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1.
Front Cell Dev Biol ; 9: 747314, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34805157

RESUMO

Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-ß, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.

2.
J Card Surg ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34796544

RESUMO

OBJECTIVE: Model for end-stage liver disease (MELD) likely has nonlinear effects on operative outcomes. We use machine learning to evaluate the nonlinear (dependent variable may not correlate one to one with an increased risk in the outcome) relationship between MELD and outcomes of cardiac surgery. METHODS: Society of Thoracic Surgery indexed elective cardiac operations between 2011 and 2018 were included. MELD was retrospectively calculated. Logistic regression models and an imbalanced random forest classifier were created on operative mortality. Cox regression models and random forest survival models evaluated survival. Variable importance analysis (VIMP) ranked variables by predictive power. Linear and machine-learned models were compared with receiver operator characteristic (ROC) and Brier score. RESULTS: We included 3872 patients. Operative mortality was 1.7% and 5-year survival was 82.1%. MELD was the fourth largest positive predictor on VIMP analysis for operative long-term survival and the strongest negative predictor for operative mortality. MELD was not a significant predictor for operative mortality or long-term survival in the logistic or Cox regressions. The logistic model ROC area was 0.762, compared to the random forest classifier ROC of 0.674. The Brier score of the random forest survival model was larger than the Cox regression starting at 2 years and continuing throughout the study period. Bootstrap estimation on linear regression demonstrated machine-learned models were superior. CONCLUSIONS: MELD and mortality are nonlinear. MELD was insignificant in the Cox multivariable regression but was strongly important in the random forest survival model and when using bootstrapping, the superior utility was demonstrated of the machine-learned models.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34776246

RESUMO

OBJECTIVE: The study objective was to determine the impact of reoperative aortic root replacement on short-term outcomes and survival. METHODS: This was a retrospective study of aortic root operations from 2010 to 2018. All patients with a complete aortic root replacement were included, and patients undergoing valve-sparing root replacements were excluded. Patients were dichotomized by first-time sternotomy versus redo sternotomy, which was defined as having had a prior sternotomy for whatever reason. Within the redo sternotomy group, reoperative aortic root replacements were identified, being defined as a complete aortic root replacement in patients with a prior aortic root replacement; 1:1 nearest neighbor propensity matching was used to compare outcomes across groups. Kaplan-Meier survival estimates were generated and compared using log-rank statistics. RESULTS: A total of 893 patients undergoing complete ARR were identified, of whom 595 (67%) underwent first-time sternotomy and 298 (33%) underwent redo sternotomy. After matching, postoperative outcomes were similar for the first-time and redo sternotomy groups, including operative mortality. Redo sternotomy was not associated with reduced survival after aortic root replacement compared with first-time sternotomy (P = .084), with 5-year survival of 73.7% for first-time sternotomy and 72.9% for redo sternotomy. In the redo sternotomy group (n = 298), 69 (23%) were reoperative aortic root replacements and 229 (77%) were first-time aortic root replacements. After matching, postoperative outcomes were similar for the first-time and reoperative aortic root replacement groups, including operative mortality. Reoperative aortic root replacement was not associated with reduced survival, compared with first-time aortic root replacement (P = .870), with 5-year survival of 67.9% for first-time aortic root replacement and 72.1% for reoperative aortic root replacement. CONCLUSIONS: Reoperative aortic root replacement can be performed safely and provides similar survival to first-time aortic root replacement.

5.
Front Cell Dev Biol ; 9: 720194, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621741

RESUMO

The effects of genotoxic stress can be mediated by activation of the Ataxia Telangiectasia Mutated (ATM) kinase, under both DNA damage-dependent (including ionizing radiation), and independent (including hypoxic stress) conditions. ATM activation is complex, and primarily mediated by the lysine acetyltransferase Tip60. Epigenetic changes can regulate this Tip60-dependent activation of ATM, requiring the interaction of Tip60 with tri-methylated histone 3 lysine 9 (H3K9me3). Under hypoxic stress, the role of Tip60 in DNA damage-independent ATM activation is unknown. However, epigenetic changes dependent on the methyltransferase Suv39H1, which generates H3K9me3, have been implicated. Our results demonstrate severe hypoxic stress (0.1% oxygen) caused ATM auto-phosphorylation and activation (pS1981), H3K9me3, and elevated both Suv39H1 and Tip60 protein levels in FTC133 and HCT116 cell lines. Exploring the mechanism of ATM activation under these hypoxic conditions, siRNA-mediated Suv39H1 depletion prevented H3K9me3 induction, and Tip60 inhibition (by TH1834) blocked ATM auto-phosphorylation. While MDM2 (Mouse double minute 2) can target Suv39H1 for degradation, it can be blocked by sirtuin-1 (Sirt1). Under severe hypoxia MDM2 protein levels were unchanged, and Sirt1 levels depleted. SiRNA-mediated depletion of MDM2 revealed MDM2 dependent regulation of Suv39H1 protein stability under these conditions. We describe a novel molecular circuit regulating the heterochromatic state (H3K9me3 positive) under severe hypoxic conditions, showing that severe hypoxia-induced ATM activation maintains H3K9me3 levels by downregulating MDM2 and preventing MDM2-mediated degradation of Suv39H1. This novel mechanism is a potential anti-cancer therapeutic opportunity, which if exploited could target the hypoxic tumor cells known to drive both tumor progression and treatment resistance.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34520838

RESUMO

To determine the impact of aortic root replacement (ARR) with a stentless bioprosthetic valve on midterm outcomes compared to a stented bioprosthetic valve-graft conduit. This was an observational study of aortic root operations from 2010 to 2018. All patients with a complete ARR for nonendocarditis reasons were included, while patients undergoing valve-sparing root replacements or primary aortic valve replacement or repair were excluded. Of the patients with a complete ARR, bioprosthetic valve implants were included, while mechanical valve implants were excluded. Patients were dichotomized into the stented ARR group and the stentless ARR group. A total of 1:1 nearest neighbor propensity matching was employed to assess the association of stentless valves with short-term and midterm outcomes. A total of 455 patients underwent a complete ARR with a bioprosthetic valve implant for nonendocarditis reasons, of which 212 (46.6%) received a stented valve, while 243 (53.4%) received a stentless valve. After matching, postoperative outcomes were similar across each group (P > 0.05), including operative mortality and adverse neurologic events. Median follow-up for the entire cohort was 4.41 years (95% CI: 4.01, 4.95). At 1 year follow-up, aortic regurgitation ≥ 2+ and ejection fraction were similar across each group (P > 0.05); however, the stentless valve group had lower aortic valve velocity and transvalvular pressure gradient. Finally, reoperations and survival were similar for each group over the study's follow-up (P > 0.05). Stentless valves may provide hemodynamic benefits after ARR; however, the clinical impact of those benefits for survival and reoperation may not yet be evident in the midterm.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34420792

RESUMO

OBJECTIVE: This study sought to report outcomes of hemiarch replacement with hypothermic circulatory arrest and retrograde cerebral perfusion, and secondarily, to report outcomes of this operative approach by type of underlying aortic disease. METHODS: This was an observational study of aortic surgeries from 2010 to 2018. All patients who underwent hemiarch replacement with retrograde cerebral perfusion were included, whereas patients undergoing partial or total arch replacement or concomitant elephant trunk procedures were excluded. Patients were dichotomized into 2 groups by underlying aortic disease; that is, acute aortic dissection (AAD) or aneurysmal degeneration of the aorta. These groups were analyzed for differences in short-term postoperative outcomes, including stroke and operative mortality (Society of Thoracic Surgeons definition). Multivariable Cox analysis was performed to identify variables associated with long-term survival after hemiarch replacement. RESULTS: A total of 500 patients undergoing hemiarch replacement with hypothermic circulatory arrest plus retrograde cerebral perfusion were identified, of whom 53.0% had aneurysmal disease and 47.0% had AAD. For the entire cohort, operative mortality was 6.4%, whereas stroke occurred in 4.6% of patients. Comparing AAD with aneurysm, operative mortality and stroke rates were similar across each group. Five-year survival was 84.4% ± 0.02% for the entire hemiarch cohort, whereas 5-year survival was 88.0% ± 0.02% for the aneurysm subgroup and was 80.5% ± 0.03% for the AAD subgroup. On multivariable analysis, AAD was not associated with an increased hazard of death, compared with aneurysm (P = .790). CONCLUSIONS: Morbidity and mortality after hemiarch replacement with hypothermic circulatory arrest plus retrograde cerebral perfusion are acceptably low, and this operative approach may be as advantageous for AAD as it is for aneurysm.

8.
J Card Surg ; 36(11): 4292-4300, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34405439

RESUMO

BACKGROUND: Open total arch replacement remains the gold standard treatment for aneurysms and dissections involving the aortic arch. However, high-risk surgical candidates may benefit from endovascular techniques to reduce the risk of perioperative mortality and morbidity, especially neurologic complications. Numerous endografts are available for investigational use in the aortic arch as part of investigational device exemption (IDE) programs. Some devices are fenestrated or scalloped, while others are branched, ranging from single branch to triple branch stent-grafts. Furthermore, chimney techniques and in situ fenestration may be utilized in bailout or emergent situations. RESULTS: Initial results describing outcomes of complete endovascular repair of the aortic arch are encouraging, with current data estimating that technical success ranges from 84.2% to 100%. Moreover, operative mortality may be as high as 13.2%, while neurologic complications also remain common, with stroke rates being as high as 20% and spinal cord ischemia being as high as 3.1%. However, more data are necessary to determine the comparative treatment effect of endovascular stent-grafting of the aortic arch, compared with conventional open and hybrid repairs. Longitudinal follow-up is also lacking, which will determine the long-term durability of endografts in the aortic arch. Nevertheless, endovascular repair represents an important opportunity for improving outcomes in patients with complex and potentially devastating pathologies of the aortic arch.


Assuntos
Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Procedimentos Endovasculares , Aneurisma da Aorta Torácica/cirurgia , Prótese Vascular , Humanos , Complicações Pós-Operatórias/epidemiologia , Desenho de Prótese , Fatores de Risco , Stents , Resultado do Tratamento
9.
Artigo em Inglês | MEDLINE | ID: mdl-34384591

RESUMO

OBJECTIVE: To evaluate the ability of intraoperative neurophysiologic monitoring (IONM) during aortic arch reconstruction with hypothermic circulatory arrest (HCA) to predict early (<48 hours) adverse neurologic events (ANE; stroke or transient ischemic attack) and operative mortality. METHODS: This was an observational study of aortic arch surgeries requiring HCA from 2010 to 2018. Patients were monitored with electroencephalogram (EEG) and somatosensory evoked potentials (SSEP). Baseline characteristics and postoperative outcomes were compared according to presence or absence of IONM changes, which were defined as any acute variation in SSEP or EEG, compared with baseline. Multivariable logistic regression analysis was used to assess the association of IONM changes with operative mortality and early ANE. RESULTS: A total of 563 patients underwent aortic arch reconstruction with HCA and IONM. Of these, 119 (21.1%) patients had an IONM change, whereas 444 (78.9%) did not. Patients with IONM changes had increased operative mortality (22.7% vs 4.3%) and increased early ANE (10.9% vs 2.9%). In multivariable analysis, SSEP changes were correlated with early ANE (odds ratio [OR], 4.68; 95% confidence interval [CI], 1.51-14.56; P = .008), whereas EEG changes were not (P = .532). Permanent SSEP changes were correlated with early ANE (OR, 4.56; 95% CI, 1.51-13.77; P = .007), whereas temperature-related SSEP changes were not (P = .997). Finally, any IONM change (either SSEP or EEG) was correlated with operative mortality (OR, 5.82; 95% CI, 2.72-12.49; P < .001). CONCLUSIONS: Abnormal IONM events during aortic arch reconstruction with HCA portend worse neurologic outcomes and operative mortality and have a negative predictive value of 97.1%. SSEP might be more sensitive than EEG for predicting early ANE, especially when SSEP changes are permanent.

10.
Can J Urol ; 28(4): 10738-10742, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34378507

RESUMO

INTRODUCTION Androgen deprivation therapy (ADT) is often used in the treatment of prostate cancer. Specific factors affecting testosterone recovery after cessation of ADT have not been well-characterized in existing literature. MATERIALS AND METHODS: We retrospectively reviewed patients at our institution who received ADT between 1999 and 2018. Patients with at least one course of ADT and subsequent testosterone level within 12 months of cessation of ADT were included. Patients received at least one of the following four agents: leuprolide, goserelin, triptorelin, and degarelix. Cox regression models were utilized to estimate the effect of patient and treatment characteristics on time to testosterone recovery(≥ 240 ng/dL) after ADT cessation. Patients without testosterone recovery were censored at last testosterone evaluation. To account for the possible dependency between multiple ADT courses within a patient, we used a robust sandwich variance estimate. RESULTS: Severty-six patients were included. Mean age was 64 +/- 8 years. Median duration of ADT was 15 months, with a median time to recovery of 19 months. On univariable analysis, age and duration of ADT were significant; a trend towards significance was noted for hypertension, diabetes, peripheral vascular disease, goserelin and bicalutamide. Patient age, duration of ADT, and treatment with the agent goserelin were significantly associated with prolonged hypogonadism on multivariable analysis (p < 0.01). CONCLUSIONS: Increasing age and duration of ADT therapy are associated with decreased likelihood to recover normal testosterone levels after cessation of therapy. The use of the ADT agent goserelin was also associated with decreased testosterone recovery for unclear reasons.

11.
J Card Surg ; 36(10): 3631-3638, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34242433

RESUMO

INTRODUCTION: Coronary artery bypass grafting (CABG) continues to be the most commonly performed cardiac surgical procedure in the world. The use of multiarterial grafting may confer a long-term survival benefit over the use of vein grafts. However, there is a paucity of data comparing the use of in situ versus free right internal mammary artery (RIMA) in isolated CABG. METHODS: Patients that underwent isolated CABG between 2010 and 2018 where RIMA was used in addition to a left internal mammary artery graft. Patients with prior cardiac surgery or percutaneous coronary intervention were excluded. Propensity matching was used for subanalysis. Mortality and major adverse cardiac and cerebrovascular events (MACCE) were analyzed with Kaplan-Meier survival curves and Cox multivariable regression. Heart failure-specific readmissions were assessed with cumulative incidence curves with Fine and Gray competing risk regression. RESULTS: A total of 667 patients underwent isolated CABG. Of those, 422 had free RIMA and 245 had in situ RIMA utilized. Mortality was similar between cohorts (p = 0.199) with 5-year mortality rates of 6.6% (free) and 4.1% (in situ). MACCE was similar between cohorts, with 5-year event rates of 33.6% and 33.9% (p = 0.99). RIMA style was not a significant predictor of any outcome. CONCLUSION: There was no difference in long-term mortality, complications, MACCE, or heart failure readmissions when comparing a contemporary cohort of patients undergoing isolated CABG utilizing RIMA as a conduit. These data may allow surgeons to consider using RIMA either as an in situ or a free conduit.


Assuntos
Doença da Artéria Coronariana , Artéria Torácica Interna , Intervenção Coronária Percutânea , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Humanos , Anastomose de Artéria Torácica Interna-Coronária , Estudos Retrospectivos , Resultado do Tratamento
14.
Urol Case Rep ; 38: 101695, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33996500

RESUMO

Neurofibromatosis 1 is a relatively rare genetic disease characterized by widespread neurofibromas originating from the peripheral nervous system. Most growths are benign, but some carry a risk of transformation to malignant peripheral nerve sheath tumors. Although these growths can be found anywhere in the body, they are rarely found in the male external genitalia. This report discusses a case of a 25-year-old male patient with neurofibromatosis 1 presenting with a scrotal mass found to have a very large para-testicular intra-scrotal malignant peripheral nerve sheath tumor that required testicle-sparing radical penectomy.

16.
Vet Surg ; 50(6): 1350-1358, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33914353

RESUMO

OBJECTIVE: To describe a novel standing trans-nasal endoscopic guided CO2 laser fenestration approach to access the sphenopalatine sinus (SPS) in the horse. STUDY DESIGN: Case report. ANIMALS: Cadaver study and client-owned 20-year-old Warmblood gelding. METHODS: The rostral palatine bone within the nasopharynx was investigated as a possible site for fenestration to access the SPS in cadavers. The ability to fenestrate the SPS was tested in cadavers using a flexible endoscope and CO2 laser fiber inserted via biopsy channel. The fenestration procedure was then performed in a clinical case presented for unilateral epistaxis where a soft tissue attenuating mass in the right SPS was identified with standing computed tomography (CT). RESULTS: The cadaver study demonstrated the appropriate site within the nasopharynx midway between the vomer and dorsal conchal wall. The CO2 laser successfully ablated the mucosa and palatine bone to enable endoscopic access to the palatine portion of the SPS. The endoscopic procedure was performed as a two-step process via standing sedation due to mucosal bleeding obscuring visualization. Access to the SPS through fenestration allowed biopsy under direct endoscopic visualization with long-handled bronchoesophageal forceps inserted via the ipsilateral middle meatus. The mass within SPS was determined to be an undifferentiated carcinoma. Further treatment was declined and the horse euthanized 6 months following the procedure due to acute onset of neurologic symptoms. CONCLUSION: Endoscopically guided fenestration of the rostral palatine bone within the nasopharynx using CO2 laser in the standing horse provided good access and visualization of the palatine portion of the SPS.


Assuntos
Endoscopia , Palato Duro , Seios Paranasais , Animais , Dióxido de Carbono , Endoscopia/veterinária , Cavalos/cirurgia , Lasers , Masculino , Palato Duro/cirurgia , Seios Paranasais/cirurgia
18.
Artigo em Inglês | MEDLINE | ID: mdl-33642109

RESUMO

OBJECTIVE: Pulmonary artery catheterization provides continuous monitoring of hemodynamic parameters that may aid in the perioperative management of patients undergoing cardiac surgery. However, prior data suggest that pulmonary artery catheterization has limited benefit in intensive care and surgical settings. Thus, this study sought to determine the impact of pulmonary artery catheter insertion on short-term postoperative outcomes in a large, contemporaneous cohort of patients undergoing open cardiac surgery compared with standard central venous pressure monitoring. METHODS: This was an observational study of open cardiac surgeries from 2010 to 2018. Patients with pulmonary artery catheter insertion were identified and matched against patients without pulmonary artery catheter insertion via 1:1 nearest neighbor propensity matching. Multivariable analysis was performed to assess the impact of pulmonary artery catheterization on operative mortality in the overall cohort, as well as recent heart failure, mitral valve disease, and tricuspid insufficiency subgroups. RESULTS: Of the 11,820 patients undergoing (Society of Thoracic Surgeons indexed) coronary or valvular surgery, 4605 (39.0%) had pulmonary artery catheter insertion. Propensity score matching yielded 3519 evenly balanced pairs. Compared with central venous pressure monitoring, pulmonary artery catheter use was not associated with improved operative mortality in the overall cohort or in the recent heart failure, mitral valve disease, or tricuspid insufficiency subgroups. Intensive care unit length of stay was longer (P < .001), and there were more packed red blood cell transfusions in the pulmonary artery catheterization group (P < .001); however, postoperative outcomes were otherwise similar, including stroke, sepsis, and new renal failure (P > .05). CONCLUSIONS: These findings suggest that pulmonary artery catheterization may have limited benefit in cardiac surgery.

19.
Semin Thorac Cardiovasc Surg ; 33(4): 1027-1034, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33600994

RESUMO

The aim of the current study was to assess the impact of hospital readmissions within 30-days of discharge, on long-term postoperative outcomes. All patients who underwent cardiac surgery from 2011 - 2018 were included. Patients who had transcatheter procedures, VAD, and transplant were excluded. Inverse probability of treatment weighting (IPTW) propensity scoring was used for population risk adjustment. Multivariable analysis was performed to identify association with long-term mortality and readmission. The total risk adjusted (propensity scoring with IPTW) patient population consisted of 14,538 patients divided into those who were not readmitted in 30-days (nonreadmitted) (n = 12,627) and patients who were readmitted within 30-days (30-day readmitted) (n = 1911). Following IPTW, all baseline characteristics and postoperative complications were equivalent between cohorts (SMD <0.10). Patients who required intraoperative [OR 1.178 (1.05, 1.32); P = 0.006] and postoperative [1.32 (1.18, 1.48); P < 0.001] blood transfusions were at greater risk for 30-day readmission. Median follow-up period was 4.19 years (2.45 - 6.10). The 30-day readmission cohort had a significantly higher mortality risk during early (6 months) follow-up [HR 2.49 (2.01-3.10); P < 0.001] and late (60 months) follow-up [HR 1.30 (1.16-1.47); P < 0.001]. After risk adjustment, the 30-day readmission cohort was significantly associated with increased mortality over the study follow-up period [HR 1.62 (1.48, 1.78); P < 0.001]. 30-day readmissions were an independent predictor of subsequent long-term hospital readmission [HR 1.61 (1.50, 1.73); P < 0.001]. Patients who require 30-day readmissions following cardiac surgery are at increased risk of long-term mortality and repeat readmissions. Early postoperative hospital readmission may be a marker for worse long-term outcomes in cardiac surgery.

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