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.

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.

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.

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.

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.

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.

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.

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.

Safety of dendritic cell and cytokine-induced killer (DC-CIK) cell-based immunotherapy in patients with solid tumor: a retrospective study in China.

Systematic assessment of adverse side effects of Adoptive T cell therapy, especially cytokine-induced killer cell and dendric cell treatment Dendritic cells-Cytokine-induced killer (DC-CIK) therapy, especially when combined with chemotherapy, has not been reported. Totally 1100 consecutive patients (2504 trail cycles) enrolled in DC-CIK treatment trials at Beijing Shijitian Hospital between August 2012 and August 2022 were retrospectively reviewed. The 370 patients (34%)/815 cycles enrolled in our trial combined with chemotherapy. In total, 548 (cases)/870 (cycles) patients experienced AEs. The AE class was mainly composed of Neurological 34 cycles (4%), Musculoskeletal 28 cycles (3%), Immunopathies 5 cycles (1%), Hematological 521 cycles (60%), 224 general disorders and administration site conditions cycles (26%), Gastrointestinal 209 cycles (24%), Skin 15 cycles (2%), and 119 Metabolism and Nutrition disorders cycles (14%). The AE class of gastrointestinal (vomiting, P=0.025), nutritional (anorexia, P=0.016), and hematological disorders (anemia P<0.0001, leukopenia P<0.0001) appeared in the DC-CIK treatment and were mainly correlated with chemotherapy. Multiple logistic regression analysis suggested that regardless of whether DC-CIK was combined with chemotherapy, multi-line treatment was more prone to nausea, anorexia, fatigue, anemia, and leukopenia than first-line treatment. However, correlation analysis verified that increasing the number of cycles of DC-CIK treatment alone could reduce the incidence rate of fatigue (P=0.001), anorexia (P<0.0001), and anxiety (P=0.01). Most of the adverse side effects that occurred during autologous DC-CIK treatment were associated with combined or previously applied chemotherapeutic treatment, which also indicated that autologous DC-CIK anti-tumor therapy was safe.

Pretreatment MRI-Based Radiomics for Prediction of Rectal Cancer Outcome: A Discovery and Validation Study.

RATIONALE AND OBJECTIVES: Accurate prediction of local recurrence or distant metastasis is critical for developing individualized therapies for locally advanced rectal cancer (LARC) patients after standard therapy. This study aims to develop and validate a multiparameter MRI-based radiomics signature (RS) for prognostic prediction in LARC patients receiving neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME) and to explore the ability of RS for personalized survival risk stratification. MATERIALS AND METHODS: In this multi-center study, 454 patients who received nCRT and TME and completed 3 years of follow-up participated. RS was constructed for prognostic prediction based on features extracted from pretreatment multiparameter MRI in a training cohort (TC; n = 298), which was tested in an internal validation cohort (IVC; n = 75) and further validated in an independent external validation cohort (EVC; n = 81). Furthermore, the ability of RS for personalized survival risk stratification was explored using the Kaplan-Meier survival curves. RESULTS: The RS model showed satisfactory accuracy for prognostic prediction with AUCs of 0.83, 0.81 and 0.82 in the TC, IVC and EVC, respectively. In addition, RS helped to refine risk stratification for LARC patients on the basis of significantly different 3-year disease-free survival rates, independent of their pathological stage, pre-surgery CEA, and even treatment modality. CONCLUSIONS: The proposed RS can be used not only to predict local recurrence or distant metastasis but also to serve as an effective postoperative survival risk stratification tool for clinicians to facilitate decision-making for LARC patients receiving standard treatment.

Multiphase and multiparameter MRI-based radiomics for prediction of tumor response to neoadjuvant therapy in locally advanced rectal cancer.

BACKGROUND: To develop and validate radiomics models for prediction of tumor response to neoadjuvant therapy (NAT) in patients with locally advanced rectal cancer (LARC) using both pre-NAT and post-NAT multiparameter magnetic resonance imaging (mpMRI). METHODS: In this multicenter study, a total of 563 patients were included from two independent centers. 453 patients from center 1 were split into training and testing cohorts, the remaining 110 from center 2 served as an external validation cohort. Pre-NAT and post-NAT mpMRI was collected for feature extraction. The radiomics models were constructed using machine learning from a training cohort. The accuracy of the models was verified in a testing cohort and an independent external validation cohort. Model performance was evaluated using area under the curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: The model constructed with pre-NAT mpMRI had favorable accuracy for prediction of non-response to NAT in the training cohort (AUC = 0.84), testing cohort (AUC = 0.81), and external validation cohort (AUC = 0.79). The model constructed with both pre-NAT and post-NAT mpMRI had powerful diagnostic value for pathologic complete response in the training cohort (AUC = 0.86), testing cohort (AUC = 0.87), and external validation cohort (AUC = 0.87). CONCLUSIONS: Models constructed with multiphase and multiparameter MRI were able to predict tumor response to NAT with high accuracy and robustness, which may assist in individualized management of LARC.

An extra-erythrocyte role of haemoglobin body in chondrocyte hypoxia adaption.

Although haemoglobin is a known carrier of oxygen in erythrocytes that functions to transport oxygen over a long range, its physiological roles outside erythrocytes are largely elusive1,2. Here we found that chondrocytes produced massive amounts of haemoglobin to form eosin-positive bodies in their cytoplasm. The haemoglobin body (Hedy) is a membraneless condensate characterized by phase separation. Production of haemoglobin in chondrocytes is controlled by hypoxia and is dependent on KLF1 rather than the HIF1/2α pathway. Deletion of haemoglobin in chondrocytes leads to Hedy loss along with severe hypoxia, enhanced glycolysis and extensive cell death in the centre of cartilaginous tissue, which is attributed to the loss of the Hedy-controlled oxygen supply under hypoxic conditions. These results demonstrate an extra-erythrocyte role of haemoglobin in chondrocytes, and uncover a heretofore unrecognized mechanism in which chondrocytes survive a hypoxic environment through Hedy.

CD146 promotes malignant progression of breast phyllodes tumor through suppressing DCBLD2 degradation and activating the AKT pathway.

BACKGROUND: As a rapid-progressing tumor, breast malignant phyllodes tumors (PTs) are challenged by the lack of effective therapeutic strategies and suitable prognostic markers. This study aimed to clarify the role and mechanism of CD146 on promoting PTs malignant progression, and to identify a novel prognosis marker and treatment target of breast malignant PTs. METHODS: The expression and prognostic significance of CD146 in PTs was detected through single-cell RNA-sequencing (scRNA-seq), immunostaining, real-time PCR and other methodologies. Functional experiments including proliferation assay, colony formation assay, transwell assay, and collagen contraction assay were conducted to validate the role of CD146 in malignant progression of PTs. The efficacy of anti-CD146 monoclonal antibody AA98 against malignant PTs was corroborated by a malignant PT organoid model and a PT patient-derived xenograft (PDX) model. Transcriptome sequencing, proteomic analysis, co-immunoprecipitation, and pull-down assay was employed to identify the modulating pathway and additional molecular mechanism. RESULTS: In this study, the scRNA-seq analysis of PTs disclosed a CD146-positive characteristic in the α-SMA+ fibroblast subset. Furthermore, a progressive elevation in the level of CD146 was observed with the malignant progression of PTs. More importantly, CD146 was found to serve as an independent predictor for recurrence in PT patients. Furthermore, CD146 was found to augment the viability and invasion of PTs. Mechanistically, CD146 acted as a protective "shield" to prevent the degradation of Discoidin, CUB, and LCCL domain-containing protein 2 (DCBLD2), thereby activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and enhancing malignant behaviors of PT cells. In the malignant PT organoid and PDX model, a significant suppression of malignant PT growth was observed after the application of AA98. CONCLUSIONS: These findings suggested that CD146 served as an efficacious marker for predicting PT malignant progression and showed promise as a prognosis marker and treatment target of breast malignant PTs. The study further unveiled the essential role of the CD146-DCBLD2/PI3K/AKT axis in the malignant progression of PTs.

Venous blood parameters in determination of respiratory impairment in amyotrophic lateral sclerosis.

This study aimed to investigate the relationship between venous blood parameters and respiratory functions in patients with amyotrophic lateral sclerosis (ALS) and develop a model to predict respiratory impairment for individual patients with ALS. A total of 416 ALS patients were included in the study, and various hematologic and biochemical laboratory parameters as well as demographic and clinical factors were collected and compared. A multivariable logistic regression model was constructed to assess the association between FVC and venous blood biomarkers and clinical factors. The results showed that along with onset age, bulbar-onset, disease duration, BMI, eosinophil count (EO#), basophil count (BASO#), creatinine (CREA), uric acid (URCI) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL/HDL) ratio were associated with reduced FVC. The area under the ROC curve is 0.735 for the test set and 0.721 for the validation set. The study also developed a relatively acceptable model for predicting respiratory impairment in ALS patients. These findings suggest that EO#, BASO#, CREA, URIC and LDL/HDL ratio can be useful in assessing FVC in ALS and can be easily accessible, accurate, and low-cost parameters.

New Mouse Models of Roux-en Y Gastric Bypass and One Anastomosis Gastric Bypass for Type 2 Diabetes.

BACKGROUND: Current bariatric surgery models primarily utilize mice with obesity, overlooking those with type 2 diabetes (T2DM). These models have limitations in replicating clinical procedures accurately and achieving broad applicability. This study aimed to develop novel mouse models of Roux-en-Y gastric bypass (RYGB) and one anastomosis gastric bypass (OAGB) surgeries specifically designed for T2DM research, utilizing simplified surgical techniques closely resembling clinical procedures. METHODS: Eight-week-old C57/Bl6 mice, except for the Blank-Control group, were induced with T2DM by combining a high-fat diet and streptozotocin injection. RYGB involved creating a 10% gastric pouch, a 4-cm biliopancreatic limb (BL), and a 4-cm Roux limb (RL). Similarly, OAGB maintained a 10% gastric pouch and a 4-cm BL. To assess the efficacy of these models, we measured the body weight and fasting blood glucose (FBG) and conducted intraperitoneal glucose tolerance test (IPGTT), insulin tolerance test (ITT), and liver B-ultrasound, as well as a histopathological analysis of multiple organs 12 weeks post-operation. RESULTS: The survival rates in the Blank-Control, T2DM-Sham, T2DM-RYGB, and T2DM-OAGB groups were 100% (6/6), 100% (6/6), 85.7% (6/7), and 100% (6/6), respectively. Both RYGB and OAGB surgeries similarly led to sustained weight loss, reduced the FBG levels, improved the IPGTT and ITT results, and alleviated the histopathological manifestations in multiple organs. CONCLUSION: The innovative mouse models of RYGB and OAGB surgeries effectively improve T2DM. Both surgeries demonstrate comparable efficacy in ameliorating T2DM, even when utilizing a gastric pouch of the same size and the same length of BL in OAGB.

Association of meat consumption with the risk of gastrointestinal cancers: a systematic review and meta-analysis.

BACKGROUND: The association between gastrointestinal cancer and types of meat consumption, including red meat, processed meat, or a combination of both, remains disputable. Therefore, we performed a systematic review and meta-analysis of prospective cohort studies to estimate the association between meat consumption and gastrointestinal cancer risk. METHODS: PubMed, EmBase, and the Cochrane library databases were searched systematically for eligible studies that investigated the relation between meat consumption and the risk of developing gastrointestinal cancers, including esophageal cancer (EC), gastric cancer (GC), colorectal cancer (CRC), colon cancer (CC), rectal cancer (RC), pancreatic cancer (PC), and hepatocellular carcinoma (HCC) throughout February, 2023. The pooled relative risk (RR) with 95% confidence interval (CI) was assigned as an effect estimate and calculated using a random-effects model with inverse variance weighting. RESULTS: Forty cohorts comprising 3,780,590 individuals were selected for the final quantitative analysis. The summary results indicated that a higher red meat consumption was associated with an increased risk of CRC (RR: 1.09; 95% CI: 1.02-1.16; P = 0.007) and CC (RR: 1.13; 95% CI: 1.03-1.25; P = 0.011). Moreover, a higher processed meat consumption was associated with an increased risk of CRC (RR: 1.19; 95% CI: 1.13-1.26; P < 0.001), CC (RR: 1.24; 95% CI: 1.13-1.26; P < 0.001), and RC (RR: 1.24; 95% CI: 1.08-1.42; P = 0.002). Furthermore, a higher total consumption of red and processed meat was associated with an increased risk of CRC (RR: 1.13; 95% CI: 1.06-1.20; P < 0.001), CC (RR: 1.17; 95% CI: 1.04-1.33; P = 0.012), and RC (RR: 1.20; 95% CI: 1.04-1.39; P = 0.016). Finally, the strength of higher consumption of total red and processed meat with the risk of GC, and higher consumption of red meat with the risk of RC in subgroup of high adjusted level was lower than subgroup of moderate adjusted level, while the strength of higher consumption of processed meat with the risk of RC and HCC in subgroup of follow-up ≥ 10.0 years was higher than subgroup of follow-up < 10.0 years. CONCLUSIONS: This study found that meat consumption was associated with an increased risk of CRC, CC, and RC, and dietary intervention could be considered an effective strategy in preventing CRC.

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

PURPOSE: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). EXPERIMENTAL DESIGN: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. RESULTS: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results. CONCLUSIONS: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

Dopant-Free Hole-Transporting Material Based on Poly(2,7-(9,9-bis(N,N-di-p-methoxylphenylamine)-4-phenyl))-fluorene for High-Performance Air-Processed Inverted Perovskite Solar Cells.

It is a great challenge to develop low-cost and dopant-free polymer hole-transporting materials (HTM) for PSCs, especially for efficient air-processed inverted (p-i-n) planar PSCs. A new homopolymer HTM, poly(2,7-(9,9-bis(N,N-di-p-methoxylphenyl amine)-4-phenyl))-fluorene (denoted as PFTPA), with appropriate photo-electrochemical, opto-electronic and thermal stability, was designed and synthesized in two steps to meet this challenge. By employing PFTPA as dopant-free hole-transport layer in air-processed inverted PSCs, a champion power conversion efficiency (PCE) of up to 16.82% (0.1 cm2) was achieved, much superior to that of commercial HTM PEDOT:PSS (13.8%) under the same conditions. Such a superiority is attributed to the well-aligned energy levels, improved morphology, and efficient hole-transporting, as well as hole-extraction characteristics at the perovskite/HTM interface. In particular, these PFTPA-based PSCs fabricated in the air atmosphere maintain a long-term stability of 91% under ambient air conditions for 1000 h. Finally, PFTPA as the dopant-free HTM was also fabricated the slot-die coated perovskite device through the same fabrication condition, and a maximum PCE of 13.84% was obtained. Our study demonstrated that the low-cost and facile homopolymer PFTPA as the dopant-free HTM are potential candidates for large-scale production perovskite solar cell.