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Microneedles are a transdermal drug delivery system in which the needle punctures the epithelium to deliver the drug directly to deep tissues, thus avoiding the influence of the first-pass effect of the gastrointestinal tract and minimizing the likelihood of pain induction. Hydrogel microneedles are microneedles prepared from hydrogels that have good biocompatibility, controllable mechanical properties, and controllable drug release and can be modified to achieve environmental control of drug release in vivo. The large epithelial tissue in the oral cavity is an ideal site for drug delivery via microneedles. Hydrogel microneedles can overcome mucosal hindrances to delivering drugs to deep tissues; this prevents humidity and a highly dynamic environment in the oral cavity from influencing the efficacy of the drugs and enables them to obtain better therapeutic effects. This article analyzes the materials and advantages of common hydrogel microneedles and reviews the application of hydrogel microneedles in the oral cavity.
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Sistemas de Liberação de Medicamentos , Hidrogéis , Boca , Agulhas , Hidrogéis/química , Humanos , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Animais , Microinjeções/instrumentação , Microinjeções/métodosRESUMO
The management strategy for IgA nephropathy (IgAN), has undergone constant improvements since the disease entity was first described 50 years ago. However, it is still unknown how these changes affected the long-term renal survival of IgAN patients. We systematically evaluate changes in IgAN renal survival by searching PubMed, Embase, and the Cochrane Library Database of Systematic Reviews from inception to 19 May 2024. We included a large sample of 103076 IgAN cases from 158 studies. Renal survival rates were 94.16% (95% CI: 94.02% to 94.31%), 88.68% (95% CI: 88.48% to 88.87%), and 78.13% (95% CI: 77.82% to 78.43%) at three, five, and ten-year, respectively. Over the past few decades, there haven't been any sound changes in the 3-year and 5-year renal survival rates. The kidney survival rate in developed countries is higher than in developing countries. Researchers consistently show that while proteinuria < 1.0 g/24 h, renal survival rates increase dramatically. In IgAN, long-term renal survival fluctuated rather than continuously improving over time. Our system review's findings indicate that supportive care-the most important recommendation for managing IgAN has shown promising results. The long-term outcomes of IgAN could be significantly improved by the latest developed treatment options.
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Glomerulonefrite por IGA , Glomerulonefrite por IGA/mortalidade , Glomerulonefrite por IGA/terapia , Humanos , Taxa de Sobrevida , Proteinúria/mortalidade , Rim/fisiopatologia , Rim/patologiaRESUMO
PURPOSE: To investigate the role of KLF4 in CI/R injury and whether Nrf2/Trx1 axis acted as a downstream pathway of KLF4 to exert the protective role in blood-brain barrier destruction after CI/R. METHODS: The tMCAO rat model in vivo was constructed and received the intracerebroventricular injection of 5 µg/kg and 10 µg/kg rhKLF4 before operation. TTC, brain water content, neurological function, ELISA, behavioral tests, HE, TUNEL, and qRT-PCR were performed to detect the protective role of KLF4 on CIR. Double-fluorescence staining and western blot were performed to determine the localization and spatiotemporal expression in brain tissues. Furthermore, we also analyzed the effect of KLF4 on the blood-brain barrier (BBB) and related mechanisms in vivo and in vitro. Nrf2 inhibitor tretinoin was applied, which was intraperitoneally injected into CIR rat. Evans blue staining was conducted. In vitro OGD/R models of bEnd.3 cells were also established, and received KLF4 overexpressed transfection and 12.5 µM tretinoin incubation. The permeability of bEnd.3 cells was evaluated by TEER and FITC-dextran leakage. BBB-related factors and oxidative stress were also analyzed, respectively. The tubular ability of KLF4 on OGD/R bEnd3 cells was also evaluated. RESULTS: In vivo study confirmed that KLF4 was expressed in astrocyte, and its content increased with time. KLF4 protected against brain injury caused by cerebral ischemia-reperfusion, reduced cerebral infarction area and oxidative stress levels, and promoted the recovery of behavioral ability in rats. Simultaneously, mechanism experiments confirmed that the repair effect of KLF4 on cerebral ischemia-reperfusion injury was closely related to the Nrf2/Trx1 pathway. KLF4 exerted the neuroprotective effect through upregulating Nrf2/Trx1 pathway. Consistent with in vivo animal study, in vitro study also confirmed the effect of KLF4 on the permeability of bEnd.3 cells after OGD/R injury through Nrf2/Trx1 pathway. CONCLUSION: Collectively, KLF4 played neuroprotective role in CIR induced MCAO and OGD/R, and the beneficial effects of KLF4 was partly linked to Nrf2/Trx1 pathway.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Animais , Camundongos , Ratos , Barreira Hematoencefálica , Infarto Cerebral/metabolismo , Células Endoteliais/metabolismo , Fármacos Neuroprotetores/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Ratos Sprague-Dawley , Reperfusão , Traumatismo por Reperfusão/metabolismoRESUMO
BACKGROUND: There is still a lack of high-level evidence on the effects of problem-based learning (PBL) in general medical and nursing education. AIMS: We aimed to summarize current evidence on the effects of PBL in delivering medical and nursing education from randomized controlled trials (RCTs). METHODS: A systematic search was performed in MEDLINE, EMBASE, Cochrane Central Library, and CINAHL Complete. RCTs that assessed the effects of a PBL module in delivering medical education were eligible. Outcomes included knowledge, performance, and satisfaction. The risk of bias was assessed according to Cochrane handbook guidelines. Standardized mean differences with 95% confidence intervals of each outcome between PBL and control groups were pooled using a random-effects model. RESULTS: In all, 22 RCTs with 1969 participants were included. Both pooled analyses of changes in scores compared with baseline and absolute post-interventional scores favored PBL module in knowledge and performance. The satisfaction degree was also higher in participants receiving PBL methods. Publication bias might exist in satisfaction; however, not in knowledge and performance. Eleven of the 22 studies were assessed as having a high risk of bias. LINKING EVIDENCE TO ACTION: Compared with traditional lecture-based modules, PBL delivered medical education in different medical science specialities more efficiently from both theoretical knowledge and practice skill perspectives. The feedback from participants receiving PBL methods was more positive than that from those receiving traditional methods. However, the high heterogeneity and low quality of the included studies prevented drawing definite conclusions.
RESUMO
As one of the most frequent complications of diabetes, diabetic neuropathy often involves peripheral and central nervous systems. Neuroinflammation is the key pathogenic factor of secondary nerve injury in diabetes. NOD-like receptor pyrin domain-containing 3(NLRP3) inflammasome is a group of subcellular multiprotein complexes, including NLRP3, apoptosis associated speck-like protein(ASC), and pro-cysteinyl aspartate specific proteinase 1(pro-caspase-1). NLRP3 inflammasome is an inducer of innate immune responses. Its activation stimulates the inflammatory cascade reaction, promotes the release of inflammatory mediators, triggers cell death and uncontrolled autophagy, activates glial cells, facilitates peripheral immune cell infiltration, and initiates amyoid ß(Aß)-tau cascade reactions. As a result, it contributes to the central nerve, somatic nerve, autonomic nerve, and retinal nerve cell damage secondary to diabetes. Therefore, due to its key role in the neuroinflammation responses of the body, NLRP3 inflammasome may provide new targets for the treatment of diabetic neuropathy. With multi-target and low-toxicity advantages, traditional Chinese medicine plays a vital role in the treatment of diabetic neuropathy. Accumulating evidence has shown that traditional Chinese medicine exerts curative effects on diabetic neuropathy possibly through regulating NLRP3 inflammasome. Although the role of NLRP3 inflammasome in diabetes and related complications has been investigated in the literature, systematical studies on drugs and mechanism analysis for secondary neuropathy are still lacking. In this article, the role of NLRP3 inflammasome in diabetic neuropathy was explored, and the research progress on traditional Chinese medicine in the treatment of diabetic neuropathy through NLRP3 inflammasome was reviewed.
Assuntos
Diabetes Mellitus , Neuropatias Diabéticas , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Medicina Tradicional Chinesa , Doenças Neuroinflamatórias , InflamaçãoRESUMO
Colorectal cancer (CRC) is a prevalent malignant tumor with a poor prognosis. Circular RNA (circRNA) circ_0007334 is related to cell proliferation in CRC. This study is designed to explore the role and mechanism of circ_0007334 in CRC progression. Circ_0007334, microRNA-577 (miR-577) and kruppel-like factor 12 (KLF12) levels were measured by real-time quantitative PCR (RT-qPCR). Exosomes were detected by a transmission electron microscope and nanoparticle tracking analysis (NTA). CD63, TSG101, matrix metallopeptidase-2 (MMP-2), MMP-9, VEGFA and KLF12 protein levels were examined by western blot assay. The binding relationship between miR-577 and circ_0007334 or KLF12 was predicted by circRNA interactome or Starbase and verified by a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Cell viability, colony number, migration, invasion and angiogenesis were detected by cell counting kit-8 (CCK-8), colony formation, wound healing, transwell and tube formation assays. The biological role of circ_0007334 was examined by the xenograft tumor model in vivo. Circ_0007334 and KLF12 were increased, and miR-577 was decreased in CRC tissues and cells. Also, circ_0007334 expression was upregulated in CRC cell-derived exosomes. Circ_0007334 deficiency repressed cell viability, colony formation, migration, invasion, and angiogenesis in CRC cells. Mechanically, circ_0007334 could regulate KLF12 expression by sponging miR-577. Circ_0007334 downregulation or exosomal circ_0007334 silencing blocked CRC tumor growth in vivo. These results presented that circ_0007334 deficiency exerts a tumor-suppressor by the miR-577/KLF12 axis in CRC, and indicated that exosomal circ_0007334 could hinder CRC tumor growth and angiogenesis in vivo. Our findings provided a novel therapeutic strategy for CRC.
Assuntos
Neoplasias Colorretais/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , RNA não Traduzido/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Exossomos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.
Assuntos
Itraconazol , Midazolam , Área Sob a Curva , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Famotidina , Humanos , Itraconazol/efeitos adversos , Masculino , Midazolam/efeitos adversos , Pirazinas , Rifampina/efeitos adversos , TriazinasRESUMO
Circular RNAs (circRNAs) have been shown to be involved in the progression of many diseases, including cancer. However, the role of circ_0101802 in the proliferation, migration and invasion of colorectal cancer (CRC) has not been studied. Our results showed that circ_0101802 was highly expressed in CRC tumor tissues and cells. Functional experiments suggested that circ_0101802 knockdown could inhibit the proliferation, migration and invasion of CRC cells in vitro and CRC tumorigenesis in vivo. In the terms of mechanism, we discovered that circ_0101802 could act as a sponge of miR-1236-3p, and miR-1236-3p could target MACC1. The rescue experiments revealed that miR-1236-3p inhibitor could reverse the inhibition effect of circ_0101802 silencing on CRC proliferation, migration and invasion, and MACC1 overexpression also could abolish the negative regulation of miR-1236-3p on CRC proliferation, migration and invasion. More important, our data confirmed that circ_0101802 sponged miR-1236-3p to positively regulate MACC1. In summary, our results revealed that circ_0101802 functioned as a tumor promoter in CRC, which could facilitate CRC proliferation, migration and invasion via regulating the miR-1236-3p/MACC1 axis.
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Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/metabolismo , MicroRNAs/fisiologia , RNA Circular/fisiologia , Transativadores/genética , Transativadores/metabolismo , Linhagem Celular Tumoral , HumanosRESUMO
BACKGROUND: Roxadustat has been shown effective in treating patients with anemia due to chronic kidney disease. However, its long-term effect on clinical outcomes and socioeconomic burden and safety remains unclear. METHODS/DESIGN: This is a multicenter, prospective, longitudinal observational cohort study assessing if Roxadustat improves prognosis in dialysis patients. Primary outcomes will be major adverse cardiovascular events (MACE), defined as composites of cardiovascular death, myocardial infarction, cerebral infarction, hospitalization because of heart failure; all-cause mortality, and annual economic costs in two years. The data will be collected via Research electronic data capture (REDCap) based database as well as software-based dialysis registry of Sichuan province. The primary outcomes for the ROAD study participants will be compared with those in the dialysis registry cohort. Data at baseline and study follow up will also be compared to assess the association between Roxadustat and long-term clinical outcomes. DISCUSSION: The main objective of this study is to the assess long-term association of Roxadustat on MACE, all-cause mortality, socio-economic burden, safety in dialysis patients, which will provide guidance for designing further large randomized controlled trials to investigate this clinic question. STUDY REGISTRATION: The study has been registered in Chinese Clinical Trials Registry (ROAD, ROxadustat in treating Anemia in Dialysis patients, registration number ChiCTR1900025765) and provincial observational cohort database (Renal disEAse observational CoHort database, REACH, ChiCTR1900024926), registered 07 September 2019, http://www.chictr.org.cn .
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Anemia/tratamento farmacológico , Anemia/etiologia , Glicina/análogos & derivados , Isoquinolinas/uso terapêutico , Estudos Multicêntricos como Assunto , Estudos Observacionais como Assunto , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Projetos de Pesquisa , Protocolos Clínicos , Estudos de Coortes , Glicina/uso terapêutico , Humanos , Estudos ProspectivosRESUMO
Thrombocytopenia is a common hematological abnormality in patients with cirrhotic hypersplenism. Splenectomy with paraesophagogastric devascularization (SPD) is a conventional surgical therapy which can reverse pancytopenia in these patients. Platelets are traditionally recognized for their central role in hemostasis. However, the status of platelet aggregation in chronic hepatitis B patients with cirrhotic hypersplenism before and after SPD has not been reported yet. A total of 41 cirrhotic patients and 31 healthy controls were included in this study. Platelet aggregation was detected by AggRAM® Advanced Modular System (Helena Laboratories, USA). ELISA was used to detect the cytokines closely related to platelet aggregation. Expressions of platelet membrane glycoproteins (GPs) were evaluated by flow cytometric analysis. Platelet aggregation was found to be decreased distinctly in the cirrhotic patients, and to be restored to normal level after SPD. The cirrhotic patients showed higher plasma levels of the cytokines HMGB1, PEDF, vWF, cAMP and cGMP, which also improved partially after SPD. Moreover, the cirrhotic patients had much lower expression of GPIIb/IIIa, GPIbα and P-selectin than either the healthy controls or SPD patients at basal or activated level. Generally, SPD benefits cirrhotic patients with bleeding tendencies by improving platelet counts and aggregation. GPIIb/IIIa may be the key membrane protein responsible for the change in platelet aggregation before and after SPD.
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Fibrose/etiologia , Hepatite B Crônica/complicações , Hepatite B Crônica/cirurgia , Hiperesplenismo/etiologia , Agregação Plaquetária/fisiologia , Esplenectomia/métodos , Adulto , Estudos de Casos e Controles , Feminino , Fibrose/patologia , Hepatite B Crônica/sangue , Humanos , Hiperesplenismo/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: To further determine the efficacy and safety of direct-acting antiviral (DAA)-based treatments in hepatitis C virus (HCV) infected patients with renal function impairment. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched for relevant studies. All studies assessing the efficacy and safety of DAA-based treatments against HCV infection in patients with renal impairment and HCV infection were eligible for inclusion. Outcomes assessed included efficacy outcomes and safety outcomes. Summary estimates were obtained using an inverse-variance weighted random effect model and Freeman-Tukey double arcsine transformation. RESULTS: Twenty-seven studies (n = 1048 participants) were included. The majority of included studies were of fair quality with Newcastle-Ottawa scale scores between 4 and 6. The pooled virologic response rates at the end of treatment or 4, 12, 24 weeks after treatment (ie, EOTR, SVR4, SVR12 and SVR24 rates) were 97.0% (95% confidence interval [CI], 94.0%-99.0%), 80.9% (95% CI, 49.3%-98.7%), 94.1% (95% CI, 91.6%-96.3%) and 89.6% (95% CI, 75.5%-98.1%), respectively. The pooled relapse rate was 6.4% (95% CI, 3.4%-10.4%). The pooled incidence of adverse events and severe adverse events leading to discontinuation were 47.6% (95% CI, 35.0%-60.4%) and 2.9% (95% CI, 1.4%-5.0%), respectively. High heterogeneity among studies exists for SVR4 and SVR24 rates. Formal statistical testing did not identify the presence of publication bias for all measured outcomes except the relapse rate. CONCLUSION: The results support the efficacy and safety of DAA-based treatments in this population. Future studies with better design, larger sample size and longer follow up will be the next step. SUMMARY AT A GLANCE This systematic review evaluated the efficacy and safety of direct-acting antiviral based therapies in hepatitis C infection in patients with renal impairment. The majority of studies were of fair quality only. These therapies were found to be highly efficacious although there were high rates of adverse events.
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Antivirais/uso terapêutico , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Insuficiência Renal Crônica/virologia , Humanos , Insuficiência Renal Crônica/terapiaRESUMO
BACKGROUND: Hematopoietic abnormality is a common cause of cirrhotic hypersplenism (CH) complications and death; it causes serious adverse effects and is associated with bleeding, anemia, infection in CH patients. However, the underlying mechanism is unclear. AIMS: We aimed to investigate the effects of the spleen on hematopoiesis and hematopoietic stem/progenitor cells (HSPCs) in CH patients. METHODS: Eleven CH patients were enrolled to assess the effects of the spleen on HSPC functions. Hematopoietic changes were examined by flow cytometry analysis. HSPC functions were detected with colony-forming assays and in vitro cell cultures. Enzyme-linked immunosorbent assay (ELISA) was used to test the concentration of epithelial growth factor (EGF). RESULTS: The number of HSPCs was decreased in CH patients and was rescued after splenectomy. Serum from CH patients dysregulated HSPCs function, and serum from splenectomy patients restored the dysregulated HSPC function in vitro. The concentration of EGF was decreased in CH patients and was restored to normal level after splenectomy. EGF rescued the dysregulated HSPCs function in vitro. CONCLUSIONS: The spleen can regulate the functions of HSPCs in CH patients by regulating EGF signaling. EGF may be a therapeutic target for CH treatment.
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Fator de Crescimento Epidérmico/metabolismo , Hematopoese Extramedular , Células-Tronco Hematopoéticas/metabolismo , Hiperesplenismo/etiologia , Cirrose Hepática/complicações , Baço/metabolismo , Proliferação de Células , Células Cultivadas , Fator de Crescimento Epidérmico/sangue , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Hiperesplenismo/metabolismo , Hiperesplenismo/patologia , Hiperesplenismo/cirurgia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Baço/patologia , Baço/cirurgia , Esplenectomia , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Kimura's disease (KD) is a rare chronic inflammatory disorder with a high incidence of renal involvement. In this report, we present a case study of KD-associated nephrotic syndrome combined with minimal change disease (MCD) and acute renal tubular injury. Meanwhile, the clinical and histopathological characteristics of 26 patients with KD presenting with renal involvement were retrospectively evaluated. CASE PRESENTATION: Here, we report a case study of a 59-year-old male patient with KD confirmed by a lymph node biopsy. He developed widespread edema and decreased urine output. A palpable swollen mobile and non-tender lymph node behind the left ear was observed upon admission. A renal biopsy revealed minimal-change lesions and acute renal tubular injury. The patient received hemodialysis because of the oliguria and renal insufficiency, and an initial dose of 40 mg/d methylprednisolone and then continued treatment with 40 mg/d prednisolone. He exhibited a good clinical response to the steroid after 6 weeks of treatment. Of the other 26 patients included in the review, 13 patients presented with mesangial proliferative glomerulonephritis, 4 with membranous nephropathy, 3 with MCD, 3 with focal segmental glomerulosclerosis, 2 with IgA nephropathy and 1 with acute tubular injury. With the exception of 2 patients who progressed to end-stage renal disease and received hemodialysis, the majority of patients responded well to treatment with corticosteroids alone. CONCLUSIONS: MCD combined with acute renal tubular injury is rare in patients with KD presenting with renal involvement. Corticosteroids may be a beneficial treatment for renal injury in patients with KD.
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Hiperplasia Angiolinfoide com Eosinofilia/complicações , Hiperplasia Angiolinfoide com Eosinofilia/diagnóstico , Nefrose Lipoide/complicações , Nefrose Lipoide/diagnóstico , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico , Hiperplasia Angiolinfoide com Eosinofilia/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Nefrose Lipoide/sangue , Síndrome Nefrótica/sangueRESUMO
BACKGROUND: THSD7A is a new target antigen of idiopathic membranous nephropathy (IMN). Moreover, malignancies are also found in patients with THSD7A-positive membranous nephropathy. We aimed to systematically evaluate the prevalence of THSD7A in IMN patients and malignancies in THSD7A-positive patients. METHODS: We searched English and Chinese database to 31 December 2017 with the term 'THSD7A' or 'thrombospondin type 1 domain-containing 7A'. Meta-analysis was used to explore the positive rate of THSD7A in the IMN patients. Subgroup analysis was performed according to the race, sample size, and detecting method of THSD7A. RESULTS: Ten studies involving 4121 participants were eventually included. The prevalence of THSD7A was 3% (95% CI, 3%-4%) in all patients and 10% (95% CI, 6%-15%) in PLA2R-negative patients. 77 patients had positive circulating antibodies, and the prevalence of THSD7A was also low at 3% (95% CI, 2%-4%). Overall, 72 patients had positive THSD7A staining on renal biopsy, and the prevalence was 3% (95% CI 2%-4%). Subgroup analysis showed significant differences in the prevalence of THSD7A based on the study sample sizes, however, no significant differences were seen in different ethnic groups. Furthermore, among THSD7A-positive patients, 3/10 studies reported malignancies with the incidence varied from 6% to 25%. CONCLUSIONS: The prevalence of THSD7A is more common in the PLA2R-negative patients than the IMN patients. Screening for malignancies in THSD7A-positive MN patients is recommended.
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Autoanticorpos/sangue , Glomerulonefrite Membranosa/diagnóstico , Neoplasias Renais/epidemiologia , Trombospondinas/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Biópsia , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Humanos , Incidência , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Neoplasias Renais/sangue , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Prevalência , Receptores da Fosfolipase A2/metabolismo , Trombospondinas/imunologiaRESUMO
AIM: Adiponectin has been implicated in the development of chronic obstructive pulmonary disease (COPD). The CDH13 gene encodes T-cadherin that is an adiponectin receptor, and genetic variants of CDH13 determine blood adiponectin levels. The aim of this study was to investigate the effects of CDH13 variants on COPD susceptibility in a Chinese population. METHODS: Ten single-nucleotide polymorphisms (SNP) in CDH13 were screened using the SNaPshot method in 279 COPD patients and 367 control subjects. Association of genotypes or haplotypes constructed from these loci with COPD was analyzed in different genetic models. RESULTS: Among the 10 SNPs tested, rs4783244 and rs12922394 exhibited significant differences in allele or genotype frequencies between COPD patients and control subjects, whereas 8 other SNPs did not. The minor allele T was associated with decreased risk of COPD in the recessive model at rs4783244 (OR=0.42, P=0.023) and in the dominant model at rs12922394 (OR=0.70, P=0.022). The genotype TT at either rs4783244 or rs12922394 was associated with a significantly low level of plasma adiponectin when compared to genotypes GG and CC (P<0.05). Haplotypes GC in block 1 (rs4783244-rs12922394) as well as GTAC and ATGT in block 3 (rs4783266-rs11640522-rs11646849-rs11860282) significantly increased the risk of COPD, whereas haplotypes TT in block 1, TG in block 2 (rs11646011- rs11640875) and ATGC in block 3 were protective against COPD. CONCLUSION: CDH13 genetic variants determine Chinese individuals' susceptibility to COPD and thus are efficient genetic biomarkers for early detection of COPD.
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Caderinas/genética , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Adiponectina/sangue , Idoso , Povo Asiático/genética , China/epidemiologia , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologiaRESUMO
Premature proliferative arrest in benign or early-stage tumors induced by oncoproteins, chromosomal instability, or DNA damage is associated with p53/p21 activation, culminating in either senescence or apoptosis, depending on cell context. Growth hormone (GH) elicits direct peripheral metabolic actions as well as growth effects mediated by insulin-like growth factor 1 (IGF1). Locally produced peripheral tissue GH, in contrast to circulating pituitary-derived endocrine GH, has been proposed to be both proapoptotic and prooncogenic. Pituitary adenomas expressing and secreting GH are invariably benign and exhibit DNA damage and a senescent phenotype. We therefore tested effects of nutlin-induced p53-mediated senescence in rat and human pituitary cells. We show that DNA damage senescence induced by nutlin triggers the p53/p21 senescent pathway, with subsequent marked induction of intracellular pituitary GH in vitro. In contrast, GH is not induced in cells devoid of p53. Furthermore we show that p53 binds specific GH promoter motifs and enhances GH transcription and secretion in senescent pituitary adenoma cells and also in nonpituitary (human breast and colon) cells. In vivo, treatment with nutlin results in up-regulation of both p53 and GH in the pituitary gland, as well as increased GH expression in nonpituitary tissues (lung and liver). Intracrine GH acts in pituitary cells as an apoptosis switch for p53-mediated senescence, likely protecting the pituitary adenoma from progression to malignancy. Unlike in the pituitary, in nonpituitary cells GH exerts antiapoptotic properties. Thus, the results show that GH is a direct p53 transcriptional target and fulfills criteria as a p53 target gene. Induced GH is a readily measurable cell marker for p53-mediated cellular senescence.
Assuntos
Senescência Celular/fisiologia , Hormônio do Crescimento/fisiologia , Hipófise/metabolismo , Adenoma/metabolismo , Adenoma/patologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Dano ao DNA , Etoposídeo/farmacologia , Hormônio do Crescimento/genética , Humanos , Imidazóis/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/farmacologia , Hipófise/citologia , Hipófise/efeitos dos fármacos , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Regiões Promotoras Genéticas , Ratos , Transcrição Gênica/fisiologia , Proteína Supressora de Tumor p53/fisiologiaRESUMO
AIM: To characterise and measure the Schneiderian membranes of individuals with periodontal diseases in China and to analyse the factors impacting maxillary sinus mucosal thickness using cone-beam computed tomography (CBCT). MATERIAL AND METHOD: A cohort of 221 patients with periodontal disease was subjected to cross-sectional CBCT examination. Various parameters, including age, sex, alveolar bone loss, furcation lesions and vertical infrabony pockets, were analysed as correlates of mucosal thickening (MT). Sinus mucosal thickness ≥ 2 mm qualified as MT. RESULTS: MT was detected in 103 (48.9%) patients, increasing in frequency as the degree of alveolar bone loss advanced (mild, 14.5%; moderate, 29.5%; severe, 87.9%). The association between MT and vertical infrabony pockets was statistically significant (P < 0.001). The likelihood of MT increased with moderate [odds ratio (OR) = 1.02] and severe (OR = 4.62) periodontal bone loss (P < 0.001), as well as with furcation lesions (OR = 2.76) and vertical infrabony pockets (OR = 13.58). CONCLUSIONS: Relative to the case in patients with periodontitis and normal mucosa, the probability of MT increased dramatically as alveolar bone loss worsened. Periodontal pathologies (i.e. furcation lesions and vertical infrabony pockets) were also more likely to coincide with MT.
Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Seio Maxilar/diagnóstico por imagem , Sinusite Maxilar/complicações , Mucosa Nasal/diagnóstico por imagem , Periodontite/complicações , Adolescente , Adulto , Fatores Etários , Perda do Osso Alveolar/complicações , Perda do Osso Alveolar/diagnóstico por imagem , Anatomia Transversal , Criança , Estudos de Coortes , Feminino , Defeitos da Furca/complicações , Defeitos da Furca/diagnóstico por imagem , Humanos , Masculino , Sinusite Maxilar/diagnóstico por imagem , Pessoa de Meia-Idade , Perda da Inserção Periodontal/complicações , Bolsa Periodontal/complicações , Fatores de Risco , Fatores Sexuais , Fumar , Adulto JovemRESUMO
Purpose: To review current evidence on the efficacy and safety outcomes of HIF-PHIs in chronic kidney disease (CKD) populations with an emphasize on the safety profile. Methods: A systematic search was conducted in the Medline, Embase, and Cochrane Central databases. Randomized controlled trials that had assessed the efficacy and safety of HIF-PHIs for anemia in CKD were included. The efficacy outcome included change of hemoglobin and the safety outcomes any adverse events, severe adverse events, major adverse cardiovascular events, and mortality. The qualities of studies were assessed using the Cochrane ROB tool. Results: 47 studies encompassing 55 RCTs for the study outcomes were included in this study. All six commercially available HIF-PHIs had direct comparisons to ESA and placebo, yet lacked direct comparisons among each other. The network analysis demonstrated all six HIF-PHIs were able to effectively elevate hemoglobin in the general CKD patients compared to placebo. All HIF-PHIs did not differ among each other in the efficacy of correcting anemia. Roxadustat and daprodustat had the largest number of reports in terms of adverse events. The overall risk of each safety outcome did not increase in comparison to erythropoiesis stimulating agent (ESA) or placebo, and did not differ among different types of HIF-PHIs. Conclusion: HIF-PHIs can effectively elevate hemoglobin without causing higher risk of safety concerns in CKD patients with anemia. Further evidence from long-term studies and the ongoing post-market surveillance is necessary.
RESUMO
Bispecific antibodies, by enabling the targeting of more than one disease-associated antigen or engaging immune effector cells, have both advantages and challenges compared with a combination of two different biological products. As of December 2023, there are 11 U.S. Food and Drug Administration-approved BsAb products on the market. Among these, 9 have been approved for oncology indications, and 8 of these are CD3 T-cell engagers. Clinical pharmacology strategies, including dose-related strategies, are critical for bispecific antibody development. This analysis reviewed clinical studies of all approved bispecific antibodies in oncology and identified dose-related perspectives to support clinical dose optimization and regulatory approvals, particularly in the context of the Food and Drug Administration's Project Optimus: (1) starting doses and dose ranges in first-in-human studies; (2) dose strategies including step-up doses or full doses for recommended phase 2 doses or dose level(s) used for registrational intent; (3) restarting therapy after dose delay; (4) considerations for the introduction of subcutaneous doses; (5) body weight vs. flat dosing strategy; and (6) management of immunogenicity. The learnings arising from this review are intended to inform successful strategies for future bispecific antibody development.
Assuntos
Anticorpos Biespecíficos , Aprovação de Drogas , Neoplasias , United States Food and Drug Administration , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/administração & dosagem , Humanos , Estados Unidos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos/métodos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/farmacologia , Farmacologia Clínica/métodos , AnimaisRESUMO
The sand-mud interbedded surrounding rock contains discontinuities, such as horizontal bedding, joints, weak planes and weak interlayers. Drilling and blasting construction in this kind of surrounding rock is very likely to cause very serious over-/under-excavation phenomenon and excessive damage to surrounding rock, and the contour flatness after smooth blasting of the tunnel is also difficult to be guaranteed, which increases subsequent construction procedures and reduces production efficiency. In order to effectively evaluate the smooth blasting effect of the sand-mud interbedded surrounding rock tunnel, taking a tunnel project in southwest China as the research background, the blasting numerical simulation of the sand-mud interbedded surrounding rock tunnel was carried out using the dynamic analysis program, and the corresponding blasting optimization scheme was obtained. Subsequently, based on fuzzy mathematical theory, the evaluation system of blasting effect of sand-mud interbedded tunnel was established by combining the evaluation criteria of tunnel smooth blasting quality. Immediately afterwards, the weights of each influencing factor index were determined, and the blasting shaping effect of the original blasting scheme and the optimized blasting scheme was evaluated. Finally, the results have shown that the optimized tunnel blasting profile effect was better than the original blasting scheme. The corresponding research results have certain guiding significance for similar tunnel blasting effect evaluation and blasting parameter design.