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1.
Nat Commun ; 15(1): 8912, 2024 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-39414766

RESUMO

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90's interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine.


Assuntos
Proliferação de Células , Proteínas de Choque Térmico HSP90 , Chaperonas Moleculares , Processamento de Proteína Pós-Traducional , Humanos , Fosforilação , Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico HSP90/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genética , Animais , Mapas de Interação de Proteínas , Camundongos , Serina/metabolismo , Linhagem Celular Tumoral
2.
Am J Cancer Res ; 14(9): 4353-4366, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39417182

RESUMO

Pancreatic cancer is an aggressive cancer with silent symptoms and high mortality with less than 11% of the 5-year survival rate. Until now, the significance of genes as clinical biomarkers in the early stages of pancreatic cancer has not been fully understood. Hence, this study aims to reveal the significant genes in the early stages of pancreatic cancer using bioinformatic analysis and in vitro experiments, and to serve as clinical biomarkers for early detection. We used Cancer RNA-Seq Nexus database and identified one tumor suppressor gene (NAGK), and five oncogenes (FXYD3, ACTR1A, B3GNT3, SIGIRR, and EXOC1) that are significant in the early stages of pancreatic cancer. The expression of NAGK, FXYD3, ACTR1A, B3GNT3, SIGIRR, and EXOC1 were determined from the GEPIA, UALCAN, and HPA database. It has been shown that pancreatic cancer tumor dissemination is an event that can occur in early lesions, rather than being solely restricted in the developed primary tumor. Thus, the six hub genes that were differentially expressed between stage I and stage II of primary pancreatic cancer tumors were compared to metastasis-related genes (1938 genes) in the human cancer metastasis database (HCMDB), yielding two overlapped genes (B3GNT3 and FXYD3). To establish the expression correlation between these two specific genes with metastatic characteristics of the early stage of pancreatic cancer and migratory ability in pancreatic cancer cell lines, the expression patterns of B3GNT3 and FXYD3 were examined in four different migratory abilities of pancreatic cancer cell lines, including HPAC, BxPC-3, AsPC-1, and PANC-1, as well as the normal pancreatic duct epithelial cell line HPDE6-C7. The results displayed that the expression of the FXYD3 gene was dramatically increased with the migratory ability enhanced of four pancreatic cancer cell lines. Thus, in the follow-up study, we will demonstrate the functional role of FXYD3 in pancreatic cancer tumorigenesis. This study revealed that the FXYD3 may act as a significant oncogene in the early stage of pancreatic cancer.

3.
Adv Healthc Mater ; : e2402864, 2024 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-39344248

RESUMO

Combination therapy based on precise phototherapies combined with immune modulation provides successful antitumor effects. In this study, a combination therapy is designed based on phototactic, photosynthetic, and phototherapeutic Chlamydomonas Reinhardtii (CHL)-glycol chitosan (GCS)-polypyrrole (PPy) nanoparticle (NP)-enhanced immunity combined with the tumor microenvironment turnover of cytotoxic T cells and M1/M2 macrophages, which is based on photothermal GCS-PPy NPs decorated onto the phototactic and photosynthetic CHL. Phototherapy based on CHL-GCS-PPy NPs alleviates hypoxia and modulates the tumor immune microenvironment, which induces tumor cell death. In particular, the precise antitumor immune response and potent immune memory induced by combining self-navigated phototherapies significantly alleviate the progression of bladder cancer in C57BL/6 mice and effectively inhibit bladder tumor growth. Furthermore, they also potentially prevent tumor recurrence, which provides a promising therapeutic strategy for clinical tumor therapy.

4.
Int J Biol Macromol ; 280(Pt 4): 135608, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39276877

RESUMO

X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive iron-glycol chitosan-polypyrrole nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with potentially high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers.

5.
Int J Chron Obstruct Pulmon Dis ; 19: 1989-2000, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39247665

RESUMO

Purpose: This study aimed to investigate the proportion and risk factors of paroxysmal atrial fibrillation (AF) and atrial arrhythmias (AA) in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in Vietnam. Patients and Methods: A prospective observational study was conducted at two major hospitals in Hanoi, Vietnam, from January 2022 to January 2023. A total of 197 AECOPD patients were recruited. ECG and 24-hour Holter ECG were used to diagnose paroxysmal AF and AA. Results: The prevalence of paroxysmal AF and AA were 15.2% and 72.6%, respectively. Factors associated with a higher likelihood of paroxysmal AF included aging 75 years old and above (aOR = 3.15; 95% CI: 1.28 to 8.48), Premature atrial complex (PAC) with 500 or more (aOR = 3.81; 95% CI: 1.48 to 10.97) and severity of COPD as group C and D (aOR = 3.41; 95% CI: 1.28 to 10.50). For AA, aging 75 years old and above (aOR = 2.25; 95% CI: 1.28 to 5.20), smoking (aOR = 2.10; 95% CI: 1.07 to 4.23) and P wave dispersion (PWD) with 40 milliseconds or more (aOR = 3.04; 95% CI: 1.54 to 6.19) were associated with a higher likelihood of AA. Conclusion: Overall, our findings highlight the associated factors with the paroxysmal AF and AA among AECOPD patients. This underscores the importance of a multifaceted approach to risk assessment and management in this vulnerable population, focusing not only on respiratory symptoms but also on comprehensive cardiovascular evaluation and intervention.


Assuntos
Fibrilação Atrial , Progressão da Doença , Hospitalização , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/terapia , Idoso , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/terapia , Masculino , Prevalência , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Fatores de Risco , Vietnã/epidemiologia , Hospitalização/estatística & dados numéricos , Fatores Etários , Medição de Risco , Idoso de 80 Anos ou mais , Complexos Atriais Prematuros/epidemiologia , Complexos Atriais Prematuros/diagnóstico , Complexos Atriais Prematuros/fisiopatologia , Eletrocardiografia Ambulatorial
6.
Cureus ; 16(7): e64243, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39130999

RESUMO

Aortoesophageal fistula (AEF) is an uncommon complication of esophageal cancer and can be extremely fatal if left untreated. Compared to open repair, thoracic endovascular aortic repair (TEVAR), a less invasive technique, is the initial recommended treatment in cases of hemorrhagic shock secondary to AEF, as this procedure showed a favorable outcome in controlling the overt bleeding. Here, we present a case of a patient with a history of stage IV esophageal cancer being treated with chemotherapy and an esophageal stent due to a previous tracheoesophageal fistula who presented to the emergency room due to severe gastroesophageal bleeding and hemorrhagic shock. A CT angiography of the chest revealed an AEF. The patient was subsequently resuscitated and treated with TEVAR. After the procedure, the hemorrhage was managed, and the patient was discharged with palliative radiation therapy. However, after one month, the patient had a major gastrointestinal hemorrhage, which caused her death. This example indicates the necessity of early detection and surgical intervention in AEF patients with unstable hemodynamics who have underlying unresectable esophageal cancer and chemotherapy. TEVAR should be conducted as soon as possible before the open surgery to achieve the best outcome for patients.

7.
J Exp Clin Cancer Res ; 43(1): 233, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39160581

RESUMO

BACKGROUND: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive. METHODS: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE. RESULTS: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters. CONCLUSION: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.


Assuntos
Areca , Diferenciação Celular , Transformação Celular Neoplásica , Macrófagos , Neoplasias Bucais , Animais , Areca/efeitos adversos , Areca/química , Transformação Celular Neoplásica/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/metabolismo , Humanos , Macrófagos/metabolismo , Cricetinae , Modelos Animais de Doenças , Nozes , Masculino , Reprogramação Metabólica
8.
Colloids Surf B Biointerfaces ; 243: 114054, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39079188

RESUMO

Creating a versatile and remotely self-assembling biocomposite for delivering therapeutics to alleviate inflammatory diseases poses significant challenges. This study introduces a novel biocomposite, created through cold-atmosphere plasma treatment, that combines fucoidan (Fu) and neutrophil lysate (Nu) to mediate the self-assembly of diferuloylmethane (DIF) and iron oxide (IO) nanoclusters, termed DIF-Nu/Fu-IO NC. This biocomposite forms a phototherapeutic and magnetically-driven in situ gel with open-porous architecture loaded with DIF, offering non-invasive theranostic capabilities for treating inflammatory diseases. It demonstrates efficacy in both an intraarticular zymosan-induced rheumatoid arthritis animal model and an intranasal LPS-induced inflammatory lung model. Upon administration, near-infrared (NIR) irradiation and magnet application significantly improved the condition of the animals with rheumatoid arthritis and lung inflammation. This breakthrough heralds a new paradigm in bioinspired, versatile, theranostic, self-assembling biocomposites for addressing clinical inflammatory diseases.


Assuntos
Neutrófilos , Polissacarídeos , Animais , Polissacarídeos/química , Neutrófilos/metabolismo , Neutrófilos/efeitos dos fármacos , Camundongos , Compostos Férricos/química , Furocumarinas/química , Furocumarinas/farmacologia , Artrite Reumatoide/terapia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Inflamação/tratamento farmacológico , Gases em Plasma/química , Fototerapia/métodos , Géis/química , Humanos , Tamanho da Partícula , Propriedades de Superfície
9.
Npj Imaging ; 2(1): 14, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38912527

RESUMO

Positron emission tomography (PET), a cornerstone in cancer diagnosis and treatment monitoring, relies on the enhanced uptake of fluorodeoxyglucose ([18F]FDG) by cancer cells to highlight tumors and other malignancies. While instrumental in the clinical setting, the accuracy of [18F]FDG-PET is susceptible to metabolic changes introduced by radiation therapy. Specifically, radiation induces the formation of giant cells, whose metabolic characteristics and [18F]FDG uptake patterns are not fully understood. Through a novel single-cell gamma counting methodology, we characterized the [18F]FDG uptake of giant A549 and H1299 lung cancer cells that were induced by radiation, and found it to be considerably higher than that of their non-giant counterparts. This observation was further validated in tumor-bearing mice, which similarly demonstrated increased [18F]FDG uptake in radiation-induced giant cells. These findings underscore the metabolic implications of radiation-induced giant cells, as their enhanced [18F]FDG uptake could potentially obfuscate the interpretation of [18F]FDG-PET scans in patients who have recently undergone radiation therapy.

10.
Sci Adv ; 10(24): eadk5747, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875333

RESUMO

In vivo molecular imaging tools are crucially important for elucidating how cells move through complex biological systems; however, achieving single-cell sensitivity over the entire body remains challenging. Here, we report a highly sensitive and multiplexed approach for tracking upward of 20 single cells simultaneously in the same subject using positron emission tomography (PET). The method relies on a statistical tracking algorithm (PEPT-EM) to achieve a sensitivity of 4 becquerel per cell and a streamlined workflow to reliably label single cells with over 50 becquerel per cell of 18F-fluorodeoxyglucose (FDG). To demonstrate the potential of the method, we tracked the fate of more than 70 melanoma cells after intracardiac injection and found they primarily arrested in the small capillaries of the pulmonary, musculoskeletal, and digestive organ systems. This study bolsters the evolving potential of PET in offering unmatched insights into the earliest phases of cell trafficking in physiological and pathological processes and in cell-based therapies.


Assuntos
Rastreamento de Células , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Análise de Célula Única , Imagem Corporal Total , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Análise de Célula Única/métodos , Rastreamento de Células/métodos , Imagem Corporal Total/métodos , Camundongos , Humanos , Fluordesoxiglucose F18 , Linhagem Celular Tumoral , Algoritmos , Melanoma/diagnóstico por imagem , Melanoma/patologia
11.
PLoS One ; 19(6): e0303354, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843274

RESUMO

BACKGROUND: Vietnam is experiencing an increasing prevalence of hypertension in its adult population. In addition to medical therapy, modifying adverse lifestyle practices is important for effective blood pressure control. There are limited data on unhealthy lifestyle practices in patients with chronic diseases, however, particularly among hypertensive patients living in rural Vietnam. Our study objectives were to examine the prevalence of unhealthy lifestyle practices and associated factors among rural Vietnamese adults with uncontrolled hypertension. METHODS: Data from the baseline survey of a cluster randomized trial among hypertensive Vietnamese adults (2017-2022) were utilized. Information on unhealthy lifestyle practices including smoking, excessive alcohol consumption, physical inactivity, and inadequate fruit and vegetable intake was collected from study participants. The primary study outcome was having ≥2 unhealthy lifestyle practices. A multivariable logistic regression model was used to examine factors associated with the primary study outcome. RESULTS: The mean age of the 671 patients was 67 years and 45.0% were men. Nearly three out of every four participants had one or fewer unhealthy practices, 24.0% had two, and 3.3% had three or all four unhealthy lifestyle practices. Men, individuals who did unpaid work or were unemployed, and individuals with hypertension level III were more likely to have ≥2 unhealthy lifestyle practices, whereas individuals with higher education were less likely to have ≥2 unhealthy lifestyle practices compared with respective comparison groups. CONCLUSIONS: We observed a high prevalence of unhealthy lifestyle practices among rural Vietnamese patients with uncontrolled hypertension. Several demographic factors were associated with a greater number of unhealthy lifestyle practices. Newer interventions and educational programs encouraging lifestyle modification practices are needed to control hypertension among adults living in rural settings of Vietnam.


Assuntos
Hipertensão , Estilo de Vida , Humanos , Hipertensão/epidemiologia , Masculino , Feminino , Vietnã/epidemiologia , Pessoa de Meia-Idade , Idoso , População Rural/estatística & dados numéricos , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Prevalência , Fatores de Risco , Fumar/epidemiologia
12.
Braz J Microbiol ; 55(3): 2169-2177, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38801640

RESUMO

OBJECTIVE: Pediocin PA-1, an antimicrobial peptide derived from Pediococcus acidilactici PAC1.0, has a potential application as a food preservative thanks to its strong inhibitory activity against the foodborne pathogen L. monocytogenes. This study aimed to produce Pediocin PA-1 from the yeast P. pastoris and evaluate its characteristics. METHODS: Gene encoding Pediocin PA-1 was integrated into P. pastoris X33 genome to establish the strain X33::ped, which could produce and secrete this peptide into culture medium. The antimicrobial activity of Pediocin PA-1 was examined using agar diffusion assay. The stability of pediocin PA-1 was determined based on its remaining antibacterial activity after exposure to proteases and extreme pH and temperatures. The potential use of this bacteriocin in food preservation was demonstrated using the L. monocytogenes infected pork bologna. The anticancer activity of Pediocin PA-1 was also investigated on some cancer cells using MTT assay. RESULTS: We established the yeast P. pastoris X33::ped capable of producing pediocin PA-1 with antimicrobial activity against L. monocytogenes and some other harmful bacteria. Pediocin PA-1 was stable at 100˚C and resistant against pH 1-12 for 1 h, but susceptible to trypsin, α-chymotrypsin, and proteinase K. This peptide could reduce the number of L. monocytogenes in pork bologna by 3.59 log CFU/g after 7 days of storage at 4˚C. Finally, Pediocin PA-1 (25 µg/ml) inhibited the proliferation of A549 and Hela cancer cells. CONCLUSION: We succeeded in producing active Pediocin PA-1 from P. pastoris and demonstrated its potential use in food preservation and pharmaceutical industry.


Assuntos
Conservação de Alimentos , Listeria monocytogenes , Pediocinas , Pediocinas/farmacologia , Pediocinas/genética , Animais , Conservação de Alimentos/métodos , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/genética , Humanos , Antibacterianos/farmacologia , Clonagem Molecular , Suínos , Testes de Sensibilidade Microbiana , Bacteriocinas/farmacologia , Bacteriocinas/genética , Bacteriocinas/metabolismo , Pediococcus acidilactici/genética , Pediococcus acidilactici/metabolismo , Expressão Gênica , Saccharomycetales/genética , Saccharomycetales/metabolismo , Saccharomycetales/efeitos dos fármacos
13.
Res Sq ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38645031

RESUMO

The intricate protein-chaperone network is vital for cellular function. Recent discoveries have unveiled the existence of specialized chaperone complexes called epichaperomes, protein assemblies orchestrating the reconfiguration of protein-protein interaction networks, enhancing cellular adaptability and proliferation. This study delves into the structural and regulatory aspects of epichaperomes, with a particular emphasis on the significance of post-translational modifications in shaping their formation and function. A central finding of this investigation is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 situated within an intrinsically disordered region, as critical determinants in epichaperome assembly. Our data demonstrate that the phosphorylation of these serine residues enhances HSP90's interaction with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Furthermore, this study establishes a direct link between epichaperome function and cellular physiology, especially in contexts where robust proliferation and adaptive behavior are essential, such as cancer and stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone complexes in diseases characterized by epichaperome dysregulation, bridging the gap between fundamental research and precision medicine.

14.
Am J Surg ; 234: 58-61, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38580566

RESUMO

BACKGROUND: The tall cell subtype of papillary thyroid cancer (TCPTC) is the most common aggressive subtype and often treated aggressively. This approach may not be necessary in smaller tumours without adverse histological characteristics. METHODS: 97 patients with TCPTC defined as a height-to-width ratio of ≥3:1 and at least 30% tall cells were compared against 390 classical papillary thyroid carcinoma (CPTC) based on tumour size with recurrence free survival (RFS) as the primary outcome. RESULTS: TCPTC are more likely to present with adverse histological characteristics. In smaller tumours (<2 â€‹cm), only central lymph node metastasis (HR7.16 p â€‹= â€‹0.03) and multifocality (HR10.11 p â€‹= â€‹0.026) increased recurrence risk. In larger tumours, TCPTC histology (HR3.78 p â€‹= â€‹0.002), lymphovascular invasion (HR3.02 p â€‹= â€‹0.014) and central lymph node metastasis (HR3.24 p â€‹< â€‹0.001) significantly increased recurrence risk. CONCLUSION: TCPTC tumours <2 â€‹cm without central lymph node metastasis and multifocality are similar in risk of recurrence to classical PTC and could be managed with lobectomy.


Assuntos
Recidiva Local de Neoplasia , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Feminino , Masculino , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/patologia , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/mortalidade , Adulto , Tireoidectomia , Metástase Linfática , Estudos Retrospectivos , Idoso , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Carga Tumoral , Medição de Risco , Fatores de Risco
15.
World J Hepatol ; 16(3): 393-404, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38577534

RESUMO

BACKGROUND: Obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC) and may influence its outcomes. However, after diagnosis of HCC, like other malignancies, the obesity paradox may exist where higher body mass index (BMI) may in fact confer a survival benefit. This is frequently observed in patients with advanced HCC and cirrhosis, who often present late with advanced tumor features and cancer related weight loss. AIM: To explore the relationship between BMI and survival in patients with cirrhosis and HCC. METHODS: This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical centers. Patient and tumor characteristics were extracted manually from medical records of each institutions' cancer registries. Patients were stratified according to BMI classes: < 25 kg/m2 (lean), 25-29.9 kg/m2 (overweight), and > 30 kg/m2 (obese). Patient and tumor characteristics were compared according to BMI classification. We performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria. A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and HCC. RESULTS: A total of 2548 patients with HCC were included in the analysis of which 11.2% (n = 286) were classified as non-cirrhotic. The three main BMI categories: Lean (n = 754), overweight (n = 861), and obese (n = 933) represented 29.6%, 33.8%, and 36.6% of the total population overall. Within each BMI class, the non-cirrhotic patients accounted for 15% (n = 100), 12% (n = 94), and 11% (n = 92), respectively. Underweight patients with a BMI < 18.5 kg/m2 (n = 52) were included in the lean cohort. Of the obese cohort, 42% (n = 396) had a BMI ≥ 35 kg/m2. Out of 2262 patients with cirrhosis and HCC, 654 (29%) were lean, 767 (34%) were overweight, and 841 (37%) were obese. The three BMI classes did not differ by age, MELD, or Child-Pugh class. Chronic hepatitis C was the dominant etiology in lean compared to the overweight and obese patients (71%, 62%, 49%, P < 0.001). Lean patients had significantly larger tumors compared to the other two BMI classes (5.1 vs 4.2 vs 4.2 cm, P < 0.001), were more likely outside Milan (56% vs 48% vs 47%, P < 0.001), and less likely to undergo transplantation (9% vs 18% vs 18%, P < 0.001). While both tumor size (P < 0.0001) and elevated alpha fetoprotein (P < 0.0001) were associated with worse survival by regression analysis, lean BMI was not (P = 0.36). CONCLUSION: Lean patients with cirrhosis and HCC present with larger tumors and are more often outside Milan criteria, reflecting cancer related cachexia from delayed diagnosis. Access to care for hepatitis C virus therapy and liver transplantation confer a survival benefit, but not overweight or obese BMI classifications.

16.
J Biomol Struct Dyn ; : 1-8, 2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38284361

RESUMO

PROTACs (Proteolysis Targeting Chimeras), heterobifunctional molecules, exhibit selectivity in degrading target proteins through E3 ubiquitin ligases. Designing effective PROTACs requires a deep understanding of the intricate binding interactions in the ternary complex (POI/PROTAC/E3 ligase), crucial for efficient target protein degradation. To address this challenge, we introduce a novel computational virtual screening method that considers essential amino acid interactions between the protein of interest and the chosen E3 ligase. This approach enhances accuracy and reliability, facilitating the strategic development of potent PROTACs. Utilizing a crystallized model of the VHL:PROTAC:SMARCA2BD ternary complex (PDB: 7Z6L), we assessed the effectiveness of our method. Our study reveals that increasing the number of essential restraints between the two proteins reduces the generated docking poses, leading to closer alignment with the experimental ternary complex. Specifically, utilizing three restraints showed the closest resemblance to the published complex, highlighting crucial interactions such as an H-bond between A:Gln 89 and B:Asn 67, along with two hydrophobic interactions: A:Gly 22 with B:Arg 69 and A:Glu 37 with B:Pro 99. This resulted in a significant decrease in the mean RMSD value from 31.8 and 31.0 Å to 24.4 Å, respectively. This underscores the importance of incorporating multiple essential restraints to enhance docking accuracy. Building on this progress, we introduce a systematic approach to design potential PROTACs between the Estrogen receptor and the E3 ligase, utilizing bridging intermediates with 4, 6, or 7 carbon atoms. By providing a more accurate and efficient means of identifying optimal PROTAC candidates, this approach has the potential to accelerate the development of targeted therapies and reduce the time and costs associated with drug discovery.Communicated by Ramaswamy H. Sarma.

17.
SAGE Open Med ; 11: 20503121231218897, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38116300

RESUMO

Introduction: Endogenous endophthalmitis-related Klebsiella pyogenic liver abscess is a rare complication of metastatic infection. In most cases, visual acuity results are often impaired, even blind, and even with aggressive treatment with topical antibiotics, the final results are unsatisfactory. The objective of this study is to retrospectively based on medical records to describe clinical features, risk factors, and visual outcomes of patients with endogenous endophthalmitis-related pyogenic liver abscesses. Methods: We reported a case series of 12 endogenous endophthalmitis-related pyogenic liver abscess patients from March 2021 to 2023. All cases of endogenous endophthalmitis were diagnosed at admission or during the hospital stay. Results: From the medical records of 588 pyogenic liver abscess patients, we found 12 cases of endogenous endophthalmitis with 2.0%. The result showed a mean age of 61.5 ± 12.0 (41-78), diabetes mellitus (7 of 12), right lobe (7 of 12), single abscess (9 of 12), and the mean largest abscess diameter of 5.8 ± 1.7 cm (3.3-9). All patients had ocular symptoms such as eye pain (9 of 12), pus discharge (3 of 12), hypopyon (1 of 12), swollen eyelids (2 of 12), and corneal edema (2 of 12), pyogenic liver abscess before endogenous endophthalmitis (10 of 12), the median interval between endogenous endophthalmitis and pyogenic liver abscess 6.1 ± 1.9 days, ocular symptoms before diagnosis endogenous endophthalmitis 4.4 ± 2.3 days. All affected eyes were injected intravitreously with ceftazidime, amikacin, and vancomycin. Two patients underwent evisceration. Conclusions: Endogenous endophthalmitis has permanent morbidity, reducing visual acuity, poor quality of life, and lacks the warning signs, so it is essential for early detection of symptoms and referral to ophthalmologists.

18.
Molecules ; 28(21)2023 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-37959661

RESUMO

Processing with heat treatment has been reported to alter several therapeutic effects of turmeric. In Vietnamese traditional medicine, turmeric has been long used for bacterial infections, and roasting techniques are sometimes applied with this material. However, there have been no studies investigating the effects of these thermal processes on the plant's antibacterial properties. Our study was therefore performed to examine the changes that roasting produced on this material. Slices of dried turmeric were further subjected to light-roasting (80 °C in 20 min) or dark-roasting (160 °C in 20 min) processes. Broth dilution and agar-well diffusion methods were applied to examine and compare the effects of ethanol extracts obtained from non-roasted, light-roasted and dark-roasted samples, on a set of 6 gram-positive and gram-negative bacteria. In both investigations, dark-roasted turmeric was significantly less antibacterial than non-roasted and light-roasted materials, as evident by the higher values of minimum inhibitory concentrations and the smaller diameters of induced inhibitory zones. In addition, dark-roasting was also found to clearly reduce curcumin contents, total polyphenol values and antioxidant activities of the extracts. These results suggest that non-roasting or light-roasting might be more suitable for the processing of turmeric materials that are aimed to be applied for bacterial infections.


Assuntos
Infecções Bacterianas , Curcuma , Antibacterianos/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Extratos Vegetais/farmacologia , Rizoma
19.
Int J Surg Case Rep ; 112: 108953, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37856974

RESUMO

INTRODUCTION AND IMPORTANCE: Intussusception in adults is a rare manifestation after traumatic abdominal surgery, because after abdominal surgery patients often have functional bowel paralysis rather than increased intestinal motility. CASE PRESENTATION: 39-year-old male patient with acute intussusception appeared after surgery for diaphragmatic rupture and is undergoing postoperative treatment on day 7. The patient has clinical manifestations of small bowel obstruction. Computed tomography image shows evidence of jejuno-jejunal intussusception. Exploratory laparotomy and resection of the necrotic bowel were performed. CLINICAL DISCUSSION: Rare cases such as intussusception should be observed postoperatively and in similar manifestations with careful examination of the characteristic CT findings, because of early detection and surgical intervention with manual reduction can prevent the need for small bowel resection and possible unwanted complications. CONCLUSION: Postoperative intussusception occurs primarily in the small intestine and should be indicated for emergency surgery in all cases, and this should be kept in mind by the surgeon and the resuscitator. The early diagnosis and intervention of patients increase the survival rate and the surgical efficiency.

20.
Curr Issues Mol Biol ; 45(9): 7417-7431, 2023 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-37754253

RESUMO

Despite the ongoing clinical trials and the introduction of novel treatments over the past few decades, ovarian cancer remains one of the most fatal malignancies in women worldwide. Platinum- and paclitaxel-based chemotherapy is effective in treating the majority of patients with ovarian cancer. However, more than 70% of patients experience recurrence and eventually develop chemoresistance. To improve clinical outcomes in patients with ovarian cancer, novel technologies must be developed for identifying molecular alterations following drug-based treatment of ovarian cancer. Recently, extracellular vesicles (EVs) have gained prominence as the mediators of tumor progression. In this study, we used mass spectrometry to identify the changes in EV protein signatures due to different chemotherapeutic agents used for treating ovarian cancer. By examining these alterations, we identified the specific protein induction patterns of cisplatin alone, paclitaxel alone, and a combination of cisplatin and paclitaxel. Specifically, we found that drug sensitivity was correlated with the expression levels of ANXA5, CD81, and RAB5C in patients receiving cisplatin with paclitaxel. Our findings suggest that chemotherapy-induced changes in EV protein signatures are crucial for the progression of ovarian cancer.

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