Selective Photoaffinity Probe for Monitoring Farnesoid X Receptor Expression in Cultured Cells.

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, is a vital ligand-activated transcriptional factor, which is highly expressed in the liver, intestine, and adrenal gland. However, FXR homeostasis is influenced by many factors, such as diet and circadian rhythm, and the expression of FXR differs in diverse organs. Currently, there is no method to monitor the FXR homeostasis in real time, which restricts us from further investigating the function of FXR under physiological and pathological conditions. In this project, classic FXR agonists were selected to be modified to targeting FXR. The photo-cross-linking diazirine group and alkynyl, a click reaction group, were incorporated to the ligands. Through biorthogonal reaction, fluorophore was linked to the ligands to realize the monitoring of FXR expression in cells.

Gasdermin E-derived caspase-3 inhibitors effectively protect mice from acute hepatic failure.

Programmed cell death (PCD), including apoptosis, apoptotic necrosis, and pyroptosis, is involved in various organ dysfunction syndromes. Recent studies have revealed that a substrate of caspase-3, gasdermin E (GSDME), functions as an effector for pyroptosis; however, few inhibitors have been reported to prevent pyroptosis mediated by GSDME. Here, we developed a class of GSDME-derived inhibitors containing the core structure of DMPD or DMLD. Ac-DMPD-CMK and Ac-DMLD-CMK could directly bind to the catalytic domains of caspase-3 and specifically inhibit caspase-3 activity, exhibiting a lower IC50 than that of Z-DEVD-FMK. Functionally, Ac-DMPD/DMLD-CMK substantially inhibited both GSDME and PARP cleavage by caspase-3, preventing apoptotic and pyroptotic events in hepatocytes and macrophages. Furthermore, in a mouse model of bile duct ligation that mimics intrahepatic cholestasis-related acute hepatic failure, Ac-DMPD/DMLD-CMK significantly alleviated liver injury. Together, this study not only identified two specific inhibitors of caspase-3 for investigating PCD but also, more importantly, shed light on novel lead compounds for treating liver failure and organ dysfunctions caused by PCD.

The predictive role of CD4+ cell count and CD4/CD8 ratio in immune reconstitution outcome among HIV/AIDS patients receiving antiretroviral therapy: an eight-year observation in China.

BACKGROUND: The immune reconstitution after initiation of highly active antiretroviral therapy (HAART) among HIV-infected individuals substantially affects patients' prognosis. However, the dynamic characteristics and predictors of reconstitution outcome remain unclear. METHODS: In this study, the HIV/AIDS patients with sustained virological suppression (viral load < 50 copies/ml) after HAART were enrolled. The patients were subgrouped into immunological non-responders (INRs) (< 200 cells/µl), immunological inadequate responders (IIRs) (200 ~ 500 cells/µl) and immunological responders (IRs) (> 500 cells/µl) according to the CD4 cell count after two-year HAART. The immune reconstitution data based on the CD4+ and CD8+ cell counts with 8-year follow-up were collected for analysis. RESULTS: The CD4+ cell counts in the immunological responders (IRs) were significantly higher than in the immunological non-responders (INRs) and immunological inadequate responders (IIRs) (P <  0.001). The overall CD4+ cell count and CD4/CD8 ratio in the IRs increased faster than the IIRs and INRs. The CD4+ cell count growth at 0.5 year and 1 year after HAART in the IRs was significantly higher than the IIRs and INRs. The ROC curve demonstrated that 1 year CD4+ cell count had the highest predictive value, with the best cut-off value of 188 cells/µl, the predictive sensitivity was 81.0%, the predictive specificity was 85.2%, false positive rate was 14.8%, false negative rate was 19.0%, positive predictive value (IR) was 63.0%, negative predictive value (INR) was 93.5%. CONCLUSIONS: Taken together, our findings suggest that early initiation of HAART can reduce the immune reconstitution failure. The combination of baseline CD4+ cell count and baseline CD4/CD8 ratio may serve as a valid predictor of immune reconstitution prognosis after HAART.

[Preliminary study on standardization of production and processing of Scutellaria baicalensis pieces].

Decoction pieces are important raw materials in the production of traditional Chinese medicine( TCM),and their quality could directly affect the clinical efficacy and medication safety. Research on the production and processing technology of TCM is the basis for the normalization and standardization of Chinese medicine decoction pieces. At present,the production and processing standards for Scutellaria baicalensis pieces are non-regulated,lacking data foundation. In this study,with baicalin,baicalein,wogonoside and wogonin contents as evaluation indicators,single factor experiment was designed to optimize the softening,drying and cutting processes of S. baicalensis,providing a basis for the standardization of their production and processing. The effects of different softening,drying and cutting processes on the contents of the main components in S. baicalensis were comprehensively analyzed by the summation of relative differences. RESULTS:: showed that the contents of the four components and comprehensive indexes were affected by different softening methods and drying temperatures. The content of wogonin in boiling method was higher than that in boiling with cold water,and the content of glycosides in 70 ℃ drying condition was higher than that in other groups. The content of baicalin was significantly affected by different cutting thicknesses,but not by comprehensive index. Eventually,the optimal preparation process for S. baicalensis was determined as follows: boiled in boiling water for 20 min,cut into thin slices( 1-2 mm),and then dried at 70 ℃ in blast drier. This process was close to the actual production,practical and feasible and meanwhile,it was of great significance to improve the quality of S. baicalensis pieces.

Ginsenosides synergize with mitomycin C in combating human non-small cell lung cancer by repressing Rad51-mediated DNA repair.

The use of ginseng extract as an adjuvant for cancer treatment has been reported in both animal models and clinical applications, but its molecular mechanisms have not been fully elucidated. Mitomycin C (MMC), an anticancer antibiotic used as a first- or second-line regimen in the treatment for non-small cell lung carcinoma (NSCLC), causes serious adverse reactions when used alone. Here, by using both in vitro and in vivo experiments, we provide evidence for an optimal therapy for NSCLC with total ginsenosides extract (TGS), which significantly enhanced the MMC-induced cytotoxicity against NSCLC A549 and PC-9 cells in vitro when used in combination with relatively low concentrations of MMC. A NSCLC xenograft mouse model was used to confirm the in vivo synergistic effects of the combination of TGS with MMC. Further investigation revealed that TGS could significantly reverse MMC-induced S-phase cell cycle arrest and inhibit Rad51-mediated DNA damage repair, which was evidenced by the inhibitory effects of TGS on the levels of phospho-MEK1/2, phospho-ERK1/2 and Rad51 protein and the translocation of Rad51 from the cytoplasm to the nucleus in response to MMC. In summary, our results demonstrate that TGS could effectively enhance the cytotoxicity of MMC against NSCLC cells in vitro and in vivo, thereby revealing a novel adjuvant anticancer mechanism of TGS. Combined treatment with TGS and MMC can significantly lower the required concentration of MMC and can further reduce the risk of side effects, suggesting a better treatment option for NSCLC patients.

The RNA-binding protein QKI suppresses cancer-associated aberrant splicing.

Lung cancer is the leading cause of cancer-related death worldwide. Aberrant splicing has been implicated in lung tumorigenesis. However, the functional links between splicing regulation and lung cancer are not well understood. Here we identify the RNA-binding protein QKI as a key regulator of alternative splicing in lung cancer. We show that QKI is frequently down-regulated in lung cancer, and its down-regulation is significantly associated with a poorer prognosis. QKI-5 inhibits the proliferation and transformation of lung cancer cells both in vitro and in vivo. Our results demonstrate that QKI-5 regulates the alternative splicing of NUMB via binding to two RNA elements in its pre-mRNA, which in turn suppresses cell proliferation and prevents the activation of the Notch signaling pathway. We further show that QKI-5 inhibits splicing by selectively competing with a core splicing factor SF1 for binding to the branchpoint sequence. Taken together, our data reveal QKI as a critical regulator of splicing in lung cancer and suggest a novel tumor suppression mechanism involving QKI-mediated regulation of the Notch signaling pathway.

[Establishment of biological assess for quality control of Fuzi based on determination of premature ventricular contractions in rats].

Aconiti Lateralis Radix (Fuzi) is a toxic traditional Chinese medicine with definite efficacy. In order to improve the quality control of its different prepared products and ensure the security in clinic, it is significant to establish a method of quality evaluation related to clinic adverse effects. Aiming at the important biological marker of early cardiac toxicity reaction, there was no method to detect it. In this manuscript, a novel approach for measuring the minimal toxic dose (MTD) of premature ventricular contractions (PVC) poisoning of rats was established. Then, the determination methodology and conditions were optimized to meet the needs of the quality and biological assessment, including animal sex, weight, stability of standards and test solutions. Using this method, the MTD value of different Fuzi products were determined, such as Heishunpian, Baifupian, Zhengfupian, Baofupian, and Paotianxiong. The results showed that the MTD of Fuzi was significantly decreased after detoxification processed (P<0.05) and the MTD of Heishunpian, Zhengfupian, Baofupian and Baifupian was as much as 15.76, 22.36, 19.65 and 20.97 times to that of unprocessed Shengfuzi. In addition, Paotianxiong could not induce PVC in rats, which indicated that Paotianxiong was nontoxic and safe.This method could appropriately reflects the cardiotoxity of Fuzi and its prepared samples. Together with the chemical composition analysis, the contents of diester alkaloids were explored including aconitine, mesaconitine and hypaconitine as well as monoester alkaloids in Fuzi and its prepared products were significantly associated with PVC. Furthermore, there may be some components undetermined facilitating arrhythmia to be worth exploring. This research provides an overall and comprehensive approach to diagnose early clinical cardiotoxity and control the quality of Fuzi, which could not only be a complementary solution for the chemical evaluation, but a new method to ensure its efficacy and security of clinical application.

Protease Omi cleaving Hax-1 protein contributes to OGD/R-induced mitochondrial damage in neuroblastoma N2a cells and cerebral injury in MCAO mice.

AIM: In the penumbra after focal cerebral ischemia, an increase of protease Omi is linked to a decrease of Hs1-associated protein X-1 (Hax-1), a protein belonging to the Bcl-2 family. In this study we investigated the mechanisms underlying the regulation of Hax-1 by protease Omi in cerebral ischemia/reperfusion (I/R) injury. METHODS: Mouse neuroblastoma N2a cells were subjected to oxygen-glucose deprivation and reoxygenation (OGD/R); cell viability was assessed with MTT assay. Mice underwent 2-h middle cerebral artery occlusion (MCAO) and reperfusion, and the infarct volume was determined with TTC staining. The expression of Omi and Hax-1 was detected using immunoblot and immunofluorescence assays. The mitochondrial membrane potential was measured using TMRM staining. RESULTS: In the brains of MCAO mice, the protein level of Omi was significantly increased, while the protein level of Hax-1 was decreased. Similar changes were observed in OGD/R-treated N2a cells, but the mRNA level of Hax-1 was not changed. Furthermore, in OGD/R-treated N2a cells, knockdown of Omi significantly increased Hax-1 protein level. Immunofluorescence assay showed that Omi and Hax-1 were co-localized in mitochondria of N2a cells. OGD/R caused marked mitochondrial damage and apoptosis in N2a cells, while inhibition of Omi protease activity with UCF-101 (10 µmol/L) or overexpression of Hax-1 could restore the mitochondrial membrane potential and attenuate cell apoptosis. Moreover, pretreatment of MCAO mice with UCF-101 (7.15 mg/kg, ip) could restore Hax-1 expression, inhibit caspase activation, and significantly reduce the infarct volume. CONCLUSION: Protease Omi impairs mitochondrial function by cleaving Hax-1, which induces apoptosis in OGD/R-treated N2a cells and causes I/R injury in MCAO mice.

[The relationship of SIRT3 with cellular metabolism and cardiovascular diseases].

Protein deacetylases play an extremely crucial role in cellular biological processes and have been categorized into four families (HDACⅠ, HDACⅡ, HDACⅢ and HDACⅣ) in human. Of them, HDACⅢ, also known as the Sir2 (Silent information regulator 2) family, contains seven members, SIRT1-7, each exhibiting different cellular localization and biological function. As a major mitochondrial deacetylase, SIRT3 not only modulates cellular metabolism, but also plays important roles in apoptosis, tumor growth, aging and a number of other diseases. In this review, we summarize recent findings related to SIRT3 with an emphasis on its biological functions in regulating cell metabolism and its possible roles in cardiovascular diseases.

Research on contents of anthraquinones in Cassiae Semen by principal component analysis.

Cassiae Semen is a common traditional Chinese medicine, and contents of anthraquinones of Cassiae Semen different significantly from area to area. According to Chinese Pharmacopoeia (2010 edition), only contents of aurantio obtusin and chrysophanol were used to evaluate the quality of Cassiae Semen, another data could be added later. Ten batches of Cassiae Semen from different areas were determined, and total anthraquinones, total free anthraquinones and total combined anthraquinones contents were assessed by ultraviolet visible spectrophotometer, contents of aurantio obtusin, rhein, aloe emodin, emodin, chrysophanol and physcion were determined by HPLC. After that, principal components analysis was used to evaluate these data determined previous by dimension reduction analysis. At last, the result suggests that three main components were found out, it shows that content of aloe emodin could be used to evaluate the quality of Cassiae Semen as well as contents of aurantio obtusin and chrysophanol. And Cassiae Semen from Hebei province posseses higher quality than Cassiae Semen from other different areas. All these results can provide a good reference for quality evaluating of Cassiae Semen medicinal materials at a certain extent.

Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats.

AIM: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. METHODS: Male SD rats were orally administered VPA (100 or 500 mg·kg⁻¹·d⁻¹) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. RESULTS: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. CONCLUSION: HFD magnifies VPA-induced impairment of mitochondrial ß-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD.

YB-1 binds to CAUC motifs and stimulates exon inclusion by enhancing the recruitment of U2AF to weak polypyrimidine tracts.

The human Y box-binding protein-1 (YB-1) is a deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)-binding protein with pleiotropic functions. Besides its roles in the regulation of transcription and translation, several recent studies indicate that YB-1 is a spliceosome-associated protein and is involved in alternative splicing, but the underlying mechanism has remained elusive. Here, we define both CAUC and CACC as high-affinity binding motifs for YB-1 by systematic evolution of ligands by exponential enrichment (SELEX) and demonstrate that these newly defined motifs function as splicing enhancers. Interestingly, on the endogenous CD44 gene, YB-1 appears to mediate a network interaction to activate exon v5 inclusion via multiple CAUC motifs in both the alternative exon and its upstream polypyrimidine tract. We provide evidence that YB-1 activates splicing by facilitating the recruitment of U2AF65 to weak polypyrimidine tracts through direct protein-protein interactions. Together, these findings suggest a vital role of YB-1 in activating a subset of weak 3' splice sites in mammalian cells.

Clinical, pathological, and genetic analysis of ten patients with MYH9-related disease.

MYH9-related disease (MYH9-RD) is an autosomal dominant disorder caused by mutations in the MYH9 gene. It is characterized by a triad of giant platelets, thrombocytopenia, and characteristic Döhle body-like granulocyte inclusions. In this study we report 10 unrelated patients with MYH9-RD in whom the following seven MYH9 gene mutations were found: W33R, p.Q1443_K1445dup, R702H, D1424N, E1841K, R1933X, and E1945X (the first two were novel mutations). The region of the MYH9 mutation determines in some regards the phenotype, but clinical expression can vary between individuals with the same mutation. The neutrophil inclusion bodies of two patients were too small to be detected, but could be found with immunofluorescence staining. Immunoblotting analysis revealed that the calculated NMMHC-IIA/ß-actin ratio for MYH9-RD neutrophils was 39% of normal controls. Kidney biopsy showed segmental glomerulosclerosis and NMMHC-IIA expression was decreased in podocytes. This disease is not as rare as originally thought. In any individual with persistent macrothrombocytopenia and no response to corticosteroids and immunosuppressive agents, even if neutrophil inclusions were inconspicuous in routine staining, MYH9-RD should be suspected.

[Identification and functional analysis of a novel missense mutation Ser250Phe underlying congenital coagulation factor â ¦ deficiency].

OBJECTIVE: To identify and characterize a missence mutation Ser250 Phe underlying coagulation factor Ⅶ (FⅦ) deficiency in a Chinese patient and his family. METHODS: The FⅦ gene (F7) was analyzed by DNA sequencing, and the FⅦ levels (including antigen and activity) in patient's plasma were determined with enzyme-linked immunoabsorbent assay (ELISA) and one stage prothrombin time based method. In addition, a FⅦ-250 Phe mutant corresponding to the identified mutation was expressed in HEK293 cells, and a subcellular localization experiment in CHO cells was performed to clarify the molecular mechanism of FⅦ deficiency caused by the FⅦ-250 Phe mutation. RESULTS: The patient had a prolonged prothrombin time (PT: 36.5 s) and low levels of both FⅦ antigen and activity (130.2 ng/mL and 4.0%, respectively). Two heterozygous mutations were identified in the F7 gene (NG-009262.1), which included a g.15975 G>A mutation at the splice receptor site of intron 6 (IVS6-1G>A) and a novel g.16750 C>T mutation in exon 8, which resulted in replacement of Ser (TCC) 250 with Phe (TTC)250 in the vicinity of a charge-stablizing system. By gene expression experiments, the antigen and activity levels of FⅦ-250 Ser and FⅦ-250 Phe in the culture medium were (37.77 ± 2.30) ng/mL and (4.02 ± 0.52) ng/mL, respectively. ELISA and Western blotting analyses indicated that expression of the mutant FⅦ-250 Phe and wild type FⅦ-250 Ser was (130.51 ± 2.32) ng/mL and (172.45 ± 2.25) ng/mL, respectively. FⅦ-250 Phe was found in endoplasmic reticulum and Golgi apparatus, suggesting that the mutant FⅦ-250 Phe could be normally synthesized in the cells but was inefficiently secreted. CONCLUSION: Compound heterozygous mutations in F7 gene (g.15975G>A and g.16750C>T) may be responsible for the FⅦ deficiency in this patient. The novel FⅦ 250 Phe can be transported from endoplasmic reticulum to Golgi apparatus, but may be degraded or inefficient.

Varicella-zoster virus meningitis with hypoglycorrhachia: A case report.

BACKGROUND: Varicella-zoster virus (VZV) is a common viral infection, but meningitis is a rare complication of VZV infection. The cerebrospinal fluid glucose of viral meningitis is usually within the normal range, which is different from bacteria, fungi, and cancerous meningitis. This paper reports a case of VZV meningitis with hypoglycorrhachia and the relevant literature was reviewed. CASE SUMMARY: We report a case of an immunocompetent 39-year-old male, presenting with severe headache and fevers, without meningeal signs or exanthem, found to have VZV meningitis by the metagenomic next-generation sequencing of cerebrospinal fluid. The cerebrospinal fluid analysis revealed hypoglycorrhachia (cerebrospinal fluid glucose of 2.16) and he was treated successfully with intravenous acyclovir. Our literature review identified only ten cases diagnosed with VZV meningitis with hypoglycorrhachia previously reported to date in the English literature whose cerebrospinal fluid glucose was from 1.6 to 2.7mmol/L, with a ratio of cerebrospinal fluid to serum glucose from 0.30 to 0.49. CONCLUSION: Although rare, the cerebrospinal fluid of patients with VZV meningitis may have hypoglycorrhachia, which broadens the understanding of the disease.

Hemoporfin-mediated photodynamic therapy with general anesthesia showed superior efficacy in the treatment of port-wine stains: a retrospective evaluation.

Background: Hemoporfin-mediated photodynamic therapy (PDT) is an effective treatment for port-wine stains (PWS), and pain is the main adverse effect of this therapy. General anesthesia is commonly used for pain management during PDT, but the effect of general anesthetics on the subsequent treatment efficacy of PDT in PWS has not been reported. Objectives: To assess the use of general anesthesia combined with PDT compared with PDT alone in 207 PWS patients, and to provide further safety and efficacy data on this combined therapy. Methods: Propensity score matching (PSM) was used at a 2:1 ratio to create a general anesthetic group (n = 138) and a highly comparable nonanesthetic group (n = 69). The clinical outcomes were evaluated, and the treatment reactions and adverse effects were recorded after one treatment with PDT. Results: After matching, there was no significant difference in the demographic data of the patients in the two groups (p > 0.05), while the treatment efficacy was significantly higher in the general anesthetic group than in the nonanesthetic group (76.81 vs. 56.52%, p < 0.05). Moreover, logistic regression analysis confirmed that patients receiving general anesthesia showed an association with a good response to PDT (OR = 3.06; 95% CI, 1.57-6.00; p = 0.0011). Purpura lasted longer in the general anesthetic group, but the other treatment reactions and adverse effects were similar in the two groups (p > 0.05). No serious systemic adverse reactions were observed. Conclusion: We recommend this combined therapy, which is associated with painless, as a high efficacy treatment option for PWS patients, especially for patients with a poor response to multiple PDT alone treatments.

Octreotide-based therapies effectively protect mice from acute and chronic gastritis.

Gastritis is a common inflammation of stomach with multiple pathogenesis. This study was designed to investigate the protective effects of oral octreotide (OCT) against ethanol-induced acute gastric injury and H. pylori-induced chronic gastritis via promoting gastric mucosa restoration, reducing gastric acid secretion and inflammation. Male C57BL/6J mice were randomly divided and treated with three doses of OCT (0.5, 2.5, 10 mg/kg) alone or combined respectively with 10 mg/kg omeprazole (OME), 0.2 g/L metronidazole (MTZ)/0.1 g/L clarithromycin (CLR) in drinking water. Oxidative stress analysis, bacterial load analysis, qPCR, gastric histopathology examinations were performed in our study. Ethanol-induced acute gastric ulcer was restored by OCT alone at doses of 2.5 mg/kg, or combined with OME as indicated by markedly reducing Gastrin, Il-6 and Il1b expression through induction of Muc5ac and Occludin, significantly improving hyperacidity and gastric bleeding. As well, OCT combined with MTZ/CLR restored the integrity of gastric mucosa damaged by H. pylori via elevating the expression of Muc5ac and somatostatin receptor 2, decreasing inflammation and increasing the number of chorionic or glands. Besides, OCT is more suitable for long-term medication in the treatment of chronic gastritis than OME. In conclusion, our results proved that the newly developed oral OCT-based therapies were more effective to reverse gastric mucosa damage and inflammation in ethanol and H. pylori infection-induced gastric injury, it is of great significance for supplementing new clinical regimens for the treatment of acute and chronic gastritis.

[Prenatal diagnosis for two families of congenital factor V deficiency].

OBJECTIVE: To provide genetic consulting and prenatal diagnosis for two families with congenital factor V deficiency based on the known mutations of factor V gene (G16088C and G69969T). METHODS: Chorionic DNA was obtained at 12 weeks of gestation and analyzed to exclude maternal cell contamination through microsatellite DNA analysis. It was then amplified with PCR and sequenced to determine the presence of mutations in exons 3 and 23. Factor V activity of the blood was assayed at 22 weeks of gestation and 6 months after birth. RESULTS: The fetus in case 1 was found to be a heterozygous carrier of the G16088C mutation, for whom factor V activity of the cord blood and peripheral blood were 15% and 53%, respectively. Fetus 2 did not carry the familiar G69969T mutation, for whom the factor V activity of cord blood and peripheral blood has measured 32% and 93%, respectively. Follow-up studies demonstrated that the two infants were both in good health without a tendency for bleeding. CONCLUSION: In both cases, the genotypes were consistent with the phenotypes. This is the first report of prenatal diagnosis of congenital factor V deficiency.

LRP1B mutation is associated with tumor HPV status and promotes poor disease outcomes with a higher mutation count in HPV-related cervical carcinoma and head & neck squamous cell carcinoma.

Human papillomavirus (HPV) infection and gene mutations were reputed as key factors in cervical carcinoma (CC) and head and neck squamous cell carcinoma (HNSCC). However, the associations of HPV status and gene mutations remain to be determined. This study aims to identify molecular patterns of LRP1B mutation and HPV status via rewiring tumor samples of HNSCC (n=1478) and CC (n=178) from the TCGA dataset. Here, we found that LRP1B mutation was associated with HPV status in CC (P=0.040) and HNSCC (P=0.044), especially in HPV 16 integrated CC (P=0.036). Cancer survival analysis demonstrated that samples with LRP1B mutation showed poor disease outcomes in CC (P=0.013) and HNSCC (P=0.0124). In addition, the expression status of LPR1B was more favorable for prediction than TP53 or RB1 in CC and HNSCC. Mutation clustering analysis showed that samples with LRP1B mutation showed higher mutation count in CC (P=1.76e-67) and HNSCC (P<10e-10). Further analysis identified 289 co-occurrence genes in these two cancer types, which were enriched in PI3K signaling, cell division process, and chromosome segregation process, et al. The 289-co-occurrence gene signature identified a cluster of patients with a higher portion of copy number variation (CNV) lost in the genome, different tumor HPV status (P<10e-10), higher mutation count (P<10e-10), higher fraction genome altered value (P=2.078e-4), higher aneuploidy score (P=3.362e-4), and earlier started the smoking year (P=2.572e-4), which were associated with shorter overall survival (P=0.0103) in CC and HNSCC samples. Overall, LRP1B mutation was associated with tumor HPV status and was an unfavorable prognostic biomarker for CC and HNSCC.

[Analysis of the clinical effect on post-stroke shoulder hand syndrome stage â treated with the along-meridian trochar acupuncture therapy].

OBJECTIVE: To compare the differences in the clinical effect on post-stroke shoulder hand syndrome (SHS) stage Ⅰ between the along-meridian trochar acupuncture therapy and the routine acupuncture therapy with filiform needles. METHODS: A total of 80 patients with post-stroke SHS stage I were divided into a treatment group (41 cases) and a control group (39 cases) according to the random number table. In the control group, the common filiform needles were used to stimulate Jianyu (LI15), Jianliao (TE14), Jianzhen (SI9), Jianzhongshu (SI15), Jianwaishu (SI14), 5 times a week, 3 weeks as 1 course. In the treatment group, along-meridian trochar acupuncture therapy was applied, 3 times a week, 3 weeks as 1 course. The patients in both groups were all treated with basic medications and routine rehabilitation training. Pain degree, edema degree, upper limb motor function and activity of daily living were observed in the two groups before the treatment, at the end of the treatment and in follow-up. At the end of treatment and in follow-up, the therapeutic effect was evaluated respectively in the patients of the two groups. RESULTS: Compared with the values before treatment, the VAS score of the upper limb was reduced obviously (P< 0.001), the score of the upper limb motor function and Barthel index were increased obviously (P<0.001, P<0.05) in the patients of the two groups, the score of edema degree of the affected limb was reduced after treatment in the patients of the treatment group (P<0.001). Compared with the control group, VAS score of the upper limb and the score of edema degree of the affected limb were obviously lower (P<0.001), and the score of the upper limb motor function and Barthel index were obviously higher in the treatment group (P<0.001). The total effective rate was 66.7% (26/39) after treatment and was 74.4% (29/39) in follow-up in the treatment group and they were 20.5% (8/39) and 28.2% (11/39) respectively in the control group. The total effective rates after treatment and in follow-up in the treatment group were all obviously higher than those in the control group respectively (P<0.001). CONCLUSION: The along-meridian trochar acupuncture therapy remarkably relieves pain and edema and improves the upper limb motor function and the activity of daily living in the patients with post-stroke shoulder hand syndrome and its clinical therapeutic effect is definite.