[Genetic and clinical analysis of a child with Shwachman-Diamond syndrome due to compound heterozygous variants of SBDS gene].

OBJECTIVE: To analyze the clinical features and genetic characteristics of a patient with Shwachman-Diamond syndrome (SDS) due to compound heterozygous variants of SBDS gene. METHODS: A female child with SDS who was admitted to the Children's Hospital Affiliated to Zhengzhou University in February 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her elder sister and parents were collected and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 1-year-and-1-month-old girl, had mainly manifested with diarrhea, hematochezia, growth retardation and malnutrition, along with increased transaminases and decreased neutrophils and hemoglobin. Anteroposterior X-ray of her left wrist indicated significantly delayed bone age. Colonoscopy revealed that her colorectal mucosa was erosive with oily food residues attached to the intestinal lumen. Genetic testing revealed that she has harbored c.258+2T>C and c.100A>G compound heterozygous variants of the SBDS gene. The c.258+2T>C variant has derived from her father and known to be pathogenic, whilst the other has derived from her mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.100A>G variant was classified as likely pathogenic (PM1+PM2_Supporting+PM3+PM5+PP3). CONCLUSION: The compound heterozygous variants of c.258+2T>C and c.100A>G probably underlay the SDS in this child. For children with refractory diarrhea, liver damage and growth retardation, SDS should be suspected, and genetic testing can facilitate the diagnosis and treatment.

Nitidine chloride regulates cell function of bladder cancer in vitro through downregulating Lymphocyte antigen 75.

Nitidine chloride (NC) is effective on cancer in many tumors, but its effect on bladder cancer (BC) is unknown. We conducted cell function experiments to verify the antineoplastic effect of NC on BC cell lines (5637, T24, and UM-UC-3) in vitro. Then, mRNAs of NC-treated and NC-untreated BC cells were extracted for mRNA sequencing. Differentially expressed genes (DEGs), expression analysis, and drug molecular docking were conducted to discover the target gene of NC. Finally, functional enrichment was analyzed to explore the underlying mechanisms. NC dramatically inhibited proliferation, migration, and invasion, and it induced apoptosis and arrested the S and G2/M phases of BC cell lines. Lymphocyte antigen 75 (LY75) appeared to be the target of NC. LY75 was highly expressed and had the ability to distinguish BC tissue from non-cancerous tissue. Then, drug molecular docking confirmed the targeting relationship between NC and LY75. Gene enrichment analysis showed that the downregulated genes, after being treated with NC, were mainly enriched in pathways relevant to cell pathophysiological processes. NC inhibits BC cell proliferation, migration, and invasion, induces apoptosis, and arrests cell cycles by downregulating the expression of LY75. This study provides molecular and theoretical bases for NC treatment of BC.

Distinguish the Value of the Benign Nevus and Melanomas Using Machine Learning: A Meta-Analysis and Systematic Review.

Background: Melanomas, the most common human malignancy, are primarily diagnosed visually, beginning with an initial clinical screening and followed potentially by dermoscopic analysis, a biopsy, and histopathological examination. We aimed to systematically review the performance and quality of machine learning-based methods in distinguishing melanoma and benign nevus in the relevant literature. Method: Four databases (Web of Science, PubMed, Embase, and the Cochrane library) were searched to retrieve the relevant studies published until March 26, 2022. The Predictive model Deviation Risk Assessment tool (PROBAST) was used to assess the deviation risk of opposing law. Result: This systematic review included thirty researches with 114007 subjects and 71 machine learning models. The convolutional neural network was the main machine learning method. The pooled sensitivity was 85% (95% CI 82-87%), the specificity was 86% (82-88%), and the C-index was 0.87 (0.84-0.90). Conclusion: The findings of our study showed that ML algorithms had high sensitivity and specificity for distinguishing between melanoma and benign nevi. This suggests that state-of-the-art ML-based algorithms for distinguishing melanoma from benign nevi may be ready for clinical use. However, a large proportion of the earlier published studies had methodological flaws, such as lack of external validation and lack of clinician comparisons. The results of these studies should be interpreted with caution.

Establishment and validation of a nomogram for predicting immune-related prognostic features in trunk melanoma-specific death.

Background: Trunk melanoma is one of the most common and deadly types of melanomas. Multiple factors are associated with the prognosis of patients with trunk melanoma. Currently, direct, and reliable clinical tools for early assessment of individual specific risk of death are limited, and most of them are prediction models for all-cause death. Their accuracy in predicting competitiveness events, which make up a relatively large portion, may be substantially compromised. Hence, we conducted this study to investigate the risk factors of trunk melanoma-specific death to establish a comprehensive prediction model suitable for clinical application. Methods: Patients with trunk melanoma analyzed in this study were from the SEER program [2010-2015]. The random sampling method was used to split the included cases into the training and validation cohorts at a ratio of 7:3. Univariate and multivariate competing risk models were used to screen the independent influencing factors of specific death, and then a nomogram covering these independent predictors was constructed. The concordance index (C-index) and a calibration curve were used to evaluate the calibration degree and accuracy of the nomogram. Results: We identified 21,198 patients with trunk melanoma from the SEER database, and 3,814 of them died (17.99%). Among the death cases, deaths from other causes accounted for 66.50%The prognostic nomogram included 8 variables and 16 independent influencing factors. The overall C-index in the training set was 0.89, and the receiver operating characteristic (ROC) curve for predicting 1-, 3-, and 5-year survival was 0.928 [95% confidence interval (CI): 0.911-0.945], 0.907 (95% CI: 0.895-0.918), and 0.891 (95% CI: 0.879-0.902), respectively. The C-index of the model in the validation set was 0.89, and the area under the ROC curve (AUC) for predicting 1-, 3-, and 5-year cancer-specific death (CSD) was 0.927 (95% CI: 0.899-0.955), 0.916 (95% CI: 0.901-0.930), and 0.905 (95% CI: 0.899-0.921). Both the training set and the validation set showed the ideal calibration degree. Conclusions: This model can be used as a potential tool for prognostic risk management of trunk melanoma in the presence of many competing events.

A Novel Electrolyte Additive Enables High-Voltage Operation of Nickel-Rich Oxide/Graphite Cells.

Nickel-rich oxide/graphite cells under high voltage operation provide high energy density but present short cycle life because of the parasitic electrolyte decomposition reactions. In this work, we report a novel electrolyte additive, N,O-bis(trimehylsilyl)-trifluoroacetamide (NOB), which enables nickel-rich oxide/graphite cells to operate stably under high voltage. When evaluated in a nickel-rich oxide-based full cell, LiNi0.5Co0.2Mn0.3O2 (NCM523)/graphite using a carbonate electrolyte, 1 wt % NOB provides the cell with capacity retention improved from 38% to 73% after 100 cycles at 1C under 4.5 V. It is found that NOB is able to eliminate hydrogen fluoride in the electrolyte. The radicals resulting from the interaction of NOB with the fluoride ion can be preferentially oxidized on the cathode compared with the electrolyte solvents, with its reaction products constructing N-containing interphases simultaneously on the cathode and anode, which suppress the parasitic electrolyte decomposition reactions, leading to the significantly improved cycle stability of nickel-rich oxide/graphite cells under high voltage.

[Clinical features and genetic analysis of a child with late-onset immune dysregulation, polyendocrinopathy, enteropathy, X-Linked syndrome].

OBJECTIVE: To report on the clinical features and result of genetic testing for a child featuring immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Clinical records, genetic testing, laboratory investigation and treatment of the child were summarized in addition with a comprehensive review of the literature. RESULTS: The 3-year-old boy was administered due to intractable diarrhea, recurrent infections, liver dysfunction and failure to thrive, though no diabetes or skin disorder was observed. Laboratory testing showed elevated liver enzymes and total IgE, decreased albumin and electrolyte imbalance. Gastrointestinal endoscopy revealed erosion and granules in the duodenum, and edema in the terminal ileum and colon. Biopsies showed villous atrophy in the duodenum and terminal ileum. Genetic testing revealed that the patient has carried a missense c.1087A>G (p.I363V) variant in the exon 10 of the FOXP3 gene. He was treated with enteral and parenteral nutrition, anti infection and Sirolimus, and was waiting for hemopoietic stem cell transplantation. CONCLUSION: Although IPEX syndrome usually occur during infancy, it should not be ruled out solely based on the age, and its presentation can be variable. For male children with refractory diarrhea, autoimmune disorder and growth retardation, the diagnosis should be suspected and confirmed by genetic testing.

CytoGPS: A large-scale karyotype analysis of CML data.

Karyotyping, the practice of visually examining and recording chromosomal abnormalities, is commonly used to diagnose diseases of genetic origin, including cancers. Karyotypes are recorded as text written in the International System for Human Cytogenetic Nomenclature (ISCN). Downstream analysis of karyotypes is conducted manually, due to the visual nature of analysis and the linguistic structure of the ISCN. The ISCN has not been computer-readable and, as such, prevents the full potential of these genomic data from being realized. In response, we developed CytoGPS, a platform to analyze large volumes of cytogenetic data using a Loss-Gain-Fusion model that converts the human-readable ISCN karyotypes into a machine-readable binary format. As proof of principle, we applied CytoGPS to cytogenetic data from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, a National Cancer Institute hosted database of over 69,000 karyotypes of human cancers. Using the Jaccard coefficient to determine similarity between karyotypes structured as binary vectors, we were able to identify novel patterns from 4,968 Mitelman CML karyotypes, such as the co-occurrence of trisomy 19 and 21. The CytoGPS platform unlocks the potential for large-scale, comparative analysis of cytogenetic data. This methodological platform is freely available at CytoGPS.org.

The Effect of Residual Triton X-100 on Structural Stability and Infection Activity of Adenovirus Particles.

To ensure the high purity and biological activity of the adenovirus vector to be used for clinical applications, a stable and linearly scalable preparation method is highly imperative. During the adenovirus-harvesting process, the Triton X-100-based lysis method possesses the advantages of higher efficiency as well as easier linearization and amplification. Most Triton X-100 can be removed from the adenovirus sample by chromatographic purification. However, there is no report that a small amount of residual Triton X-100, present in adenovirus sample, can affect the particle integrity, infectivity, and structure of adenoviruses. Here, we found that although residual Triton X-100 affected the short-term stability, purity, infectivity, and structure of adenoviruses at 37°C, it did not hamper these properties of adenoviruses at 4°C. This study suggests that although the Triton X-100-based lysis method is a simple, efficient, and easy-to-scale process for lysing host cells to release the adenovirus, the storage conditions of adenovirus products must be taken into consideration.

Unsupervised machine learning and prognostic factors of survival in chronic lymphocytic leukemia.

OBJECTIVE: Unsupervised machine learning approaches hold promise for large-scale clinical data. However, the heterogeneity of clinical data raises new methodological challenges in feature selection, choosing a distance metric that captures biological meaning, and visualization. We hypothesized that clustering could discover prognostic groups from patients with chronic lymphocytic leukemia, a disease that provides biological validation through well-understood outcomes. METHODS: To address this challenge, we applied k-medoids clustering with 10 distance metrics to 2 experiments ("A" and "B") with mixed clinical features collapsed to binary vectors and visualized with both multidimensional scaling and t-stochastic neighbor embedding. To assess prognostic utility, we performed survival analysis using a Cox proportional hazard model, log-rank test, and Kaplan-Meier curves. RESULTS: In both experiments, survival analysis revealed a statistically significant association between clusters and survival outcomes (A: overall survival, P = .0164; B: time from diagnosis to treatment, P = .0039). Multidimensional scaling separated clusters along a gradient mirroring the order of overall survival. Longer survival was associated with mutated immunoglobulin heavy-chain variable region gene (IGHV) status, absent Zap 70 expression, female sex, and younger age. CONCLUSIONS: This approach to mixed-type data handling and selection of distance metric captured well-understood, binary, prognostic markers in chronic lymphocytic leukemia (sex, IGHV mutation status, ZAP70 expression status) with high fidelity.

CytoGPS: a web-enabled karyotype analysis tool for cytogenetics.

SUMMARY: Karyotype data are the most common form of genetic data that is regularly used clinically. They are collected as part of the standard of care in many diseases, particularly in pediatric and cancer medicine contexts. Karyotypes are represented in a unique text-based format, with a syntax defined by the International System for human Cytogenetic Nomenclature (ISCN). While human-readable, ISCN is not intrinsically machine-readable. This limitation has prevented the full use of complex karyotype data in discovery science use cases. To enhance the utility and value of karyotype data, we developed a tool named CytoGPS. CytoGPS first parses ISCN karyotypes into a machine-readable format. It then converts the ISCN karyotype into a binary Loss-Gain-Fusion (LGF) model, which represents all cytogenetic abnormalities as combinations of loss, gain, or fusion events, in a format that is analyzable using modern computational methods. Such data is then made available for comprehensive 'downstream' analyses that previously were not feasible. AVAILABILITY AND IMPLEMENTATION: Freely available at http://cytogps.org.

MicroRNA­634 alters nerve apoptosis via the PI3K/Akt pathway in cerebral infarction.

In the present study, the role and mechanism of microRNA­634 (miRNA­634) in the adjustment of nerve inflammation and apoptosis in cerebral infarction were investigated. In a cerebral infarction rat model, the expression of miRNA­634 was increased, compared with that in the normal control group. The upregulated expression of miRNA­634 in an in vitro model of cerebral infarction increased cell apoptosis and the protein expression of capsase­3/B­cell lymphoma 2­associated X protein (Bax) via inactivation of the phosphoinositide 3­kinase (PI3K)/Akt pathway. The downregulation of miRNA­634 enhanced cell growth and inhibited cell apoptosis in the in vitro model of cerebral infarction through induction of the PI3K/Akt pathway. Subsequently, a PI3K inhibitor was used to inhibit the expression of PI3K in the in vitro model of cerebral infarction via the downregulation of miRNA­634, which showed that cell apoptosis and the protein expression of capsase­3/Bax were also increased. A PI3K agonist reduced the effects of the upregulation of miRNA­634 in the in vitro model of cerebral infarction. In conclusion, the data obtained demonstrated the possible future use of miRNA­634 as a therapeutic target in cerebral infarction through the PI3K/Akt pathway.

Effects of diesel exhaust particles on microRNA-21 in human bronchial epithelial cells and potential carcinogenic mechanisms.

Air pollution plays a role in cancer risk, particularly in lung cancer, which is the leading cause of cancer-related mortality worldwide. Diesel exhaust particles (DEPs), a component of diesel exhaust products, is a complex mixture of particle compounds that include a large number of known and suspected human carcinogens. Historically, lung cancer, which is associated with DEPs, has been the focus of attention as a health risk in human and animal studies. However, the mechanism by which DEPs cause lung cancer remains unclear. The present study reports that DEPs increased miR-21 expression and then activated the PTEN/PI3K/AKT pathway in human bronchial epithelial (HBE) cells, which may serve as an important carcinogenic mechanism. However, the data revealed that short-term exposure to a high DEP concentration did not cause evident cell carcinogenesis in HBE cells.

[Impact of huolong moxibustion on TNF-α and pain degree in the patients of discogenic low back pain].

OBJECTIVE: To discuss the impact of huolong moxibustion on pain degree in the patients of discogenic low back pain and the effect mechanism. METHODS: Sixty-five patients were randomized into an observation group (33 cases) and a control group (32 cases). In the observation group, huolong moxibustion was applied along the distribution of the Governor Vessel, once a day. In the control group, the routine traction combined with massage therapy was adopted, once a day. In the two groups, the treatment was given 6 times a week, at interval of 1 day. In 3 weeks of treatment, pain score and serum tumor necrosis factor α (TNF-α) level were compared with those before treatment in the two groups. RESULTS: Compared with those before treatment, pain score and TNF-α level were reduced significantly after treatment in the two groups (both P < 0.05). The results in the observation group were lower than those in the control group (pain score: 1.95 ± 0.61 vs 2.11 ± 0.61; TNF-α: (1.33 ± 0.30) nmol/L vs (1.55 ± 0.48) nmol/L, (both P < 0.05). CONCLUSION: Huolong moxibustion significantly alleviates pain in the patients of discogenic low back pain and its effect mechanism is possibly relevant with TNF-α reducing.

Expression of 15-hydroxyprostaglandin dehydrogenase and cyclooxygenase-2 in non-small cell lung cancer: Correlations with angiogenesis and prognosis.

The aim of the present study was to investigate the function of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and cyclooxygenase-2 (COX-2) in angiogenesis and their association with the prognosis of non-small cell lung cancer (NSCLC). Using immunohistochemical staining, the expression of 15-PGDH and COX-2, and the microvessel density (MVD) levels were evaluated in 35 NSCLC specimens. Paracancerous normal lung tissue was collected as control samples from six patients. The correlation of 15-PGDH with COX-2, clinicopathological characteristics, MVD and overall survival (OS) was studied. NSCLC tissues showed a significantly lower expression level of 15-PGDH (P=0.009) and a significantly higher expression level of COX-2 (P=0.004) compared with normal lung tissue. The expression level of 15-PGDH was negatively correlated with MVD (P<0.001) and COX-2 expression (P=0.032). A low expression level of 15-PGDH, a high expression level of COX-2 and high levels of MVD were significantly correlated with a shorter OS time (15-PGDH, P<0.0001; COX-2, P=0.038; MVD, P<0.0001). This study provided clinical evidence that a low expression level of 15-PGDH is associated with a poor prognosis in NSCLC. Furthermore, it was shown that 15-PGDH and COX-2 reciprocally regulate cancer angiogenesis, which may affect the prognosis of patients with NSCLC.