A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1.

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

Comprehensive mRNA and microRNA analysis revealed the effect and response strategy of freshwater fish, grass carp (Ctenopharyngodon idella) under geosmin exposure.

Geosmin is an environmental pollutant that causes off-flavor in water and aquatic products. The high occurrence of geosmin contamination in aquatic systems and aquaculture raises public awareness, however, few studies have investigated the response pathways of geosmin stress on freshwater fish. In this research, grass carp were exposed to 50 µg/L geosmin for 96 h, liver tissue was sequenced and validated using real-time qPCR. In total of 528 up-regulated genes and 488 down-regulated genes were observed, includes cytochrome P450 and uridine diphosphate (UDP)-glucuronosyltransferase related genes. KEGG analysis showed that chemical carcinogenesis-DNA adducts, metabolism of xenobiotics by cytochrome P450, drug metabolism-cytochrome P450 pathway was enriched. Common genes from the target genes of microRNAs and differential expression genes are enriched in metabolism of xenobiotics cytochrome P450 pathway. Two miRNAs (dre-miR-146a and miR-212-3p) down regulated their target genes (LOC127510138 and adh5, respectively) which are enriched cytochrome P450 related pathway. The results present that geosmin is genetoxic to grass carp and indicate that cytochrome P450 system and UDP-glucuronosyltransferase play essential roles in biotransformation of geosmin. MicroRNAs regulate the biotransformation of geosmin by targeting specific genes, which contributes to the development of strategies to manage its negative impacts in both natural and artificial environments.

[Detection and Significance of Molecular Markers in Immunotherapy and Targeted Therapy of Colorectal Cancer in Tibet].

Objective To study the expression of SWI/SNF-related,matrix-associated,actin-dependent regulator of chromatin,subfamily A,member 4(SMARCA4)/Brahma-related gene 1,V-raf murine sarcoma viral oncogene homolog B(BRAF),P53,programmed cell death protein-1(PD-1),and programmed death-ligand 1(PD-L1),and changes in the expression of BRAF and neurotrophic tyrosine receptor kinase(NTRK) in the patients with colorectal cancer in Tibet,thereby providing a basis for targeted therapy and immunotherapy for this disease in Tibet. Methods A total of 64 patients with colorectal cancer resected in the Tibet Autonomous Region People's Hospital from January 2015 to July 2021 were enrolled in this study.The expression of SMARCA4,BRAF,P53,PD-1,and PD-L1 was detected by immunohistochemical staining.The gene fusion involving NTRK1,NTRK2,and NTRK3 was detected by fluorescence in situ hybridization,and the BRAF V600E gene mutation by polymerase chain reaction. Results The 64 patients with colorectal cancer were at a male-to-female ratio of 1.21∶1,with the mean age of (56.59±13.27) years.The tumors were located in the colon in 46(71.88%) patients and in the rectum in 18(28.12%) patients.Sixty(93.75%) patients presented adenocarcinoma,and 4(6.25%) patients presented other types of tumors.The patients in T1/T2 and T3/T4 phases accounted for 17.19%(n=11) and 82.81%(n=53),respectively.Lymph node metastasis occurred in 24(37.50%) patients.The immunohistochemical staining results showed partially down-regulated or absent expression of SMARCA4 in 1(1.56%) patient,positive BRAF expression in 4(6.25%) patients,and mutant expression of P53 in 35(54.69%) patients.The PD-1-expressing tumor associated immune cell was proportion score<10% in 45(70.31%) patients and≥10% in 19(29.69%) patients.The PD-L1 combined positive score was<10 in 52(81.25%) patients and≥10 in 12(18.75%) patients.The gene fusion of NTRK1,NTRK2,and NTRK3 was negative in all the patients,and BRAF V600E gene mutation was positive in 4(6.25%) patients.The SMARCA4 gene alteration was not detected in the patient with partial expression missing of SMARCA4.The PD-L1 combine positive score was correlated with the deficient mismatch repair(dMMR)/microsatellite instability-high (MSI-H) and the PD-1 expression (χ2=10.223,P=0.001;χ2=11.979,P=0.001). Conclusions The down-regulated or absent SMARCA4 expression and NTRK gene fusion are rare in the patients with colorectal cancer in Tibet.A few patients present BRAF V600E gene mutations,and Pan-TRK and BRAF expression can be used for the primary screening of NTRK gene fusion and BRAF gene mutation.The patients with dMMR/MSI-H are prone to high expression of PD-L1 and expected to benefit from immunotherapy.No significant correlation exists between P53 mutation and PD-L1 expression.The high expression of PD-1 is positively correlated with the high expression of PD-L1.

Role of bZIP transcription factors in the regulation of plant secondary metabolism.

MAIN CONCLUSION: This study provides an overview of the structure, classification, regulatory mechanisms, and biological functions of the basic (region) leucine zipper transcription factors and their molecular mechanisms in flavonoid, terpenoid, alkaloid, phenolic acid, and lignin biosynthesis. Basic (region) leucine zippers (bZIPs) are evolutionarily conserved transcription factors (TFs) in eukaryotic organisms. The bZIP TFs are widely distributed in plants and play important roles in plant growth and development, photomorphogenesis, signal transduction, resistance to pathogenic microbes, biotic and abiotic stress, and secondary metabolism. Moreover, the expression of bZIP TFs not only promotes or inhibits the accumulation of secondary metabolites in medicinal plants, but also affects the stress response of plants to the external adverse environment. This paper describes the structure, classification, biological function, and regulatory mechanisms of bZIP TFs. In addition, the molecular mechanism of bZIP TFs regulating the biosynthesis of flavonoids, terpenoids, alkaloids, phenolic acids, and lignin are also elaborated. This review provides a summary for in-depth study of the molecular mechanism of bZIP TFs regulating the synthesis pathway of secondary metabolites and plant molecular breeding, which is of significance for the generation of beneficial secondary metabolites and the improvement of plant varieties.

Hospital information system-based pharmacovigilance for elderly patients: practices and results.

OBJECTIVE: To evaluate the effect of a pharmacovigilance system on potentially inappropriate medication prescriptions for elderly patients. METHODS: The retrospective study was conducted at Shaanxi Provincial People's Hospital, China, after approval from the ethics review committee, and comprised data from May 2020 to April 2021, and comprised prescriptions related to elderly patients aged at least 65 years. Number of medication risk assessment entries, number of intervened medical orders on outpatients and inpatients number of medical order prompts, and number of physician communication with prescription-checking pharmacists were noted. Potential drug interaction rate was compared between pre- implementation from May to October 2020 and post-implementation from November 2020 to April 2021. Besides, the usage of sedatives and hypnotics and potentially inappropriate medication was noted for the period from January to June 2021 to evaluate the sustained effect of pharmacovigilance system. Data was analysed using SPSS 19. Results: A total of 118 drugs were involved in the 3911 entries of outpatient prescription warnings, of which 19 drugs accounted for 3156 (80%). Besides, a total of 113 drugs were involved in the 3999 entries of inpatient prescription warnings, of which 19 drugs accounted for 3199 (80%) The overall prevalence of potentially inappropriate medication related to sedatives and hypnotics decreased post-intervention as warning percentage was 16.1% in January and 6.7% in June among outpatients. On inpatients, the warning percentage was 30.6% in January and 6.1% in June. CONCLUSIONS: The pharmacovigilance system could reduce potentially inappropriate medication and provide deeper technical support for the safety of medical behaviour and individualised treatment of patients.

[Pathological Types,Expression of Mismatch Repair Protein,Human Epidermal Growth Factor Receptor 2,and Pan-TRK,and Eostein-Barr Virus Infection in Patients With Colorectal Cancer Resected in Tibet].

Objective To study the pathological types,expression of mismatch repair protein,human epidermal growth factor receptor 2(HER2),and Pan-TRK,and Epstein-Barr virus(EBV)infection in patients with colorectal cancer resected in Tibet. Methods A total of 79 patients with colorectal cancer resected in Tibet Autonomous Region People's Hospital from December 2013 to July 2021 were enrolled in this study.The clinical and pathological data of the patients were collected.The expression of mismatch repair protein,HER2,and Pan-TRK was detected by immunohistochemical(IHC)staining,and detection of HER2 gene by fluorescence in situ hybridization(FISH)in the patients with HER2 IHC results of 2+ or above.EBV was detected by in situ hybridization with EBV-encoded small RNA. Results A total of 79 colorectal cancer patients were included in this study,with the male-to-female ratio of 1.26:1 and the mean age of(57.06±12.74)years(24-83 years).Among them,4 patients received preoperative neoadjuvant therapy.Colonic cancer and rectal cancer occurred in 57(57/79,72.15%,including 31 and 26 in the right colon and left colon,respectively)and 22(22/79,27.85%)patients,respectively.The maximum diameter of tumor varied within the range of 1-20 cm,with the mean of(6.61±3.33)cm.Among the 79 colorectal cancer patients,75(75/79,94.94%)patients showed adenocarcinoma.Lymph node metastasis occurred in 12(12/21,57.14%)out of the 21 patients with severe tumor budding,13(13/23,56.52%)out of the 23 patients with moderate tumor budding,and 2(2/31,6.45%)out of the 31 patients with mild tumor budding,respectively.The lymph node metastasis rate showed differences between the patients with severe/moderate tumor budding and the patients with mild tumor budding(all P<0.001).The IHC staining showed that mismatch repair protein was negative in 10(10/65,15.38%)patients,including 5 patients with both MSH2 and MSH6 negative,4 patients with both MLH1 and PMS2 negative,and 1 patient with MSH6 negative.Pan-TRK was negative in 65 patients.The IHC results of HER2 showed 0 or 1+ in 60 patients and 2+ in 5 patients.FISH showed no positive signal in the 5 patients with HER2 IHC results of 2+.The detection with EBV-encoded small RNA showed positive result in 1(1/65,1.54%)patient. Conclusions Non-specific adenocarcinoma of the right colon is the most common in the patients with colorectal cancer resected in Tibet,and 15% of the patients showed mismatch repair protein defects.EBV-associated colorectal carcer is rare,Pan-TRK expression and HER2 gene amplification are seldom.The colorectal cancer patients with moderate and severe tumor budding are more likely to have lymph node metastasis.

Electrochemical Impedimetric Real-Time Polymerase Chain Reactions Using Anomalous Charge Transfer Enhancement.

We developed a new electrochemical impedimetric method for the real-time detection of polymerase chain reactions (PCR) based on our recent discovery that the DNA intercalator, [Ru(bpy)2DPPZ]2+, anomalously enhances charge transfer between redox mediators, K4[Fe(CN)6]/K3[Fe(CN)6], and a carbon electrode. Three mM [Fe(CN)6]3-/4- and 5 µM [Ru(bpy)2DPPZ]2+ were added to the PCR solution, and electrochemical impedance spectroscopy (EIS) measurements were performed at each elongation heat cycle. The charge transfer resistance (Rct) was initially low due to the presence of [Ru(bpy)2DPPZ]2+ in the solution. As PCR progressed, amplicon dsDNA was produced exponentially, and intercalated [Ru(bpy)2DPPZ]2+ ions, which could be detected as a steep Rct, increased at specific heat cycles depending on the amount of template DNA. The Rct increase per heat cycle, ΔRct, showed a peak at the same heat cycle as optical detection, proving that PCR can be accurately monitored in real time by impedance measurement. This simple method will enable a cost-effective and portable PCR device.

[Primary Cutaneous Anaplastic Large Cell Lymphoma:Report of One Case].

Primary cutaneous anaplastic large cell lymphoma is a rare non-Hodgkin's lymphoma.The tumor cells have the characteristics of anaplastic cells,expressing CD30 but not anaplastic lymphoma kinase.In this study,we reported a case of primary cutaneous anaplastic large cell lymphoma in a Tibetan child and summarized the clinicopathological features,aiming to strengthen the understanding of this disease.

[Retrospective Analysis of Pathological Diagnosis of Central Nervous System Diseases in Tibet].

Objective To analyze the disease spectrum and clinicopathological characteristics of central nervous system(CNS)diseases diagnosed based on pathological findings in Tibet. Methods We collected the data of all the cases with CNS lesions in Tibet Autonomous Region People's Hospital from January 2013 to December 2020.The clinicopathological features were analyzed via light microscopy,immunohistochemical staining,and special staining. Results A total of 383 CNS cases confirmed by pathological diagnosis were enrolled in this study,with a male-to-female ratio of 188∶195 and an average age of(40.03±17.39)years(0-74 years).Among them,127(33.2%)cases had non-neoplastic diseases,with a male-to-female ratio of 82∶45 and an average age of(31.99±19.29)years;256(66.8%)cases had neoplastic diseases,with a male-to-female ratio of 106∶150 and an average age of(44.01±14.87)years.The main non-neoplastic diseases were nervous system infectious diseases,cerebral vascular diseases,meningocele,cerebral cyst,and brain trauma.Among the infectious diseases,brain abscess,granulomatous inflammation,cysticercosis,and hydatidosis were common.The main neoplastic diseases included meningioma,pituitary adenoma,neuroepithelial tumor,schwannoma,metastatic tumor,and hemangioblastoma.The meningioma cases consisted of 95.4%(103/108)cases of grade Ⅰ,3.7%(4/108)cases of grade Ⅱ,and only 1(1/108,0.9%)case of grade Ⅲ.Among the neuroepithelial tumor cases,the top three were glioblastoma,grade Ⅲ diffuse glioma,and ependymoma. Conclusions There are diverse CNS diseases confirmed by pathological diagnosis in Tibet,among which non-neoplastic diseases account for 1/3 of all the cases.Infectious and vascular diseases are the most common non-neoplastic diseases in Tibet,and tuberculosis and parasitic infections are relatively common.The types and proportion of brain tumors in Tibet are different from those in other regions of China,and meningioma is the most common in Tibet,with higher proportion than neuroepithelial tumor.

[Correlations of Androgen Receptor Expression with Molecular Subtypes and Clinopathological Features of Invasive Breast Carcinoma of No Special Type in Tibet].

Objective To investigate the expression of androgen receptor(AR)and its correlations with different molecular subtypes and clinicopathological features of breast invasive carcinoma of no special type(IBC-NST)in females of Tibetan ethnic minority in Tibet.Methods This study enrolled 54 female patients of Tibetan ethnic minority with IBC-NST surgically removed in the Tibet Autonomous Region People's Hospital from December 2015 to March 2021 for retrospective analysis.The clinical and pathological data of all the enrolled patients were collected.The immunohistochemical method was employed to determine the expression of AR,cell proliferation marker antigen (Ki-67),estrogen receptor(ER),human epidermal growth factor receptor 2(HER-2),and progesterone receptor(PR).For those with unclear HER-2 results,fluorescence in situ hybridization was employed for the determination.The relationship of AR expression with molecular subtypes and clinicopathological features was then analyzed.Results The expression of AR in Tibetan female patients with IBC-NST was correlated with ER(χ2=8.200,P=0.004),PR(χ2=9.900,P=0.003),and molecular subtype(χ2=11.690,P=0.009)and not correlated with tumor location,age,size,histological grade,lymph node metastasis,vascular invasion,clinical stage,or expression of HER-2 and Ki-67(all P>0.05).Molecular subtype was correlated with histological grade(χ2=24.970, P=0.001),clinical stage(χ2=9.035, P=0.029),and lymph node metastasis(χ2=9.691,P=0.021).Conclusions The positive expression rate of AR in the triple-negative IBC-NST patients of Tibetan ethnic minority was significantly lower than that in ER-or PR-positive patients in Tibet.Molecular subtype was correlated with histological grade,clinical stage,and lymph node metastasis.

[Clinicopathological Features of Meningiomas in Tibet].

Objective To analyze the clinicopathological features and immunohistochemical expression of meningiomas in the Tibetan population in Tibet,and improve the understanding of meningiomas. Methods The clinical and pathological data of all the meningiomas diagnosed by pathology in Tibet Autonomous Region People's Hospital from April 2013 to March 2021 were analyzed retrospectively.All the cases underwent immunohistochemical staining of trimethylation of lysine 27 on histone H3 (H3K27me3),mucin 4 (MUC4),somatostatin receptor 2 (SSTR2),progesterone receptor,epithelial membrane antigen,glial fibrillary acidic protein,vimentin,S-100,P53,and Ki-67.The histopathological features and the staining results were observed under a light microscope. Results A total of 116 cases of meningiomas were included in this study,with the male-to-female ratio of 1.0∶2.6 and the age of 4-73 years.The main clinical symptom was headache.The imaging examination showed that 114 cases had single lesions and 2 cases had multiple lesions.The tumors were located in the cranium (108 cases) and spinal canal (8 cases).The maximum diameter of the tumors ranged from 0.3 cm to 10.0 cm,with a mean of (5.7±2.2) cm.In terms of microscopic grading and histological types,the 116 cases included 111 cases of WHO grade Ⅰ (including 53 cases of fibrous type,20 cases of meningothelial type,24 cases of transitional type,10 cases of psammomatous type,etc.),4 cases of WHO grade Ⅱ (3 cases of atypical type and 1 case of clear cell type),and 1 case of WHO grade Ⅲ (papillary type).The immunohistochemical staining showed H3K27me3 expression absent in 9 cases (9/116,7.8%),MUC4 positive in 64 cases (64/116,55.2%),SSTR2 positive in 101 cases (101/116,87.1%).Eighty cases had follow-up results,among which 71 cases had no recurrence,while 9 cases recurred. Conclusions Meningioma is the most common tumor in the central nervous system in the pathological file of Tibet.It mainly attacks the middle-aged female patients,occupying the parasagittal sinus,falx,and convex surface of the brain.Fibrous meningioma of WHO grade Ⅰ is common,while the meningiomas of WHO grades Ⅱ and Ⅲ are rare.The expression degree of MUC4 is higher in meningothelial and transitional meningiomas but lower in fibrous meningiomas.There may be no correlation between the absence of H3K27me3 expression and prognosis.

[Clinical Analysis of ABO-Incompatible Living-Donor Liver Transplantation in Children].

Objective: To evaluate the safety and clinical efficacy of ABO-incompatible living-donor liver transplantation (LDLT) in children. Methods: The clinical data of 62 children who underwent for the first time living donor liver transplantation in our hospital from April 2019 to July 2020 were retrospectively analyzed. According to the blood type matching of donor and recipient, the patients were divided into 3 groups, ABO-identical (ABO-Id, n=33), ABO-compatible (ABO-C, n=10) and ABO-incompatible (ABO-In, n=19), the median age of recipients in the three groups being 5 months. In the ABO-In group, 4 recipients whose condition was combined with liver failure and 2 recipients who had blood group antibody titers≥1∶32 received preoperative plasma exchange. All ABO-incompatible recipients had preoperative blood group antibody titers<1∶32. All recipients in the three groups underwent piggyback liver transplantation and received immunosuppressive and anticoagulation therapy. Postoperative follow-up was 5 to 20 months, the median being 12 months, measured until December 31, 2020 or until the date of death. Baseline clinical data, postoperative survival, and postoperative complications of recipients in the three groups were analyzed. Results: There were no significant differences in age, gender, underlying disease, operation history, Child Pugh score, donor age, graft to recipient weight ratio (GR/WR), cold ischemia time, warm ischemia time, duration of surgery, intraoperative blood loss and the use of immunosuppressants among the recipients in the three groups (all P>0.05). There was one death in the perioperative period and two deaths in the postoperative period in the ABO-Id group. There was one death in the postoperative period in the ABO-C group. There was one death in the perioperative period and one death in the postoperative period in the ABO-In group. There was no significant difference in the overall cumulative survival rate among the three groups ( P>0.05). There were no significant differences in the incidence of postoperative infection, acute rejection, biliary anastomotic stenosis and vascular complications among the three groups ( P>0.05). Conclusion: ABO-In LDLT is an effective and safe treatment option that can effectively expand the pool of live donors for liver transplantation and save the life of children with end-stage liver disease.

Clinical characteristics of COVID-19 patients with hepatitis B virus infection - a retrospective study.

BACKGROUND & AIMS: The outbreak of coronavirus disease 2019 (COVID-19) has been declared a pandemic. Although COVID-19 is caused by infection in the respiratory tract, extrapulmonary manifestations including dysregulation of the immune system and hepatic injury have been observed. Given the high prevalence of hepatitis B virus (HBV) infection in China, we sought to study the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HBV coinfection in patients. METHODS: Blood samples of 50 SARS-CoV-2 and HBV coinfected patients, 56 SARS-CoV-2 mono-infected patients, 57 HBeAg-negative chronic HBV patient controls and 57 healthy controls admitted to Renmin Hospital of Wuhan University were collected in this study. Complete blood count and serum biochemistry panels including markers indicative of liver functions were performed. Cytokines including IFN-γ, TNF-α, IL-2, IL-4, IL-6 and IL-10 were evaluated. T cell, B cell and NK cell counts were measured using flow cytometry. RESULTS: SARS-CoV-2 and HBV coinfection did not significantly affect the outcome of the COVID-19. However, at the onset of COVID-19, SARS-CoV-2 and HBV coinfected patients showed more severe monocytopenia and thrombocytopenia as well as more disturbed hepatic function in albumin production and lipid metabolism. Most of the disarrangement could be reversed after recovery from COVID-19. CONCLUSIONS: While chronic HBV infection did not predispose COVID-19 patients to more severe outcomes, our data suggest SARS-CoV-2 and HBV coinfection poses a higher extent of dysregulation of host functions at the onset of COVID-19. Thus, caution needs to be taken with the management of SARS-CoV-2 and HBV coinfected patients.

[Clinicopathological Features and Expression of P504s,E-cadherin,Erythroblast Transformation-specific Related Gene and Estrogen Receptor in Prostate Adenocarcinoma in Tibet].

Objective To investigate the clinicopathological features and immunohistochemical expression of P504s,E-cadherin,erythroblast transformation-specific related gene(ERG)and estrogen receptor(ER)in prostate adenocarcinoma in Tibet.Methods The clinical data of 15 patients with prostate adenocarcinoma diagnosed by the Department of Pathology of Tibet Autonomous Region People's Hospital from September 2013 to September 2020 were analyzed retrospectively.All patients were assigned to prognostic grade groups based on Gleason score according to the WHO 2016 criteria.Immunostaining of P504s,E-cadherin,ERG,and ER was performed.Results The age of all 15 patients ranged from 61 to 86 years.The serum prostate specific antigen(PSA)concentration was ≥20 ng/ml in 12 patients and<20 ng/ml in 3 patients.Among the 15 patients,11 underwent needle biopsy,1 transurethral resection of the prostate,and 3 radical prostatectomy.Prognostic grouping results revealed 5 cases in grade groups 1-3,4 cases in grade group 4,and 6 cases in grade group 5.Immunohistochemistrically,15 cases(100%)were positive for P504s,E-cadherin and PSA;one case(7%)was positive for ERG;all cases were negative for P63,ER and CK34ßE12.Thirteen cases were followed up for 2-48 months,with 2 cases treated with total prostatectomy and 11 cases with non-surgical treatment.Two cases were lost to follow-up. Conclusions Prostate adenocarcinoma is rare relatively in Tibet.The accuracy of diagnosis can be improved by using multiple immunohistochemical markers.The cases of grades 4 and 5 by pathological confirmed are relatively common in Tibet.P504s and E-cadherin are highly expressed in prostate adenocarcinoma patients in Tibet,while ERG presents low expression,ER is unexpressed.

[Clinicopathological Analysis of Brain Metastatic Carcinoma in Tibet].

Objective To investigate the clinicopathological features and immunohistochemical phenotypes of brain metastatic carcinoma in Tibetan patients. Methods The clinical and pathological data of all patients with brain metastases from 2014 to 2020 in Tibet Autonomous Region People's Hospital were retrospectively analyzed,including 13 cases of brain metastatic carcinoma.All cases were diagnosed and classified by immunohistochemical staining. Results 13 cases(9 males and 4 females)of brain metastatic carcinoma,aged 26-62 years old,present with headache,dizziness,nausea and vomiting clinically.Four patients had a medical history of tumor,and among the 9 patients with no history of tumor,7 present space occupying lesions in both the brain and other organs.Imaging data could be found in 10 cases,including 4 cases of single lesion and 6 cases of multiple lesions.Primary tumors were identified in 11 cases(8 located in the lung,including 4 cases of adenocarcinoma,3 cases of small cell carcinoma,and 1 case of squamous cell carcinoma;1 case of urothelial carcinoma of the renal pelvis;1 case of thyroid papillary carcinoma;1 case of uterine choriocarcinoma),whereas the primary tumor was unknown for the other 2 cases(1 case of small cell carcinoma and 1 case of adenocarcinoma). Conclusions Brain metastatic carcinoma are more common among middle-aged and elderly people in Tibet.Most of the cases have no history of tumor,with the initial site at the brain metastatic lesions.The most common primary site is the lung,and the primary site of some cases is unknown.Multiple lesions are common in brain metastatic carcinoma,especially in the cerebral hemisphere.For older patients with multiple brain space occupying lesions,the possibility of brain metastatic carcinoma increases.

Peptide SMIM30 promotes HCC development by inducing SRC/YES1 membrane anchoring and MAPK pathway activation.

BACKGROUND & AIMS: Growing evidence shows that some non-coding RNAs (ncRNAs) contain small open reading frames (smORFs) that are translated into short peptides. Herein, we aimed to determine where and how these short peptides might promote hepatocellular carcinoma (HCC) development. METHODS: We performed an RNA-immunoprecipitation followed by high-throughput sequencing (RIP-seq) assay with an antibody against ribosomal protein S6 (RPS6) on 4 cancer cell lines. Focusing on 1 long non-coding RNA (lncRNA), LINC00998, we used qPCR and public databases to evaluate its expression level in patients with HCC. Special vectors were constructed to confirm its coding potential. We also explored the function and mechanism of LINC00998-encoded peptide in tumor growth and metastasis. RESULTS: We discovered that many lncRNAs bind to RPS6 in cancer cells. One of these lncRNAs, LINC00998, encoded a small endogenous peptide, termed SMIM30. SMIM30, rather than the RNA itself, promoted HCC tumorigenesis by modulating cell proliferation and migration, and its level was correlated with poor survival in patients with HCC. Furthermore, SMIM30 was transcribed by c-Myc and then drove the membrane anchoring of the non-receptor tyrosine kinases SRC/YES1. Moreover, the downstream MAPK signaling pathway was activated by SRC/YES1. CONCLUSIONS: Our results not only unravel a new mechanism of HCC tumorigenesis promoted by ncRNA-encoded peptides, but also suggest that these peptides can serve as a new target for HCC cancer therapy and a new biomarker for HCC diagnosis and prognosis. LAY SUMMARY: Very little is known about how peptides activate signaling pathways that play a crucial role in diseases such as cancer. Specifically, we reported on a conserved peptide encoded by LINC00998, SMIM30. This peptide promoted the tumorigenesis of hepatocellular carcinoma (HCC) by modulating cell proliferation and migration. Of note, it bound the non-receptor tyrosine kinases, SRC/YES1, to drive their membrane anchoring and phosphorylation, activating the downstream MAPK signaling pathway. Our work not only unravels a new mechanism of HCC tumorigenesis promoted by peptides, but also demonstrates how the peptide works to activate a signaling pathway.

Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan, China.

An outbreak of severe acute respiratory syndrome novel coronavirus (SARS-CoV-2) epidemic spreads rapidly worldwide. SARS-CoV-2 infection caused mildly to seriously and fatally respiratory, enteric, cardiovascular, and neurological diseases. In this study, we detected and analyzed the main laboratory indicators related to heart injury, creatine kinase isoenzyme-MB (CK-MB), myohemoglobin (MYO), cardiac troponin I (ultra-TnI), and N-terminal pro-brain natriuretic peptide (NT-proBNP), in 273 patients with COVID-19 and investigated the correlation between heart injury and severity of the disease. It was found that higher concentration in venous blood of CK-MB, MYO, ultra-TnI, and NT-proBNP were associated with the severity and case fatality rate of COVID-19. Careful monitoring of the myocardiac enzyme profiles is of great importance in reducing the complications and mortality in patients with COVID-19.

The value of urine biochemical parameters in the prediction of the severity of coronavirus disease 2019.

Background Among patients with coronavirus disease 2019 (COVID-19), the cases of a significant proportion of patients are severe. A viral nucleic acid test is used for the diagnosis of COVID-19, and some hematological indicators have been used in the auxiliary diagnosis and identification of the severity of COVID-19. Regarding body fluid samples, except for being used for nucleic acid testing, the relationship between COVID-19 and routine body fluid parameters is not known. Our aim was to investigate the value of urine biochemical parameters in the prediction of the severity of COVID-19. Methods A total of 119 patients with COVID-19 were enrolled at Renmin Hospital of Wuhan University. According to the severity of COVID-19, the patients were divided into three groups (moderate 67, severe 42 and critical 10), and 45 healthy persons were enrolled in the same period as healthy controls. The relationship between the results of urine biochemical parameters and the severity of COVID-19 was analyzed. Results The positive rates of urine occult blood (BLOOD) and proteinuria (PRO) were higher in COVID-19 patients than in healthy controls (p < 0.05); the urine specific gravity (SG) value was lower in patients than in healthy controls (p < 0.05), and the urine potential of hydrogen (pH) value was higher in patients than in healthy controls (p < 0.01). The positive rates of urine glucose (GLU-U) and PRO in the severe and critical groups were higher than those in the moderate group (p < 0.01 and p < 0.05, respectively); other biochemical parameters of urine were not associated with the severity of COVID-19. Conclusions Some urine biochemical parameters are different between patients with severe acute respiratory syndrome (SARS)-CoV-2 and healthy controls, and GLU-U and PRO may be helpful for the differentiation of COVID-19 severity.

Prominent changes in blood coagulation of patients with SARS-CoV-2 infection.

Background As the number of patients increases, there is a growing understanding of the form of pneumonia sustained by the 2019 novel coronavirus (SARS-CoV-2), which has caused an outbreak in China. Up to now, clinical features and treatment of patients infected with SARS-CoV-2 have been reported in detail. However, the relationship between SARS-CoV-2 and coagulation has been scarcely addressed. Our aim is to investigate the blood coagulation function of patients with SARS-CoV-2 infection. Methods In our study, 94 patients with confirmed SARS-CoV-2 infection were admitted in Renmin Hospital of Wuhan University. We prospectively collect blood coagulation data in these patients and in 40 healthy controls during the same period. Results Antithrombin values in patients were lower than that in the control group (p < 0.001). The values of D-dimer, fibrin/fibrinogen degradation products (FDP), and fibrinogen (FIB) in all SARS-CoV-2 cases were substantially higher than those in healthy controls. Moreover, D-dimer and FDP values in patients with severe SARS-CoV-2 infection were higher than those in patients with milder forms. Compared with healthy controls, prothrombin time activity (PT-act) was lower in SARS-CoV-2 patients. Thrombin time in critical SARS-CoV-2 patients was also shorter than that in controls. Conclusions The coagulation function in patients with SARS-CoV-2 is significantly deranged compared with healthy people, but monitoring D-dimer and FDP values may be helpful for the early identification of severe cases.

Discovery of Two New Sorbicillinoids by Overexpression of the Global Regulator LaeA in a Marine-Derived Fungus Penicillium dipodomyis YJ-11.

Overexpression of the global regulator LaeA in a marine-derived fungal strain of Penicillium dipodomyis YJ-11 induced obvious morphological changes and metabolic variations. Further chemical investigation of the mutant strain afforded a series of sorbicillinoids including two new ones named 10,11-dihydrobislongiquinolide (1) and 10,11,16,17-tetrahydrobislongiquinolide (2), as well as four known analogues, bislongiquinolide (3), 16,17-dihydrobislongiquinolide (4), sohirnone A (5), and 2',3'-dihydrosorbicillin (6). The results support that the global regulator LaeA is a useful tool in activating silent gene clusters in Penicillium strains to obtain previously undiscovered compounds.