RESUMO
BACKGROUND: Most genetic skeletal disorders (GSD) were complex, disabling and life-threatening without effective diagnostic and treatment methods. However, its impacts on health system have not been well studied. The study aimed to systematically evaluate the health-care utilization and economic burden in GSD patients. METHODS: The patients were derived from 2018 Nationwide Inpatient Sample and Nationwide Readmissions Database. GSD patients were extracted based on International Classification of Diseases-10th revision codes. RESULTS: A total of 25,945 (0.12%) records regarding GSD were extracted from all 21,400,282 records in NIS database. GSD patients were likely to have significantly longer length of stay (6.50 ± 0.08 vs. 4.63 ± 0.002, P < 0.001), higher total charges ($85,180.97 ± 1,239.47 vs. $49,884.26 ± 20.99, P < 0.001), suffering more procedure, diagnosis and transferring records in comparison to patients with common conditions. GSD patients had a significantly higher 30-day all-cause readmission rate based on Nationwide Readmissions Database. CONCLUSIONS: The heavy health-care utilization and economic burden emphasized the urgency for policy leaders, scientific and pharmaceutical researchers, health care providers and employers to identify innovative ways and take effective measurements immediately, and eventually to help improve the care, management, and treatment of these devastating diseases.
Assuntos
Estresse Financeiro , Aceitação pelo Paciente de Cuidados de Saúde , Humanos , Pacientes Internados , Bases de Dados Factuais , Pessoal de SaúdeRESUMO
BACKGROUND: Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) plays a crucial role in regulating insulin signaling and glucose metabolism. Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14). Currently, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been identified in association with this disease. Given the limited understanding of MODY14, it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations. AIM: To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain. METHODS: Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study. Whole exome sequencing was performed on the patients as well as their family members. The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis. In addition, the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments. Finally, the impact of these variants on APPL1 protein expression and the insulin pathway were assessed, and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored. RESULTS: A total of five novel mutations were identified, including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions. The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster. In addition, multiple alignment of amino acid sequences showed that the Arg532Gln, Asp632Tyr, and Arg633His variants were conserved across different species. Moreover, in in vitro functional experiments, both the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels, indicating their pathogenic nature. Therefore, based on the patient's clinical and family history, combined with the results from bioinformatics analysis and functional experiment, the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were classified as pathogenic mutations. Importantly, all these mutations were located within the phosphotyrosine-binding domain of APPL1, which plays a critical role in the insulin sensitization effect. CONCLUSION: This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.
RESUMO
OBJECTIVE: To explore the combined effect of abdominal obesity and depressive symptoms on the risk to type 2 diabetes, while also assessing the potential influence of various glycemic states and gender on this combined relationship. METHODS: Data is acquired from the China Health and Retirement Longitudinal Study, and 5949 participants were included for analysis. Participants were divided into four groups: neither have abdominal obesity nor depressive symptoms (AO-/DS-), only have depressive symptoms (AO-/DS+), only have abdominal obesity (AO+/DS-), and have both abdominal obesity and depressive symptoms (AO+/DS+). Stratified analyses differentiating the glycemic statuses and sex of the participants were also carried out. RESULTS: After adjusting for the confounders, the AO-/DS+, AO+/DS- and AO+/DS+ phenotypes were all discovered to be risk factors for type 2 diabetes (OR = 1.38, 95%CI: 1.06-1.79; OR = 2.07, 95%CI: 1.63-2.63; OR = 2.38, 95%CI: 1.83-3.11, respectively) compared with the AO-/DS- phenotype in the overall population. In further stratified analyses, we arrived at the same conclusion for normoglycemic individuals, especially in females. For prediabetes and males, the AO+/DS- and AO+/DS+ phenotypes are risk factors for type 2 diabetes compared with the AO-/DS- phenotype, but not with AO-/DS+. CONCLUSION: Regardless of glycemic status and sex, the coexistence of abdominal obesity and depressive symptoms were associated with an increased risk of type 2 diabetes. Depressive symptoms were independent risk factors for type 2 diabetes only in normoglycemic individuals and females.
Assuntos
Diabetes Mellitus Tipo 2 , Masculino , Feminino , Humanos , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologia , Estudos Longitudinais , Depressão/complicações , Obesidade/complicações , Fatores de RiscoRESUMO
BACKGROUND/AIMS: To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. METHODS: We conducted Mendelian randomization (MR) to assess the causal role of circulating complements in the risk of non-viral liver diseases. A complement-centric protein interaction network was constructed to explore biological functions and identify potential therapeutic options. RESULTS: In the MR analysis, genetically predicted levels of complement C1q C chain (C1QC) were positively associated with the risk of autoimmune hepatitis (odds ratio 1.125, 95% confidence interval 1.018-1.244), while complement factor H-related protein 5 (CFHR5) was positively associated with the risk of primary sclerosing cholangitis (PSC;1.193, 1.048- 1.357). On the other hand, CFHR1 (0.621, 0.497-0.776) and CFHR2 (0.824, 0.703-0.965) were inversely associated with the risk of alcohol-related cirrhosis. There were also significant inverse associations between C8 gamma chain (C8G) and PSC (0.832, 0.707-0.979), as well as the risk of metabolic dysfunction-associated steatotic liver disease (1.167, 1.036-1.314). Additionally, C1S (0.111, 0.018-0.672), C7 (1.631, 1.190-2.236), and CFHR2 (1.279, 1.059-1.546) were significantly associated with the risk of hepatocellular carcinoma. Proteins from the complement regulatory networks and various liver diseaserelated proteins share common biological processes. Furthermore, potential therapeutic drugs for various liver diseases were identified through drug repurposing based on the complement regulatory network. CONCLUSION: Our study suggests that certain complement components, including C1S, C1QC, CFHR1, CFHR2, CFHR5, C7, and C8G, might play a role in non-viral liver diseases and could be potential targets for drug development.
Assuntos
Carcinoma Hepatocelular , Hepatite Autoimune , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Hepatite Autoimune/complicações , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/genética , Neoplasias Hepáticas/genéticaRESUMO
Background: There is an inconsistent association between overweight/obesity and chronic obstructive pulmonary disease (COPD). Considering that different metabolic characteristics exist among individuals in the same body mass index (BMI) category, the classification of overweight/obesity based on metabolic status may facilitate the risk assessment of COPD. Our study aimed to explore the relationship between metabolic overweight/obesity phenotypes and unplanned readmission in patients with COPD. Methods: We conducted a retrospective cohort study using the Nationwide Readmissions Database (NRD). According to metabolic overweight/obesity phenotypes, patients were classified into four groups: metabolically healthy non-overweight/obesity (MHNO), metabolically unhealthy non-overweight/obesity (MUNO), metabolically healthy with overweight/obesity (MHO), and metabolically unhealthy with overweight/obesity (MUO). The primary outcome was unplanned readmission to hospital within 30 days of discharge from index hospitalization. Secondary outcomes included in-hospital mortality, length of stay (LOS) and total charges of readmission within 30 days. Results: Among 1,445,890 patients admitted with COPD, 167,156 individuals were unplanned readmitted within 30 days. Patients with the phenotype MUNO [hazard ratio (HR), 1.049; 95%CI, 1.038-1.061; p < 0.001] and MUO (HR, 1.061; 95%CI, 1.045-1.077; p < 0.001) had a higher readmission risk compared with patients with MHNO. But in elders (≥65yr), MHO also had a higher readmission risk (HR, 1.032; 95%CI, 1.002-1.063; p = 0.039). Besides, the readmission risk of COPD patients with hyperglycemia or hypertension regardless of overweight/obesity increased (p < 0.001). Conclusion: In patients with COPD, overweight/obesity alone had little effect on unplanned readmission, whereas metabolic abnormalities regardless of overweight/obesity were associated with an increased risk of unplanned readmission. Among the metabolic abnormalities, particular attention should be paid to hyperglycemia and hypertension. But in elders (≥65yr) overweight/obesity and metabolic abnormalities independently exacerbated the adverse outcomes.
RESUMO
Patients with HNF1A variants may develop liver steatosis, while the underlying mechanism is still unclear. Here, we established a mouse model carrying the dominant-negative HNF1α P291fsinsC mutation (hHNF1Amut/-) and found that the mutant mice developed liver steatosis spontaneously under the normal chow diet. Transcriptome analysis showed significant upregulation of Cfd and other genes related to innate immune response in the liver of hHNF1Amut/- mice. The changes in lipid metabolism and complement pathways were also confirmed by proteomics. We demonstrated that HNF1α inhibited CFD expression in hepatocytes, and the P291fsinsC mutant could reverse this inhibitory effect. Furthermore, the suppression of CFD with specific inhibitor or siRNAs reduced triglyceride levels in hepatocytes, suggesting that CFD regulated hepatocyte lipid deposition. Our results demonstrate that the HNF1α P291fsinsC mutant promotes hepatic steatosis and inflammation by upregulating CFD expression, and targeting CFD may delay the progression of nonalcoholic fatty liver disease.
RESUMO
INTRODUCTION: The study aimed to determine if hepatic steatosis assessed by fatty liver index (FLI) was an independent risk factor for male low testosterone level and whether the FLI was the strongest risk factor for low testosterone level in two different age groups. METHODS: Two cross-sectional studies were performed. A total of 3,443 male participants (aged 46-75) were recruited into study A (part of lONgitudinal study (REACTION)). Then a total of 267 male participants (aged 25-45) were recruited into study B. Serum total testosterone (TT) and sex hormone-binding globulin (SHBG) levels, indicators for assessing hepatic steatosis were measured. The Pearson correlation and regression analysis were performed to investigate the risk factors for low testosterone level. RESULTS: The FLI had the strongest negative correlation with serum testosterone in the study A (r = -0.436) and B (r = -0.542). Compared with patients with a FLI lower than 30, the risk for low testosterone level increased by 3.48-fold in subjects with a FLI higher than 60 adjusted for potential risk factors in study A. In study B, the odds ratio of low testosterone level in patients with potential hepatic steatosis was 4.26 (1.57-11.60) after adjusted for age and homeostasis model assessment of insulin resistance (HOMA-IR) and 0.59 (0.14-2.60) after adjusted for age, HOMA-IR, waist circumference, body mass index, and SHBG. CONCLUSIONS: FLI was the strongest risk factor for male low testosterone level independent of insulin resistance in male populations of different ages; however, the association can be modulated by SHBG levels in the young. SIGNIFICANCE STATEMENT: In the study, FLI was the strongest negative risk factor for low testosterone level in the Chinese adult male population. The results suggested that hepatic steatosis assessed by the FLI was the main risk factor for male low testosterone level, independent of age, insulin resistance, smoking, and drinking status; however, the association of FLI and TT levels can be modulated by SHBG levels. Taken together these findings indicate that clinical physicians should pay more attention to the FLI index and hepatic steatosis, so that they can take advantage of them for assessing the risk of developing of low testosterone level in the male population.
Assuntos
Fígado Gorduroso , Resistência à Insulina , Adulto , Humanos , Masculino , Estudos Longitudinais , Estudos Transversais , Fatores de Risco , Fígado Gorduroso/etiologia , Índice de Massa Corporal , TestosteronaRESUMO
The hypothalamus, as a vital brain region for endocrine and metabolism regulation, undergoes functional disruption during obesity.The anti-aging effect of metformin has come into focus. However, whether it has the potential to ameliorate hypothalamic aging and dysfunction in the obese state remains unclear. In this study, obese mice were utilized to investigate the effects of metformin on the hypothalamus of obese mice. According to the results, metformin treatment resulted in improved insulin sensitivity, reduced blood glucose and lipid levels, as well as attenuation of hypothalamic aging, demonstrated by decreased SA-ß-gal staining and downregulation of senescence markers. Additionally, metformin decreased the expression of endoplasmic reticulum stress-related proteins in neurons and reduced the inflammatory response triggered by microglia activation. Further mechanistic analysis revealed that metformin inhibited the expression and activation of STING and NLRP3 in microglia. These results reveal a possible mechanism by which metformin ameliorates hypothalamic aging.
RESUMO
BACKGROUND: Obesity often co-exists with metabolic abnormalities, but the results of studies on the relationship between obesity, metabolic abnormalities and the risk of gout are inconsistent. OBJECTIVE: We aimed to study whether there was a mutual regulation between obesity, metabolic abnormalities and the risk of gout. METHOD: We conducted a cross-sectional study to expound the association between obesity based on different metabolic statuses and the risk of gout. Patients were derived from Nationwide Readmission Database (2018 sample). RESULTS: A total of 9,668,330 records were recruited for analysis from January to December. The risk of gout in the obesity group, metabolic abnormalities group and obesity combined with metabolic abnormalities group was 1.67 times (OR=1.67, 95%CI 1.64-1.70), 3.12 times (OR=3.12, 95%CI 3.09-3.15) and 4.27 times (OR=4.27, 95%CI 4.22-4.32) higher than that in the normal control group. For different metabolic components, OR value was highest in hypertension group (OR=2.65, 95%CI 2.60-2.70 and OR=4.85, 95%CI 4.73-4.97), followed by dyslipidemia group (OR=2.23, 95%CI 2.16-2.30 and OR=3.74, 95%CI 3.55-3.95) and in hyperglycemia group (OR=1.73, 95%CI 1.66-1.80 and OR=2.94, 95%CI 2.78-3.11). Fewer components of metabolic syndrome were associated with a lower risk of gout in both nonobese and obese patients. CONCLUSION: When metabolic abnormalities were present, obesity induced a higher risk of gout. Different components of metabolic abnormalities had different effects on the risk of gout occurrence, and the number of metabolic abnormalities was closely related to the risk of gout occurrence. Follow-up and intervention methods targeting obesity and metabolic abnormalities should be considered for patients with gout.
RESUMO
INTRODUCTION: Obesity is associated with an increased risk of inflammatory bowel disease (IBD), whereas not all obese individuals have the same effect. In individuals with obesity, the role of metabolic status in the readmission of IBD remains unclear. Our study aimed to evaluate the association between different obesity metabolic phenotypes and the prognosis of IBD patients. METHODS: We conducted a longitudinal cohort study using Nationwide Readmissions Database (NRD) (2018 sample). Out of 12,928,231 discharge records, 63,748 records with a discharge diagnosis of IBD were identified for analysis. Cox proportional hazard ratio (HR) with 95% confidence interval (CI) was calculated, adjusting for potential confounders. RESULTS: During a 180-day follow-up in IBD patients with different obesity metabolic phenotypes, all-cause readmission rate, inpatient mortality rate, unplanned readmission rate, total charge, hospitalized length of stay were statistically different (all p < 0.001). After multivariate Cox regression analysis, IBD patients with metabolically unhealthy nonobese (MUNO) had higher risk of readmission (all-cause and unplanned) (HR 1.04, 95% CI: 1.00-1.08 and HR 1.06, 95% CI: 1.02-1.10), and those with metabolically unhealthy obesity (MUO) had higher risk of unplanned readmission (HR 1.08, 95% CI: 1.02-1.15). In subgroup analysis, both the MUNO group and MUO group had higher risk of readmission (all-cause and unplanned) in the ulcerative colitis (UC) subgroup, but only the MUNO group had higher risk of readmission (all-cause and unplanned) (HR 1.05, 95% CI: 1.00-1.10 and HR 1.06, 95% CI: 1.01-1.12) in the Crohn's disease (CD) subgroup. CONCLUSION: Metabolic abnormalities were associated with an increased risk of readmission in patients with IBD, regardless of obesity.
Assuntos
Doenças Inflamatórias Intestinais , Obesidade , Humanos , Estudos de Coortes , Fatores de Risco , Estudos Longitudinais , Obesidade/complicações , Doenças Inflamatórias Intestinais/complicações , PrognósticoRESUMO
PURPOSE: Hypercholesterolemia due to a high-cholesterol diet is linked to numerous diseases and may lead to male infertility. However, the underlying mechanism remains unknown. The maintenance of male fertility requires intact testicular structures (including seminiferous tubules and mesenchyme) and functioning cells (Leydig cells, Sertoli cells and germ cells, etc.), production of appropriate concentrations of sex hormones, and cooperation among testicular cells. Thus, we considered whether male fertility declined as the structure and function of testicular cells were altered in rats on a high-cholesterol diet. METHODS: Male Sprague Dawley rats were fed either a standard or a high-cholesterol diet for 16 weeks. Serum sex hormones, lipid components, semen quality, and fertility rate were assayed in the rats. The 3ß-hydroxysteroid dehydrogenase (3ß-HSD), Wilms tumor 1 (WT-1), and deleted in azoospermia-like (DAZL) were regarded as specific markers of Leydig, Sertoli, and germ cells in rats. In addition, the ultrastructure of the testis and expression levels of particular marker molecules of testicular cells were further investigated. RESULTS: Compared to rats fed on a regular diet, the serum testosterone levels and sperm progressive motility decreased in rats fed high cholesterol. Moreover, we observed a deformed nucleus, dilated smooth endoplasmic reticulum, and swollen mitochondria of Leydig cells and a schizolytic nucleus of Sertoli cells in rats on a high-cholesterol diet. The 3ß-HSD, WT-1, and DAZL protein expression levels were significantly reduced in rats on a high-cholesterol diet. CONCLUSIONS: Our results showed that a high-cholesterol diet adversely affected testosterone production and sperm progressive motility, possibly due to Leydig, Sertoli, and germ cell abnormalities.
Assuntos
Hipercolesterolemia , Doenças Testiculares , Humanos , Masculino , Ratos , Animais , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Análise do Sêmen , Ratos Sprague-Dawley , Sêmen , Testículo/fisiologia , Células Intersticiais do Testículo/metabolismo , Células Intersticiais do Testículo/patologia , Testosterona , Doenças Testiculares/etiologia , Dieta , ColesterolRESUMO
Background: In a previous study, a total of 568 differentially expressed proteins including the signal peptidase SPC21 were identified from lung adenocarcinoma (LUAD) and paired normal lung tissues. In this study, the role of SPC21 in LUAD progression was investigated. Methods: The relationships and protein-protein interaction network of proteins differentially expressed between paired LUAD samples and adjacent normal tissues samples were identified via the String and Pajek software, respectively. The expression levels of the hub protein SPC21 were analyzed in 84 LUAD-normal paired tissues via immunohistochemistry. The prognostic value of SPC21 mRNA was investigated in 478 LUAD patients from TCGA and GTEx datasets. siRNAs were used in A549 and NCI-H1299 cells to knockdown SPC21. The SPC21 biological function was evaluated using the CCK-8, EdU, plate colony formation, transwell, wound healing, and adhesion assays. Results: Patients with lower SPC21 mRNA levels tended to have worse prognosis (overall survival) than those with higher mRNA levels. SPC21 expression was significantly downregulated in LUAD tumor tissues compared with that in paired normal tissues (P < 0.001). Functionally, SPC21 knockdown promoted cell growth, migration, and invasion. Further analyses showed that SPC21 inactivated Akt signaling, and the Akt inhibitor MK-2206 blocked the tumor-promoting effects of SPC21 knockdown. Conclusions: SPC21 plays a tumor suppressor role in LUAD cells by targeting the PTEN-PI3K/Akt axis and might be used as a prognostic indicator and therapeutic target in LUAD patients.
Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-akt/genética , Fosfatidilinositol 3-Quinases/genética , Movimento Celular/genética , Adenocarcinoma de Pulmão/genética , Transdução de Sinais/genética , Processos Neoplásicos , Proliferação de Células/genética , RNA Mensageiro , PTEN Fosfo-Hidrolase/genéticaRESUMO
RO7297089, an anti-B-cell maturation antigen (BCMA)/CD16A bispecific tetravalent antibody, is being developed as a multiple myeloma (MM) therapeutic. This study characterized nonclinical pharmacokinetics (PK), pharmacodynamics (PD), soluble BCMA (sBCMA), and soluble CD16 (sCD16) changes following administration of RO7297089 to support clinical trials. Unbound and total RO7297089 concentrations were measured in cynomolgus monkeys. RO7297089 exhibited a bi-phasic systemic concentration-time profile, similar to a typical human immunoglobulin 1 antibody. Target engagement by RO7297089 led to a robust increase (~100-fold) in total systemic sBCMA levels and relatively mild increase (~2-fold) in total sCD16 levels. To describe the relationship of nonclinical PK/PD data, we developed a target-mediated drug disposition (TMDD) model that includes the systemic target engagement of membrane BCMA (mBCMA), sBCMA, membrane CD16 (mCD16), and sCD16. We then used this model to simulate the PK/PD relationship of RO7297089 in MM patients by translating relevant PK parameters and target levels, based on the literature and newly generated data such as baseline sCD16A levels. Our model suggested that the impact of TMDD on RO7297089 exposure may be more significant in MM patients due to significantly higher expression levels of both mBCMA and sBCMA compared to healthy cynomolgus monkeys. Based on model simulations, we propose more frequent dosing of RO7297089 compared to regular monthly frequency in the clinic at the beginning of treatment to ensure sustained target engagement. This study demonstrates a translational research strategy for collecting relevant nonclinical data, establishing a TMDD model, and using simulations from this model to inform clinical dose regimens.
Assuntos
Mieloma Múltiplo , Animais , Humanos , Imunoterapia , Macaca fascicularis , Mieloma Múltiplo/tratamento farmacológicoRESUMO
Objectives: Peripheral artery disease (PAD) in diabetic populations is a vital chronic disease all over the world due to its high morbidity and mortality. It is important to find early simple screening biomarkers and find residual risk factors that may provide a new target for prevention and treatment of PAD in diabetic patients besides traditional cardiometabolic risk factors. Methods: We performed a cross-sectional retrospective study, and a total of 1671 T2DM participants were recruited. Receiver operating characteristic analysis, stepwise logistic regression analysis, points score system, and decision curve analysis were performed to assess the risk factors for PAD. Results: The prevalence of PAD in the study was 7.18% (n = 120). Compared to the participants with the lowest quartile of cystatin C (CysC), the risk of developing PAD in participants with the highest quartile of CysC increased 6.339-fold. The CysC was the superior indicators to distinguish participants with PAD from those without PAD, with an AUC of 0.716. Stepwise logistic regression analysis showed that CysC was independent risk factor for PAD besides traditional risk factors. Combined exposure to these traditional risk factors and CysC was associated with a stepwise increase in the risk of developing PAD and even increased 11.976-fold in participants with the highest quintiles of combined exposure score (CES) based on traditional risk factors and CysC compared to the participants with the lowest quintiles of CES. Conclusions: CysC was associated with PAD independent of potential risk factors in diabetic populations. The CysC was a reliable marker for the early screening of PAD in diabetic patients besides traditional cardiometabolic risk factors.
Assuntos
Diabetes Mellitus Tipo 2 , Doença Arterial Periférica , Biomarcadores , China/epidemiologia , Estudos Transversais , Cistatina C , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Doença Arterial Periférica/complicações , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/epidemiologia , Estudos Retrospectivos , Fatores de RiscoRESUMO
Objective: This study aimed at investigating the association between testosterone levels and gut microbiota in male patients with type 2 diabetes mellitus (T2DM) and providing a new strategy to elucidate the pathological mechanism of testosterone deficiency in T2DM patients. Methods: In an observational study including 46 T2DM male patients, the peripheral venous blood and fecal samples of all subjects were collected. The V3-V4 regions of bacterial 16S rDNA were amplified and sequenced. Alpha and beta diversities were calculated by QIIME software. The possible association between gut microbial community and clinical indicators was assessed using the Spearman correlation coefficient. The association between the relative abundance of bacteria and testosterone levels was discovered using linear regression analysis in R language. Results: There was no substantial difference in alpha and beta diversity. Blautia and Lachnospirales were significantly much higher in the testosterone deficiency group. Linear regression analysis showed that the abundance of Firmicutes at the phylum level and Lachnospirales at the order level were negatively correlated with testosterone level. After correcting for C-reactive protein (CRP) and homeostatic model assessment of insulin resistance (HOMA-IR), the relative abundance of Lachnospirales still had a significant negative correlation with testosterone level. Meanwhile, at the genus level, Lachnoclostridium, Blautia, and Bergeyella had a statistically significant negative association with testosterone level, respectively. Blautia was positively associated with FPG and total cholesterol level. Streptococcus was found positively associated with insulin, connecting peptide, and index of homeostatic model assessment of insulin resistance. Conclusion: T2DM patients with testosterone deficiency have different gut microbiota compositions compared with T2DM patients alone. Low serum testosterone patients tend to have an increased abundance of opportunistic pathogens, which may be related to the occurrence and development of testosterone deficiency.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Resistência à Insulina , Microbiota , Diabetes Mellitus Tipo 2/complicações , Humanos , Masculino , TestosteronaRESUMO
The antibody-drug conjugate (ADC) is a well-validated modality for the cell-specific delivery of small molecules with impact expanding rapidly beyond their originally-intended purpose of treating cancer. However, antibody-mediated delivery (AMD) remains inefficient, limiting its applicability to targeting highly potent payloads to cells with high antigen expression. Maximizing the number of payloads delivered per antibody is one key way in which delivery efficiency can be improved, although this has been challenging to carry out; with few exceptions, increasing the drug-to-antibody ratio (DAR) above â¼4 typically destroys the biophysical properties and in vivo efficacy for ADCs. Herein, we describe the development of a novel bioconjugation platform combining cysteine-engineered (THIOMAB) antibodies and recombinant XTEN polypeptides for the unprecedented generation of homogeneous, stable "TXCs" with DAR of up to 18. Across three different bioactive payloads, we demonstrated improved AMD to tumors and Staphylococcus aureus bacteria for high-DAR TXCs relative to conventional low-DAR ADCs.
RESUMO
Despite the recent progress, multiple myeloma (MM) is still essentially incurable and there is a need for additional effective treatments with good tolerability. RO7297089 is a novel bispecific BCMA/CD16A-directed innate cell engager (ICE®) designed to induce BCMA+ MM cell lysis through high affinity binding of CD16A and retargeting of NK cell cytotoxicity and macrophage phagocytosis. Unlike conventional antibodies approved in MM, RO7297089 selectively targets CD16A with no binding of other Fcγ receptors, including CD16B on neutrophils, and irrespective of 158V/F polymorphism, and its activity is less affected by competing IgG suggesting activity in the presence of M-protein. Structural analysis revealed this is due to selective interaction with a single residue (Y140) uniquely present in CD16A opposite the Fc binding site. RO7297089 induced tumor cell killing more potently than conventional antibodies (wild-type and Fc-enhanced) and induced lysis of BCMA+ cells at very low effector-to-target ratios. Preclinical toxicology data suggested a favorable safety profile as in vitro cytokine release was minimal and no RO7297089-related mortalities or adverse events were observed in cynomolgus monkeys. These data suggest good tolerability and the potential of RO7297089 to be a novel effective treatment of MM patients.