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1.
Int J Pharm ; 665: 124664, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39260751

RESUMO

Drying time, velocity, and temperature are important aspects of the drying process for pharmaceutical granules observed during tablet manufacturing. However, the drying mechanism of single granules is often limited to modelling and simulation, with the internal and physical changes difficult to quantify at an experimental level. In this study, in-situ synchrotron-based X-ray imaging techniques were used for the first time to investigate the dynamic drying of single pharmaceutical granules, quantifying internal changes occurring over the drying time. Two commonly used excipients (lactose monohydrate (LMH) and microcrystalline cellulose (MCC)) were used as pure components and binary mixtures with one of either two active pharmaceutical ingredients of differing hydrophilicity/hydrophobicity (acetaminophen (APAP) and carbamazepine (CBZ)). Water was used as a liquid binder to generate single granules of 25 % to 30 % moisture content. Results showed that for most samples, the drying time and composition significantly influences the pore volume evolution and the moisture ratio, with the velocity and temperature of the drying air possessing mixed significance on increasing the rate of pore connectivity and moisture removal depending on the sample composition. Effects of active ingredient loading resulted in minimal influence on the drying of CBZ and generated binary mixtures, with APAP and its respective mixtures' drying behaviour dominated by the material's hydrophilic nature.

2.
Virol Sin ; 2024 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-39270985

RESUMO

China's dynamic zero-COVID policy has effectively curbed the spread of SARS-CoV-2, while inadvertently creating immunity gaps within its population. Subsequent surges in COVID-19 cases linked to various SARS-CoV-2 lineages post-policy termination necessitate a thorough investigation into the epidemiological landscape. This study addresses this issue by analyzing a comprehensive dataset of 39,456 high-quality genomes collected nationwide over an 11-month period since policy termination. Through lineage assignment, phylogenetic analysis, pandemic pattern comparison, phylodynamic reconstruction, and recombination detection, we found that China's post-epidemic period could be divided into three stages, along with dynamic changes in dominant lineages. Geographical clustering of similar lineages implies the importance of cross-border cooperation among neighboring regions. Compared to the USA, UK, and Japan, China exhibits unique trajectories of lineage epidemics, characterized by initial lagging followed by subsequent advancement, indicating the potential influence of diverse prevention and control policies on lineage epidemic patterns. Hong Kong, Shanghai, and Hubei emerge as pivotal nodes in the nationwide spread, marking a shift in the transmission center from east to central regions of China. Although China hasn't experienced significant variant emergence, the detection and validation of the novel recombination event, XCN lineage, underscore the ongoing virus evolution. Overall, this study systematically analyzes the spatiotemporal transmission of SARS-CoV-2 virus in China since the termination of the dynamic zero-COVID policy, offering valuable insights for regional surveillance and evidence-based public health policymaking.

4.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(9): 961-966, 2024.
Artigo em Chinês | MEDLINE | ID: mdl-39267512

RESUMO

A 2-year-and-10-month-old boy presented with multiple masses in the neck and chest for over 3 months. The child had a history of unstable walking, with hard lumps visible at the injury sites after falls, which would resolve on their own. Following a recent injury, a mass was discovered in the posterior neck, protruding above the skin surface and accompanied by limited joint movement. Gradually, new masses were found on the left side of the neck, back near the scapular lower angle, in the scapular fossa, and along the left axillary midline. Magnetic resonance imaging examination showed diffuse low signal on T1-weighted images and high signal on T2-weighted images in the bilateral posterior neck and back muscles two months ago. A CT scan revealed muscle swelling, with areas of patchy low density and multiple nodular high-density ossifications within some muscles. Genetic testing results indicated a mutation in the ACVR1 gene, leading to the final diagnosis of progressive ossifying myositis in this patient. This article summarizes the etiology, diagnosis, and treatment of one case of progressive ossifying myositis, providing a reference for clinicians.


Assuntos
Receptores de Ativinas Tipo I , Mutação , Miosite Ossificante , Humanos , Masculino , Miosite Ossificante/genética , Miosite Ossificante/diagnóstico por imagem , Receptores de Ativinas Tipo I/genética , Pré-Escolar
6.
J Foot Ankle Surg ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39299483

RESUMO

The objective of this study is to conduct a prospective trial comparing the therapeutic efficacy of Omega toenail correction and the Winograd procedure in treating stage II-III paronychia. From August 2018 to August 2023, ninety cases from eighty-three patients were randomly divided into two groups, one receiving Omega toenail correction (experimental group) and the other receiving the Winograd procedure (control group). The clinical therapeutic effects of both treatments were evaluated based on time to resume movement, treatment cycle, one-year recurrence rate, and visual analogue scale (VAS) scores before and after treatment. The clinical efficacy was compared between Omega toenail correction and Winograd procedure treating paronychia of stage Ⅱ-Ⅲ. It has been demonstrated that the time to resume movement in the experimental group is obviously shorter than that in the control group (P = 0.024), while the treatment cycle is longer (P = 0.009) with no significant difference (P = 0.734) in the aspect of one-year recurrence rate. However, the VAS after the correction in the experimental group is significantly lower than that in the control group (P = 0.019). It has been suggested that Omega toenail correction characterized by easy operation, sure efficacy and lower recurrence rate can be widely applied in clinic work.

8.
Medicine (Baltimore) ; 103(37): e39497, 2024 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-39287309

RESUMO

The objective of this study is to assess the influence of blended education methodologies, utilizing an online education platform, among stage III cardiac rehabilitation (CR) patients diagnosed with coronary heart disease (CHD). Between June and August 2021, a cohort of 90 patients diagnosed with CHD, previously discharged from a second-class hospital 1 year earlier, were randomly allocated into 2 groups: the experimental and control groups, with each comprising 45 patients. Patients in the control group received out-of-hospital CR education via WeChat, while those in the experimental group received blended CR education utilizing an online education platform. Following a 24-week period, the self-management behavior and negative emotions of both groups were compared before and after the intervention. The final count of patients in the control and experimental groups was 39 and 37, respectively. Post the intervention, in terms of self-management behavior, the control group achieved an average score of 90.69 ±â€…7.13, while the experimental group scored 96.11 ±â€…5.42 (P < .05). Concerning negative emotions, the anxiety scores for the control and experimental groups were 3.03 ±â€…2.63 and 1.86 ±â€…1.80, respectively, and the depression scores were 3.00 (3.00) and 2.00 (3.00), respectively (P < .05). The differences in the outcomes mentioned above were statistically significant. The implementation of a blended educational approach utilizing an online platform has resulted in notable improvements in self-management skills and the reduction of negative emotions among patients with CHD. As a result, this educational strategy has demonstrated effectiveness in providing post-discharge CR education for patients with CHD.


Assuntos
Reabilitação Cardíaca , Doença das Coronárias , Educação de Pacientes como Assunto , Humanos , Masculino , Feminino , Reabilitação Cardíaca/métodos , Doença das Coronárias/reabilitação , Doença das Coronárias/psicologia , Pessoa de Meia-Idade , Educação de Pacientes como Assunto/métodos , Idoso , Educação a Distância/métodos , Autogestão/métodos , Autogestão/educação
9.
Eur J Med Chem ; 279: 116877, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39303515

RESUMO

Although immune checkpoint inhibitors (ICIs) have been a revelation for treating several cancers, an unmet need remains to broaden ICI therapeutic scope and increase their response rates in clinical trials. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T cell activation and has previously been identified as a promising target for immunotherapy. Herein, we report the discovery of a series of HPK1 inhibitors with novel 1(2H)-phthalazinone and 1(2H)-isoquinolinone scaffolds. Among them, compound 24 demonstrated potent in vitro activity (HPK1 IC50 value of 10.4 nM) and cellular activity (pSLP76 EC50 = 41 nM & IL-2 EC50 = 108 nM). Compound 24 exhibited favorable mouse and rat pharmacokinetic profiles with reasonable oral exposure. Compound 24 showed potent in vivo anti-tumor activity in a CT26 syngeneic tumor model with 95 % tumor growth inhibition in combination with anti-PD-1.

10.
BMC Cardiovasc Disord ; 24(1): 448, 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39182065

RESUMO

OBJECTIVE: This study aimed to identify the incidence, risk factors, and outcomes of permanent pacemaker (PPM) implantation after transcatheter aortic valve implantation (TAVI) procedures. METHODS: A retrospective analysis was conducted on 70 patients who underwent TAVI at the Department of Cardiology, Fujian Provincial Hospital, from January 2018 to March 2022. Based on whether a new PPM was implanted after TAVI, all patients were divided into two groups: NEW PPM and NO PPM. Baseline characteristics and clinical data were compared between the two groups. Univariate analysis was used to analyze different variables between the two groups. A binary logistic regression analysis was used to evaluate independent correlates for PPM implantation after TAVI. RESULTS: The mean age of the 70 patients was 73.1 ± 8.8 years. The incidence of PPM implantation was 17.1%. Patients with diabetes and chronic kidney disease were more likely to require PPM (50% vs. 20.7%, p = 0.042, 25% vs. 5.2%, p = 0.042). Our study did not identify any significant differences in the incidence of electrocardiographic conduction disturbances except for the previous right bundle branch block (RBBB) (NO PPM 6.9% vs. NEW PPM 33.3%, p < 0.05). We found that prosthesis size, implantation depth, procedural duration, and length of hospital and intensive care unit (ICU) stays were comparable between the two groups. The leading independent predictors of PPM implantation were previous RBBB (odds ratio 10.129, p = 0.034). CONCLUSION: The previous RBBB was the leading independent predictor of PPM implantation. New PPM was not associated with significantly new-onset left BBB, extended post-procedure hospitalization, ICU stay, or procedural duration.


Assuntos
Estenose da Valva Aórtica , Estimulação Cardíaca Artificial , Marca-Passo Artificial , Substituição da Valva Aórtica Transcateter , Humanos , Masculino , Feminino , Substituição da Valva Aórtica Transcateter/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Idoso , Resultado do Tratamento , Estimulação Cardíaca Artificial/efeitos adversos , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/fisiopatologia , Idoso de 80 Anos ou mais , Fatores de Tempo , Medição de Risco , China/epidemiologia , Incidência , Valva Aórtica/cirurgia , Valva Aórtica/fisiopatologia , Valva Aórtica/diagnóstico por imagem , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/terapia , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/etiologia , Arritmias Cardíacas/epidemiologia
11.
Front Med (Lausanne) ; 11: 1410051, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39175820

RESUMO

Background: Alterations in metabolites and metabolic pathways are thought to be important triggers of idiopathic pulmonary fibrosis (IPF), but our lack of a comprehensive understanding of this process has hampered the development of IPF-targeted drugs. Methods: To fully understand the metabolic profile of IPF, C57BL/6 J male mice were injected intratracheally with bleomycin so that it could be used to construct a mouse model of IPF, and lung tissues from 28-day and control IPF mice were analyzed by pathology and immunohistochemistry. In addition, serum metabolites from IPF mice were examined using LC-ESI-MS/MS, and the differential metabolites were analyzed for KEGG metabolic pathways and screened for biomarkers using machine learning algorithms. Results: In total, the levels of 1465 metabolites were detected, of which 104 metabolites were significantly altered after IPF formation. In IPF mouse serum, 52% of metabolite expression was downregulated, with lipids (e.g., GP, FA) and organic acids and their derivatives together accounting for more than 70% of the downregulated differentially expressed metabolites. In contrast, FA and oxidised lipids together accounted for 60% of the up-regulated differentially expressed metabolites. KEGG pathway enrichment analyses of differential metabolites were mainly enriched in the biosynthesis of unsaturated fatty acids, pentose phosphate pathway, and alanine, aspartate, and glutamate metabolism. Seven metabolites were screened by machine learning LASSO models and evaluated as ideal diagnostic tools by receiver operating characteristic curves (ROCs). Discussion: In conclusion, the serum metabolic disorders found to be associated with pulmonary fibrosis formation will help to deepen our understanding of the pathogenesis of pulmonary fibrosis.

12.
Nurse Educ Today ; 142: 106357, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39154593

RESUMO

BACKGROUND: Most nursing managers are not fully aware of second victims and may not be able to provide support. Moreover, there are relatively few training courses for nursing managers about second victims. AIM: To describe the construction and evaluation of a second victim course for nursing managers. DESIGN: A single-group pretest-posttest study design was used. SETTING: A large comprehensive tertiary hospital with over 3000 beds in China. PARTICIPANTS: Forty-nine nursing managers who met the inclusion and exclusion criteria participated in this training. Sixteen clinical frontline nurses who experienced adverse events within three months following the training were also invited. METHODS: The course "Second Victim & Empathy Communication" was developed through a literature review and expert consultation and consisted of 4 unit modules: (1) adverse events & second victims, (2) the recovery trajectory of second victims, (3) second victim supportive resources, and (4) key strategies of empathy communication. A course evaluation questionnaire, an empathy communication questionnaire for nursing managers, a second victim evaluation questionnaire, and an open-ended question were used to measure the feasibility, acceptability and effectiveness of the course. RESULTS: >97.96 % of the nursing managers were satisfied with the course, >97.96 % had learned new knowledge, and >95.92 % had changed their behavior and attitudes toward second victims. Their levels of empathetic communication differed significantly before and after training (t = -2.170, P = 0.035). Among these nursing managers, twenty-six participants provided positive and meaningful feedback and suggestions to the course by answering an open-ended question. A total of 66.6 % to 100 % of second victims were satisfied with the empathetic communication behavior exhibited by nursing managers. CONCLUSION: The second victim training course is feasible and can be used for clinical training to enhance nursing managers' understanding of second victims and enhance their empathetic communication.

13.
Nat Sci Sleep ; 16: 1141-1152, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39109266

RESUMO

Purpose: There is scarce evidence to support the effectiveness of faecal microbiota transplantation (FMT) in improving sleep among individuals with inflammatory bowel disease (IBD). Our study aimed to evaluate the effect of washed microbiota transplantation (WMT) (the new method of FMT) on the sleep of patients with IBD in short term. Patients and Methods: This prospective study was conducted as part of two interventional clinical trials (starting on February 2013 and expected to end on December 2025) and placed significant emphasis on evaluating sleep quality in patients with IBD. To measure subjective sleep, we used the Pittsburgh sleep quality index (PSQI). The primary endpoint was the PSQI score one month after WMT. Results: This stage study included 52 eligible patients evaluated by PSQI questionnaire who underwent WMT from January 2020 to March 2021 and 47 patients were enrolled for analysis. The age of the patients ranged from 13 to 60 years, with a mean of 33.4 years, and 57.4% (25/47) of the patients were male. The PSQI scores for all 47 patients one month after undergoing WMT were significantly lower (Cohen d = 0.59, p < 0.001) compared to the baseline. Moreover, baseline PSQI score was correlated with the difference value of the PSQI score before and after WMT (post-PSQI minus pre-PSQI) (r = 0.61, p < 0.05). Conclusion: The study suggests that WMT might be a helpful intervention for improving the sleep quality of patients with IBD, encouraging clinicians to consider its use in clinical practice for addressing poor sleep in IBD patients. Clinical Trial Registration: ClinicalTrials.gov; ID: NCT01793831, NCT01790061.

14.
Postgrad Med J ; 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39102373

RESUMO

BACKGROUND: With the rapid advancement of deep learning network technology, the application of facial recognition technology in the medical field has received increasing attention. OBJECTIVE: This study aims to systematically review the literature of the past decade on facial recognition technology based on deep learning networks in the diagnosis of rare dysmorphic diseases and facial paralysis, among other conditions, to determine the effectiveness and applicability of this technology in disease identification. METHODS: This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for literature search and retrieved relevant literature from multiple databases, including PubMed, on 31 December 2023. The search keywords included deep learning convolutional neural networks, facial recognition, and disease recognition. A total of 208 articles on facial recognition technology based on deep learning networks in disease diagnosis over the past 10 years were screened, and 22 articles were selected for analysis. The meta-analysis was conducted using Stata 14.0 software. RESULTS: The study collected 22 articles with a total sample size of 57 539 cases, of which 43 301 were samples with various diseases. The meta-analysis results indicated that the accuracy of deep learning in facial recognition for disease diagnosis was 91.0% [95% CI (87.0%, 95.0%)]. CONCLUSION: The study results suggested that facial recognition technology based on deep learning networks has high accuracy in disease diagnosis, providing a reference for further development and application of this technology.

15.
RSC Med Chem ; 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39185449

RESUMO

Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(iv) conjugates derived from Pt(ii) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.

16.
BMC Geriatr ; 24(1): 634, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39068440

RESUMO

BACKGROUND: Malnutrition is linked to a higher risk of unfavorable outcomes in various illnesses. The present investigation explored the correlation between inadequate nutritional condition and outcomes in older individuals diagnosed with hyperlipidemia. METHODS: The geriatric nutritional risk index (GNRI) was used to evaluate the nutritional status. All patients were divided into two groups according to GNRI. A Kaplan-Meier analysis was used to assess the survival rates of different groups at risk of malnutrition. In addition, GNRI was used in COX proportional risk regression models to evaluate its predictive effect on both overall mortality and cardiovascular mortality among patients with hyperlipidemia. Furthermore, the study employed restricted cubic splines (RCS) to examine the nonlinear correlation between GNRI and mortality. RESULTS: The study included 4,532 elderly individuals diagnosed with hyperlipidemia. During a median follow-up duration of 139 months, a total of 1498 deaths from all causes and 410 deaths from cardiovascular causes occurred. The Kaplan-Meier analysis demonstrated significantly poorer survival among individuals at risk of malnutrition, as indicated by the GNRI. In the malnutrition risk group, the modified COX proportional hazards model revealed that a decrease in GNRI was associated with a higher risk of all-cause mortality (HR=1.686, 95% CI 1.212-2.347) and cardiovascular mortality (HR=3.041, 95% CI 1.797-5.147). Furthermore, the restricted cubic splines revealed a non-linear association between GNRI and both all-cause mortality and cardiovascular mortality (p-value for non-linearity = 0.0039, p-value for non-linearity=0.0386). CONCLUSIONS: In older patients with hyperlipidemia, lower levels of GNRI are associated with mortality. The GNRI could potentially be used to predict all-cause mortality and cardiovascular mortality.


Assuntos
Doenças Cardiovasculares , Hiperlipidemias , Desnutrição , Humanos , Feminino , Idoso , Masculino , Doenças Cardiovasculares/mortalidade , Hiperlipidemias/mortalidade , Hiperlipidemias/epidemiologia , Hiperlipidemias/complicações , Desnutrição/mortalidade , Desnutrição/diagnóstico , Desnutrição/epidemiologia , Idoso de 80 Anos ou mais , Avaliação Geriátrica/métodos , Inquéritos Nutricionais/métodos , Inquéritos Nutricionais/tendências , Causas de Morte/tendências , Avaliação Nutricional , Estado Nutricional , Medição de Risco/métodos , Fatores de Risco , Estimativa de Kaplan-Meier , Modelos de Riscos Proporcionais
17.
Phytomedicine ; 132: 155833, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39008915

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and is characterised by extensive invasive and metastatic potential. Previous studies have shown that vitexicarpin extracted from the fruits of Vitex rotundifolia can impede tumour progression. However, the molecular mechanisms involved in CRC treatment are still not fully established. PURPOSE: Our study aimed to investigate the anticancer activity, targets, and molecular mechanisms of vitexicarpin in CRC hoping to provide novel therapies for patients with CRC. STUDY DESIGN/METHODS: The impact of vitexicarpin on CRC was assessed through various experiments including MTT, clone formation, EDU, cell cycle, and apoptosis assays, as well as a tumour xenograft model. CETSA, label-free quantitative proteomics, and Biacore were used to identify the vitexicarpin targets. WB, Co-IP, Ubiquitination assay, IF, molecular docking, MST, and cell transfection were used to investigate the mechanism of action of vitexicarpin in CRC cells. Furthermore, we analysed the expression patterns and correlation of target proteins in TCGA and GEPIA datasets and clinical samples. Finally, wound healing, Transwell, tail vein injection model, and tissue section staining were used to demonstrate the antimetastatic effect of vitexicarpin on CRC in vitro and in vivo. RESULTS: Our findings demonstrated that vitexicarpin exhibits anticancer activity by directly binding to inosine monophosphate dehydrogenase 2 (IMPDH2) and that it promotes c-Myc ubiquitination by disrupting the interaction between IMPDH2 and c-Myc, leading to epithelial-mesenchymal transition (EMT) inhibition. Vitexicarpin hinders the migration and invasion of CRC cells by reversing EMT both in vitro and in vivo. Additionally, these results were validated by the overexpression and knockdown of IMPDH2 in CRC cells. CONCLUSION: These results demonstrated that vitexicarpin regulates the interaction between IMPDH2 and c-Myc to inhibit CRC proliferation and metastasis both in vitro and in vivo. These discoveries introduce potential molecular targets for CRC treatment and shed light on new mechanisms for c-Myc regulation in tumours.


Assuntos
Neoplasias Colorretais , Flavonoides , Ubiquitinação , Vitex , Animais , Humanos , Masculino , Camundongos , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , IMP Desidrogenase/metabolismo , IMP Desidrogenase/antagonistas & inibidores , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ubiquitinação/efeitos dos fármacos , Vitex/química , Ensaios Antitumorais Modelo de Xenoenxerto , Flavonoides/farmacologia
18.
Cell Host Microbe ; 32(8): 1365-1379.e10, 2024 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-39059397

RESUMO

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in ApcMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the integrin α6/ß4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/ß4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.


Assuntos
Carcinogênese , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Peptostreptococcus , Receptor ErbB-2 , Animais , Humanos , Camundongos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais/patologia , Frutose-Bifosfato Aldolase/metabolismo , Frutose-Bifosfato Aldolase/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , /farmacologia
19.
Adv Sci (Weinh) ; 11(33): e2402086, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38946582

RESUMO

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP.


Assuntos
Aminoácidos de Cadeia Ramificada , Diabetes Mellitus Experimental , Neuropatias Diabéticas , Canal de Potássio Kv1.2 , Transportador 1 de Aminoácidos Neutros Grandes , Regulação para Cima , Animais , Aminoácidos de Cadeia Ramificada/metabolismo , Camundongos , Humanos , Masculino , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/genética , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Canal de Potássio Kv1.2/genética , Canal de Potássio Kv1.2/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/genética , Modelos Animais de Doenças , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações , Neuralgia/metabolismo , Neuralgia/genética , Feminino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
20.
Eur J Med Res ; 29(1): 366, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39014466

RESUMO

PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.


Assuntos
Algoritmos , Antraciclinas , Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Antraciclinas/uso terapêutico , Antraciclinas/administração & dosagem , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , China/epidemiologia , Adulto , Recombinação Homóloga , Mutação , Idoso , Variações do Número de Cópias de DNA , Proteína BRCA1/genética
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