysis to examine the expression of PKM1 and PKM2 in mouse and human prostatic tissues. Results: We found that PKM2 was the predominant isoform expressed throughout prostate development and PCa progression, with slightly reduced expression in murine NEPCa. PKM1 was mostly expressed in stromal cells but low-level PKM1 was also detected in prostate basal epithelial cells. Its expression was absent in the majority of prostate adenocarcinoma (AdPCa) specimens but present in a subset of NEPCa. Additionally, we evaluated the mRNA levels of ten PKM isoforms that express exon 9 (PKM1-like) or exon 10 (PKM2-like). Some of these isoforms showed notable expression levels in PCa cell lines and human PCa specimens. Discussion: Our study characterized the expression pattern of PKM1 and PKM2 in prostatic tissues including developing, benign, and cancerous prostate. These findings lay the groundwork for understanding the metabolic changes in different PCa subtypes.

ZNF397 Deficiency Triggers TET2-driven Lineage Plasticity and AR-Targeted Therapy Resistance in Prostate Cancer.

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide coactivator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that a TET2 inhibitor can eliminate the resistance to AR targeted therapies in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate cancer acquires lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity.

Analyzing the associations between tertiary lymphoid structures and postoperative prognosis, along with immunotherapy response in gastric cancer: findings from pooled cohort studies.

BACKGROUND: The clinical significance of tertiary lymphoid structure (TLS) in gastric cancer (GC) was uncertain. METHODS: A systematic search was performed in public databases for eligible studies as of April 2, 2023. Meta-analyses were performed to interrogate the associations between TLS levels and prognosis and immunotherapy response of GC. Bioinformatic analyses based on the nine-gene signature of TLS were further conducted to capture the biological underpinnings. RESULTS: Eleven studies containing 4224 GC cases were enrolled in the meta-analysis. TLS levels positively correlated with smaller tumor size, earlier T stage and N stage. Moreover, higher TLS levels were detected in diffuse and mix subtypes of GC (P < 0.001). Higher TLS levels strongly predicted favorable postoperative overall survival of GC, with HR of 0.36 (95%CI 0.26-0.50, P < 0.001) and 0.55 (95%CI 0.45-0.68, P < 0.001) of univariate and multivariate Cox analysis, respectively. Higher TLS levels were also in favor of the treatment response of anti-PD-1 inhibitors as later-line therapy of GC. TLS levels positively correlated with immune effector cells infiltration, diversity and richness of T cell receptor and B cell receptor repertoire, immune checkpoint genes expression, and immune-related genes mutation of GC in the TCGA-STAD cohort, representing higher immunogenicity and immunoactivity. Moreover, moderate accuracy of TLS levels in predicting benefit from anti-PD-1 inhibitors in the PRJEB25780 cohort was also validated (AUC 0.758, 95%CI 0.583-0.933), higher than the microsatellite instability-score and Epstein-Barr virus status. CONCLUSIONS: TLS levels demonstrated potential in predicting the postoperative prognosis and immunotherapy response of GC.

PCTA, a pan-cancer cell line transcriptome atlas.

A substantial volume of RNA sequencing data have been generated from cancer cell lines. However, it requires specific bioinformatics skills to compare gene expression levels across cell lines. This has hindered non-bioinformaticians from fully utilizing these valuable datasets in their research. To bridge this gap, we established a curated Pan-cancer Cell Line Transcriptome Atlas (PCTA) dataset. This resource aims to provide a user-friendly platform, allowing researchers without extensive bioinformatics expertise to access and leverage the wealth of information within the dataset for their studies. The PCTA dataset encompasses the expression matrix of 24,965 genes, featuring data from 84,385 samples derived from 5677 studies. This comprehensive compilation spans 535 cell lines, representing a spectrum of 114 cancer types originating from 30 diverse tissue types. On UMAP plots, cell lines originating from the same type of tissue tend to cluster together, illustrating the dataset's ability to capture biological relationships. Additionally, an interactive and user-friendly web application (https://pcatools.shinyapps.io/PCTA_app/) was developed for researchers to explore the PCTA dataset. This platform allows users to examine the expression of their genes of interest across a diverse array of samples.

Hepatic perivascular epithelioid cell tumor resembling hepatic adenoma and hepatocellular carcinoma on preoperative imaging: a case report.

Perivascular epithelioid cell tumor (PEComa), an uncommon mesenchymal neoplasm, arises from specialized perivascular epithelioid cells exhibiting distinct features of smooth muscle and melanocytic differentiation with unpredictable behavior. PEComa tends to occur more commonly in the uterus and kidneys; its occurrence in the liver is exceedingly rare. We presented a case of a 29-year-old woman with hepatic PEComa and evaluated the tumor with MRI, integrated 18F-fluorodeoxyglucose (FDG), and 68Ga-fibroblast activation protein inhibitor (FAPI) PET/CT scans at presentation. The patient had a history of intermittent utilization of oral contraceptive drugs for several years. An abdominal ultrasound in a physical examination from an outside institution revealed a mass in the liver. A contrast-enhanced abdominal MRI revealed restricted diffusion on diffusion-weighted imaging (DWI) and rapid contrast enhancement and washout patterns in the hepatic lesion, suggesting hepatic adenoma (HA) or hepatocellular carcinoma (HCC). Further assessment was carried out using 18F-FDG and 68Ga-FAPI PET/CT scans. The hepatic lesion was non-FDG avid, whereas increased tracer uptake was observed on the 68Ga-FAPI PET/CT. Subsequently, laparoscopic partial resection of liver segment V was performed. Immunohistochemical analyses demonstrated positive staining for HMB45, Melan-A, and SMA while showing negative results for AFP, glypican-3, hepatocyte, and arginase-1. The results were indicative of a hepatic PEComa diagnosis based on these findings. We also review the current literature on the clinical characteristics, pathological features, and challenges in the diagnosis of hepatic PEComa.

The expression of PKM1 and PKM2 in developing, benign, and cancerous prostatic tissues.

Neuroendocrine prostate cancer (NEPCa) is the most aggressive type of prostate cancer. However, energy metabolism, one of the hallmarks of cancer, in NEPCa has not been well studied. Pyruvate kinase M (PKM), which catalyzes the final step of glycolysis, has two main splicing isoforms, PKM1 and PKM2. PKM2 is known to be upregulated in various cancers, including prostate adenocarcinoma (AdPCa). In this study, we used immunohistochemistry, immunofluorescence staining, and bioinformatic analysis to examine the expression of PKM1 and PKM2 in mouse and human prostatic tissues, including developing, benign and cancerous prostate. We found that PKM2 was the predominant isoform expressed throughout prostate development and PCa progression, with slightly reduced expression in some NEPCa samples. PKM1 was mostly expressed in stromal cells but low-level PKM1 was also detected in prostate basal epithelial cells. Its expression was absent in the majority of PCa specimens but present in a subset of NEPCa. Additionally, we evaluated the mRNA levels of ten PKM isoforms that express exon 9 (PKM1-like) or exon 10 (PKM2-like). Some of these isoforms showed notable expression levels in PCa cell lines and human PCa specimens. These findings lay the groundwork for understanding PKMs' role in PCa carcinogenesis and NEPCa progression. The distinct expression pattern of PKM isoforms in different PCa subtypes may offer insights into potential therapeutic strategies for treating PCa.

Investigation of the Association Between e-Cigarette Smoking and Oral Mucosal Health Status Among Young People: Protocol for a Case-Control Trial.

BACKGROUND: Given the paucity of current safety studies related to e-cigarettes, there are no definitive studies on whether e-cigarettes cause oral mucosal lesions or even oral cancer. Although it is still undetermined whether e-cigarettes are harmless, an increasing number of teenagers choose to smoke e-cigarettes and believe that they are not harmful to the human body. OBJECTIVE: This aims to determine whether e-cigarettes cause damage to the oral mucosa. This study also aims to evaluate the association between e-cigarette smoking and oral mucous membrane lesions in young adults. The objectives are to (1) compare the oral mucosal conditions in participants with and without e-cigarette smoking habits, (2) assess the effect of the amount of e-cigarette smoking on oral mucosal conditions, and (3) assess the effect of the duration of e-cigarette smoking on oral mucosal conditions. METHODS: In this prospective study, 304 youths aged 15 to 24 years (n=152, 50% who smoke only e-cigarettes and n=152, 50% who do not smoke e-cigarettes or cigarettes) will be divided into 2 groups for a controlled study. Whether e-cigarettes cause oral mucosal lesions will be verified by comparing the odds of oral mucosal lesions in the 2 experimental groups. For this experiment, the predefined power is 80% (P=.04), and the predefined proportions of groups 1 and 2 are 11% and 2.5%, respectively. RESULTS: This experiment is at the conceptualization phase and has not yet been carried out. Experimenters have not been recruited and no data have been collected. CONCLUSIONS: e-Cigarettes are still an unfamiliar topic to the public, and it is still unknown whether they can cause damage to the oral mucosa. This experiment aims to find out whether there is a link between the 2. There are still many limitations in this study, such as the lack of categorization of e-cigarettes and the lack of testing methods for oral mucosal status. These limitations are expected to be addressed in the future as the experiment is formally conducted and further optimized. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53644.

Multi-omics of the gut microbial ecosystem in patients with microsatellite-instability-high gastrointestinal cancer resistant to immunotherapy.

Despite the encouraging efficacy of anti-PD-1/PD-L1 immunotherapy in microsatellite-instability-high/deficient mismatch repair (MSI-H/dMMR) advanced gastrointestinal cancer, many patients exhibit primary or acquired resistance. Using multi-omics approaches, we interrogate gut microbiome, blood metabolome, and cytokines/chemokines of patients with MSI-H/dMMR gastrointestinal cancer (N = 77) at baseline and during the treatment. We identify a number of microbes (e.g., Porphyromonadaceae) and metabolites (e.g., arginine) highly associated with primary resistance to immunotherapy. An independent validation cohort (N = 39) and mouse model are used to further confirm our findings. A predictive machine learning model for primary resistance is also built and achieves an accuracy of 0.79 on the external validation set. Furthermore, several microbes are pinpointed that gradually changed during the process of acquired resistance. In summary, our study demonstrates the essential role of gut microbiome in drug resistance, and this can be utilized as a preventative diagnosis tool and therapeutic target in the future.

PCTA, A PAN-CANCER CELL LINE TRANSCRIPTOME ATLAS.

Background: A substantial volume of RNA sequencing data were generated from cancer cell lines. However, it requires specific bioinformatics skills to compare gene expression levels across cell lines. This has hindered non-bioinformaticians from fully utilizing these valuable datasets in their research. To bridge this gap, we established a curated Pan-cancer Cell Line Transcriptome Atlas (PCTA) dataset. This resource aims to provide a user-friendly platform, allowing researchers without extensive bioinformatics expertise to access and leverage the wealth of information within the dataset for their studies. Importantly, PCTA stands out by offering sufficient sample numbers per cell line in comparison to other pan-cancer datasets. Methods: Cell lines' meta data and RNA sequencing data were retrieved from the Cancer Cell Line Encyclopedia (CCLE), SRA and ARCHS4 databases. Utilizing the programming language R, we conducted data retrieval, normalization, and visualization. Only expression data for protein-coding genes and long-non-coding RNAs (LncRNAs) were considered in this study, streamlining the focus to enhance the precision and relevance of the analysis. Results: The resulting PCTA dataset encompasses the expression matrix of 24,965 genes, featuring data from 84,385 samples derived from 5,677 studies. This comprehensive compilation spans 535 cell lines, representing a spectrum of 114 cancer types originating from 30 diverse tissue types. On UMAP plots, cell lines originating from the same type of tissue tend to cluster together, illustrating the dataset's ability to capture biological relationships. To unravel molecular signatures, marker genes were identified for each cancer type. Additionally, an interactive and user-friendly web application (https://pcatools.shinyapps.io/PCTA_app/ ) was developed for researchers to explore the PCTA dataset. This platform allows users to examine the expression pattern of their genes of interest across a diverse array of samples. Data are visualized as violin-, box-, and point- plots, enhancing the interpretability of the findings. Conclusion: The PCTA stands as a comprehensive resource, offering insights into gene expression patterns across diverse cancer cell lines and providing a valuable tool to explore molecular signatures and potential therapeutic targets in cancer research.

Use of suboptimal control arms in randomized clinical trials of investigational cancer drugs in China, 2016-2021: An observational study.

BACKGROUND: The use of suboptimal controls in randomized trials of new cancer drugs can produce potentially unreliable clinical efficacy results over the current standard of care and expose patients to substandard therapy. We aim to investigate the proportion of randomized trials of investigational cancer drugs that used a suboptimal control arm and the number of trial participants at risk of exposure to suboptimal treatments in China. The association between the use of a suboptimal control and concluding statistical significance on the primary endpoint was also examined. METHODS AND FINDINGS: This observational study included randomized controlled trials (RCTs) of cancer drugs that were authorized by specific Chinese institutional review boards between 2016 and 2021, supporting investigational new drug applications of these drugs in China. The proportion of trials that used a suboptimal control arm and the total number of trial participants at risk of exposure to suboptimal treatments were calculated. In a randomized trial for a specific condition, a comparator was deemed suboptimal if it was not recommended by clinical guidelines published in priori or if there existed a regimen with a higher level of recommendation for the indication. The final sample included 453 Phase II/III and Phase III randomized oncology trials. Overall, 60 trials (13.2%) adopted a suboptimal control arm. Among them, 58.3% (35/60) used comparators that were not recommended by a prior guideline for the indication. The cumulative number of trial participants at risk of exposure to suboptimal treatments totaled 18,610 by the end of 2021, contributing 15.1% to the total number of enrollees of all sampled RCTs in this study. After adjusting for the year of ethical approval, region of participant recruitment, line of therapy, and cancer site, second-line therapies (adjusted odds ratio [aOR] = 2.7, 95%CI [1.2, 5.9]), adjuvant therapies (aOR = 8.9, 95% CI [3.4, 23.1]), maintenance therapies (aOR = 5.2, 95% CI [1.6, 17.0]), and trials recruiting participants in China only (aOR = 4.1, 95% CI [2.1, 8.0]) were more likely to adopt a suboptimal control. For the 105 trials with publicly available results, no statistically significant difference was observed between the use of a suboptimal control and concluding positive on the primary endpoint (100.0% [12/12] versus 83.9% [78/93], p = 0.208). The main limitation of this study is its reliance on clinical guidelines that could vary across cancer types and time in assessing the quality of the control groups. CONCLUSIONS: In this study, over one-eighth of randomized trials of cancer drugs registered to apply for regulatory approval in China used a suboptimal comparator. Our results highlight the necessity to refine the design of randomized trials to generate optimal clinical evidence for new cancer therapies.

Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.

Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.

The gut microbiome affects response of treatments in HER2-negative advanced gastric cancer.

BACKGROUND: Common treatments for metastatic/unresectable HER2-negative gastric cancer include chemotherapy, immune checkpoint inhibitor monotherapy and chemotherapy plus immune checkpoint inhibitor. However, significant drug resistance exists regardless of the treatment regimen. METHODS: Patients with metastatic/unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma were enrolled. All patients were divided into three groups according to the treatment regimen and were further divided into responders and non-responders according to efficacy evaluation. Metagenomics sequencing were performed to analyze gut microbiome signature of patients receiving different treatments at baseline and throughout treatment. RESULTS: One hundred seventeen patients with HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma receiving chemotherapy alone, anti PD-1/PD-L1 immunotherapy alone or combined regimen were included in this study. Microbiome signatures related to clinical response are distinct among the three treatment groups. Among which, 14, 8 and 13 species were significantly different between responders and non-responders in immunotherapy, immunotherapy plus chemotherapy and chemotherapy group, respectively. Patients with higher relative abundance of Lactobacillus possessed higher microbiome diversity and significantly better response to anti-PD-1/PD-L1 immunotherapy and had a trend to achieve better progression-free survival. Another cohort of 101 patients has been used as an external validation set to confirm the stability and reliability of these findings. CONCLUSIONS: Gut microbiome affects response of treatments in HER2-negative advanced gastric cancer in a treatment-specific way, immunotherapy plus chemotherapy did not equal to a simple superposition of immunotherapy and chemotherapy. Lactobacillus is expected to become a novel choice as an adjuvant agent in promoting the efficacy of immunotherapy in gastric cancer.

Correlation of the gut microbiome and immune-related adverse events in gastrointestinal cancer patients treated with immune checkpoint inhibitors.

Introduction: The wide application of immune checkpoint inhibitors has significantly improved the survival expectation of cancer patients. While immunotherapy brings benefits to patients, it also results in a series of immune-related adverse events (irAEs). Increasing evidence suggests that the gut microbiome is critical for immunotherapy response and the development of irAEs. Methods: In this prospective study, we recruited 95 patients with advanced/unresectable gastrointestinal cancers treated with immunotherapy and report a comprehensive analysis of the association of the gut microbiome with irAEs. Metagenome sequencing was used to analyze the differences in bacterial composition and metabolic pathways of baseline fecal samples. Results: In summary, we identified bacterial species and metabolic pathways that might be associated with the occurrence of irAEs in gastric, esophageal, and colon cancers. Ruminococcus callidus and Bacteroides xylanisolvens were enriched in patients without severe irAEs. Several microbial metabolic pathways involved in the urea cycle, including citrulline and arginine biosynthesis, were associated with irAEs. We also found that irAEs in different cancer types and toxicity in specific organs and the endocrine system were associated with different gut microbiota profiles. These findings provide the basis for future mechanistic exploration.

Hepatic IDH2 regulates glycolysis and gluconeogenesis.

BACKGROUND AND AIMS: The liver plays a central role in controlling glucose and lipid metabolism. IDH2, a mitochondrial protein, controls TCA cycle flux. However, its role in regulating metabolism in obesity is still unclear. This study intends to investigate the impact of hepatic IDH2 expression on overnutrition-regulated glucose and lipid metabolism. METHODS: Hepatic IDH2 was knocked-out in mice by the approach of CRISPR-Cas9. Mice were subjected to starvation and refeeding for hepatic glucose and lipid studies in vivo. Primary hepatocytes and mouse normal liver cell line, AML12 cells were used for experiments in vitro. RESULTS: This study found that IDH2 protein levels were elevated in the livers of obese people and mice with high-fat diet consumption or hepatic steatosis. Liver IDH2-deletion mice (IDH2LKO) were resistant to high-fat diet-induced body weight gain, with lower serum glucose and TG levels, increased insulin sensitivity, and higher FGF21 secretion, despite the higher TG content in the liver. Consistently, overexpression of IDH2 in hepatocytes promoted gluconeogenesis and enhanced glycogenesis. By performing mass spectrometry and proteomics analyses, we further demonstrated that IDH2-deficiency in hepatocytes accelerated ATP production by increasing forward TCA cycle flux, thus promoting glycolysis pathway and decreasing glycogen synthesis at refeeding state, and inhibiting hepatic gluconeogenesis, increasing ß-oxidation during starvation. Moreover, experiments in vivo demonstrated that IDH2-knockout might not exacerbate hepatic inflammatory responses in the NASH model. CONCLUSIONS: Elevated hepatic IDH2 under over-nutrition state contributes to elevated gluconeogenesis and glycogen synthesis. Inhibition of IDH2 in the liver could be a potential therapeutic target for obesity and diabetes.

Surgical treatment of patellar dislocation: A network meta-analysis of randomized control trials and cohort studies.

Background: Currently, there are many surgical options for patellar dislocation. The purpose of this study is to perform a network meta-analysis of the randomized controlled trials (RCTs) and cohort studies to determine the better treatment. Method: We searched the Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, clinicaltrials.gov and who.int/trialsearch. Clinical outcomes included Kujala score, Lysholm score, International Knee Documentation Committee (IKDC) score, redislocation or recurrent instability. We conducted pairwise meta-analysis and network meta-analysis respectively using the frequentist model to compare the clinical outcomes. Results: There were 10 RCTs and 2 cohort studies with a total of 774 patients included in our study. In network meta-analysis, double-bundle medial patellofemoral ligament reconstruction (DB-MPFLR) achieved good results on functional scores. According to the surface under the cumulative ranking (SUCRA), DB-MPFLR had the highest probabilities of their protective effects on outcomes of Kujala score (SUCRA 96.5 %), IKDC score (SUCRA 100.0%) and redislocation (SUCRA 67.8%). However, DB-MPFLR (SUCRA 84.6%) comes second to SB-MPFLR (SUCRA 90.4%) in Lyshlom score. It is (SUCRA 70%) also inferior to vastus medialis plasty (VM-plasty) (SUCRA 81.9%) in preventing Recurrent instability. The results of subgroup analysis were similar. Conclusion: Our study demonstrated that MPFLR showed better functional scores than other surgical options.

CTPC, a combined transcriptome data set of human prostate cancer cell lines.

BACKGROUND: Cell lines are the most used model system in cancer research. The transcriptomic data of established prostate cancer (PCa) cell lines help researchers explore differential gene expressions across the various PCa cell lines. METHODS: Through large scale datamining, we established a curated Combined Transcriptome dataset of PCa Cell lines (CTPC) which contains the transcriptomic data of 1840 samples of 9 commonly used PCa cell lines including LNCaP, LNCaP-95, LNCaP-abl, C4-2, VCaP, 22Rv1, PC3, DU145, and NCI-H660. RESULTS: The CTPC dataset provides an opportunity for researchers to not only compare gene expression across different PCa cell lines but also retrieve the experiment information and associate the differential gene expression data with meta data, such as gene manipulation and drug treatment information. Additionally, based on the CTPC dataset, we built a platform for users to visualize the data (https://pcatools.shinyapps.io/CTPC_V2/). CONCLUSIONS: It is our hope that the combined CTPC dataset and the user-friendly platform are of great service to the PCa research community.