Exploring the clinical implications of novel SRD5A2 variants in 46,XY disorders of sex development.

This study was conducted retrospectively on a cohort of 68 patients with steroid 5 α-reductase 2 (SRD5A2) deficiency and 46,XY disorders of sex development (DSD). Whole-exon sequencing revealed 28 variants of SRD5A2, and further analysis identified seven novel mutants. The preponderance of variants was observed in exon 1 and exon 4, specifically within the nicotinamide adenine dinucleotide phosphate (NADPH)-binding region. Among the entire cohort, 53 patients underwent initial surgery at Sichuan Provincial People's Hospital (Chengdu, China). The external genitalia scores (EGS) of these participants varied from 2.0 to 11.0, with a mean of 6.8 (standard deviation [s.d.]: 2.5). Thirty patients consented to hormone testing. Their average testosterone-to-dihydrotestosterone (T/DHT) ratio was 49.3 (s.d.: 23.4). Genetic testing identified four patients with EGS scores between 6 and 9 as having this syndrome; and their T/DHT ratios were below the diagnostic threshold. Furthermore, assessments conducted using the crystal structure of human SRD5A2 have provided insights into the potential pathogenic mechanisms of these novel variants. These mechanisms include interference with NADPH binding (c.356G>C, c.365A>G, c.492C>G, and c.662T>G) and destabilization of the protein structure (c.727C>T). The c.446-1G>T and c.380delG variants were verified to result in large alterations in the transcripts. Seven novel variations were identified, and the variant database for the SRD5A2 gene was expanded. These findings contribute to the progress of diagnostic and therapeutic approaches for individuals with SRD5A2 deficiency.

Length-scale study in deep learning prediction for non-small cell lung cancer brain metastasis.

Deep learning-assisted digital pathology has demonstrated the potential to profoundly impact clinical practice, even surpassing human pathologists in performance. However, as deep neural network (DNN) architectures grow in size and complexity, their explainability decreases, posing challenges in interpreting pathology features for broader clinical insights into physiological diseases. To better assess the interpretability of digital microscopic images and guide future microscopic system design, we developed a novel method to study the predictive feature length-scale that underpins a DNN's predictive power. We applied this method to analyze a DNN's capability in predicting brain metastasis from early-stage non-small-cell lung cancer biopsy slides. This study quantifies DNN's attention for brain metastasis prediction, targeting features at both the cellular scale and tissue scale in H&E-stained histological whole slide images. At the cellular scale, the predictive power of DNNs progressively increases with higher resolution and significantly decreases when the resolvable feature length exceeds 5 microns. Additionally, DNN uses more macro-scale features associated with tissue architecture and is optimized when assessing visual fields greater than 41 microns. Our study computes the length-scale requirements for optimal DNN learning on digital whole-slide microscopic images, holding the promise to guide future optical microscope designs in pathology applications and facilitating downstream deep learning analysis.

Overexpression of long noncoding RNA DUXAP8 inhibits ER-phagy through activating AKT/mTOR signaling and contributes to preeclampsia.

Preeclampsia (PE) is a life-threatening pregnancy-specific complication with controversial mechanisms and no effective treatment except delivery is available. Currently, increasing researchers suggested that PE shares pathophysiologic features with protein misfolding/aggregation disorders, such as Alzheimer disease (AD). Evidences have proposed defective autophagy as a potential source of protein aggregation in PE. Endoplasmic reticulum-selective autophagy (ER-phagy) plays a critical role in clearing misfolded proteins and maintaining ER homeostasis. However, its roles in the molecular pathology of PE remain unclear. We found that lncRNA DUXAP8 was upregulated in preeclamptic placentae and significantly correlated with clinical indicators. DUXAP8 specifically binds to PCBP2 and inhibits its ubiquitination-mediated degradation, and decreased levels of PCBP2 reversed the activation effect of DUXAP8 overexpression on AKT/mTOR signaling pathway. Function experiments showed that DUXAP8 overexpression inhibited trophoblastic proliferation, migration, and invasion of HTR-8/SVneo and JAR cells. Moreover, pathological accumulation of swollen and lytic ER (endoplasmic reticulum) was observed in DUXAP8-overexpressed HTR8/SVneo cells and PE placental villus trophoblast cells, which suggesting that ER clearance ability is impaired. Further studies found that DUXAP8 overexpression impaired ER-phagy and caused protein aggregation medicated by reduced FAM134B and LC3II expression (key proteins involved in ER-phagy) via activating AKT/mTOR signaling pathway. The increased level of FAM134B significantly reversed the inhibitory effect of DUXAP8 overexpression on the proliferation, migration, and invasion of trophoblasts. In vivo, DUXAP8 overexpression through tail vein injection of adenovirus induced PE-like phenotypes in pregnant rats accompanied with activated AKT/mTOR signaling, decreased expression of FAM134B and LC3-II proteins and increased protein aggregation in placental tissues. Our study reveals the important role of lncRNA DUXAP8 in regulating trophoblast biological behaviors through FAM134B-mediated ER-phagy, providing a new theoretical basis for understanding the pathogenesis of PE.

T-cell lymphoblastic lymphoma/leukaemia involving bilateral breast: a case report.

T-cell lymphoblastic lymphoma of the breast represents a highly uncommon subtype of non-Hodgkin's lymphoma. This study presents a case of T-cell lymphoblastic lymphoma/acute lymphoblastic leukaemia (T-LBL/ALL) in a 73-year-old female patient exhibiting bilateral breast masses, bilateral axillary lymphadenopathy, swollen lymph nodes in the left neck, and petechiae on the chest. The breast ultrasound revealed heterogeneous hypoechoic findings in the skin layer and subcutaneous tissue of the upper outer quadrant of both breasts. Contrast-enhanced ultrasound (CEUS) demonstrated rapid homogeneous hyperenhancement of bilateral breast masses, and with a small unenhanced area noted in the centre of the left breast mass. The fine-needle aspiration cytology (FNAC) of bilateral axillary lymph nodes revealed metastatic adenocarcinoma, whereas the FNAC of the left cervical lymph nodes indicated non-Hodgkin's lymphoma. Biopsy of the breast mass demonstrated multifocal growth of lymphocyte-like cells, with immunohistochemical analysis confirming T-LBL/ALL. This case study outlines the clinical and CEUS features of breast T-LBL/ALL.

[Effect of Erchen Decoction on liver mitochondrial function by inhibiting mTORC1/SREBP1/CAV1 pathway in mice with high-fat diet].

This study aims to investigate the effect of Erchen Decoction(ECD) on liver mitochondrial function in mice with a high-fat diet and its possible mechanism. A total of sixty C57BL/6J mice were randomly divided into a normal group, high-fat group, ECD group, mTORC1 activator(MHY) group, ECD+MHY group, and polyene phosphatidyl choline(PPC) group, with 10 rats in each group. The normal group was given a normal diet, and the other groups were fed a high-fat diet for 20 weeks. At the 17th week, the ECD group and ECD+MHY group were given ECD(8.7 g·kg~(-1)) daily, and the PPC group was given PPC(0.18 g·kg~(-1)) daily, while the remaining groups were given normal saline(0.01 mL·g~(-1)) daily for four weeks. In the 19th week, the MHY group and ECD+MHY group were injected intraperitoneally with MHY(5 mg·kg~(-1)) every other day for two weeks. During the experiment, the general conditions of the mice were observed. The contents of triglyceride(TG) and total cholesterol(TC) in serum were measured. Morphological changes in liver tissue were examined through HE and oil red O staining. The content of adenosine triphosphate(ATP) was determined using chemiluminescence, and mitochondrial membrane potential was assessed using a fluorescence probe(JC-1). Western blot was performed to detect the expression of rapamycin target protein complex 1(mTOR1), ribosomal protein S6 kinase B1(S6K), sterol regulatory element binding protein 1(SREBP1), and caveolin 1(CAV1). RESULTS:: revealed that compared with the normal group, the mice in the high-fat group exhibited significant increases in body weight and abdominal circumference(P<0.01). Additionally, there were significant increases in TG and TC levels(P<0.01). HE and oil red O staining showed that the boundaries of hepatic lobules were unclear; hepatocytes were enlarged, round, and irregularly arranged, with obvious lipid droplet deposition and inflammatory cell infiltration. The liver ATP content and mitochondrial membrane potential decreased significantly(P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 increased significantly(P<0.01), while the expression of CAV1 decreased significantly(P<0.01). Compared with the high-fat group, the body weight and TG content of mice in the ECD group and PPC group decreased significantly(P<0.05). Improvements were observed in hepatocyte morphology, lipid deposition, and inflammatory cell infiltration. Furthermore, there were significant increases in ATP content and mitochondrial membrane potential(P<0.05 or P<0.01). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly in the ECD group(P<0.01), while CAV1 expression increased significantly(P<0.01). However, the indices mentioned above did not show improvement in the MHY group. When the ECD+MHY group was compared with the MHY group, there were significant reductions in body weight and TG contents(P<0.05). The morphological changes of hepatocytes, lipid deposition, and inflammatory cell infiltration were recovered. Moreover, there were significant increases in liver ATP content and mitochondrial membrane potential(P<0.05 or P<0.05). The expression of p-mTOR, p-S6K, and n-SREBP1 decreased significantly(P<0.01), while CAV1 expression increased significantly(P<0.01). In conclusion, ECD can improve mitochondrial function by regulating the mTORC1/SREBP1/CAV1 pathway. This mechanism may be involved in the resolution of phlegm syndrome and the regulation of lipid metabolism.

Nickel-catalysed asymmetric hydromonofluoromethylation of 1,3-enynes for enantioselective construction of monofluoromethyl-tethered chiral allenes.

An unprecedented nickel-catalysed enantioselective hydromonofluoromethylation of 1,3-enynes is developed, allowing the diverse access to monofluoromethyl-tethered axially chiral allenes, including the challenging deuterated monofluoromethyl (CD2F)-tethered ones that are otherwise inaccessible. It represents the first asymmetric 1,4-hydrofunctionalization of 1,3-enynes using low-cost asymmetric nickel catalysis, thus opening a new avenue for the activation of 1,3-enynes in reaction development. The utility is further verified by its broad substrate scope, good functionality tolerance, mild conditions, and diversified product elaborations toward other valuable fluorinated structures. Mechanistic experiments and DFT calculations provide insights into the reaction mechanism and the origin of the enantioselectivity.

Long non-coding RNA CASC7 is a promising serum biomarker for hepatocellular carcinoma.

BACKGROUND: At present, a large number of studies have found that long non-coding RNAs (lncRNAs) can be used as biomarkers for diagnosis and monitoring prognosis of hepatocellular carcinoma (HCC). The expression of lncRNA cancer susceptibility candidate 7 (CASC7) in HCC has rarely been studied. The purpose of this study was to explore the expression of CASC7 and its correlation with clinical features, and to further analyze its diagnostic value in HCC. METHODS: Serum samples were collected from 80 patients with HCC, 80 patients with chronic hepatitis B (CHB), and 80 healthy people. The expression level of serum CASC7 was detected by droplet digital PCR. Appropriate parametric and nonparametric tests were used for data analysis. RESULTS: The results showed that the expression of CASC7 in serum of patients with HCC was significantly higher than that of patients with CHB (median: 8.8 versus 2.2 copies/µl, p < 0.001) and healthy controls (median: 8.8 versus 3.8 copies/µl, p < 0.001). High expression of serum CASC7 was significantly correlated with tumor number (p = 0.005), intrahepatic metastasis (IM) (p < 0.001), tumor size (p = 0.007) and tumor-node-metastasis (TNM) stage (p = 0.008). The area under the curve (AUC) of CASC7 to distinguish HCC patients from CHB patients and healthy controls was 0.808 (95% CI: 0.742-0.874) at the cut-off value of 7.24 copies/µl with 63.8% sensitivity and 95.2% specificity. CONCLUSIONS: This study suggested that CASC7 was significantly up-regulated in serum of patients with HCC and closely related to tumor number, IM, tumor size and TNM stage, which may serve as a promising diagnostic biomarker.

Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

BACKGROUND: Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. METHODS: This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. RESULTS: We finally analyzed 304 patients (mean age 54.86 ± 12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR = 1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR = 0.965 [95% CI 0.939-0.992], p = .013; OR = 1.068 [95% CI 1.008-1.130], p = .025; OR = 4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR = 0.200 [95% CI 0.071-0.563], p = .002; OR = 0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. CONCLUSIONS: Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

Assessing overdiagnosis of fecal immunological test screening for colorectal cancer with a digital twin approach.

Evaluating the magnitude of overdiagnosis associated with stool-based service screening for colorectal cancer (CRC) beyond a randomized controlled trial is often intractable and understudied. We aim to estimate the proportion of overdiagnosis in population-based service screening programs for CRC with the fecal immunochemical test (FIT). The natural process of overdiagnosis-embedded disease was first built up to learn transition parameters that quantify the pathway of non-progressive and progressive screen-detected cases calibrated with sensitivity, while also taking competing mortality into account. The Markov algorithms were then developed for estimating these transition parameters based on Taiwan FIT service CRC screening data on 5,417,699 residents aged 50-69 years from 2004 to 2014. Following the digital twin design with the parallel universe structure for emulating the randomized controlled trial, the screened twin, mirroring the control group without screening, was virtually recreated by the application of the above-mentioned trained parameters to predict CRC cases containing overdiagnosis. The ratio of the predicted CRCs derived from the screened twin to the observed CRCs of the control group minus 1 was imputed to measure the extent of overdiagnosis. The extent of overdiagnosis for invasive CRCs resulting from FIT screening is 4.16% (95% CI: 2.61-5.78%). The corresponding figure is increased to 9.90% (95% CI: 8.41-11.42%) for including high grade dysplasia (HGD) and further inflated to 15.83% (95% CI: 15.23-16.46%) when the removal adenoma is considered. The modest proportion of overdiagnosis modelled by the digital twin method, dispensing with the randomized controlled trial design, suggests the harm done to population-based FIT service screening is negligible.

A feedback loop between NONHSAT024276 and PTBP1 inhibits tumor progression and glycolysis in HCC by increasing the PKM1/PKM2 ratio.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a hallmark of aberrant metabolism. The mechanism of long noncoding RNAs (lncRNAs) underlying the aggressive behaviors and glycolysis of HCC is poorly understood. In this study, we identified, via microarray, novel lncRNA NONHSAT024276 as a potential tumor suppressor in HCC. The downregulation of NONHSAT024276 closely correlated with larger tumor volume and higher aspartate transaminase levels. Functional experiments were performed to verify the role of NONHSAT024276 in HCC progression, and the negative effects of NONHSAT024276 expression on cell proliferation and migration were identified. Mechanistically, NONHSAT024276 directly bound to polypyrimidine tract-binding protein 1 (PTBP1), downregulating it and forming a feedback loop. Furthermore, NONHSAT024276 increased the ratio of M1 and M2 isoforms of pyruvate kinase (PKM1/PKM2) and also obstructed the PTBP1/PKM-mediated glycolysis. Finally, the rescue assays confirmed that NONHSAT024276 functioned in HCC via downregulating PTBP1 to increase the PKM1/PKM2 ratio. Hence, this study supported a model in which NONHSAT024276 downregulated PTBP1 and formed a feedback loop to increase the PKM1/PKM2 ratio to inhibit glycolysis and progression of HCC, opening new prospects for preventing or treating HCC.

Nickel-catalyzed regio- and enantio-selective Markovnikov hydromonofluoroalkylation of 1,3-dienes.

A highly enantio- and regio-selective Markovnikov hydromonofluoro(methyl)alkylation of 1,3-dienes was developed using redox-neutral nickel catalysis. It provided a facile strategy to construct diverse monofluoromethyl- or monofluoroalkyl-containing chiral allylic molecules. Notably, this represents the first catalytic asymmetric Markovnikov hydrofluoroalkylation of olefins. The practicability of this methodology is further highlighted by its broad substrate scope, mild base-free conditions, excellent enantio- and regio-selectivity, and diversified product elaborations to access useful fluorinated building blocks.

Overexpression of Karyopherin α2 in small cell carcinoma of the cervix correlates with poor prognosis.

BACKGROUND: Cervical small cell carcinoma (SCCC) is uncommon and little is known about its molecular markers. Karyopherin α2 (KPNA2) has been demonstrated in a variety of malignancies. Our objective was to determine whether the KPNA2 level is predictive of clinical outcome in patients with SCCC. METHODS: We detected KPNA2 expression by immunohistochemistry in SCCC tumors from 62 patients. The staining results were evaluated by H-score. The correlation among KPNA2 expression level, clinical characteristics, and prognosis was analyzed. RESULTS: KPNA2 expression was detected in tumor tissue from 55 patients with SCCC (55/62, 89%). High KPNA2 expression correlated significantly with International Federation of Gynecology and Obstetrics staging (P=0.035), tumor size (P=0.019), poorer overall survival (OS) (P=0.008), and poorer disease-free survival (P=0.004) compared to low KPNA2 expression. Multivariate analysis showed that KPNA2 expression level (P=0.037) and tumor size (P=0.046) were independent prognostic factors of OS. CONCLUSIONS: KPNA2 may be a molecular marker and indicator of prognosis in SCCC.

Concurrence of imatinib-induced massive pleural/pericardial effusion and Campylobacter bacteremia in an adolescent with chronic myeloid leukemia.

Imatinib is a crucial therapeutic strategy against chronic myeloid leukemia. Though superficial edema is a common adverse effect of imatinib, massive fluid retention is rarely reported. Here, we report the case of an adolescent who had tolerated imatinib for a long time, and then presented with massive pleural/pericardial effusion during an episode of Campylobacter jejuni bacteremia. A stepwise and comprehensive survey excluded all other plausible causes of disease. The Naranjo scale was used to assess the probability of an adverse effect of medication, and the score turned out to be 9, indicating severe fluid retention to be a definite reaction to imatinib. Drug discontinuation, antibiotic administration, and invasive procedures improved this condition. After this episode, the patient could tolerate imatinib again, illustrating the transient and reversible nature of this reaction. Since prolonged imatinib usage is crucial for chronic myeloid leukemia control, alertness to drug-related adverse effects is recommended, even if the subject has previously shown a good tolerance to the drug due to various physical conditions, especially physiological stressors, like infection or inflammation.

A proactive remote pharmaceutical care for rural elderly population: The Houston-Apollo polypharmacy project.

AIMS: To evaluate polypharmacy-related problems in the elderly people who live in rural through a proactive pharmaceutical care project under a novel remote medical service infrastructure (the Houston-Apollo polypharmacy project). METHODS: It is a prospectively cross-sectional study. The elderly aged 65 years old lived in communities executed the congregate meal service and joined the Houston-Apollo project were included. During March and July on 2020, the pharmaceutical care team of Houston-Apollo polypharmacy project interviewed old people and collected their medications by remote video. Polypharmacy situation and drug-related problems, including potentially inappropriate medications (PIMs), anticholinergic burden (ACB) and risk of sarcopaenia, were evaluated by clinical pharmacists. In addition, we analysed the categories of the prescription types between polypharmacy and non-polypharmacy users, polypharmacy users with and without PIMs or ACB. A patient-specific integrated pharmacist's note for medication education and a dear doctor letter (as needed) were generated and delivered within 2-weeks postinterviewed. Age- and sex-adjusted logistic regression model was used to evaluate the association between polypharmacy and these potential medication problems. RESULTS: There were 87 older people (mean age = 75.9) and 536 long-term medications were collected. Among them, 52% were defined as polypharmacy users. Polypharmacy was significantly associated with higher risk of PIMs and ACB. The adjusted odd ratio was 5.31 (95% CI: 2.02-13.9) and 10.1 (95% CI: 3.4-29.7), respectively. Among polypharmacy users, there were nearly double the prescriptions for the nervous system and musculoskeletal system among patients with PIMs compared with those without PIMs. Besides, polypharmacy users with ACB showed higher rate of prescriptions for the nervous system and the alimentary tract and metabolism system compared with those without ACB. CONCLUSION: Polypharmacy was significantly associated with negative impact of medication safety among the elderly people in rural area. A persistent remote pharmaceutical care intervention was crucial for improving this problem.

TIGAR mitigates atherosclerosis by promoting cholesterol efflux from macrophages.

BACKGROUND AND AIMS: TP53-induced glycolysis and apoptosis regulator (TIGAR) is now characterized as a fructose-2,6-bisphosphatase to reduce glycolysis and protect against oxidative stress. Recent studies have demonstrated that TIGAR is associated with cardiovascular disease. However, little is known about its role in atherosclerogenesis. In this study, we aimed to investigate the effect of TIGAR on atherosclerosis and explore the underlying molecular mechanism. METHODS: The Gene Expression Omnibus (GEO) datasets were used to analyze the differential expression of relative proteins. THP-1-derived macrophages were used as an in vitro model and apolipoprotein E-deficient (Apoe-/-) mice were used as an in vivo model. [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). Both qPCR and Western blot were used to evaluate the mRNA and protein expression, respectively. Lentiviral vectors were used to disturb the expression of TIGAR in vitro and in vivo. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaques in Apoe-/- mice fed a Western diet. Conventional assay kits were used to measure the levels of reactive oxygen species (ROS), plasma lipid profiles and 27-hydroxycholesterol (27-HC). RESULTS: Our results showed that TIGAR is increased upon the formation of macrophage foam cells and atherosclerosis. TIGAR knockdown markedly promoted lipid accumulation in macrophages. Silencing of TIGAR impaired cholesterol efflux and down-regulated the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 by interfering with liver X receptor α (LXRα) expression and activity, but did not influence cholesterol uptake by macrophages. Additionally, this inhibitory effect of TIGAR deficiency on cholesterol metabolism was mediated through the ROS/CYP27A1 pathway. In vivo experiments revealed that TIGAR deficiency decreased the levels of ABCA1 and ABCG1 in plaques and aorta and impaired the capacity of RCT, thereby leading to the progression of atherosclerosis in Apoe-/- mice. CONCLUSIONS: TIGAR mitigates the development of atherosclerosis by up-regulating ABCA1 and ABCG1 expression via the ROS/CYP27A1/LXRα pathway.

Long non-coding RNA PCA3 inhibits lipid accumulation and atherosclerosis through the miR-140-5p/RFX7/ABCA1 axis.

OBJECTIVE: The purpose of this study was to explore the role of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in atherosclerosis and the underlying mechanism. METHODS: The Gene Expression Omnibus (GEO) datasets were used to divide differentially expressed lncRNAs, microRNAs (miRNAs), and mRNAs. The expression of PCA3, miR-140-5p, RFX7 and ABCA1 were determined by qPCR or Western blot in ox-LDL-treated macrophages. Macrophage lipid accumulation s was evaluated using the Oil Red O staining and high-performance liquid chromatography. Target relationships among PCA3, miR-140-5p, RFX7, and ABCA1 promoter area were validated via dual-luciferase reporter gene assay or chromatin immunoprecipitation assay. The apoE-/- mouse model in vivo was designed to evaluate the effect of PCA3 on the reverse cholesterol transport (RCT) and atherosclerosis. RESULTS: PCA3 was down-regulated in foam cells, whereas miR-140-5p was highly expressed. Overexpression of PCA3 promoted ABCA1-mediated cholesterol efflux and reduced lipid accumulation in macrophages. Besides, RFX7 bound to the ABCA1 promoter and increased ABCA1 expression. Targeted relationships and interactions on the expression between miR-140-5p and PCA3 or RFX7 were elucidated. PCA3 up-regulated ABCA1 expression by binding to miR-140-5p to up-regulate RFX7 and ABCA1 expression in macrophages. PCA3 promoted RCT and impeded the progression of atherosclerosis by sponging miR-140-5p in apoE-/- mice. Meanwhile, miR-140-5p also inhibit ABCA1 expression via downregulation of RFX7 to impede RCT and aggravate atherosclerosis. CONCLUSIONS: lncRNA PCA3 promotes ABCA1-mediated cholesterol efflux to inhibit atherosclerosis through sponging miR-140-5p and up-regulating RFX7.

Patient with EGFR-mutant lung cancer harboring de novo MET amplification successfully treated with gefitinib combined with crizotinib.

While 50% of lung adenocarcinoma patients in Asia have mutations in the epidermal growth factor receptor (EGFR) site, there are few patients with the EGFR mutation accompanied by de novo mesenchymal-epithelial transition (MET) amplification. Due to the low incidence rate, there is no consensus regarding treatment. Here, a case of a 62-year-old never smoker presented with EGFR Exon19del and de novo MET amplification. A radiographic examination and computed tomography (CT) imaging were conducted on the chest and middle abdomen. A pulmonary puncture was performed and a sample of the lung tissue was used for pathologic diagnosis. Immunohistochemistry was performed for the expression of CK, P40, P63, ttf-1, NapsinA, alk-d5f3, and ki-67 on the cancer cells. Craniocerebral magnetic resonance and whole body bone imaging were completed. Second-generation gene sequencing (next-generation sequencing [NGS]) and fluorescence in situ hybridization examination were also performed to further characterize the cancer cells. A radiographic examination was performed and revealed space-occupying lesions in the lungs. CT results revealed a mass in the upper lobe of the left lung. The pathologic diagnosis was non-small cell carcinoma T3N2M1a. Second-generation gene sequencing (NGS) indicated EGFR Exon 19del (p.E746_A750del, mutant abundance: 13.99%) with de novo MET amplification (CHR: q31.2, CN = 4.0). Fluorescence in situ hybridization examination confirmed MET amplification. Targeted therapy with gefitinib combined with crizotinib was administered as treatment. Four weeks later, the CT results revealed a substantial reduction in the lesion size. The patient was followed up with favorable complete recovery and no tumor-related symptoms. Although crizotinib is efficacious when used alone in follow-up treatment; however, these results of this case and others indicate that it is likely safe to use both drugs together in the case of drug resistance.

Extremely low frequency electromagnetic fields promote cognitive function and hippocampal neurogenesis of rats with cerebral ischemia.

Extremely low frequency electromagnetic fields (ELF-EMF) can improve the learning and memory impairment of rats with Alzheimer's disease, however, its effect on cerebral ischemia remains poorly understood. In this study, we established rat models of middle cerebral artery occlusion/reperfusion. One day after modeling, a group of rats were treated with ELF-EMF (50 Hz, 1 mT) for 2 hours daily on 28 successive days. Our results showed that rats treated with ELF-EMF required shorter swimming distances and latencies in the Morris water maze test than those of untreated rats. The number of times the platform was crossed and the time spent in the target quadrant were greater than those of untreated rats. The number of BrdU+/NeuN+ cells, representing newly born neurons, in the hippocampal subgranular zone increased more in the treated than in untreated rats. Up-regulation in the expressions of Notch1, Hes1, and Hes5 proteins, which are the key factors of the Notch signaling pathway, was greatest in the treated rats. These findings suggest that ELF-EMF can enhance hippocampal neurogenesis of rats with cerebral ischemia, possibly by affecting the Notch signaling pathway. The study was approved by the Institutional Ethics Committee of Sichuan University, China (approval No. 2019255A) on March 5, 2019.

Screening and Functional Prediction of Key Candidate Genes in Hepatitis B Virus-Associated Hepatocellular Carcinoma.

BACKGROUND: The molecular mechanism by which hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) is still unknown. The genomic expression profile and bioinformatics methods were used to investigate the potential pathogenesis and therapeutic targets for HBV-associated HCC (HBV-HCC). METHODS: The microarray dataset GSE55092 was downloaded from the Gene Expression Omnibus (GEO) database. The data was analyzed by the bioinformatics software to find differentially expressed genes (DEGs). Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, ingenuity pathway analysis (IPA), and protein-protein interaction (PPI) network analysis were then performed on DEGs. The hub genes were identified using Centiscape2.2 and Molecular Complex Detection (MCODE) in the Cytoscape software (Cytoscape_v3.7.2). The survival data of these hub genes was downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA). RESULTS: A total of 2264 mRNA transcripts were differentially expressed, including 764 upregulated and 1500 downregulated in tumor tissues. GO analysis revealed that these DEGs were related to the small-molecule metabolic process, xenobiotic metabolic process, and cellular nitrogen compound metabolic process. KEGG pathway analysis revealed that metabolic pathways, complement and coagulation cascades, and chemical carcinogenesis were involved. Diseases and biofunctions showed that DEGs were mainly associated with the following diseases or biological function abnormalities: cancer, organismal injury and abnormalities, gastrointestinal disease, and hepatic system disease. The top 10 upstream regulators were predicted to be activated or inhibited by Z-score and identified 25 networks. The 10 genes with the highest degree of connectivity were defined as the hub genes. Cox regression revealed that all the 10 genes (CDC20, BUB1B, KIF11, TTK, EZH2, ZWINT, NDC80, TPX2, MELK, and KIF20A) were related to the overall survival. CONCLUSION: Our study provided a registry of genes that play important roles in regulating the development of HBV-HCC, assisting us in understanding the molecular mechanisms that underlie the carcinogenesis and progression of HCC.

[A new antiviral isoquinoline alkaloid from Thalictrum glandulosissimum].

A new isoquinoline alkaloid(1) has been isolated from the whole plant of Thalictrum glandulosissimum by using various chromatographic techniques, including silica gel, sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 1-(6-hydroxy-7-methylisoquinolin-1-yl) ethantone by physicochemical properties and spectroscopic data. This compound was evaluated for anti-tobacco mosaic virus(TMV) activity. The results showed that it had prominent anti-TMV activity with inhibition rates of 28.4%. This rate was closed to that of positive control.