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1.
BMC Neurol ; 21(1): 432, 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34740330

RESUMO

OBJECTIVE: To explore the sensitivity of median and ulnar nerve sensory latency differences in diagnosing carpal tunnel syndrome (CTS) at different severities. METHODS: CTS patients were divided into three groups based on disease severity (mild, moderate, and severe). Distal latency of sensory nerve action potential (SNAP) for the median and ulnar nerves was recorded. The sensitivity of SNAP distal latency to CTS and its correlation with CTS severity were analyzed. RESULTS: Significant differences were found in the median nerve sensory action potential distal latency (MSDL) and in the median and ulnar sensory latency difference to ring finger (MUD) but not in the ulnar nerve sensory action potential distal latency (USDL) between CTS and control. The sensitivity and specificity were 92.2 and 99.4% with an MSDL cutoff value of 2.40 ms, respectively, and were both 100% with a MUD cutoff value of 0.33 ms. There was no significant difference in USDL among the CTS and control groups. Significant differences were found in MSDL and MUD among the CTS severities and between mild and moderate CTS, but not between mild and severe CTS or between moderate and severe CTS. Correlations with CTS severity were observed for MSDL and MUD but not for USDL. CONCLUSION: The ulnar nerve of the CTS patients was not damaged. A smaller MSDL reflected median nerve damage, which can be used for the early diagnosis of CTS. MUD correlated with CTS severity with a higher sensitivity than MSDL, which can provide therapeutic insight without pain to patients.


Assuntos
Síndrome do Túnel Carpal , Síndrome do Túnel Carpal/diagnóstico , Síndrome do Túnel Carpal/terapia , Dedos , Humanos , Nervo Mediano , Condução Nervosa , Nervo Ulnar
2.
Ann Transl Med ; 9(17): 1374, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34733926

RESUMO

Background: Gallbladder carcinoma (GBC) remains a highly lethal disease worldwide. MiR-552 family members promote the malignant progression of a variety of digestive system tumors, but the role of miR-552-3p in GBC has not been elucidated. miR-552-3p was predicted to target the 3'-untranslated region (3'UTR) of the mRNA for the tumor suppressor gene "repulsive guidance molecule BMP co-receptor a" (RGMA). The aim of the present study was to clarify the roles and mechanisms of miR-552-3p targeting RGMA in the malignant progression of GBC. Methods: In vitro: expression of miR-552-3p was detected by real-time quantitative PCR (qRT-PCR) in tumor and non-tumor adjacent tissues (NATs). Lentivirus-miR-552-3p was employed to knockdown this miRNA in GBC cell lines. Stem cell-related transcription factors and markers were assessed by qRT-PCR. Cell Counting Kit-8 (CCK-8), sphere formation and transwell assays were used to determine the malignant phenotypes of GBC cells. Targeting the 3'UTR of RGMA by miR-552-3p was verified by integrated analysis including bioinformatics prediction, luciferase assays, measures of changes of gene expression and rescue experiments. In vivo: mouse models of subcutaneous tumors and lung metastases were established to observe the effect of miR-552-3p on tumorigenesis and organ metastasis, respectively. Results: MiR-552-3p was abnormally highly expressed in GBC tissues and cancer stem cells. Interference with miR-552-3p in SGC-996 and GBC-SD cells significantly inhibited GBC stem cell expansion. Reciprocally, miR-552-3p promoted GBC cell proliferation, migration and invasion both in vitro and in vivo; hence, interference with this miRNA impeded the malignant progression of GBC. Furthermore, the important tumor suppressor gene RGMA was identified as a target of miR-552-3p. The effects of miR-552-3p on cell proliferation and metastasis were abrogated or enhanced by gain or loss of RGMA function, respectively. Mechanistically, miR-552-3p promoted GBC progression by reactivating the Akt/ß-catenin pathway and epithelial-mesenchymal transformation (EMT). Clinically, miR-552-3p correlated with multi-malignant characteristics of GBC and acted as a prognostic marker for GBC outcome. Conclusions: MiR-552-3p promotes the malignant progression of GBC by inhibiting the mRNA of the tumor suppressor gene RGMA, resulting in reactivation of the Akt/ß-catenin signaling pathway.

3.
Plant Commun ; 2(6): 100234, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34778748

RESUMO

Arsenic is a metalloid that is toxic to plants. Arsenate (As(V)), the prevalent chemical form of arsenic, is a phosphate (Pi) analog and is incorporated into plant cells via Pi transporters. Here, we found that the MYB40 transcription factor played important roles in the control of Arabidopsis As(V) resistance. The expression of MYB40 was induced by As(V) stress. MYB40-overexpressing lines had an obvious As(V)-resistant phenotype and a reduced As(V)/Pi uptake rate, whereas myb40 mutants were sensitive to As(V) stress. Upon exposure to As(V), MYB40 directly repressed the expression of PHT1;1, which encodes a main Pi transporter. The As(V)-resistant phenotypes of MYB40-overexpressing lines were impaired by overexpression of PHT1;1, demonstrating an epistatic genetic relationship between MYB40 and PHT1;1. Moreover, overexpression of MYB40 enhanced, and disruption of MYB40 reduced, thiol-peptide contents. Upon exposure to As(V), MYB40 positively regulated the expression of PCS1, which encodes a phytochelatin synthase, and ABCC1 and ABCC2, which encode the major vacuolar phytochelatin transporters. Together, our data demonstrate that AtMYB40 acts as a central regulator of As(V) responses, providing a genetic strategy for enhancing plant As(V) tolerance and reducing As(V) uptake to improve food safety.

4.
Zhongguo Zhong Yao Za Zhi ; 46(19): 4930-4935, 2021 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-34738386

RESUMO

The endophytes of medicinal plants play an important role in promoting the quality formation of the host. Therefore, this paper made a review of endophytes of medicinal plant Atractylodes lancea. According to previous studies, A. lancea boasts endophytes, such as fungi, bacteria, and actinomycetes, among which the beneficial microorganisms help the growth and development of A. lancea. There is a close interaction between the volatile oil of A. lancea and endophytes. Different endophytes vary in regulating the composition and content of the volatile oil of A. lancea, which might contribute to the quality formation of A. lancea. However, the information of the endophytic flora of A. lancea obtained by traditional culture and isolation is not enough to reflect the real situation of the endophytes of A. lancea. Little is known about the endophytes of A. lancea from different chemical types and different habitats, which is not conducive to the study of the ecological relationship between A. lancea and endophytes and limits the development and utilization of the endophytes. Therefore, at the end of this paper, the authors put forward suggestions for future research on endophytes in A. lancea, including:(1)mining the core endophyte resources of A. lancea by combining high-throughput sequencing with traditional culture and isolation;(2)exploring the relationship between the diversity of endophytes and chemical types of A. lancea;(3)strengthening the application of endophytes in A. lancea cultivation, in order to facilitate the cultivation efficiency and quality of A. lancea.


Assuntos
Atractylodes , Óleos Voláteis , Plantas Medicinais , Endófitos , Fungos
5.
Infect Drug Resist ; 14: 4039-4046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34616161

RESUMO

Objective: This study aimed to determine the prevalence of antibiotic resistance and virulence genes of Escherichia coli strains among patients with urinary tract infections (UTIs) after kidney transplantation from deceased donors. Methods: Between January 2014 and June 2018, 64 patients who received kidney transplants from deceased donors at our institution developed a UTI due to E. coli. Polymerase chain reaction was used to detect virulence genes in E. coli strains. The Kirby-Bauer method was used to evaluate the antibiotic susceptibility pattern of the isolates. Results: Among the study cohort, 46 (71.9%) UTIs were community-acquired (CA), and 18 (28.1%) were hospital-acquired (HA). The percentages of isolated E. coli strains that showed antibiotic resistance were as follows: 92.2% to ampicillin, 76.6% to cefalotin, 81.3% to carbenicillin, 29.7% to ciprofloxacin, 62.5% to cotrimoxazole, 35.9% to gentamicin, 34.4% to levofloxacin, 28.1% to norfloxacin, 68.8% to pefloxacin, 57.8% to trimethoprim/sulfamethoxazole, and 20.3% to amikacin. HA E. coli showed higher resistance to ciprofloxacin, cotrimoxazole, trimethoprim/sulfamethoxazole and amikacin, compared with CA E. coli (P<0.05). The most prevalent virulence genes among the E. coli strains were fim (64.1%), followed by irp2 (56.3%), iroN (46.9%), pap GII (45.3%), sfa (31.3%), pap (25%), iuc (23.4%), pap GI (15.6%), pap GIII (14.1%), hly (9.4%), and cnf (4.7%). The irp2 and iroN genes were found more frequently in the HA E. coli than in the CA E. coli (P<0.05). Conclusion: The E. coli strains, especially HA E. coli, isolated from UTI patients after kidney transplantation from deceased donors showed resistance to multiple antibiotics and harbored numerous virulence genes. These findings provide insight for genetic characterizations and epidemiological studies of E. coli strains causing UTIs in patients after kidney transplantation from deceased donors.

6.
Sci Rep ; 11(1): 19566, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599231

RESUMO

The high-quality development of the manufacturing industry is an important strategic task for Chinese economic development. The rapid development of the manufacturing industry is also accompanied by problems such as overcapacity and environmental pollution. This paper analyzes the impact of capacity utilization on the high-quality development of manufacturing and establishes a nonlinear threshold regression model on this basis, and studies and analyzes environmental regulations as a threshold variable under the influence of capacity utilization rate on the high-quality development of the manufacturing industry. The research results show that: capacity utilization, profitability, foreign direct investment, and government participation all have a significant positive impact on the high-quality development of the manufacturing industry; environmental regulations have a significant negative impact on the high-quality development of the manufacturing industry. And in the model of the effect of capacity utilization on the high-quality development of the manufacturing industry, environmental regulation has a single threshold effect. With the increase in the intensity of environmental regulation, the coefficient and significance of the effect of capacity utilization on the high-quality development of the manufacturing industry have changed. Finally, this article puts forward corresponding policies and suggestions based on the results of data analysis.

7.
Front Cell Dev Biol ; 9: 749484, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34692702

RESUMO

Objective: The objective of this study is to analyze the genotype-phenotype correlation of patients with auditory neuropathy (AN), which is a clinical condition featuring normal cochlear responses and abnormal neural responses, and ATP1A3 c.2452 G > A (p.E818K), which has been generally recognized as a genetic cause of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. Methods: Four patients diagnosed as AN by clinical evaluation and otoacoustic emission and auditory brainstem responses were recruited and analyzed by next-generation sequencing to identify candidate disease-causing variants. Sanger sequencing was performed on the patients and their parents to verify the results, and short tandem repeat-based testing was conducted to confirm the biological relationship between the parents and the patients. Furthermore, cochlear implantation (CI) was performed in one AN patient to reconstruct hearing. Results: Four subjects with AN were identified to share a de novo variant, p.E818K in the ATP1A3 gene. Except for the AN phenotype, patients 1 and 2 exhibited varying degrees of neurological symptoms, implying that they can be diagnosed as CAPOS syndrome. During the 15 years follow-up of patient 1, we observed delayed neurological events and progressive bilateral sensorineural hearing loss in pure tone threshold (pure tone audiometry, PTA). Patient 2 underwent CI on his left ear, and the result was poor. The other two patients (patient 3 and patient 4, who were 8 and 6 years old, respectively) denied any neurological symptoms. Conclusion: ATP1A3 p.E818K has rarely been documented in the Chinese AN population. Our study confirms that p.E818K in the ATP1A3 gene is a multiethnic cause of AN in Chinese individuals. Our study further demonstrates the significance of genetic testing for this specific mutation for identifying the special subtype of AN with somewhat favorable CI outcome and offers a more accurate genetic counseling about the specific de novo mutation.

8.
Dokl Biochem Biophys ; 500(1): 408-414, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34697750

RESUMO

Acute kidney injury (AKI), one of the frequently diagnosed and serious sepsis induced complication has high morbidity and mortality. The present study investigated the bioprotective and functional effect of carnosine on AKI induced pathological damage in Male Albino rat model in vivo. AKI in Albino rats was induced by cecal ligation and puncture surgery where as TNF-α and IL-1ß levels were detected using ELISA assay. Protein expression was examined by western blotting and pathological damage using hematoxylin and eosin (H&E). Treatment with carnosine suppressed AKI induced urea nitrogen and creatinine in Male Albino rat serum in dose-dependent manner. Development of sepsis mediated renal injury in Albino rats was also effectively prevented on treatment with carnosine. Secretion of AKI-induced IL-1ß, IL-18, and TNF-α in renal tissues was alleviated significantly in Albino rats by carnosine treatment. Additionally, in carnosine-treated Albino rats renal tissues AKI induced Bax expression was alleviated while as Bcl-2 was promoted compared to AKI Albino rats. Carnosine treatment improved the survival rate of the Albino rats with AKI. Carnosine inhibits renal tissue damage and increases survival rate in AKI Albino rat model. The mechanism involves alleviation of inflammatory cytokine secretion and promotion of Bcl-2 expression. Thus, carnosine may be used as a therapeutic agent for treatment of AKI.

9.
Ying Yong Sheng Tai Xue Bao ; 32(9): 3159-3166, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34658201

RESUMO

We analyzed soil water, nutrients, and yields in three different slope sites in the sloping farmland under Yuluxiang pear planted in the loess hilly region of Western Shanxi, across the growth periods and different soil depths. The results showed that: 1) The yield of pear was in the order of high slope site > middle slope site > low slope site. In high slope site, the yield was significantly correlated with soil water content (SWC), soil organic matter (SOM), available potassium (AK), with AK showing the most significant effect. The yield of pear in middle and low slope sites was significantly correlated with SWC, SOM, and total nitrogen (TN), with SWC having the most significant effect on yield. The contents of SWC, SOM, available phosphorus (AP) and TN in high slope site were higher than in middle and low slope sites, while AK was the highest in middle slope site. 2) Among different soil depths, soil nutrient contents were the highest within 0-20 cm soil layer, but the lowest within 20-40 cm soil layer. The SWC was significantly lower within 0-20 cm than the other soil layers and was the highest within 20-40 cm soil layer. 3) Among different growth periods, the contents of SOM, AP, and TN were the highest in flowering period, the SWC was the highest in fruiting period, and AK content was the highest in maturing period. It was suggested that in the future management of pear water and fertilizer in the region, more K fertilizer should be applied in the high slope sites in the flowering period, while N and P compound fertilizer should be applied in the fruiting period, to enhance irrigation in middle and low slope sites to decrease the limitation of water with 300 m3·hm-2. Our results could provide theoretical support and data refe-rence for planting precision irrigation and scientific fertilization of pear planted in loess hilly areas.


Assuntos
Pyrus , Solo , Nutrientes , Fósforo , Água
10.
Nanotechnology ; 33(3)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34614489

RESUMO

This study reported a novel method to obtain rutile TiO2with excellent photocatalytic activity for degradation of organic dyes. In this study, the concentrated HCl was selected as the inhibitor to make TiO2precursor hardly hydrolyzed at room temperature. And a certain amount of urea was added, which results in TiO2precursor hydrolyzed to produce rutile TiO2due to urea thermally decomposed into alkaline substances to neutralize the concentrated HCl. To further explore the mechanism of excellent photocatalytic performance of rutile TiO2, a series of experiments, characterizations, and DFT computations were carried out. Based on DFT computations and experimental results, it could be concluded that the introduction of surface oxygen vacancies was the main reason for the excellent photocatalytic performance of the samples, and the concentration of surface oxygen vacancies would affect the physical and chemical properties of rutile TiO2. Meaningfully, this unique and innovative work broke the traditional preconception of rutile TiO2and provided a theoretical possibility for rutile TiO2to be applied in other research fields.

11.
ASN Neuro ; 13: 17590914211043087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34579557

RESUMO

Maternal social stress among breastfeeding women can be adapted in chronic process. However, neuroendocrine mechanisms underlying such adaptation remain to be identified. Here, we report the effects of 2 hr/day unfamiliar male rat invasion (UMI) stress on maternal behaviors in lactating rats during postpartum day 8 (UMI8) to postpartum day 12 (UMI12). Rat dams at UMI8 presented signs of maternal anxiety, depression, and attacks toward male intruder. These changes partially reversed at UMI12 except the sign of anxiety. In the supraoptic nucleus (SON), UMI12 but not UMI8 significantly increased the expression of c-Fos and phosphorylated extracellular signal-regulated protein kinase 1/2. At UMI8 but not UMI12, length of glial fibrillary acidic protein (GFAP, astrocytic cytoskeletal element) filaments around oxytocin (OT) neurons was significantly longer than that of their controls; the amount of GFAP fragments at UMI12 was significantly less than that at UMI8. Expression of cystathionine ß-synthase (CBS, enzyme for H2S synthesis) at UMI12 was significantly higher than that at UMI8. CBS expression did not change significantly in the somatic zone of the SON but decreased significantly at the ventral glia lamina at UMI8. In brain slices of the SON, aminooxyacetate (a CBS blocker) significantly increased the expression of GFAP proteins that were molecularly associated with CBS. Aminooxyacetate also reduced the firing rate of OT neurons whereas Na2S, a donor of H2S, increased it. The adaptation during chronic social stress is possibly attributable to the increased production of H2S by astrocytes and the subsequent retraction of astrocytic processes around OT neurons.

12.
Cancer Biol Med ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34591416

RESUMO

The Wnt/ß-catenin signaling pathway regulates many aspects of tumor biology, and many studies have focused on the role of this signaling pathway in tumor cells. However, it is now clear that tumor development and metastasis depend on the two-way interaction between cancer cells and their environment, thereby forming a tumor microenvironment (TME). In this review, we discuss how Wnt/ß-catenin signaling regulates cross-interactions among different components of the TME, including immune cells, stem cells, tumor vasculature, and noncellular components of the TME in hepatocellular carcinoma. We also investigate their preclinical and clinical insights for primary liver cancer intervention, and explore the significance of using Wnt/ß-catenin mutations as a biomarker to predict resistance in immunotherapy.

13.
Acta Pharmacol Sin ; 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34349236

RESUMO

An epidemic of pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading worldwide. SARS-CoV-2 relies on its spike protein to invade host cells by interacting with the human receptor protein Angiotensin-Converting Enzymes 2 (ACE2). Therefore, designing an antibody or small-molecular entry blockers is of great significance for virus prevention and treatment. This study identified five potential small molecular anti-virus blockers via targeting SARS-CoV-2 spike protein by combining in silico technologies with in vitro experimental methods. The five molecules were natural products that binding to the RBD domain of SARS-CoV-2 was qualitatively and quantitively validated by both native Mass Spectrometry (MS) and Surface Plasmon Resonance (SPR). Anti-viral activity assays showed that the optimal molecule, H69C2, had a strong binding affinity (dissociation constant KD) of 0.0947 µM and anti-virus IC50 of 85.75 µM.

14.
Eur J Med Genet ; 64(10): 104311, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34416374

RESUMO

Hereditary hearing loss (HL) has high genetic and phenotypical heterogeneity including the overlapping and variable phenotypic features. For sporadic HL without a family history, it is more difficult to indicate the contribution of genetic factors to define a pattern of inheritance. We assessed the contribution of genetic variants and patterns of inheritance by a family trio-based sequencing and provided new insight into genetics. We conducted an analysis of data from unrelated sporadic patients with HL (n = 404) who underwent trio-based whole-exome sequencing (trio-WES) or proband-only WES (p-WES) or targeted exome sequencing (TES), and the samples of their unaffected-parents (n = 808)were validated. A molecular diagnosis was rendered for 191 of 404 sporadic HL patients (47.3%) in multiple modes of inheritance, including autosomal recessive (AR), autosomal dominant (AD) caused by de novo variants, copy-number variants (CNVs), X-linked recessive, and dual genetic diagnosis. Among these patients, 83 (43.5%) cases were diagnosed with variants in rare genes. Sporadic HL patients were identified by multiple modes of transmission. Observed variations in rare genes and multiple modes of inheritance can strikingly emphasize the important etiological contribution of recessive and de novo genetic variants to a large cohort of sporadic HL cases plus their parents.


Assuntos
Genes Recessivos , Perda Auditiva Neurossensorial/genética , Mutação , Adolescente , Adulto , Variações do Número de Cópias de DNA , Feminino , Frequência do Gene , Genes Dominantes , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Humanos , Masculino , Linhagem
15.
Hepatobiliary Surg Nutr ; 10(4): 464-475, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34430525

RESUMO

Background: Intrahepatic cholangiocarcinoma has heterogeneous outcomes after resection. There remains a need for broadly applicable recurrence-specific tool offering precise evaluation on curativeness of resection. Methods: A four hospital-based clinical cohort involving 1,655 patients with intrahepatic cholangiocarcinoma who received surgical resection were studied. Cox and logistic models were networked into one system containing risk categories with distinctive probabilities of recurrence. Prediction of time-to-recurrence was performed by formulizing time-dependent risk probabilities. The model was validated in three clinical cohorts (n=332). Results: From the training cohort, 10 and 11 covariates, including diabetes, cholelithiasis, albumin, platelet count, alpha fetoprotein, carbohydrate antigen 19-9, carcinoembryonic antigen, hepatitis B virus infection, tumor size and number, resection type, and lymph node metastasis, from Cox and logistic models were identified significant for recurrence-free survival (RFS). The combined Cox & logistic ranking system (CCLRS)-adjusted time-dependent probabilities were categorized into seven ranks (5-yr RFS for lowest and highest ranks were 75% vs. 0%; hazard ratio 18.5, 95% CI: 14.7-24.9, P<0.0001). The CCLRS was validated with a minimum area under curve value of 0.8086. Prediction of time-to-recurrence was validated to be excellent (Pearson r, 0.8204; P<0.0001). Conclusions: The CCLRS allows precise estimation on risk of recurrence for intrahepatic cholangiocarcinoma after resection. It could be applicative when estimating time-dependent disease status and stratifying individuals who sole resection of the tumor would not be curative.

16.
Hepatology ; 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34343359

RESUMO

BACKGROUND AND AIMS: Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS: A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS: In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.

17.
Liver Int ; 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34459095

RESUMO

BACKGROUND & AIMS: Preoperative obstructive jaundice is usually associated with higher post-operative mortality. Although external biliary drainage (EBD) has been widely used to relieve obstructive jaundice, the role of bile reinfusion after EBD is still controversial. The aim of our study was to study the effects of biliary obstruction, biliary drainage and bile reinfusion on bile acid metabolism and gut microbiota. METHODS: Firstly, we created a mice bile drainage collection (BDC) model to simulate the process of biliary obstruction, drainage and bile reinfusion. Then, we analysed the faecal, serum, liver and bile samples to investigate the effects of the process on bile acid profiles and gut microbiota. Finally, we evaluated the clinical effects of bile reinfusion. RESULTS: We evaluated the bile acid profiles of faeces, serum, liver and bile of normal mice. During biliary obstruction, secondary bile acids can still be produced, and increased in the liver and serum of mice. Compared with no bile reinfusion, bile reinfusion was beneficial to the recovery of T-ωMCA in the liver and bile, and can restore the colon crypt length shortened by biliary obstruction. Only Ruminococcus_1 proliferated when the biliary obstruction lasted for 12 days. In the clinic, bile reinfusion cannot accelerate the patient's perioperative recovery or prolong long-term survival. CONCLUSION: We have successfully created a mice bile drainage collection model. Short-term bile reinfusion can partially benefit the recovery of the secondary bile acids in the liver and bile, but hardly benefit the patient's perioperative recovery or long-term survival. (247 words).

18.
Cell Discov ; 7(1): 64, 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34373443

RESUMO

Coronavirus disease 2019 (COVID-19), driven by SARS-CoV-2, is a severe infectious disease that has become a global health threat. Vaccines are among the most effective public health tools for combating COVID-19. Immune status is critical for evaluating the safety and response to the vaccine, however, the evolution of the immune response during immunization remains poorly understood. Single-cell RNA sequencing (scRNA-seq) represents a powerful tool for dissecting multicellular behavior and discovering therapeutic antibodies. Herein, by performing scRNA/V(D)J-seq on peripheral blood mononuclear cells from four COVID-19 vaccine trial participants longitudinally during immunization, we revealed enhanced cellular immunity with concerted and cell type-specific IFN responses as well as boosted humoral immunity with SARS-CoV-2-specific antibodies. Based on the CDR3 sequence and germline enrichment, we were able to identify several potential binding antibodies. We synthesized, expressed and tested 21 clones from the identified lineages. Among them, one monoclonal antibody (P3V6-1) exhibited relatively high affinity with the extracellular domain of Spike protein, which might be a promising therapeutic reagent for COVID-19. Overall, our findings provide insights for assessing vaccine through the novel scRNA/V(D)J-seq approach, which might facilitate the development of more potent, durable and safe prophylactic vaccines.

19.
Curr Med Sci ; 41(4): 673-679, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34403091

RESUMO

OBJECTIVE: To investigate the genetic causes of sudden sensorineural hearing loss (SSNHL) patients in China. This study focused on analyzing variations of coding sequence of common genes related to deafness, revealing the molecular pathogenesis of sudden deafness from a genomics perspective, discovering molecular markers associated with the onset of deafness, and then supplying prevention to high-risk populations, classifying disease according to accurate etiology, and choosing a much more precision therapy. METHODS: We retrospectively analyzed the clinical characteristics of 51 patients diagnosed as SSNHL with vertigo treated in the Chinese PLA General Hospital. In this study, mutation screening of 307 nuclear genes and mitochondrial genome responsible for human or mouse deafness was performed on the 51 cases of unilateral sudden deafness patients with vertigo. RESULTS: We identified 51 cases of unilateral sudden deafness, including 2 cases of low-mid frequency hearing impairment, 18 cases of mid-high frequency hearing loss, 11 cases of flat-type hearing loss, and 20 cases of all frequency hearing loss. Among the 51 cases, 8 (15.69%) cases of GJB2 heterozygous variations, 1 (1.96%) case of GJB3 heterozygous variations, 5 (9.8%) cases of SLC26A4 heterozygous variations, 2 (3.92%) cases of COCH heterozygous variations, 14 (27.45%) cases of CDH23 heterozygous variations, 14 (27.45%) cases of OTOF heterozygous variations, 1 (1.96%) case of SLC17A8 heterozygous variations and 2 (3.92%) cases of KCNE1 heterozygous variations. No mtDNA gene variations were identified. CONCLUSION: SSNHL has some relationship with hereditary in Chinese population, but its complex genetic pathogenic mechanisms need further study.

20.
Cancer Res ; 81(18): 4778-4793, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34301762

RESUMO

N6-methyladenosine (m6A) has been reported as an important mechanism of posttranscriptional regulation. Programmed death-ligand 1 (PD-L1) is a primary immune inhibitory molecule expressed on tumor cells that promotes immune evasion. Here we report ALKBH5 as an important m6A demethylase that orchestrates PD-L1 expression in intrahepatic cholangiocarcinoma (ICC). Regulation of PD-L1 expression by ALKBH5 was confirmed in human ICC cell lines. Sequencing of the m6A methylome identified PD-L1 mRNA as a direct target of m6A modification whose levels were regulated by ALKBH5. Furthermore, ALKBH5 and PD-L1 mRNA were shown to interact. ALKBH5 deficiency enriched m6A modification in the 3'UTR region of PD-L1 mRNA, thereby promoting its degradation in a YTHDF2-dependent manner. In vitro and in vivo, tumor-intrinsic ALKBH5 inhibited the expansion and cytotoxicity of T cells by sustaining tumor cell PD-L1 expression. The ALKBH5-PD-L1-regulating axis was further confirmed in human ICC specimens. Single-cell mass cytometry analysis unveiled a complex role of ALKBH5 in the tumor immune microenvironment by promoting the expression of PD-L1 on monocytes/macrophages and decreasing the infiltration of myeloid-derived suppressor-like cells. Analysis of specimens from patients receiving anti-PD1 immunotherapy suggested that tumors with strong nuclear expression patterns of ALKBH5 are more sensitive to anti-PD1 immunotherapy. Collectively, these results describe a new regulatory mechanism of PD-L1 by mRNA epigenetic modification by ALKBH5 and the potential role of ALKBH5 in immunotherapy response, which might provide insights for cancer immunotherapies. SIGNIFICANCE: This study identifies PD-L1 mRNA as a target of ALKBH5 and reveals a role for ALKBH5 in regulating the tumor immune microenvironment and immunotherapy efficacy.

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