A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation.

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.

Phenotypic and mutational spectrum of 17 Chinese patients with Menkes Disease.

BACKGROUND: Menkes Disease (MD) is a fatal X-linked recessive disorder caused by mutations in the ATP7A gene. Severe cases typically die before the age of three. Mild MD and occipital horn syndrome are variants of MD characterized by a less severe phenotype and longer survival. OBJECTIVE: This case series aims to validate previous findings, expand the clinical phenotype, identify novel ATP7A mutations of MD patients. METHODS: Observational data with follow-up were collected from 17 genetically diagnosed Chinese MD patients. RESULTS: All 17 patients exhibited neurological symptoms, including delayed motor milestones (100%) and seizures (58.8%). Unspecific pregnancy or delivery complications occurred in 9 patients (52.9%). The most prevalent connective tissue problems were abnormal hair (76.5%), followed by skeletal and dental abnormalities (52.9%), skin problems (41.2%) and hernia (35.3%). Sensorineural hearing loss (17.6%) was previously unreported. Coronary artery aneurysm and patent foramen ovale (5.9%) were infrequent. One 16-year-old boy carries pathological exon 3-4 deletion, presents novel mild phenotype including short stature and cerebellar ataxia. Out of 13 patients with follow-up (median: 24 months), 7 patients (53.8%) died with median survival of 40 months (range: 21-48 months), 3 patients (23.1%) show severe motor development delay and 2 (15.4%) have refractory epilepsy, only the mild MD patient shows improved cerebellar ataxia. Sixteen ATP7A mutations were identified including 6 small indels (37.5%), 5 nonsense mutations (31.2%), 2 missense mutations (12.5%), 2 exon deletions (12.5%), and 1 splice site mutation (6.25%). Fourteen mutations were novel. CONCLUSIONS: Our study further broadens the phenotypic and genotypic spectrums of Menkes disease.

Clinical characteristics and prognostic factors of adult brainstem gliomas: A retrospective analysis of histologically-proven 40 cases.

To illustrate the clinical characteristics and prognostic factors of adult patients pathologically confirmed with brainstem gliomas (BSGs). Clinical data of 40 adult patients pathologically diagnosed with BSGs admitted to Beijing Shijitan Hospital from 2009 to 2022 were recorded and retrospectively analyzed. The primary parameters included relevant symptoms, duration of symptoms, Karnofsky performance status (KPS), tumor location, type of surgical resection, diagnosis, treatment, and survival. Univariate and multivariate analyses were evaluated by Cox regression models. The gliomas were located in the midbrain of 9 patients, in the pons of 14 cases, in the medulla of 5 cases, in the midbrain and pons of 6 cases and invading the medulla and pons of 6 cases, respectively. The proportion of patients with low-grade BSGs was 42.5%. Relevant symptoms consisted of visual disturbance, facial paralysis, dizziness, extremity weakness, ataxia, paresthesia, headache, bucking, dysphagia, dysacousia, nausea, dysphasia, dysosmia, hypomnesia and nystagmus. 23 (57.5%) patients accepted stereotactic biopsy, 17 (42.5%) patients underwent surgical resection. 39 patients received radiotherapy and 34 cases were treated with temozolomide. The median overall survival (OS) of all patients was 26.2 months and 21.5 months for the median progression-free survival (PFS). Both duration of symptoms (P = .007) and tumor grading (P = .002) were the influencing factors for OS, and tumor grading was significantly associated with PFS (P = .001). Duration of symptoms for more than 2 months and low-grade are favorable prognostic factors for adult patients with BSGs.

Post-marketing safety concern of PI3K inhibitors in the cancer therapies: an 8-year disproportionality analysis from the FDA adverse event reporting system.

BACKGROUND: ThePhosphoinositide 3-kinases (PI3Ks) family plays a crucial role intumorigenesis. Alpelisib (inhibiting PI3Kα), copanlisib (inhibiting PI3Kα andPI3Kδ), duvelisib (inhibiting PI3Kδ and PI3Kγ), and idelalisib (inhibitingPI3Kδ) were developed to target the PI3K pathway. However, the toxicity limitstheir application to some extent. It's necessary to investigate the adverseeffects (AEs) of these inhibitors. RESEARCH DESIGNAND METHODS: We conducted acomparative analysis of the safety signals of AEs in PI3K inhibitors usingdisproportionality analysis in the FDA Adverse Event Reporting System database(FAERS). RESULTS: Our studyidentified significant safety signals for metabolic disorders with all PI3Kinhibitors. Notable safety signals for gastrointestinal disorders were observedwith most PI3K inhibitors, with the exception of copanlisib. Common AEs shared amongall PI3K inhibitors included colitis and dehydration. Alpelisib displayedunique AEs associated with metabolic disorders, whereas copanlisib exhibitedidiosyncratic AEs linked to cardiac and vascular disorders. Stevens-Johnsonsyndrome emerged as a common severe adverse event (SAE) among alpelisib,copanlisib, and idelalisib, while febrile neutropenia was prevalent amongcopanlisib, duvelisib, and idelalisib. Intestinal perforation was solelyassociated with alpelisib. CONCLUSIONS: The safety profiles of the five PI3K inhibitorsvary concerning adverse events. These findings could guide drug selection andinform future prospective research.

NKILA is a novel suppressor of local recurrence in women breast malignant phyllodes tumor patients via inhibition of the NF-κB pathway.

The aim of the present study was to explore the functional mechanism of NF-Kappa B-interacting Long non-protein coding RNA (NKILA) in breast malignant phyllodes tumors (BMPTs). The expression and functional role of NKILA were investigated by performing qRT‒PCR, Transwell assays, and CCK‒8 assays in primary BMPT cells. A Kaplan‒Meier curve was used to assess overall survival (OS) and local recurrence-free survival (LRFS). The location and expression levels of NKILA and P65 were determined by fluorescence in situ hybridization (FISH) and immunofluorescence (IF), respectively. NKILA was downregulated in patients with BMPT, especially in patients with local recurrence. NKILA had an antitumor effect and promoted the chemosensitivity of cells to cisplatin by blocking P65 phosphorylation and nuclear translocation. In conclusion, NKILA may be a potential therapeutic target for BMPT, especially for BMPT patients with local recurrence.

Human lung cancer-derived mesenchymal stem cells promote tumor growth and immunosuppression.

BACKGROUND: The presence of mesenchymal stem cells has been confirmed in some solid tumors where they serve as important components of the tumor microenvironment; however, their role in cancer has not been fully elucidated. The aim of this study was to investigate the functions of mesenchymal stem cells isolated from tumor tissues of patients with non-small cell lung cancer. RESULTS: Human lung cancer-derived mesenchymal stem cells displayed the typical morphology and immunophenotype of mesenchymal stem cells; they were nontumorigenic and capable of undergoing multipotent differentiation. These isolated cells remarkably enhanced tumor growth when incorporated into systems alongside tumor cells in vivo. Importantly, in the presence of mesenchymal stem cells, the ability of peripheral blood mononuclear cell-derived natural killer and activated T cells to mediate tumor cell destruction was significantly compromised. CONCLUSION: Collectively, these data support the notion that human lung cancer-derived mesenchymal stem cells protect tumor cells from immune-mediated destruction by inhibiting the antitumor activities of natural killer and T cells.

In situ growth engineering of ultrathin dendritic PdNi nanosheets on nitrogen-doped V2CTx MXenes for efficient hydrogen evolution.

Immobilizing metal nanoparticles on a support is crucial for catalysts' stability and spatial distribution. MXenes are promising substrates for in situ growth engineering of various electrocatalysts owing to their merits. A stronger binding capacity can be achieved between the in situ-fabricated catalysts and MXenes compared to a common physical combination. Thus, synergistically utilizing morphology modulation, composition optimization, and the interfacial interaction between metal catalysts and supports will maximize the electrocatalytic activity. However, most reported in situ-formed catalysts on MXenes result in solid 0D nanoparticles and in situ growth of nanoalloy catalysts on MXenes with a precisely controlled morphology is still lacking. Herein, nanodendritic PdNi alloys are in situ grown on nitrogen-doped V2CTx, serving as efficient electrocatalysts toward the hydrogen evolution reaction (HER). Thanks to the synergistic effect of the unique nanodendritic structure of PdNi, the merits of N-TBA-V2CTx nanosheets, and the strong metal-support interaction between the PdNi and the N-TBA-V2CTx support, the in situ-formed Pd58Ni42/N-TBA-V2CTx electrocatalyst shows excellent HER performance with an ultralow overpotential of 44.1 mV to achieve 10 mA cm-2 and a lowest Tafel slope of 39.4 mV dec-1, which outperforms Pd58Ni42/TBA-V2CTx, Pd58Ni42, and Pd/C. Remarkably, the Pd58Ni42/N-TBA-V2CTx catalyst can maintain 92.3% of its initial activity even after 50 h of continuous operation.

lncRNA-WAL promotes triple-negative breast cancer aggression by inducing ß-catenin nuclear translocation.

Because of its insensitivity to existing radiotherapy, namely chemotherapy and targeted treatments, triple-negative breast cancer (TNBC) remains a great challenge to overcome. Increasing evidence has indicated abnormal Wnt/ß-catenin pathway activation in TNBC but not luminal or HER2+ breast cancer, and lncRNAs play a key role in a variety of cancers. Through lncRNA microarray profiling between activated and inactivated wnt/ß-catenin pathway of TNBC tissues, lnc-WAL (wnt/ß-catenin associated lncRNA; WAL) was selected as the top upregulated lncRNA in wnt/ß-catenin pathway activation compared with the inactivation group. RIP-seq was used to compare the ß-catenin and IgG groups, where lnc-WAL could interact with ß-catenin. Clinically, increased lnc-WAL in TNBC tumor tissue was associated with shorter survival. lnc-WAL promoted EMT, the proliferation, migration and invasion of breast cancer stem cells (BCSCs), and TNBC cells. Mechanistically, lnc-WAL inhibited ß-catenin protein degradation via Axin-mediated phosphorylation at serine 45. Subsequently, ß-catenin accumulated in the nucleus and activated the target genes. Importantly, wnt/ß-catenin pathway activation stimulated the transcription of lnc-WAL. These results pointed to a master regulatory role of lnc-WAL/Axin/ß-catenin in the malignant progression of TNBC. Our findings provide important clinical translational evidence that lnc-WAL may be a potential therapeutic target against TNBC. Implications: The positive feedback between lnc-WAL and the Wnt/ß-catenin pathway promotes TNBC progression, and lnc-WAL could be a potential prognostic marker for TNBC patients.

Single-Cell RNA Sequencing Identifies Crucial Genes Influencing the Polarization of Tumor-Associated Macrophages in Liver Cancer.

Background: In the context of hepatocellular carcinoma (HCC), tumor-associated macrophages (TAMs) are pivotal for the immunosuppressive nature of the tumor microenvironment (TME). This investigation delves into the functional transformations of TAMs within the TME by leveraging single-cell transcriptomics to pinpoint critical genes influencing TAM subset polarization. Methods: We procured single-cell and bulk transcriptomic data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), implementing quality assurance, dimensional reduction, clustering, and annotation on the single-cell sequencing data. To examine cellular interactions, CellChat was utilized, while single-cell regulatory network inference and clustering (SCENIC) was applied to deduce transcription factors (TFs) and their associated targets. Through gene enrichment, survival, and immune infiltration correlation analyses, we sought to pinpoint and validate influential genes. A TAM model under HCC conditions was then established to confirm the expression levels of these key genes. Results: Our analysis encompassed 74,742 cells and 23,110 genes. Through postdimensional reduction and clustering, we identified seven distinct cell types and nine TAM subtypes. Analysis via CellChat highlighted a predominance of M2-phenotype-inclined TAM subsets within the tumor's core. SCENIC pinpointed the transcription factor PRDM1 and its target genes as pivotal in this region. Further analysis indicated these genes' involvement in macrophage polarization. Employing trajectory analysis, survival analysis, and immune infiltration correlation, we scrutinized and validated genes likely directing M2 polarization. Experimental validation confirmed PRDM1's heightened expression in TAMs conditioned by HCC. Conclusions: Our findings suggest the PRDM1 gene is a key regulator of M2 macrophage polarization, contributing to the immunosuppressive TME in HCC.

Four New Species and a New Combination of Boletaceae (Boletales) from Subtropical and Tropical China.

Previous studies have shown that boletes are abundant and diverse in China, especially in tropical and subtropical regions. In the present study, morphological, ecological, host relationship, and a four-locus (28S, tef1, rpb1, and rpb2) molecular phylogenetic analyses were used to study the family Boletaceae in subtropical and tropical China. Four new bluing species are described from three genera, viz. Boletellus verruculosus (Chinese name), Xerocomellus tenuis (Chinese name), Xer. brunneus (Chinese name), and Xerocomus zhangii (Chinese name). Moreover, the genus Nigroboletus is treated as a synonym of Xerocomellus, and a new combination, namely Xer. roseonigrescens (Chinese name), is proposed.

Skin locations inference and body fluid identification from skin microbial patterns for forensic applications.

Given that microbiological analysis can be an alternative method that overcomes the shortcomings of traditional forensic technology, and skin samples may be the most common source of cases, the analysis of skin microbiome was investigated in this study. High-throughput sequencing targeting the V3-V4 region of 16S rRNA gene was performed to reveal the skin microbiome of healthy individuals in Guangdong Han. The bacterial diversity of the palm, navel, groin and plantar of the same individual was analyzed. The overall classification based on 16S rRNA gene amplicons revealed that the microbial composition of skin samples from different anatomical parts was different, and the dominant bacterial genus of the navel, plantar, groin and palm skin were dominated by Cutibacterium, Staphylococcus, Corynebacterium and Staphylococcus, respectively. PCoA analysis showed that the skin at these four anatomical locations could only be grouped into three clusters. A predictive model based on random forest algorithm showed the potential to accurately distinguish these four anatomical locations, which indicated that specific bacteria with low abundance were the key taxa. In addition, the skin microbiome in this study is significantly different from the dominant microbiome in saliva and vaginal secretions identified in our previous study, and can be distinguished from these two tissue fluids. In conclusion, the present findings on the community and microbial structure details of the human skin may reveal its potential application value in assessing the location of skin samples and the type of body fluids in forensic medicine.

[EMP3 inhibits the formation of heterotypic cell-in-cell structures in hepatocellular carcinoma].

Heterotypic cell-in-cell (heCIC) structures represent a unique intercellular interaction where tumor cells internalize immune cells to enhance the killing efficiency of immune cells. However, the mechanism of heCIC structure formation remains to be fully elucidated. In this study, we explored the role of epithelial membrane protein 3 (EMP3), a PMP-22/EMP/MP20 protein family member highly expressed in the patients with hepatocellular carcinoma and poor prognosis, in the formation of the heCIC structure formed by natural killer cells and hepatocellular carcinoma cells. The analysis of monoclonal hepatocellular carcinoma cell lines revealed that EMP3 presented low expression in the cells with high capability to form heCIC structure and high expression in those with low capability. Knocking down the expression of EMP3 by gene editing promoted the formation of heCIC structures, while overexpression of EMP3 significantly inhibited this process. Additionally, the expression of factors involved in the heCIC structure formation suggested that EMP3 inhibited the formation of heCIC structures by modulating the adhesion ability and cytoskeleton of tumor cells. The findings lay a foundation for enhancing the heCIC-mediated tumor immunotherapy by targeting EMP3.

Combined oral low-dose cyclophosphamide endocrine therapy may improve clinical response among patients with metastatic breast cancer via Tregs in TLSs.

Despite limited research on refractory and/or endocrine therapy failure in elderly metastatic breast cancer (MBC) patients, a prior study showed that low-dose oral cyclophosphamide (CY) can improve the overall survival rate of MBC patients, possibly through the immunoregulation of regulatory T cells (Tregs). We preliminarily investigated the combination of endocrine therapy (ET) with oral low-dose CY as salvage therapy in elderly patients via peripheral blood regulatory T-cell analyses. In addition, we evaluated the associations of tumor tertiary lymphoid structures (TLSs) with therapeutic outcomes. HR+/HER2- advanced breast cancer patients who received low-dose CY combined with ET or ET only from April 2015 to August 2021 were enrolled in this retrospective study. The primary outcome was the clinical control rate (CCR), and the secondary outcome was progression-free survival (PFS). Circulating T lymphocyte subpopulations represented by Tregs were monitored during treatment by flow cytometry methods. TLSs wereconfirmed by hematoxylin-eosin staining of pretreatment specimens, and CD3, CD4, and Foxp3 were detected using Opal multicolor immunofluorescence. A total of 85 patients who received CY + ET and 50 patients who received ET only were enrolled, the percentage of patients who received CCR was 73% (62/85) vs. 70% (45/50), and the objective response rate (ORR) was 28% (24/85) vs. 24% (12/50). No deaths occurred during the study period. The mean PFS time was 13 vs. 11 months (P = 0.03). In the CY + ET group, decreases in CD4+/CD25+/Foxp3+ T cells (P < 0.001) were favorable for both clinical control and prolonged PFS (P < 0.001). Compared with patients without TLSs, those with TLSs were more likely to have better clinical control and PFS (mean time = 6 months), and a greater number of Treg cells during TLS pretreatment correlated with longer PFS (P = 0.043). Oral low-dose CY combined with standard ET exerts immunological effects by decreasing Treg levels to achieve improved clinical responses. Moreover, patients with TLSs might benefit more from such therapy than those without TLSs, and a high Treg cell count in TLSs before treatment predicts better therapeutic efficacy.

Identification and Validation of JAM-A as a Novel Prognostic and Immune Factor in Human Tumors.

Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used multiple databases to gain a comprehensive understanding of JAM-A in human cancers. JAM-A was widely expressed in various tissues, mainly located on the microtubules and cell junctions. Aberrant expression of JAM-A was detected in multiple cancers at both mRNA and protein levels, which can be correlated with poorer prognosis and may be attributed to genetic alterations and down-regulated DNA methylation. JAM-A expression was also associated with immune infiltration and may affect immunotherapy responses in several cancers. Functional enrichment analysis indicated that JAM-A participated in tight junction and cancer-related pathways. In vitro experiments verified that JAM-A knockdown suppressed the proliferation and migration abilities of breast cancer cells and liver cancer cells. Overall, our study suggests that JAM-A is a pan-cancer regulator and a potential biomarker for predicting prognosis and immune-therapeutic responses for different tumors.

LncRNA ZFPM2-AS1 promotes phyllodes tumor progression by binding to CDC42 and inhibiting STAT1 activation.

Breast phyllodes tumor (PT) is a rare fibroepithelial neoplasm with potential malignant behavior. Long non-coding RNAs (lncRNAs) play multifaceted roles in various cancers, but their involvement in breast PT remains largely unexplored. In this study, microarray was leveraged for the first time to investigate the role of lncRNA in PT. We identified lncRNA ZFPM2-AS1 was significantly upregulated in malignant PT, and its overexpression endowed PT with high tumor grade and adverse prognosis. Furthermore, we elucidated that ZFPM2-AS1 promotes the proliferation, migration, and invasion of malignant PT in vitro. Targeting ZFPM2-AS1 through nanomaterial-mediated siRNA delivery in patient-derived xenograft (PDX) model could effectively inhibit tumor progression in vivo. Mechanistically, our findings showed that ZFPM2-AS1 is competitively bound to CDC42, inhibiting ACK1 and STAT1 activation, thereby launching the transcription of TNFRSF19. In conclusion, our study provides evidence that ZFPM2-AS1 plays a pivotal role in the pathogenesis of breast PT, and suggests that ZFPM2-AS1 could serve as a prognostic indicator for patients with PT as well as a promising novel therapeutic target.

Association between dietary intake and risk of Parkinson's disease: cross-sectional analysis of survey data from NHANES 2007-2016.

Background: While dietary factors have shown an association with Parkinson's disease (PD), the available data remains a subject of ongoing debate and controversy. Aim: We sought to evaluate potential relationships between dietary consumption of nutrients and micronutrients and risk of PD in a large sample. Methods: Cross-sectional data were retrospectively analyzed for 10,651 adults aged 40-80 years that had been collected in the US between 2007 and 2016 as a component of the nationwide National Health and Nutrition Examination Survey. Aspects of dietary intake were compared between those who reported having specific PD medication regimens or not when they completed the survey, and potential associations between diet and risk of PD were explored using binomial logistic regression. We employed Propensity Score Matching (PSM) to minimize the impact of potential confounding factors, thus enhancing the reliability of the results. Additionally, subgroup analysis based on gender and age was conducted to investigate these relationships. Results: Higher dietary intake of iron was linked to greater PD risk [odds ratio (OR) 1.065, 95% confidence interval (CI) 1.019-1.114, p = 0.006], whereas risk decreased with higher intake of vitamin K (OR 0.999, 95% CI 0.998-1.000, p = 0.024) or vitamin C (OR 0.998, 95% CI 0.996-0.999, p = 0.039). Even after applying PSM, the connection between dietary iron intake and dietary vitamin C intake with PD risk remained substantial. Subgroup analysis results revealed a significant positive association between dietary intake of iron from food and the PD risk, which was evident among individuals under 60 years of age and among males. Conclusion: The intake of micronutrients can influence risk of PD, which should be verified and explored further in prospective samples with other dietary habits and ethnic backgrounds.