Prevalence, treatment efficacy, and risk factors of vascular complications in acute pancreatitis: A case-control study.

OBJECTIVE: We aimed to investigate the prevalence of vascular complications in acute pancreatitis (AP), to compare patient outcomes using various treatments, and to explore the related risk factors. METHODS: Consecutive AP patients admitted from January 2010 to July 2017 were retrospectively included. Demographics, vascular complications, laboratory indices, and imaging findings were collected. Univariate and multivariate analyses were used to explore potential risk factors of vascular complications. RESULTS: Of 3048 AP patients, 808 (26.5%) had vascular complications, including visceral vein thrombosis, sinistral portal hypertension, and arterial complications. And 38 (4.7%) patients received anticoagulant therapy and had a higher rate of recanalization (P < 0.001). Bleeding occurred in 95 (11.8%) patients, who received further treatment. Multivariate analysis identified male gender (odds ratio [OR] 1.650, 95% confidence interval [CI] 1.101-2.472), hyperlipidemia (OR 1.714, 95% CI 1.356-2.165), disease recurrence (OR 3.727, 95% CI 2.713-5.118), smoking (OR 1.519, 95% CI 1.011-2.283), hemoglobin level (OR 0.987, 95% CI 0.981-0.993), white blood cell (WBC) count (OR 1.094, 95% CI 1.068-1.122), non-vascular local complications (OR 3.018, 95% CI 1.992-4.573), computed tomography severity index (CTSI) (OR 1.425, 95% CI 1.273-1.596), and acute physiology and chronic health evaluation (APACHE) II score (OR 1.057, 95% CI 1.025-1.090) were related to vascular complications. CONCLUSIONS: Vascular complications in AP is prevalent and their treatment is challenging. Further investigations are warranted to determine the optimal treatment strategy. Independent risk factors included male gender, hyperlipidemia, disease recurrence, smoking, WBC count, non-vascular local complications, CTSI, and APACHE II score.

The effect of detoxification on acoustic features of Mandarin speech in male heroin users.

This study aims to investigate the effect of detoxification on acoustic features of Mandarin speech. Speech recordings were collected from 66 male abstinent heroin users with different durations of drug detoxification, specifically early abstinent users with a detoxification duration of less than 2 years, sustained abstinent users with 2 years of detoxification, and long-term abstinent users with a detoxification duration of more than 2 years. The results of the acoustic analyses showed that early abstinent users exhibited lower loudness, relative energies of F1, F2, and F3, higher H1-A3, and fewer loudness peaks per second, as well as a longer average duration of unvoiced segments, compared to the sustained and long-term abstinent users. The findings suggest that detoxification may lead to a rehabilitation process in the speech production of abstinent heroin users (e.g., less vocal hoarseness). This study not only provides valuable insights into the effect of detoxification on speech production but also provides a theoretical basis for the speech rehabilitation and detoxification treatment of heroin users.

Continuous quality improvement project to reduce the downtime of medical linear accelerators: A case study at Zhejiang Cancer Hospital.

Objective: To analyse and continually improve existing issues in the quality improvement process of medical linear accelerators (LINACs) and enhance the quality control management of LINACs. Methods: Data were collected from eight LINACs (sourced from three manufacturers) at Zhejiang Cancer Hospital using Excel diaries between January 2019 and December 2020. The data description and analysis were performed using the analytic hierarchy process, SPSSAU and Excel software, and mean-time-to-repair (MTTR)/mean-time-between-failure (MTBF) metrics. Continuous quality improvement was executed using the quality control circle (QCC) quality management method. Results: After quality improvement, the risk frequency of 'LINAC down' events decreased by 43.63% and downtime was reduced by 40.45%. The weight of downtime risk improved by 73.69%. The MTTR recovery value increased by 31.90%, and MTBF reliability increased by 2.97 h. The simulation results demonstrated that the proposed quality improvement measures could effectively decrease the frequency and duration of downtimes, consequently extending the normal operational time of LINACs. Conclusion: Transitioning from instant repair to preventative maintenance can enhance the operational efficiency of equipment and yield economic benefits for hospitals. The QCC method and the event risk evaluation model are effective in reducing the downtime of LINACs and improving their quality control management.

Pancreas-directed AAV8-hSPINK1 gene therapy safely and effectively protects against pancreatitis in mice.

OBJECTIVE: Currently, there is no cure for chronic pancreatitis (CP). Germline loss-of-function variants in SPINK1 (encoding trypsin inhibitor) are common in patients with CP and are associated with acute attacks and progression of the disease. This preclinical study was conducted to explore the potential of adeno-associated virus type 8 (AAV8)-mediated overexpression of human SPINK1 (hSPINK1) for pancreatitis therapy in mice. DESIGN: A capsid-optimised AAV8-mediated hSPINK1 expression vector (AAV8-hSPINK1) to target the pancreas was constructed. Mice were treated with AAV8-hSPINK1 by intraperitoneal injection. Pancreatic transduction efficiency and safety of AAV8-hSPINK1 were dynamically evaluated in infected mice. The effectiveness of AAV8-hSPINK1 on pancreatitis prevention and treatment was studied in three mouse models (caerulein-induced pancreatitis, pancreatic duct ligation and Spink1 c.194+2T>C mouse models). RESULTS: The constructed AAV8-hSPINK1 vector specifically and safely targeted the pancreas, had low organ tropism for the heart, lungs, spleen, liver and kidneys and had a high transduction efficiency (the optimal expression dose was 2×1011 vg/animal). The expression and efficacy of hSPINK1 peaked at 4 weeks after injection and remained at significant level for up to at least 8 weeks. In all three mouse models, a single dose of AAV8-hSPINK1 before disease onset significantly alleviated the severity of pancreatitis, reduced the progression of fibrosis, decreased the levels of apoptosis and autophagy in the pancreas and accelerated the pancreatitis recovery process. CONCLUSION: One-time injection of AAV8-hSPINK1 safely targets the pancreas with high transduction efficiency and effectively ameliorates pancreatitis phenotypes in mice. This approach is promising for the prevention and treatment of CP.

Berberine modulates the immunometabolism and differentiation of CD4+ T cells alleviating experimental arthritis by suppression of M1-exo-miR155.

BACKGROUND: The inflammatory cascade mediated by macrophages and T cells is considered to be an important factor in promoting the progression of rheumatoid arthritis (RA). Our previous study found that berberine (BBR) can therapeutically impact adjuvant arthritis (AA) in rats through the regulation of macrophage polarization and the balance of Th17/Treg. However, whether BBR's effects on CD4+T cells response are related to its suppression of M1 macrophage still unclear. PURPOSE: The study aimed to estimate the mechanism of BBR in regulating the immunometabolism and differentiation of CD4+T cells are related to exosome derived from M1-macrophage (M1-exo). STUDY-DESIGN/METHODS: Mice model of collagen-induced arthritis (CIA) was established to investigate the antiarthritic effect of BBR was related with regulation of M1-exo to balance T cell subsets. Bioinformatics analysis using the GEO database and meta-analysis. In vitro, we established the co-culture system involving M1-exo and CD4+ T cells to examine whether BBR inhibits CD4+T cell activation and differentiation by influencing M1-exo-miR155. Exosome was characterized using transmission electron microscopy and western blot analysis, macrophage and CD4+T cell subpopulation were detected by flow cytometry. Further, the metabolic profiles of CD4+T cells were assessed by ECAR, OCR, and the level of glucose, lactate, intracellular ATP. RESULT: BBR reinstates CD4+ T cell homeostasis and reduces miR155 levels in both M1-exo and CD4+ T cells obtained from mice with CIA. In vitro, we found exosomes are indispensable for M1-CM on T lymphocyte activation and differentiation. BBR reversed M1-exo facilitating the activation and differentiation of CD4+T cells. Furthermore, BBR reversed glycolysis reprogramming of CD4+T cells induced by M1-exo, while these regulation effects were significantly weakened by miR155 mimic. CONCLUSION: The delivery of miR-155 by M1-exo contributes to CD4+ T cell immunometabolism dysfunction, a process implicated in the development of RA. The anti-arthritic effect of BBR is associated with the suppression of glycolysis and the disruption of CD4+ T cell subsets balance, achieved by reducing the transfer of M1-exo-miR155 into T cells.

Gut microbial structural variation associates with immune checkpoint inhibitor response.

The gut microbiota may have an effect on the therapeutic resistance and toxicity of immune checkpoint inhibitors (ICIs). However, the associations between the highly variable genomes of gut bacteria and the effectiveness of ICIs remain unclear, despite the fact that merely a few gene mutations between similar bacterial strains may cause significant phenotypic variations. Here, using datasets from the gut microbiome of 996 patients from seven clinical trials, we systematically identify microbial genomic structural variants (SVs) using SGV-Finder. The associations between SVs and response, progression-free survival, overall survival, and immune-related adverse events are systematically explored by metagenome-wide association analysis and replicated in different cohorts. Associated SVs are located in multiple species, including Akkermansia muciniphila, Dorea formicigenerans, and Bacteroides caccae. We find genes that encode enzymes that participate in glucose metabolism be harbored in these associated regions. This work uncovers a nascent layer of gut microbiome heterogeneity that is correlated with hosts' prognosis following ICI treatment and represents an advance in our knowledge of the intricate relationships between microbiota and tumor immunotherapy.

Induced Overexpression of B Cell-Activating Factor by Triiodothyronine Results in Abnormal B Cell Differentiation in Mice.

Breakdown of tolerance and abnormal activation in B cells is an important mechanism in the pathogenesis of Graves' disease (GD) and high levels of thyroid hormones (THs) can drive the progression of GD. However, the interactions between THs and abnormal activation of B cells in the context of GD are not well understood. The aim of this study was to investigate B cell-activating factor (BAFF) mediating the cross talk between THs and B cells and the possible underlying mechanisms. A high-level triiodothyronine (T3) mouse model was used to verify T3-mediated induction of overexpression of BAFF and B cell abnormal differentiation. The possible promotion of BAFF overexpression in the mice spleen macrophages during polarization to M1 by T3 was also studied. We showed that high levels of T3 can induce BAFF overexpression and lead to abnormal differentiation of B cells in the mice. While the overexpression of BAFF was observed across many tissue types in the mice, high levels of T3 could induce M1 macrophages polarization by IFN (interferon-gamma)-γ in the spleen of the mice, which in turn generated BAFF overexpression. Our findings provide a novel insight into the interactions between the endocrine and immune systems, as well as provide insight into the role of TH in the pathogenesis of GD.

Rare de novo gain-of-function missense variants in DOT1L are associated with developmental delay and congenital anomalies.

Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease.

Contamination, ecological-health risks, and sources of potentially toxic elements in road-dust sediments and soils of the largest urban riverfront scenic park in China.

Identifying the contamination and sources of potentially toxic elements (PTEs) in road-dust sediment (RDS) and the surrounding greenspace soil of urban environments and understanding their ecological-health risks are important for pollution management and public health. The contamination characteristics, ecological and probabilistic health risks, and source apportionment of eight PTEs (Cd, Pb, Cr, Cu, Ni, As, Zn, and Hg) in the Yellow River Custom Tourist Line of Lanzhou, which is the largest open urban riverfront scenic park in China, were investigated. The results showed that all the RDS PTE mean concentrations exceeded their soil background values, whereas for the surrounding greenspace soils, the concentrations of the PTEs, except for Cr and Ni, were also higher than their local background levels. Moreover, the RDS-soil system was mainly contaminated by Cd, Zn, Pb, Cu, and Hg to varying degrees, and the integrated ecological risks of PTEs in the RDS and soil were high and considerable at most sites, respectively. The probabilistic health risk assessment results demonstrated that the non-carcinogenic hazard risk for humans was negligible, but the total carcinogenic risks should be considered. Source apportionment using a positive matrix factorization model combined with multivariate statistical analyses revealed that Cr, Ni, and As in the RDS-soil system were from natural and industrial sources, Cd, Pb, Zn, Cu came from vehicle emissions and pesticide and fertilizer applications, and Hg was from natural and industrial sources and utilization of pesticides with fertilizers. This work provides scientific evidence for urban planning and human health protection in urban environments.

Clinical significance of regulatory T cells and T lymphocyte subsets in peripheral blood in neoadjuvant chemotherapy for breast cancer.

The impact of the immune response on the therapeutical efficacy of neoadjuvant chemotherapy for breast cancer remains largely unknown. To characterize the role of regulatory T cells (CD4+CD25+CD127lowTreg), T lymphocyte subsets (CD3+, CD4+, CD4+/CD8+) and NK cells in neoadjuvant chemotherapy, we investigated the correlation patterns of these immune cell subsets with the progression of breast cancer. A total of 120 breast cancer patients receiving neoadjuvant chemotherapy in Nanjing Maternal and Child Health Hospital from May 2019 to November 2021 were retrospectively collected as the breast cancer group, and 46 healthy women were selected as the control group. The number of regulatory T cells, T lymphocyte subsets and NK cells in the peripheral blood were analyzed by flow cytometry. Compared with the control group, CD3+, CD4+, CD4+/CD8+ ratio and NK cells were significantly decreased in patients with breast cancer (P < 0.05), while the levels of Treg and CD8+ cells were significantly increased (P < 0.05). In addition, the status of the immune response among breast cancer patients at different clinical stages was obviously different. In higher tumor stages, the level of CD3+, CD4+, CD4+/CD8+ ratio and NK cell were reduced, while the level of Treg and CD8+ T cells gradually increased. Furthermore, we found a lower percentage of CD3+, CD4+, CD4+/CD8+ and NK cells in association with lymph node metastasis, accompanied by a higher number of CD8+ T cells. Interestingly, after treatment with neoadjuvant chemotherapy, the levels of Tregs, CD3+, CD4+ and CD4+/CD8+ ratio of patients were all upregulated compared with the levels before treatment, indicating the recovery of cytotoxic lymphocytes and a consolidation of the immunosuppressive microenvironment at the same time (P < 0.05). Immune dysfunction is commonly observed in breast cancer patients, which is closely associated with tumor progression and lymph node metastasis. Neoadjuvant chemotherapy was found to highly influence the number of T lymphocytes and improve the immune function of T lymphocyte subsets in breast cancer patients. At the same time, as immunosuppressive cells, the proportion of Tregs (CD4+CD25+CD127lowTreg) also increased after treatment with neoadjuvant chemotherapy. Our results provide guidance for the development of new combination strategies during neoadjuvant chemotherapy to reverse the immunosuppressive microenvironment and achieve better clinical outcomes.

Mechanistic insight into lysyl oxidase in vascular remodeling and angiogenesis.

Vascular remodeling and angiogenesis are two key processes in the maintenance of vascular homeostasis and involved in a wide array of vascular pathologies. Following these processes, extracellular matrix (ECM) provides the mechanical foundation for vascular walls. Lysyl oxidase (LOX), the key matrix-modifying enzyme, has been demonstrated to significantly affect structural abnormality and dysfunction in the blood vessels. The role of LOX in vascular remodeling and angiogenesis has always been the subject in the current medical research. Therefore, we presently make a summarization of the biosynthesis of LOX and the mechanisms involved in vascular remodeling and angiogenesis, as well as the role of LOX in diseases associated with vascular abnormalities and the therapeutic potential via targeting LOX. In particular, we give a proposal that LOX likely reshapes matrisome-associated genes expressions in the regulation of vascular remodeling and angiogenesis, which serves as a mechanistic insight into the critical role of LOX in these two aspects. Additionally, LOX has also dual effects on the vascular dysfunction, namely, inhibition of LOX for improving hypertension, restenosis and malignant tumor while activation of LOX for curing arterial aneurysm and dissection. LOX-targeted therapy may provide a promising therapeutic strategy for the treatment of various vascular pathologies associated with vascular remodeling and angiogenesis.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.

[Pollution Characteristics and Risk Assessment of Heavy Metals in Surface Dusts and Surrounding Green Land Soils from Yellow River Custom Tourist Line in Lanzhou].

In order to investigate the contamination levels of dust and its surrounding green land soil heavy metal pollution and potential ecological and health risks in the scenic areas of urban waterfront parks, the gardens, squares, and theme parks of the Yellow River Custom Tourist Line in Lanzhou were selected as the research area, using 27 dust samples and 26 soil samples from its surrounding green lands. The contamination characteristics and potential ecological risks of eight heavy metals (Cr, Ni, Cu, Zn, As, Cd, Hg, and Pb) were evaluated using the geo-accumulation index (Igeo), single-factor pollution index (Pi), Nemerow integrated pollution index (PN), and improved potential ecological risk index (RI). The human health risk assessment was also evaluated using the exposure risk model. The results showed that the average concentrations of the other heavy metals in the surface dusts were higher than the background values of Gansu Province and Lanzhou City, except that the As mean concentrations in the surface dusts and the surrounding green land soils were slightly lower than the Gansu Province background values. For its surrounding green land soils, the mean concentrations of the other heavy metals (Cu, Zn, Cd, Hg, and Pb) exceeded the soil background values of Gansu Province and Lanzhou City, whereas the Cr and Ni mean concentrations were lower than their corresponding soil background values of Gansu Province and Lanzhou City. The geo-accumulation and single-factor pollution indices demonstrated that a slight to moderate pollution of Cr, Cu, Zn, Cd, Hg, and Pb occurred in surface dusts, and Cu, Zn, Cd, Hg, and Pb appeared in varying degrees of contamination levels in its surrounding green land soils. The Nemerow integrated pollution index analysis manifested that the overall contamination status of the study areas was between slightly and heavily polluted. The potential ecological risk index suggested that Cd and Hg were recognized as significant pollutant elements and that the RI of the other heavy metals were all below 40, presenting slight ecological risk. The health risk assessment indicated that ingestion was the dominant exposure pathway for heavy metals from the surface dusts and the surrounding green land soils, and no carcinogenic and noncarcinogenic risks posed threats to adults and children.

eIF3a sustains non-small cell lung cancer stem cell-like properties by promoting YY1-mediated transcriptional activation of ß-catenin.

Cancer stem cells (CSCs) are the leading cause of recurrence and poor prognosis in non-small cell lung cancer (NSCLC). Eukaryotic translation initiation factor 3a (eIF3a) participates in many tumor development processes, such as metastasis, therapy resistance, and glycolysis, all of which are closely associated with the presence of CSCs. However, whether eIF3a maintains NSCLC-CSC-like properties remains to be elucidated. In this study, eIF3a was highly expressed in lung cancer tissues and was linked to poor prognosis. eIF3a was also highly expressed in CSC-enriched spheres compared with adherent monolayer cells. Moreover, eIF3a is required for NSCLC stem cell-like traits maintenance in vitro and in vivo. Mechanistically, eIF3a activates the Wnt/ß-catenin signaling pathway, promoting the transcription of cancer stem cell markers. Specifically, eIF3a promotes the transcriptional activation of ß-catenin and mediates its nuclear accumulation to form a complex with T cell factor 4 (TCF4). However, eIF3a has no significant effect on protein stability and translation. Proteomics analysis revealed that the candidate transcription factor, Yin Yang 1 (YY1), mediates the activated effect of eIF3a on ß-catenin. Overall, the findings of this study implied that eIF3a contributes to the maintenance of NSCLC stem cell-like characteristics through the Wnt/ß-catenin pathway. eIF3a is a potential target for the treatment and prognosis of NSCLC.

An integrated approach of network pharmacology, molecular docking, and experimental verification uncovers kaempferol as the effective modulator of HSD17B1 for treatment of endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological malignancies globally, and the development of innovative, effective drugs against EC remains a key issue. Phytoestrogen kaempferol exhibits anti-cancer effects, but the action mechanisms are still unclear. METHOD: MTT assays, colony-forming assays, flow cytometry, scratch healing, and transwell assays were used to evaluate the proliferation, apoptosis, cell cycle, migration, and invasion of both ER-subtype EC cells. Xenograft experiments were used to assess the effects of kaempferol inhibition on tumor growth. Next-generation RNA sequencing was used to compare the gene expression levels in vehicle-treated versus kaempferol-treated Ishikawa and HEC-1-A cells. A network pharmacology and molecular docking technique were applied to identify the anti-cancer mechanism of kaempferol, including the building of target-pathway network. GO analysis and KEGG pathway enrichment analysis were used to identify cancer-related targets. Finally, the study validated the mRNA and protein expression using real-time quantitative PCR, western blotting, and immunohistochemical analysis. RESULTS: Kaempferol was found to suppress the proliferation, promote apoptosis, and limit the tumor-forming, scratch healing, invasion, and migration capacities of EC cells. Kaempferol inhibited tumor growth and promotes apoptosis in a human endometrial cancer xenograft mouse model. No significant toxicity of kaempferol was found in human monocytes and normal cell lines at non-cytotoxic concentrations. No adverse effects or significant changes in body weight or organ coefficients were observed in 3-7 weeks' kaempferol-treated animals. The RNA sequencing, network pharmacology, and molecular docking approaches identified the overall survival-related differentially expressed gene HSD17B1. Interestingly, kaempferol upregulated HSD17B1 expression and sensitivity in ER-negative EC cells. Kaempferol differentially regulated PPARG expression in EC cells of different ER subtypes, independent of its effect on ESR1. HSD17B1 and HSD17B1-associated genes, such as ESR1, ESRRA, PPARG, AKT1, and AKR1C1\2\3, were involved in several estrogen metabolism pathways, such as steroid binding, 17-beta-hydroxysteroid dehydrogenase (NADP+) activity, steroid hormone biosynthesis, and regulation of hormone levels. The molecular basis of the effects of kaempferol treatment was evaluated. CONCLUSIONS: Kaempferol is a novel therapeutic candidate for EC via HSD17B1-related estrogen metabolism pathways. These results provide new insights into the efficiency of the medical translation of phytoestrogens.

Clinical manifestations of adult hereditary spherocytosis with novel SPTB gene mutations and hyperjaundice: A case report.

BACKGROUND: The aim of the present study was to enhance understanding of the diagnosis and treatment of atypical hereditary spherocytosis (HS), and to broaden the diagnostic thoughts of physicians for patients with jaundice. CASE SUMMARY: A 28-year-old male presented with jaundice, bile duct stone, and splenomegaly, but without anemia. Other causes of jaundice were excluded, and gene sequencing revealed a novel heterozygous variant of c.1801C>T (p.Q601X) in exon 14 of the SPTB (NM_01355436) gene on chromosome 14 (chr14: 65260580) in the patient's blood; the biological parents and child of the patient did not have similar variants. A splenectomy was performed on the patient and his bilirubin levels returned to normal after surgery. Thus, a novel gene variant causing HS was identified. This variant may result in the truncation of ß-hemoglobin in the erythrocyte membrane, leading to loss of normal function, jaundice, and hemolytic anemia. The clinical manifestations of the patient were hyperjaundice and an absence of typical hemolysis during the course of the disease, which caused challenges for diagnosis by the clinicians. CONCLUSION: Following a definitive diagnosis, genetic testing and response to treatment identified a gene variant site for a novel hemolytic anemia.

Volume Incentive Spirometry Reduces Pulmonary Complications in Patients After Open Abdominal Surgery: A Randomized Clinical Trial.

Objective: To compare the effect of diaphragmatic breathing and volume incentive spirometry (VIS) on hemodynamics, pulmonary function, and blood gas in patients following open abdominal surgery under general anesthesia. Methods: A total of 58 patients who received open abdominal surgery were randomly assigned to the control group (n=29) undergoing diaphragmatic breathing exercises and the VIS group (n=29) undergoing VIS exercises. All the participants performed the six-minute walk test (6MWT) preoperatively to evaluate their functional capacity. Hemodynamic indexes, pulmonary function tests, and blood gas indexes were recorded before surgery and on the 1st, 3rd, and 5th postoperative day. Results: The functional capacity was not significantly different between the two groups during the preoperative period (P >0.05). At 3 days and 5 days postoperatively, patients in the VIS group had a significantly higher SpO2 than that in the control group (P <0.05). Pulmonary function test values were reduced in both two groups postoperatively when compared to the preoperative values but improved for three and five days afterward (P <0.05). Of note, the significantly elevated levels of peak expiratory flow (PEF), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio were observed on the 1st, 3rd, and 5th postoperative days in the VIS group compared with those in the control group (P <0.05). Besides, bass excess (BE), and pH values were significantly higher in the VIS group on the 1st postoperative day than those in the control group (P <0.05). Conclusion: Diaphragmatic breathing and VIS could improve postoperative pulmonary function, but VIS exercise might be a better option for improving hemodynamics, pulmonary function, and blood gas for patients after open abdominal surgery, hence lowering the incidence of postoperative pulmonary complications.

Significance of thyroid dysfunction in the patients with primary membranous nephropathy.

BACKGROUND: Thyroid dysfunction is common in patients with nephrotic syndrome, especially patients with primary membranous nephropathy (pMN). In view of both MN and thyroid dysfunction are associated with autoimmunity, the current study aimed to elucidate the significance of thyroid dysfunction in patients with pMN. METHODS: Four hundred and twenty patients with biopsy-proven pMN from 2018-2021 were retrospectively enrolled. Clinical and pathological parameters, and treatment response of patients with and without thyroid dysfunction were analyzed. RESULTS: Ninety-one (21.7%) patients with pMN suffered from thyroid dysfunction, among which subclinical hypothyroidism (52.7%) was the main disorder. Compared to patients with normal thyroid function, patients with thyroid dysfunction presented with a higher level of proteinuria, a lower level of serum albumin, a higher level of serum creatinine and more severe tubulointerstitial injury at the time of biopsy. But the positive rate and level of circulating anti-phospholipase A2 receptor (PLA2R) antibody were comparable between these two groups. Though following the similar treatment, the percentage of no response to treatment were significantly higher in the patients with thyroid dysfunction (38.6 vs. 20.0%, P = 0.003). Similar to the urinary protein and the positivity of anti-PLA2R antibody, multivariate COX analysis showed thyroid dysfunction was also identified as an independent risk factor for the failure to remission (HR = 1.91, 95%CI, 1.07-3.40, P = 0.029). CONCLUSION: In conclusion, thyroid dysfunction is common in the patients with pMN and might predict a severe clinical manifestation and a poor clinical outcome, which indicated that the thyroid dysfunction might be involved in the disease progression of pMN.

De novo variants in FRMD5 are associated with developmental delay, intellectual disability, ataxia, and abnormalities of eye movement.

Proteins containing the FERM (four-point-one, ezrin, radixin, and moesin) domain link the plasma membrane with cytoskeletal structures at specific cellular locations and have been implicated in the localization of cell-membrane-associated proteins and/or phosphoinositides. FERM domain-containing protein 5 (FRMD5) localizes at cell adherens junctions and stabilizes cell-cell contacts. To date, variants in FRMD5 have not been associated with a Mendelian disease in OMIM. Here, we describe eight probands with rare heterozygous missense variants in FRMD5 who present with developmental delay, intellectual disability, ataxia, seizures, and abnormalities of eye movement. The variants are de novo in all for whom parental testing was available (six out of eight probands), and human genetic datasets suggest that FRMD5 is intolerant to loss of function (LoF). We found that the fly ortholog of FRMD5, CG5022 (dFrmd), is expressed in the larval and adult central nervous systems where it is present in neurons but not in glia. dFrmd LoF mutant flies are viable but are extremely sensitive to heat shock, which induces severe seizures. The mutants also exhibit defective responses to light. The human FRMD5 reference (Ref) cDNA rescues the fly dFrmd LoF phenotypes. In contrast, all the FRMD5 variants tested in this study (c.340T>C, c.1051A>G, c.1053C>G, c.1054T>C, c.1045A>C, and c.1637A>G) behave as partial LoF variants. In addition, our results indicate that two variants that were tested have dominant-negative effects. In summary, the evidence supports that the observed variants in FRMD5 cause neurological symptoms in humans.

Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma.

Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification. Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively. Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels. Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.