Cross-cancer pleiotropic analysis identifies three novel genetic risk loci for colorectal cancer.

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC. METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. Single nucleotide polymorphism (SNP)-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC genome-wide association study meta-analysis and the pleiotropic analysis under composite null hypothesis (PLACO) pleiotropy test. Gene-based, co-expression and pathway enrichment analyses were performed to explore potential shared biological pathways. The interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC. RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378 and rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1 and RTEL1) to be associated with CRC. These genetic variants were significant expressions quantitative trait loci in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis. CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.

Epidemiological characteristics of respiratory syncytial virus infection in pediatric patients before, during the COVID-19 pandemic and after easing of COVID-19 restrictive measures in China.

We aimed to assess the epidemiological characteristics of respiratory syncytial virus (RSV) infection in Chinese children at different phases of the coronavirus disease 2019 (COVID-19) pandemic, that is, before, during the pandemic and after easing of restrictive measures. We included 123 623 patients aged 0-18 years with respiratory infection symptoms who were suspected with RSV infection from January 1, 2019 to June 30, 2023 in Hangzhou Children's Hospital. Clinical information and RSV test result were extracted from the laboratory information system. We calculated the positive rate of RSV detection by age groups, gender, seasons, types of patients and phases of COVID-19 pandemic. Nonlinear associations between age and risk of RSV infection in three phases of pandemic were assessed by restricted cubic spline regression models. Among 123 623 patients, 3875 (3.13%) were tested as positive. The highest positive rate was observed in children aged 0-28 days (i.e., 12.28%). RSV infection was most prevalent in winter (6.04%), and followed by autumn (2.52%). Although there is no statistical significance regarding the positive rate at three phases of the pandemic, we observed that the rate was lowest during the pandemic and increased after easing the measures in certain age groups (p < 0.05), which was consisted with results from the nonlinear regression analyses. In addition, regression analyses suggested that the age range of children susceptible to RSV got wider, that is, 0-3.5 years, after easing all restrictive measures compared with that before (i.e., 0-3 years) and during the pandemic (i.e., 0-1 year). Based on our findings, we called for attention from health professionals and caregivers on the new epidemiological characteristics of RSV infection in the post-pandemic era after easing the restrictive measures.

Inhibition of squalene epoxidase linking with PI3K/AKT signaling pathway suppresses endometrial cancer.

Endometrial cancer (EC) is a common malignant tumor that lacks any therapeutic target and, in many cases, recurrence is the leading ca use of morbidity and mortality in women. Widely known EC has a strongly positive correlation with abnormal lipid metabolism. Squalene epoxidase (SQLE), a crucial enzyme in the cholesterol synthesis pathway regulating lipid metabolic processes has been found to be associated with various cancers in recent years. Here, we focused on studying the role of SQLE in EC. Our study revealed that SQLE expression level was upregulated significantly in EC tissues. In vitro experiments showed that SQLE overexpression significantly promoted the proliferation, and inhibited cell apoptosis of EC cells, whereas SQLE knockdown or use of terbinafine showed the opposite results. Furthermore, we found out that the promotional effect of SQLE on the proliferation of EC cells might be achieved by activating the PI3K/AKT pathway. In vivo, studies confirmed that the knockdown of SQLE or terbinafine can observably inhibit tumor growth in nude mice. These results indicate that SQLE may promote the progression of EC by activating the PI3K/AKT pathway. Moreover, SQLE is a potential target for EC treatment and its inhibitor, terbinafine, has the potential to become a targeted drug for EC treatment.

Metabolomic profiles in serum and urine uncover novel biomarkers in children with nephrotic syndrome.

BACKGROUND: Nephrotic syndrome is common in children and adults worldwide, and steroid-sensitive nephrotic syndrome (SSNS) accounts for 80%. Aberrant metabolism involvement in early SSNS is sparsely studied, and its pathogenesis remains unclear. Therefore, the goal of this study was to investigate the changes in initiated SSNS patients-related metabolites through serum and urine metabolomics and discover the novel potential metabolites and metabolic pathways. METHODS: Serum samples (27 SSNS and 56 controls) and urine samples (17 SSNS and 24 controls) were collected. Meanwhile, the non-targeted analyses were performed by ultra-high-performance liquid chromatography-quadrupole time of flight-mass spectrometry (UHPLC-QTOF-MS) to determine the changes in SSNS. We applied the causal inference model, the DoWhy model, to assess the causal effects of several selected metabolites. An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to validate hits (D-mannitol, dulcitol, D-sorbitol, XMP, NADPH, NAD, bilirubin, and α-KG-like) in 41 SSNS and 43 controls. In addition, the metabolic pathways were explored. RESULTS: Compared to urine, the metabolism analysis of serum samples was more clearly discriminated at SSNS. 194 differential serum metabolites and five metabolic pathways were obtained in the SSNS group. Eight differential metabolites were identified by establishing the diagnostic model for SSNS, and four variables had a positive causal effect. After validation by targeted MS, except XMP, others have similar trends like the untargeted metabolic analysis. CONCLUSION: With untargeted metabolomics analysis and further targeted quantitative analysis, we found seven metabolites may be new biomarkers for risk prediction and early diagnosis for SSNS.

Effects of a novel ANLN E841K mutation associated with SRNS on podocytes and its mechanism.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is characterized by unrelieved proteinuria after an initial 4-8 weeks of glucocorticoid therapy. Genes in podocytes play an important role in causing SRNS. OBJECTIVE: This study aimed to report a pathogenic mutation in SRNS patients and investigate its effects on podocytes, as well as the pathogenic mechanism. METHODS: We screened out a novel mutation by using whole-exon sequencing in the SRNS cohort and verified it via Sanger sequencing. Conservative analysis and bioinformatic analysis were used to predict the pathogenicity of the mutation. In vitro, stable podocyte cell lines were constructed to detect the effect of the mutation on the function of the podocyte. Moreover, an in vivo mouse model of podocyte ANLN gene knockout (ANLNpodKO) was used to confirm clinical manifestations. Transcriptome analysis was performed to identify differential gene expression and related signaling pathways. RESULTS: ANLN E841K was screened from three unrelated families. ANLN E841K occurred in the functional domain and was predicted to be harmful. The pathological type of A-II-1 renal biopsy was minimal change disease, and the expression of ANLN was decreased. Cells in the mutation group showed disordered cytoskeleton, faster cell migration, decreased adhesion, increased endocytosis, slower proliferation, increased apoptosis, and weakened interaction with CD2 association protein. ANLNpodKO mice exhibited more obvious proteinuria, more severe mesangial proliferation, glomerular atrophy, foot process fusion, and increased tissue apoptosis levels than ANLNflox/flox mice after tail vein injection of adriamycin. Upregulated differentially expressed genes in cells of the mutation group were mainly enriched in the PI3K-AKT pathway. CONCLUSION: The novel mutation known as ANLN E841K affected the function of the ANLN protein by activating the PI3K/AKT/mTOR/apoptosis pathway, thus resulting in structural and functional changes in podocytes. Our study indicated that ANLN played a vital role in maintaining the normal function of podocytes. Video Abstract.

Stress granules in the spinal muscular atrophy and amyotrophic lateral sclerosis: The correlation and promising therapy.

Increasing genetic and biochemical evidence has broadened our view of the pathomechanisms that lead to Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), two fatal neurodegenerative diseases with similar symptoms and causes. Stress granules are dynamic cytosolic storage hubs for mRNAs in response to stress exposures, that are evolutionarily conserved cytoplasmic RNA granules in somatic cells. A lot of previous studies have shown that the impaired stress granules are crucial events in SMA/ALS pathogenesis. In this review, we described the key stress granules related RNA binding proteins (SMN, TDP-43, and FUS) involved in SMA/ALS, summarized the reported mutations in these RNA binding proteins involved in SMA/ALS pathogenesis, and discussed the mechanisms through which stress granules dynamics participate in the diseases. Meanwhile, we described the applications and limitation of current therapies targeting SMA/ALS. We futher proposed the promising targets on stress granules in the future therapeutic interventions of SMA/ALS.

Lanosterol reverses protein aggregation in cataracts.

The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

Virus-like mesoporous silica-coated plasmonic Ag nanocube with strong bacteria adhesion for diabetic wound ulcer healing.

The Gram-positive bacterium Staphylococcus aureus (MRSA) and the Gram-negative bacillus Escherichia coli (E. coli) can be commonly found in diabetic foot ulcers. However, the multi-drug resistant pathogenic bacteria infection is often difficult to eradicate by the conventional antibiotics and easy to spread which can lead to complications such as gangrene or sepsis. In this work, in order to pull through the low cell wall adhesion capability of typical antibacterial Ag nanoparticles, we fabricated biomimic virus-like mesoporous silica coated Ag nanocubes with gentamicin loading, and then the core-shell nanostructure was entrapped in the FDA approved hydrogel dressing. Interestingly, the Ag nanocubes with virus-like mesoporous silica coating are capable of effectively adsorbing on the rigid cell wall of both E. coli and MRSA. The intracellular H2S in natural bacterial environment can induce generation of small Ag nanospheres, which are the ideal antibacterial nanoagents. Combined with the gentamicin delivery, the pathogenic bacteria in diabetic wound can be completely eradicated by our dressing to improve the wound healing procedure. This virus-like core-shell nanostructure sheds light for the future wound healing dressing design to promote the clinical applications on antibacterial eradication.

The combination therapy with esomeprazole and flupenthixol/melitracen in symptom improvement of erosive gastritis complicated with negative feelings compared with Esomeprazole alone.

The purpose of this study was to evaluate the co-prescription efficacy of esomeprazole and flupenthixol/melitracen relative to that of solitary esomeprazole on erosive gastritis complicated with negative feelings. 140 erosive gastritis patients complicated with negative feelings enrolled in the present study. Seventy cases in the control group took esomeprazole, and 70 cases in the observation group received esomeprazole plus flupenthixol/Melitracen, both for 4 weeks. We gastroscopically checked the clinical symptoms, mucosal erosion, PGE2 and MDA levels in gastric mucosa, anxiety, depression, and recurrence before and after treatment in the groups. After treatment, the observation group had lower scores of clinical symptoms, mucosal erosions, Hamilton Depression Rating Scale (HAMD), and Hamilton Depression Rating Scale (HAMA) than the control group (p<0.05); as well, the observation group showed higher PGE2 and lower MDA levels than the control group (p<0.05); during six months of follow-up (100% follow-up rate), 16 and 34 recurrent cases occurred, respectively, in the observation and control groups (p<0.05).  Co-prescription of esomeprazole and flupenthixol/melitracen improved the clinical symptoms and mucosal erosions, relieved negative feelings and reduced the recurrence rate. The efficacy of the co-prescription is higher than that of the solitary prescription.

Downshifting nanoprobes with follicle stimulating hormone peptide fabrication for highly efficient NIR II fluorescent bioimaging guided ovarian tumor surgery.

Failure of intraoperative detection, early minimal lesion and microscopic residual tumor margins elimination causes metastatic diffusion and lethal recurrence. However, during surgical process, surgeons can only rely largely on palpation and visual examination. Intraoperative bioimaging with the aid of the second near-infrared fluorescent (NIR II FL) light has entered the surgical excision area to bridge the gap of preoperative bioimaging and intraoperative resection. Here, we demonstrate that the follicle-stimulating hormone peptide (FSHP) engineered NIR II downshifting nanoparticles (DSNPs@FSHP) selectively undergo efficient ovarian tumor targeting property. Owing to the special biocompatibility of nanoprobes, this strategy provided rapid body clearance and efficient tumor targeting with significantly tumor to background (T/B) ratio enhanced for surgical excision. Based on these, this strategy can successfully empower the detection and surgical removal for both ovarian tumor lesions and ovarian tumor margins by NIR II FL bioimaging.

Lanosterol and 25-hydroxycholesterol dissociate crystallin aggregates isolated from cataractous human lens via different mechanisms.

Cataract, a crystallin aggregation disease, is the leading cause of human blindness worldwide. Surgery is the only established treatment of cataracts and no anti-cataract drugs are available thus far. Recently lanosterol and 25-hydroxycholesterol have been reported to redissolve crystallin aggregates and partially restore lens transparency in animals. However, the efficacies of these two compounds have not been quantitatively studied ex vivo using patient tissues. In this research, we developed a quantitative assay applicable to efficacy validations and mechanistic studies by a protocol to isolate protein aggregates from the surgically removed cataractous human lens. Our results showed that both compounds were effective for human cataractous samples with EC50 values at ten micromolar level. The efficacies of both compounds strongly depended on cataract severity. Lanosterol and 25-hydroxycholesterol were two mechanistically different lead compounds of anti-cataract drug design.

Progress of Mesoporous Silica Coated Gold Nanorods for Biological Imaging and Cancer Therapy.

For unique surface plasmon absorption and fluorescence characteristics, gold nanorods have been developed and widely employed in the biomedical field. However, limitations still exist due their low specific surface area, instability and tendency agglomerate in cytoplasm. Mesoporous silica materials have been broadly applied in field of catalysts, adsorbents, nanoreactors, and drug carriers due to its unique mesoporous structure, highly comparative surface area, good stability and biocompatibility. Therefore, coating gold nanorods with a dendritic mesopore channels can effectively prevent particle agglomeration, while increasing the specific surface area and drug loading efficiency. This review discusses the advancements of GNR@MSN in synthetic process, bio-imaging technique and tumor therapy. Additionally, the further application of GNR@MSN in imaging-guided treatment modalities is explored, while its promising superior application prospect is highlighted. Finally, the issues related to in vivo studies are critically examined for facilitating the transition of this promising nanoplatform into clinical trials.

Clinical Characteristics and Induced Pluripotent Stem Cells (iPSCs) Disease Model of Fabry Disease Caused by a Novel GLA Mutation.

BACKGROUND: Fabry disease (FD) is a rare X-linked inherited disease caused by mutations in the GLA gene. We established a cohort of FD patients and performed whole-exome sequencing (WES) to identify some novel mutations. AIM: The aim of this study is to investigate the etiology of the novel mutation (c.72G > A, p.Trp24*）in the GLA gene in affected patients by using induced pluripotent stem cells (iPSCs) as a valuable tool. METHODS: We explored the clinical implications of this proband and examined the deleteriousness and conservation of the mutation site through bioinformatics analysis. Simultaneously, we collected the peripheral blood mononuclear cells (PBMCs) of the affected patient, then reprogrammed them into iPSCs and assessed their enzymatic activity to confirm the function of lysosomal enzyme α-galactosidase A (α-Gal A). RESULTS: Clinical examination of the patient demonstrated a classical FD, such as neuropathic pain, gastrointestinal disorders, deficiency of α-Gal A activity, and accumulation of Lyso-Gb-3. The novel mutation located on the N-terminal region, leading to a truncation of the protein and remaining only 24 amino acids. The α-Gal A activity of the patient-specific iPSC (iPS-FD) was significantly lower (60%) than that of normal iPSCs derived from healthy donors (iPS-B1). CONCLUSION: This work not only elucidated the etiology of novel mutations in affected patients but also highlighted the utility of iPSCs as a valuable tool for clarifying the molecular mechanisms and providing new insights into the therapy of FD.

Celastrol regulates the oligomeric state and chaperone activity of αB-crystallin linked with protein homeostasis in the lens.

Protein misfolding and aggregation are crucial pathogenic factors for cataracts, which are the leading cause of visual impairment worldwide. α-crystallin, as a small molecular chaperone, is involved in preventing protein misfolding and maintaining lens transparency. The chaperone activity of α-crystallin depends on its oligomeric state. Our previous work identified a natural compound, celastrol, which could regulate the oligomeric state of αB-crystallin. In this work, based on the UNcle and SEC analysis, we found that celastrol induced αB-crystallin to form large oligomers. Large oligomer formation enhanced the chaperone activity of αB-crystallin and prevented aggregation of the cataract-causing mutant ßA3-G91del. The interactions between αB-crystallin and celastrol were detected by the FRET (Fluorescence Resonance Energy Transfer) technique, and verified by molecular docking. At least 9 binding patterns were recognized, and some binding sites covered the groove structure of αB-crystallin. Interestingly, αB-R120G, a cataract-causing mutation located at the groove structure, and celastrol can decrease the aggregates of αB-R120G. Overall, our results suggested celastrol not only promoted the formation of large αB-crystallin oligomers, which enhanced its chaperone activity, but also bound to the groove structure of its α-crystallin domain to maintain its structural stability. Celastrol might serve as a chemical and pharmacological chaperone for cataract treatment.

Cholesterol metabolism: physiological regulation and diseases.

Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.

Health-related quality of life measurements in children and adolescents with refractive errors: A scoping review.

Background: Refractive errors, particularly myopia, are the leading visual disorders worldwide, significantly affecting the quality of life (QOL) even after correction. This scoping review focuses on health-related quality of life (HRQOL) measurements for children and adolescents with refractive errors. Main text: We explored generic and disease-specific HRQOL tools, examining their content, psychometric properties, and the impact of various interventions on QOL. Two English databases-PubMed, Embase, and one Chinese database, CNKI, were searched for relevant studies published from January 2001 to October 2023. Inclusion criteria encompassed studies using standardized instruments to assess the QOL of children aged 0-18 with refractive errors. The review compares prevalent HRQOL measurements, analyzes children's refractive error assessments, and discusses intervention effects on patient QOL. Conclusions: The study underlines the necessity of developing disease-specific QOL instruments for very young children and serves as a practical guide for researchers in this field. The findings advocate for a targeted approach in HRQOL assessment among the pediatric population, identifying critical gaps in current methodologies.

Cataract-related variant R114C increases ßA3-crystallin susceptibility to environmental stresses by disrupting the protein senior structure.

Congenital cataract is a major cause of childhood blindness worldwide, with crystallin mutations accounting for over 40 % of gene-mutation-related cases. Our research focused on a novel R114C mutation in a Chinese family, resulting in bilateral coronary cataract with blue punctate opacity. Spectroscopic experiments revealed that ßA3-R114C significantly altered the senior structure, exhibiting aggregation, and reduced solubility at physiological temperature. The mutant also displayed decreased resistance and stability under environmental stresses such as UV irradiation, oxidative stress, and heat. Further, cellular models confirmed its heightened sensitivity to environmental stresses. These data suggest that the R114C mutation impairs the hydrogen bond network and structural stability of ßA3-crystallin, particularly at the boundary of the second Greek-key motif. This study revealed the pathological mechanism of ßA3-R114C and may help in the development of potential treatment strategies for related cataracts.

Dent disease 1-linked novel CLCN5 mutations result in aberrant location and reduced ion currents.

Dent disease is a rare renal tubular disease with X-linked recessive inheritance characterized by low molecular weight proteinuria (LMWP), hypercalciuria, and nephrocalcinosis. Mutations disrupting the 2Cl-/1H+ exchange activity of chloride voltage-gated channel 5 (CLCN5) have been causally linked to the most common form, Dent disease 1 (DD1), although the pathophysiological mechanisms remain unclear. Here, we conducted the whole exome capture sequencing and bioinformatics analysis within our DD1 cohort to identify two novel causal mutations in CLCN5 (c.749 G > A, p. G250D, c.829 A > C, p. T277P). Molecular dynamics simulations of ClC-5 homology model suggested that these mutations potentially may induce structural changes, destabilizing ClC-5. Overexpression of variants in vitro revealed aberrant subcellular localization in the endoplasmic reticulum (ER), significant accumulation of insoluble aggregates, and disrupted ion transport function in voltage clamp recordings. Moreover, human kidney-2 (HK-2) cells overexpressing either G250D or T277P displayed higher cell-substrate adhesion, migration capability but reduced endocytic function, as well as substantially altered transcriptomic profiles with G250D resulting in stronger deleterious effects. These cumulative findings supported pathogenic role of these ClC-5 mutations in DD1 and suggested a cellular mechanism for disrupted renal function in Dent disease patients, as well as a potential target for diagnostic biomarker or therapeutic strategy development.