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1.
J Vasc Surg ; 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38821431

RESUMO

OBJECTIVE: This study utilizes the latest data from the Vascular Quality Initiative (VQI), which now encompasses over 50,000 transcarotid artery revascularization (TCAR) procedures, to offer a sizeable dataset for comparing the effectiveness and safety of TCAR, transfemoral carotid artery stenting (tfCAS), and carotid endarterectomy (CEA). Given this substantial dataset, we are now able to compare outcomes overall and stratified by symptom status across revascularization techniques. METHODS: Utilizing VQI data from September 2016 to August 2023, we conducted a risk-adjusted analysis by applying inverse probability of treatment weighting to compare in-hospital outcomes between TCAR vs tfCAS, CEA vs tfCAS, and TCAR vs CEA. Our primary outcome measure was in-hospital stroke/death. Secondary outcomes included myocardial infarction and cranial nerve injury. RESULTS: A total of 50,068 patients underwent TCAR, 25,361 patients underwent tfCAS, and 122,737 patients underwent CEA. TCAR patients were older, more likely to have coronary artery disease, chronic kidney disease, and undergo coronary artery bypass grafting/percutaneous coronary intervention as well as prior contralateral CEA/CAS compared with both CEA and tfCAS. TfCAS had higher odds of stroke/death when compared with TCAR (2.9% vs 1.6%; adjusted odds ratio [aOR], 1.84; 95% confidence interval [CI], 1.65-2.06; P < .001) and CEA (2.9% vs 1.3%; aOR, 2.21; 95% CI, 2.01-2.43; P < .001). CEA had slightly lower odds of stroke/death compared with TCAR (1.3% vs 1.6%; aOR, 0.83; 95% CI, 0.76-0.91; P < .001). TfCAS had lower odds of cranial nerve injury compared with TCAR (0.0% vs 0.3%; aOR, 0.00; 95% CI, 0.00-0.00; P < .001) and CEA (0.0% vs 2.3%; aOR, 0.00; 95% CI, 0.0-0.0; P < .001) as well as lower odds of myocardial infarction compared with CEA (0.4% vs 0.6%; aOR, 0.67; 95% CI, 0.54-0.84; P < .001). CEA compared with TCAR had higher odds of myocardial infarction (0.6% vs 0.5%; aOR, 1.31; 95% CI, 1.13-1.54; P < .001) and cranial nerve injury (2.3% vs 0.3%; aOR, 9.42; 95% CI, 7.78-11.4; P < .001). CONCLUSIONS: Although tfCAS may be beneficial for select patients, the lower stroke/death rates associated with CEA and TCAR are preferred. When deciding between CEA and TCAR, it is important to weigh additional procedural factors and outcomes such as myocardial infarction and cranial nerve injury, particularly when stroke/death rates are similar. Additionally, evaluating subgroups that may benefit from one procedure over another is essential for informed decision-making and enhanced patient care in the treatment of carotid stenosis.

2.
Surg Obes Relat Dis ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38556419

RESUMO

BACKGROUND: Patients who undergo metabolic and bariatric surgery (MBS) are at risk for thromboembolism. Patients are susceptible to coronavirus throughout the perioperative period, which also has a well-known association with thrombotic complications. OBJECTIVES: To identify and define the association between venous thromboembolism (VTE) and postoperative coronavirus diagnosis in bariatric surgery patients. SETTING: United States. METHODS: We conducted a retrospective cohort study using the MBS Accreditation and Quality Improvement Program (MBSAQIP) 2021 database to analyze the incidence of VTE within 30 days of surgery. VTE was a composite variable defined as either postoperative pulmonary embolism or postoperative venous thrombus requiring treatment. Cohorts were stratified by whether the patient was diagnosed with postoperative coronavirus. We created a multivariable logistic regression model to determine the adjusted odds of postoperative VTE based on various factors. Additionally, we conducted subset analyses of sleeve gastrectomy and Roux-en-Y bypass cases, the 2 most frequent bariatric operations in the United States. RESULTS: Patients diagnosed with postoperative coronavirus were significantly more likely to develop postoperative VTE (1.1% versus .3%, P < .001). In our logistic regression model, the adjusted odds of postoperative VTE for patients with postoperative coronavirus was 3.55 (95% CI: 2.15-5.87, P < .001). For patients who underwent Roux-en-Y bypass, the adjusted odds was even greater at 5.69 (95% CI: 2.76-11.70, P < .001). CONCLUSIONS: Early postoperative coronavirus infection after MBS is associated with higher odds of postoperative VTE. This persisted on subset analyses of the 2 most common procedures and appeared particularly important for Roux-en-Y bypass. COVID infection after MBS may warrant prolonged VTE prophylaxis.

3.
J Vasc Surg ; 80(1): 138-150.e8, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38428653

RESUMO

OBJECTIVE: With the recent expansion of the Centers for Medicare and Medicaid Services coverage, transfemoral carotid artery stenting (tfCAS) is expected to play a larger role in the management of carotid disease. Existing research on the tfCAS learning curve, primarily conducted over a decade ago, may not adequately describe the current effect of physician experience on outcomes. Because approximately 30% of perioperative strokes/deaths post-CAS occur after discharge, appropriate thresholds for in-hospital event rates have been suggested to be <4% for symptomatic and <2% for asymptomatic patients. This study evaluates the tfCAS learning curve using Vascular Quality Initiative (VQI) data. METHODS: We identified VQI patients who underwent tfCAS between 2005 and 2023. Each physician's procedures were chronologically grouped into 12 categories, from procedure counts 1-25 to 351+. The primary outcome was in-hospital stroke/death rate; secondary outcomes were in-hospital stroke/death/myocardial infarction (MI), 30-day mortality, in-hospital stroke/transient ischemic attack (stroke/TIA), and access site complications. The relationship between outcomes and procedure counts was analyzed using the Cochran-Armitage test and a generalized linear model with restricted cubic splines. Our results were then validated using a generalized estimating equations model to account for the variability between physicians. RESULTS: We analyzed 43,147 procedures by 2476 physicians. In symptomatic patients, there was a decrease in rates of in-hospital stroke/death (procedure counts 1-25 to 351+: 5.2%-1.7%), in-hospital stroke/death/MI (5.8%-1.7%), 30-day mortality (4.6%-2.8%), in-hospital stroke/TIA (5.0%-1.1%), and access site complications (4.1%-1.1%) as physician experience increased (all P values < .05). The in-hospital stroke/death rate remained above 4% until 235 procedures. Similarly, in asymptomatic patients, there was a decrease in rates of in-hospital stroke/death (2.1%-1.6%), in-hospital stroke/death/MI (2.6%-1.6%), 30-day mortality (1.7%-0.4%), and in-hospital stroke/TIA (2.8%-1.6%) with increasing physician experience (all P values <.05). The in-hospital stroke/death rate remained above 2% until 13 procedures. CONCLUSIONS: In-hospital stroke/death and 30-day mortality rates after tfCAS decreased with increasing physician experience, showing a lengthy learning curve consistent with previous reports. Given that physicians' early cases may not be included in the VQI, the learning curve was likely underestimated. Nevertheless, a substantially high rate of in-hospital stroke/death was found in physicians' first 25 procedures. With the recent Centers for Medicare and Medicaid Services coverage expansion for tfCAS, a significant number of physicians would enter the early stage of the learning curve, potentially leading to increased postoperative complications.


Assuntos
Competência Clínica , Artéria Femoral , Mortalidade Hospitalar , Curva de Aprendizado , Sistema de Registros , Stents , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Idoso , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Estados Unidos , Fatores de Tempo , Fatores de Risco , Resultado do Tratamento , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Cateterismo Periférico/efeitos adversos , Cateterismo Periférico/mortalidade , Indicadores de Qualidade em Assistência à Saúde , Pessoa de Meia-Idade , Punções , Estenose das Carótidas/mortalidade , Estenose das Carótidas/cirurgia , Estenose das Carótidas/terapia , Estenose das Carótidas/diagnóstico por imagem , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/etiologia , Medição de Risco , Doenças das Artérias Carótidas/mortalidade , Doenças das Artérias Carótidas/cirurgia , Doenças das Artérias Carótidas/terapia , Ataque Isquêmico Transitório/etiologia
5.
J Vasc Surg ; 79(6): 1287-1294.e1, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38185213

RESUMO

OBJECTIVE: The high frequency of reinterventions after fenestrated endovascular aortic repair (FEVAR) with physician-modified endografts (PMEGs) has been well-studied. However, the impact of prior EVAR on reinterventions and sac behavior following these procedures remains unknown. We analyzed 3-year rates of reinterventions and sac dynamics following PMEG for index aneurysm repair compared with PMEG for prior EVAR with loss of proximal seal. METHODS: We performed a retrospective analysis of 122 consecutive FEVARs with PMEGs at a tertiary care center submitted to the United States Food and Drug Administration in support of an investigational device exemption trial. We excluded patients with aortic dissection (n = 5), type I to III thoracoabdominal aneurysms (n = 13), non-elective procedures (n = 4), and prior aortic surgery other than EVAR (n = 8), for a final cohort of 92 patients. Patients were divided into those who underwent PMEG for index aneurysm repair (primary FEVAR) and those who underwent PMEG for rescue of prior EVAR with loss of proximal seal (secondary FEVAR). The primary outcomes were freedom from reintervention and sac dynamics (regression as ≥5 mm decrease, expansion as ≥5 mm increase, and stability as <5 mm increase or decrease) at 3 years. Secondary outcomes were perioperative mortality and 3-year survival. RESULTS: Of the 92 patients included, 56 (61%) underwent primary FEVAR and 36 (39%) underwent secondary FEVAR. Secondary FEVAR patients were older (78 years [interquartile range (IQR), 74.5-83.5 years] vs 73 years [IQR, 69-78.5 years]; P < .001), more frequently male (86% vs 68%; P = .048), and had larger aneurysms (72.5 mm [IQR, 65.5-81 mm] vs 59 mm [IQR, 55-65 mm]; P < .001). Perioperative mortality was 1.8% for primary FEVAR and 2.7% for secondary FEVAR (P = .75). At 3 years, overall survival was 84% for primary FEVAR and 71% for secondary FEVAR (P = .086). Freedom-from reintervention was significantly higher for primary FEVAR than secondary FEVAR, specifically 82% vs 38% at 3 years (P < .001). Primary FEVAR also had more desirable sac dynamics relative to secondary FEVAR at 3 years (primary: 54% stable, 46% regressed, 0% expanded vs secondary: 33% stable, 28% regressed, and 39% expanded; P = .038). CONCLUSIONS: FEVAR for primary aortic repair and FEVAR for rescue of prior EVAR with loss of proximal seal are two distinct entities. Following primary FEVAR, less than a quarter of patients have undergone reintervention at 3 years, and sac expansion was not seen in our cohort. Comparatively, 3 years after secondary FEVAR, over one-half of patients have undergone reintervention and over one-third have had ongoing sac expansion. Vigilant surveillance and a low threshold for further interventions are crucial following secondary FEVAR.


Assuntos
Implante de Prótese Vascular , Prótese Vascular , Procedimentos Endovasculares , Desenho de Prótese , Reoperação , Humanos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Procedimentos Endovasculares/mortalidade , Estudos Retrospectivos , Masculino , Feminino , Idoso , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Implante de Prótese Vascular/mortalidade , Fatores de Tempo , Idoso de 80 Anos ou mais , Fatores de Risco , Aneurisma da Aorta Abdominal/cirurgia , Aneurisma da Aorta Abdominal/mortalidade , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/fisiopatologia , Stents , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Falha de Tratamento , Resultado do Tratamento , Correção Endovascular de Aneurisma
6.
J Vasc Surg ; 79(4): 954-961, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37931886

RESUMO

OBJECTIVE: Despite the advantages that fenestrated endovascular aortic repair has over open repair, it is accompanied by the consequence of radiation exposure, which can result in long-term complications for both the patient and surgical staff. Fiber Optic RealShape (FORS) technology is a novel advancement that uses emitted light from a fiber optic wire and enables the surgeon to cannulate vessels in real time without live fluoroscopy. This technology has been implemented at select centers to study its effectiveness for cannulation of target vessels and its impact on procedural radiation. METHODS: We collected prospective data on physician-modified endograft (PMEG) cases before and after the introduction of FORS technology. FORS PMEGs were matched with up to three conventional fluoroscopy cases by number of target vessels, inclusion of a bifurcated device below, aneurysm extent, and patient body mass index. The procedural radiation parameters were compared between these cohorts. Within the FORS cohort, we analyzed the rate of successful target vessel cannulation for all cases done with this technology (including cases other than PMEGs), and we compared the radiation between the cannulations using only FORS with those that abandoned FORS for conventional fluoroscopy. RESULTS: Nineteen FORS PMEGs were able to be matched to 45 conventional fluoroscopy cases. Procedures that used FORS technology had significantly reduced total air kerma (527 mGy vs 964 mGy), dose area product (121 Gy∗cm2 vs 186 Gy∗cm2), fluoroscopy dose (72.1 Gy∗cm2 vs 132.5 Gy∗cm2), and fluoroscopy time (45 minutes vs 72 minutes). There was no difference in procedure length, total contrast, or digital subtraction angiography. Within FORS cases, 66% of cannulations were completed using only FORS. Cannulations using only FORS had significant reduction of navigation air kerma (5.0 mGy vs 26.5 mGy), dose area product (1.2 Gy∗cm2 vs 5.1 Gy∗cm2), and fluoroscopy time (0.6 minutes vs 2.3 minutes) compared with cannulations abandoning FORS for conventional fluoroscopy. CONCLUSIONS: This study demonstrates the advantages of FORS for total procedural radiation as well as during individual cannulation tasks. The implementation of FORS for target vessel catheterization has the potential to decrease the total degree of radiation exposure for the patient and surgical staff during complex endovascular aortic surgeries.


Assuntos
Implante de Prótese Vascular , Procedimentos Endovasculares , Exposição à Radiação , Humanos , Estudos Prospectivos , Aortografia/métodos , Resultado do Tratamento , Tecnologia , Doses de Radiação , Fluoroscopia , Exposição à Radiação/efeitos adversos , Exposição à Radiação/prevenção & controle , Estudos Retrospectivos
7.
medRxiv ; 2023 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-38014117

RESUMO

Objective: With the recent expansion of the Centers for Medicare and Medicaid Services (CMS) coverage, transfemoral carotid artery stenting (tfCAS) is expected to play a larger role in the management of carotid disease. Existing research on the tfCAS learning curve, primarily conducted over a decade ago, may not adequately describe the current effect of physician experience on outcomes. This study evaluates the tfCAS learning curve using VQI data. Methods: We analyzed tfCAS patient data from 2005-2023. Each physician's procedures were chronologically grouped into 12 categories, from procedure counts 1-25 to 351+. Primary outcome was in-hospital stroke/death rate; secondary outcomes were in-hospital stroke/death/MI, 30-day mortality, and in-hospital stroke/TIA. The relationship between outcomes and procedure counts was analyzed using Cochran Armitage test and a generalized linear model with restricted cubic splines, validated using generalized estimating equations. Results: We analyzed 43,147 procedures by 2,476 physicians. In symptomatic patients, there was a decrease in rates of in-hospital stroke/death (procedure counts 1-25 to 351+: 5.2% to 1.7%), in-hospital stroke/death/MI (5.8% to 1.7%), 30-day mortality (4.6% to 2.8%), in-hospital stroke/TIA (5.0% to 1.1%) (all p-values<0.05). The in-hospital stroke/death rate remained above 4% until 235 procedures. Similarly, in asymptomatic patients, there was a decrease in rates of in-hospital stroke/death (2.1% to 1.6%), in-hospital stroke/death/MI (2.6% to 1.6%), 30-day mortality (1.7% to 0.4%), and in-hospital stroke/TIA (2.8% to 1.6%) with increasing physician experience (all p-values<0.05). The in-hospital stroke/death rate remained above 2% until 13 procedures. Conclusions: In-hospital stroke/death and 30-day mortality rates post-tfCAS decreased with increasing physician experience, showing a lengthy learning curve consistent with previous reports. Given that physicians' early cases may not be included in the VQI, the learning curve was likely underestimated. With the recent CMS coverage expansion for tfCAS, a significant number of physicians would enter the early stage of the learning curve, potentially leading to increased post-operative complications.

9.
Chin J Cancer Res ; 35(4): 365-385, 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37691891

RESUMO

Objective: Striatins (STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase (STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established. Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas (TCGA) dataset was used to evaluate the breast cancer patients' response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SK-BR-3, were subsequently adopted for in vitro work. Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival (OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio (HR)=2.04, 95% confidence interval (95% CI), 1.36-3.07] and disease-free survival (DFS) (P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent. Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients' responses to drug treatment.

10.
Anticancer Res ; 43(4): 1463-1475, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36974802

RESUMO

BACKGROUND/AIM: Activated leukocyte cell adhesion molecule (ALCAM/CD166), a member of the immunoglobulin superfamily, has been shown to regulate cell adhesion through both homotypic and heterotypic interactions. In cancer, it might be involved in disease progression and chemotherapy drug resistance. The present study explored the clinical and prognostic significance of ALCAM in gastric cancer and its impact on patient's responses to neoadjuvant chemotherapies and cancer cells' response to chemodrugs in vitro. MATERIALS AND METHODS: Two independent cohorts were included to evaluate the link between ALCAM and the clinical outcomes and pathological factors of the patients. The gastric cancer cell lines HGC27 and AGS were used to generate ALCAM knockdown cell models. The cytotoxicity of chemotherapy drugs was examined using ALCAM knockdown cell models. RESULTS: Patients with gastric cancer who had high levels of ALCAM transcripts showed a significantly shorter overall survival in both cohorts (p=0.043 and 0.006, respectively). Patients who resisted to neoadjuvant chemotherapy had marginally higher levels of ALCAM than those responded (p=0.056). Patients with low levels of ALCAM expression and resisted to neoadjuvant chemotherapy had the worst clinical outcome with a significantly shorter overall survival (p=0.004) and disease-free survival (p=0.006), whereas such results did not appear in high ALCAM expression patients. ALCAM knockdown cells were more sensitive to Cisplatin, Oxaliplatin and 5-Fluorouracil compared with their respective control cells. CONCLUSION: ALCAM acts as a negative prognostic indicator in patients with gastric cancer and high levels of ALCAM expression result in increased chemotherapy drug resistance.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Prognóstico , Progressão da Doença , Intervalo Livre de Doença , Adesão Celular
11.
Biomolecules ; 13(2)2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36830748

RESUMO

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling.


Assuntos
Transdução de Sinais , Cicatrização , Humanos , Camundongos , Animais , Fosforilação , Glicoproteínas de Membrana
12.
Proteins ; 91(7): 991-998, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36811550

RESUMO

In this perspective, we propose that the folding energy landscapes of model proteases including pepsin and alpha-lytic protease (αLP), which lack thermodynamic stability and fold on the order of months to millennia, respectively, should be viewed as not evolved and fundamentally distinct from their extended zymogen forms. These proteases have evolved to fold with prosegment domains and robustly self-assemble as expected. In this manner, general protein folding principles are strengthened. In support of our view, αLP and pepsin exhibit hallmarks of frustration associated with unevolved folding landscapes, such as non-cooperativity, memory effects, and substantial kinetic trapping. The evolutionary implications of this folding strategy are considered in detail. Direct applications of this folding strategy on enzyme design, finding new drug targets, and constructing tunable folding landscapes are also discussed. Together with certain proteases, growing examples of other folding "exceptions"-including protein fold switching, functional misfolding, and prevalent inability to refold-suggests a paradigm shift in which proteins may evolve to exist in a wide range of energy landscapes and structures traditionally thought to be avoided in nature.


Assuntos
Pepsina A , Dobramento de Proteína , Pepsina A/química , Pepsina A/metabolismo , Cinética
13.
Int J Mol Sci ; 24(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36614319

RESUMO

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell-cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a 'seed' receptor in these tumour cells and a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients' clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal 'soil' receptor of tumour seeding but also a 'soil' receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases.


Assuntos
Molécula de Adesão de Leucócito Ativado , Neoplasias Pancreáticas , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Molécula de Adesão de Leucócito Ativado/genética , Molécula de Adesão de Leucócito Ativado/metabolismo , Adesão Celular , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Quinases da Família src/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Peritoneais/secundário , Neoplasias Pancreáticas
14.
Anticancer Res ; 43(1): 291-296, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36585193

RESUMO

Transglutaminase-4, also known as prostate transglutaminase, is a protein encoded by the TGM4 gene. TGase-4 was thought to be exclusively expressed in the prostate gland and has been suggested to be involved in certain medical conditions, such as infertility and possibly prostate cancer. In recent years, substantial progress has been made in the understanding of this unique protein in prostate cancer, with emerging clinical evidence. The present concise review summarised the current understanding of this intriguing enzyme in prostate cancer and presents an argument that TGase-4 is a useful indicator of both the development and progression of the disease.


Assuntos
Próstata , Neoplasias da Próstata , Humanos , Masculino , Prognóstico , Próstata/metabolismo , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Transglutaminases/metabolismo
15.
Int J Oncol ; 62(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36382667

RESUMO

Death associated protein­3 (DAP3) was identified as a responsive protein to interferon­gamma­induced cell death which possibly exerts this regulation by interacting with DAP3 binding cell Death enhancer­1 (DELE1), a newly discovered mitochondrial stress protein in response to cell stress signals. Whilst DAP3 has been shown to be aberrantly expressed in several cancer types (i.e. breast cancer), little is known about the relationship between DAP3 and DELE1 in cancers. The present study examined the expression levels of both DAP3 and DELE1 in clinical colorectal cancers (CRCs), as well as their implication on chemoresistance and mechanism behind the action. Firstly, transcript levels of both DAP3 and DELE1 were quantitatively assessed in a clinical cohort of CRC (n=94). Tumour tissues had significantly higher levels of DAP3, but not DELE1 compared with normal tissues. Levels of DAP3 and DELE1 had a significant association with patient's clinical outcomes and local recurrence. DAP3 and DELE1 significantly correlated in normal colorectal tissues but not in tumour tissues. Secondly, the protein levels of DAP3 and DELE1 were evaluated in both normal and tumour colon tissues which showed that both proteins were highly aberrant in CRC tissues. In addition, both DAP3 and DELE1 at transcript and protein levels were identified as prognostic factors for patient's clinical outcomes. Furthermore, in in vitro assays, knocking down DAP3 or DELE1, and in particular both DAP3 and DELE1 together rendered the CRC cells more sensitive to chemotherapy drugs, consistent with clinical findings of the TCGA­COAD datasets. The acquisition of drug sensitivity following the genetic knockdown was independent of the mitochondrial metabolism, as neither DAP3 knockdown nor DELE1 knockdown showed a significant change. In summary, DAP3 and DELE1 are highly aberrant in CRCs, and both molecules are prognostic factors for patient's clinical outcomes and local recurrence, and are indicators for chemoresistance.


Assuntos
Proteínas Reguladoras de Apoptose , Neoplasias Colorretais , Humanos , Proteínas Reguladoras de Apoptose/genética , Morte Celular , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Proteínas de Ligação a RNA
16.
Int J Mol Sci ; 23(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36499558

RESUMO

Colorectal cancer is a serious threat to human health. Poor prognosis and frequently reported drug resistance urges research into novel biomarkers and mechanisms to aid in the understanding of the development and progression of colorectal cancer and to optimise therapeutic strategies. In the current study, we investigated the roles of a putative tumour suppressor, EPLIN, in colorectal cancer. Our clinical colorectal cancer cohort and online databases revealed a downregulation of EPLIN in colorectal cancer tissues compared with normal tissues. The reduced expression of EPLIN was associated with poor clinical outcomes of patients. In vitro cellular function assays showed that EPLIN elicited an inhibitory effect on cellular growth, adhesion, migration and invasion. Utilising a protein microarray on protein samples from normal and tumour patient tissues suggested HSP60, Her2 and other signalling events were novel potential interacting partners of EPLIN. It was further revealed that EPLIN and HSP60 were negative regulators of Her2 in colorectal cancer cells. The clinical cohort also demonstrated that expression of HSP60 and Her2 affected clinical outcomes, but most interestingly the combination of EPLIN, HSP60 and Her2 was able to identify patients with the most unfavourable clinical outcome by independently predicting patient overall survival and disease free survival. Furthermore, EPLIN and HSP60 exhibited potential to regulate cellular response to chemotherapeutic and EGFR/Her2 targeted therapeutic agents. In conclusion, EPLIN is an important prognostic factor for patients with colon cancer and reduced EPLIN in CRC contributes to aggressive traits of CRC cells and their responses to chemotherapeutic drugs. Collectively, EPLIN is a pivotal factor for the development and progression of colorectal cancer and has important clinical and therapeutic values in this cancer type.


Assuntos
Neoplasias Colorretais , Proteínas do Citoesqueleto , Humanos , Proteínas do Citoesqueleto/metabolismo , Regulação para Baixo , Transdução de Sinais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Resistência a Medicamentos
18.
Comput Struct Biotechnol J ; 20: 2745-2758, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35685372

RESUMO

Background: Bone metastasis is the most common metastatic destination in advanced breast cancer, presenting a poor prognosis and clinical challenges in management. To date, the mechanism of bone metastasis in breast cancer remains largely unclear. Methods: Differentially expressed genes in primary tumours that developed bone metastases were systematically analysed using both TCGA-BRCA and E-MTAB-4003 databases. Adaptive phenotype in the subsequent bone lesions was analysed in the GSE46161 database. A series of biomarkers including homing, immune escape, angiogenesis, and factors involved in both osteoblastogenesis and osteoclastogenesis were included to dissect the molecular events underlying bone metastasis in breast cancer. Results: Upregulated expressions of GDF11 expression is positively correlated with colonization, osteoblastogenesis and osteoclastogenesis, whilst CD151 is positively associated with angiogenesis and immune escape. PAFAH1B2 expression is inversely correlated with the angiogenic process. Reduced YTHDF2 may facilitate cancer cell homing, osteoclastogenesis and immune escape in breast cancer. DPP9, FAS, ZNF519, RPP14 and FAU were evaluated for their potential involvement in for the homing to bone, escaping from immune surveillance, angiogenesis, osteoblastic activity and osteoclastic activity in the multi-step process of bone metastasis. Conclusion: GDF11, CD151, PAFAH1B2 and YTHDF2 may play a pivotal role in the predisposition of metastasis to the bone from breast cancer, whilst DPP9, FAS, ZNF519, RPP14 and FAU may be actively involved in the adaptative colonisation of metastatic breast cancer cells in bone.

19.
Cancer Gene Ther ; 29(10): 1405-1417, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35354949

RESUMO

The specific biological function of transient receptor potential vanilloid 1 (TRPV1) in pathogenesis of lung adenocarcinoma (LUAD) remains unclear. In this study, TRPV1 expression in tumor tissues, primary cells and cell lines of LUAD, as well as the mechanism mediating its hyperexpression were systematically studied. Multiple models and techniques were adopted to elucidate the relationship between TRPV1 hyperexpression and tumor recurrence and metastasis. Results showed that TRPV1 expression was increased in tumor tissues and primary tumor cells of LUAD patients. The increased expression was associated with worse overall survival outcome and raised HIF1α levels. TRPV1 expression in A549 and NCI-H292 cells was increased after pretreatment with cigarette smoke extract or spermine NONOate. Moreover, A549 cells with TRPV1 overexpression has enhanced tumor growth rates in subcutaneous grafted tumor models, and increased intrapulmonary metastasis after tail vein infusion in nude BALB/c nude mice. Mechanistically, TRPV1 overexpression in A549 cells promoted HIF1α expression and nuclear translocation by promoting CREB phosphorylation and activation of NOS1-NO pathway, ultimately leading to accelerated cell proliferation and stronger invasiveness. In addition, based on photothermal effects, CuS-TRPV1 mAb effectively targeted and induced apoptosis of TRPV1-A549 cells both in vivo and in vitro, thereby mitigating tumor growth and metastasis induced by xenotransplantation of TRPV1-A549 cells. In conclusion, TRPV1 hyperexpression in LUAD is a risk factor for tumor progression and is involved in proliferation and migration of tumor cells through activation of HIF1α. Our study also attempted a new strategy inhibiting the recurrence and metastasis of LUAD: by CuS-TRPV1 mAb precisely kill TRPV1 hyperexpression cells through photothermal effects.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Animais , Camundongos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Cobre , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Camundongos Endogâmicos BALB C , Camundongos Nus , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo
20.
Biomolecules ; 12(2)2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-35204839

RESUMO

BACKGROUND: HAVcR-1 has been linked to cancer aetiology and may regulate junctional complexes, with its role in prostate cancer still unexplored. This study aims to investigate the expression of HAVcR-1 in prostate cancer samples and the exploration of the cellular/molecular impact of HAVcR-1. METHODS: Levels of HAVcR-1 ectodomain in the serum of prostate cancer patients were compared to healthy controls, and assessed as the total protein and gene expression of HAVcR-1 and tissues sections. The manipulation of HAVcR-1 levels within prostate cancer cell lines determined changes in cell behaviour using in vitro cell models and barrier function assays. Protein/phosphoprotein levels were assessed using Western blotting. RESULTS: Levels of HAVcR-1 ectodomain from serum were decreased in patients with prostate cancer. Ectodomain levels correlated with the Gleason score. Histologically, the total protein/gene expression of HAVcR-1 was overexpressed in prostate cancer. The overexpression of HAVcR-1 in prostate cancer cell lines resulted in key changes in cell behaviour and the phosphorylation of ß-catenin with a concurrent decrease in membranous E-cadherin, increased nuclear ß-catenin and increased cyclin D1 protein expression, which were associated with HGF-promoted changes in the barrier function. CONCLUSIONS: HAVcR-1 expression and ectodomain release coincides with the presence of prostate cancer; thus, indicating HAVcR-1 as a potential biomarker to aid in diagnostics, and implicating HAVcR-1 in the dysregulation of junctional complexes.


Assuntos
Receptor Celular 1 do Vírus da Hepatite A , Fator de Crescimento de Hepatócito , Junções Intercelulares , Neoplasias da Próstata , Caderinas , Linhagem Celular Tumoral , Humanos , Junções Intercelulares/fisiologia , Masculino , Neoplasias da Próstata/genética , Receptores Virais , beta Catenina
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