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1.
Can J Surg ; 67(3): E206-E213, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38692680

RESUMEN

BACKGROUND: Although robotic surgery has several advantages over other minimally invasive surgery (MIS) techniques for rectal cancer surgery, the uptake in Canada has been limited owing to a perceived increase in cost and lack of training. The objective of this study was to determine the impact of access to robotic surgery in a Canadian setting. METHODS: We conducted a retrospective cohort study involving consecutive adults undergoing surgical resection for rectal cancer between 2017 and 2020. The primary exposure was access to robotic surgery. Outcomes included MIS utilization, short-term outcomes, total cost of care, and quality of surgical resection. We completed univariate and multivariate analyses. RESULTS: We included 171 individuals in this cohort study (85 in the prerobotic period and 86 in the robotic period). The 2 groups had similar baseline characteristics. A higher proportion of individuals underwent successful MIS in the robotic phase (86% v. 46%, p < 0.001). Other benefits included a shorter mean length of hospital stay (5.1 d v. 9.2 d, p < 0.001). The quality of surgical resection was similar between groups. The total cost of care was $16 746 in the robotic period and $18 808 in the prerobotic period (mean difference -$1262, 95% confidence interval -$4308 to $1783; p = 0.4). CONCLUSION: Access to robotic rectal cancer surgery increased successful completion of MIS and shortened hospital stay, with a similar total cost of care. Robotic rectal cancer surgery can enhance patient outcomes in the Canadian setting.


Asunto(s)
Neoplasias del Recto , Procedimientos Quirúrgicos Robotizados , Humanos , Procedimientos Quirúrgicos Robotizados/estadística & datos numéricos , Procedimientos Quirúrgicos Robotizados/economía , Estudios Retrospectivos , Neoplasias del Recto/cirugía , Masculino , Femenino , Persona de Mediana Edad , Anciano , Canadá , Tiempo de Internación/estadística & datos numéricos , Instituciones Oncológicas/estadística & datos numéricos
2.
Lancet Neurol ; 23(6): 636-648, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38760101

RESUMEN

Anthropogenic climate change is affecting people's health, including those with neurological and psychiatric diseases. Currently, making inferences about the effect of climate change on neurological and psychiatric diseases is challenging because of an overall sparsity of data, differing study methods, paucity of detail regarding disease subtypes, little consideration of the effect of individual and population genetics, and widely differing geographical locations with the potential for regional influences. However, evidence suggests that the incidence, prevalence, and severity of many nervous system conditions (eg, stroke, neurological infections, and some mental health disorders) can be affected by climate change. The data show broad and complex adverse effects, especially of temperature extremes to which people are unaccustomed and wide diurnal temperature fluctuations. Protective measures might be possible through local forecasting. Few studies project the future effects of climate change on brain health, hindering policy developments. Robust studies on the threats from changing climate for people who have, or are at risk of developing, disorders of the nervous system are urgently needed.


Asunto(s)
Cambio Climático , Enfermedades del Sistema Nervioso , Humanos , Enfermedades del Sistema Nervioso/epidemiología
3.
Colorectal Dis ; 2024 Apr 08.
Artículo en Inglés | MEDLINE | ID: mdl-38590019

RESUMEN

AIM: Transanal total mesorectal (taTME) excision is a method used to assist in the radical removal of the rectum. By adopting the concept of natural orifice surgery, it offers potential benefits over conventional techniques. Early enthusiasm for this strategy led to its rapid and widespread adoption. The imposing of a local moratorium was precipitated by the discovery in Norway of an uncommon multifocal pattern of locoregional recurrence. The aim of this systematic review and meta-analysis was to determine the incidence of local recurrence after taTME for rectal cancer. METHOD: Conforming to the Cochrane Handbook for Systematic Reviews of Interventions and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines checklist, a systematic review and meta-analysis was conducted. This included case series and comparative studies between taTME and preferentially laparoscopic procedures published between 2010 and 2021. RESULTS: There were a total of 1175 studies retrieved. After removal and screening for quality and relevance, the final analysis contained 40 studies. The local recurrence rate following taTME was 3.4% (95% CI 2.9%-3.9%, I2 = 0%) in 4987 patients with follow-up durations ranging from 0.7 to 5.5 years. Compared with laparoscopic TME, local recurrence was not statistically different for the taTME group (p = 0.076); however, it was less probable (OR = 0.51, 95% CI 0.24-1.09, I2 = 0%). Systemic recurrence and circumferential resection margin status were secondary outcomes; however, the differences were not statistically significant. CONCLUSION: Our data suggest that the local recurrence for regular laparoscopic and transanal TME surgeries may be comparable, suggesting that taTME can be performed without influencing locoregional oncological outcomes in patients treated at specialized institutions and who have been cautiously selected.

4.
J Can Assoc Gastroenterol ; 7(2): 160-168, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38596800

RESUMEN

Background: Those with cirrhosis who require emergency colorectal surgery are at risk for poor outcomes. Although risk predictions models exists, these tools are not specific to colorectal surgery, nor were they developed in a contemporary setting. Thus, the objective of this study was to assess the outcomes in this population and determine whether cirrhosis etiology and/or the Model for End Stage Liver Disease (MELD-Na) is associated with mortality. Methods: This population-based study included those with cirrhosis undergoing emergent colorectal surgery between 2009 and 2017. All eligible individuals in Ontario were identified using administrative databases. The primary outcome was 90-day mortality. Results: Nine hundred and twenty-seven individuals (57%) (male) were included. The most common cirrhosis etiology was non-alcoholic fatty liver disease (NAFLD) (50%) and alcohol related (32%). Overall 90-day mortality was 32%. Multivariable survival analysis demonstrated those with alcohol-related disease were at increased risk of 90-day mortality (hazards ratio [HR] 1.53, 95% confidence interval [CI] 1.2-2.0 vs. NAFLD [ref]). Surgery for colorectal cancer was associated with better survival (HR 0.27, 95%CI 0.16-0.47). In the subgroup analysis of those with an available MELD-Na score (n = 348/927, 38%), there was a strong association between increasing MELD-Na and mortality (score 20+ HR 6.6, 95%CI 3.9-10.9; score 10-19 HR 1.8, 95%CI 1.1-3.0; score <10 [ref]). Conclusion: Individuals with cirrhosis who require emergent colorectal surgery have a high risk of postoperative complications, including mortality. Increasing MELD-Na score is associated with mortality and can be used to risk stratify individuals.

5.
Accid Anal Prev ; 198: 107397, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38271896

RESUMEN

Novice drivers are at a greatly inflated risk of crashing. This led in the 20th century to numerous attempts to develop training programs that could reduce their crash risk. Yet, none proved effective. Novice drivers were largely considered careless, not clueless. This article is a case study in the United States of how a better understanding of the causes of novice driver crashes led to training countermeasures targeting teen driving behaviors with known associations with crashes. These effects on behaviors were large enough and long-lasting enough to convince insurance companies to develop training programs that they offered around the country to teen drivers. The success of the training programs at reducing the frequency of behaviors linked to crashes also led to several large-scale evaluations of the effect of the training programs on actual crashes. A reduction in crashes was observed. The cumulative effect has now led to state driver licensing agencies considering as a matter of policy both to include items testing the behaviors linked to crashes on licensing exams and to require training on safety critical behaviors. The effort has been ongoing for over a quarter century and is continuing. The case study highlights the critical elements that made it possible to move from a paradigm shift in the understanding of crash causes to the development and evaluation of crash countermeasures, to the implementation of those crash countermeasures, and to subsequent policy changes at the state and federal level. Key among these elements is the development of simple, scalable solutions.


Asunto(s)
Accidentes de Tránsito , Conducción de Automóvil , Adolescente , Humanos , Estados Unidos , Accidentes de Tránsito/prevención & control , Concesión de Licencias , Políticas , Causalidad
6.
Respir Res ; 25(1): 28, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38217012

RESUMEN

BACKGORUND: Tissue-engineered tracheal grafts (TETG) can be recellularized by the host or pre-seeded with host-derived cells. However, the impact of airway disease on the recellularization process is unknown. METHODS: In this study, we determined if airway disease alters the regenerative potential of the human tracheobronchial epithelium (hTBE) obtained by brushing the tracheal mucosa during clinically-indicated bronchoscopy from 48 pediatric and six adult patients. RESULTS: Our findings revealed that basal cell recovery and frequency did not vary by age or region. At passage 1, all samples produced enough cells to cellularize a 3.5 by 0.5 cm2 graft scaffold at low cell density (~ 7000 cells/cm2), and 43.75% could cellularize a scaffold at high cell density (~ 100,000 cells/cm2). At passage 2, all samples produced the number of cells required for both recellularization models. Further evaluation revealed that six pediatric samples (11%) and three (50%) adult samples contained basal cells with a squamous basal phenotype. These cells did not form a polarized epithelium or produce differentiated secretory or ciliated cells. In the pediatric population, the squamous basal cell phenotype was associated with degree of prematurity (< 28 weeks, 64% vs. 13%, p = 0.02), significant pulmonary history (83% vs. 34%, p = 0.02), specifically with bronchopulmonary dysplasia (67% vs. 19%, p = 0.01), and patients who underwent previous tracheostomy (67% vs. 23%, p = 0.03). CONCLUSIONS: In summary, screening high-risk pediatric or adult population based on clinical risk factors and laboratory findings could define appropriate candidates for airway reconstruction with tracheal scaffolds. LEVEL OF EVIDENCE: Level III Cohort study.


Asunto(s)
Carcinoma de Células Escamosas , Trastornos Respiratorios , Adulto , Recién Nacido , Humanos , Niño , Estudios de Cohortes , Epitelio , Células Epiteliales/patología , Tráquea/cirugía , Tráquea/patología , Células Madre
7.
Otol Neurotol ; 45(2): e113-e122, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38082472

RESUMEN

OBJECTIVE: A subset of vestibular schwannomas (VSs), including cystic tumors, have higher postoperative morbidity because of the presence of adhesions between the tumor, facial nerve (FN), and brainstem. We identify tumor microenvironment (TME) biomarkers to better classify these tumors and predict the degree of tumor adherence. STUDY DESIGN: Retrospective case series. SETTING: Tertiary skull base referral center. METHODS: Adult patients with cystic and solid VS matched in tumor size who underwent surgical resection were included. Expressions of seven biomarkers of extracellular matrix remodeling and tumor immune response were quantified via immunohistochemistry. The distribution of CD45+ immune cells was evaluated in intratumoral and perivascular compartments. The degree of tumor adherence was categorized as none, adherent to FN, or adherent to both FN and brainstem. RESULTS: Twenty-eight patients were included. Cystic VSs were significantly more adherent than solid VSs ( p = 0.02). Patients with adherent VS had shorter duration of symptoms and were more likely to undergo subtotal resection. In solid tumors, matrix metalloproteinase (MMP)-2 expression ( p = 0.02) and CD163+ macrophage infiltration ( p = 0.007) were correlated with tumor size. Linear discriminant analyses (LDAs) demonstrated MMP-2, MMP-14, CD80, CD163, and perivascular CD45 to be individually predictive of the degree of tumor adherence (all p < 0.05), with perivascular CD45 being the best independent predictor ( p = 0.005). An LDA model including these biomarkers demonstrated 100% accurate discrimination of all three levels of tumor adherence ( p = 0.04). CONCLUSIONS: Adherent VS have a distinct proinflammatory TME characterized by elevated MMP expression, enrichment of tumor-associated macrophages, and perivascular immune cell infiltration.


Asunto(s)
Neuroma Acústico , Adulto , Humanos , Neuroma Acústico/cirugía , Neuroma Acústico/patología , Biomarcadores de Tumor , Estudios Retrospectivos , Microambiente Tumoral , Resultado del Tratamiento , Procedimientos Neuroquirúrgicos
8.
Ann Surg ; 279(1): 88-93, 2024 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-37436871

RESUMEN

OBJECTIVE: To assess whether delaying appendectomy until the following morning is non-inferior to immediate surgery in those with acute appendicitis presenting at night. BACKGROUND: Despite a lack of supporting evidence, those with acute appendicitis who present at night frequently have surgery delayed until the after morning. METHODS: The delay trial is a noninferiority randomized controlled trial conducted between 2018 and 22 at 2 tertiary care hospitals in Canada. Adults with imaging confirmed acute appendicitis who presented at night (8:00 pm -4:00 am ). Delaying surgery until after 6:00 am was compared with immediate surgery. The primary outcome was 30-day postoperative complications. An a prior noninferiority margin of 15% was deemed clinically relevant. RESULTS: One hundred twenty-seven of the planned 140 patients were enrolled in the Delayed Versus Early Laparoscopic Appendectomy (DELAY) trial (59 in the delayed group and 68 in the immediate group). The two groups were similar at baseline. The mean time between the decision to operate and surgery was longer in the delayed group (11.0 vs 4.4 hours, P < 0.0001). The primary outcome occurred in 6/59 (10.2%) of those in the delayed group versus 15/67 (22.4%) of those in the immediate group ( P = 0.07). The difference between groups met the a priori noninferiority criteria of +15% (risk difference -12.2%, 95% CI: -24.4% to +0.4%, test of noninferiority P < 0.0001). CONCLUSIONS: The DELAY study is the first trial to assess delaying appendectomy in those with acute appendicitis. We demonstrate the noninferiority of delaying surgery until the after morning.


Asunto(s)
Apendicitis , Laparoscopía , Adulto , Humanos , Enfermedad Aguda , Apendicectomía/métodos , Apendicitis/cirugía , Apendicitis/complicaciones , Laparoscopía/métodos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía
9.
Otol Neurotol ; 45(1): 92-99, 2024 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-38085765

RESUMEN

OBJECTIVE: Cystic vestibular schwannomas (cVSs) have more variable and less favorable clinical outcomes after microsurgical resection compared with solid VS (sVS). This study compares the preoperative presentation and postoperative outcomes between cVS and sVS. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary skull base referral centers. METHODS: Consecutive adult patients who underwent VS resection from 2016 to 2021 were included. Univariate and multivariate analyses compared differences in baseline symptoms and postoperative outcomes between cVS and sVS. RESULTS: There were a total of 315 patients (64% female; mean age, 54 yrs) and 46 (15%) were cystic. cVS were significantly larger than sVS (maximum diameter, 28 vs. 18 mm, p < 0.001) and had higher rates of dysphagia and dysphonia preoperatively (p < 0.02). cVSs were more likely to undergo translabyrinthine resection (76 vs. 50%, p = 0.001) and have a higher rate of subtotal resection (STR) compared with sVS (30 vs. 13%, p = 0.003). At latest follow-up, fewer cVS achieved good facial nerve (FN) outcome (House-Brackmann [HB] I/II) (80 vs. 90%, p = 0.048). Subanalysis of cVS and sVS matched in tumor size, and surgical approach did not show differences in the rate of STR or FN outcomes (HB I/II, 82 vs. 78%, p = 0.79). CONCLUSION: In this large multi-institutional series, cVSs represent a distinct entity and are characterized by larger tumor size and higher incidence of atypical symptoms. Although cVSs were more likely to undergo STR and portend worse FN outcomes than sVSs, this may be due to their larger tumor size rather than the presence of the cystic component.


Asunto(s)
Neuroma Acústico , Adulto , Humanos , Femenino , Persona de Mediana Edad , Masculino , Neuroma Acústico/patología , Estudios Retrospectivos , Resultado del Tratamiento , Estudios de Seguimiento , Procedimientos Neuroquirúrgicos/efectos adversos , Nervio Facial/cirugía , Complicaciones Posoperatorias/etiología
10.
Laryngoscope ; 134(6): 2857-2863, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38158610

RESUMEN

OBJECTIVE(S): Despite undergoing thorough cochlear implant (CI) candidacy evaluation and counseling, some patients ultimately elect against implantation. This study sought to identify patient-related and socioeconomic factors predicting CI deferral. METHODS: A retrospective study of adult (≥18 years old) CI candidates presenting between 2007 and 2021 at a tertiary academic CI center was performed. The primary outcome was device implantation. Data collected included age, gender, hearing status, race, zip code of residence, median family income (MFI), distance traveled from the CI center, marital status, employment status, and insurance status. Multivariable binary logistic regression was performed to identify predictors of implantation. RESULTS: A total of 200 patients qualifying for CI were included, encompassing 77 adults deferring surgery (CI-deferred) and 123 consecutive adults electing for surgery (CI-pursued). Age, gender, hearing status, insurance type, employment status, distance from the implant center, and MFI were comparable between the groups (p > 0.05). Compared to CI-pursued patients, CI-deferred patients were more likely to be non-Caucasian (24.7% vs. 9.8%, p = 0.015) and unmarried (55.8% vs. 38.2%, p = 0.015). On multivariable logistic regression, older age (OR 0.981, 0.964-0.998, p = 0.027), African American race (OR 0.227, 0.071-0.726, p = 0.012), and unmarried status (OR 0.505, 0.273-0.935, p = 0.030) were independent predictors of implant deferral. CONCLUSION: This study demonstrates that increasing age at evaluation, African American race, and unmarried status are predictors for deferring CI surgery despite being implant candidates. These patients may benefit from increased outreach in the form of counseling, education, and social support prior to undergoing CI surgery. LEVEL OF EVIDENCE: 3 - retrospective study with internal control group Laryngoscope, 134:2857-2863, 2024.


Asunto(s)
Implantación Coclear , Humanos , Masculino , Femenino , Estudios Retrospectivos , Implantación Coclear/estadística & datos numéricos , Persona de Mediana Edad , Estudios de Casos y Controles , Anciano , Adulto , Factores Socioeconómicos , Implantes Cocleares/estadística & datos numéricos , Selección de Paciente
11.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166874, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37666439

RESUMEN

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-α deficiency in GSD-Ia is characterized by impaired gluconeogenesis, nephromegaly due to elevated glycogen accumulation, and nephropathy caused, in part, by renal fibrosis, mediated by activation of the renin-angiotensin system (RAS). The Wnt/ß-catenin signaling regulates the expression of a variety of downstream mediators implicated in renal fibrosis, including multiple genes in the RAS. Sustained activation of Wnt/ß-catenin signaling is associated with the development and progression of renal fibrotic lesions that can lead to chronic kidney disease. In this study, we examined the molecular mechanism underlying GSD-Ia nephropathy. Damage to the kidney proximal tubules is known to trigger acute kidney injury (AKI) that can, in turn, activate Wnt/ß-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/ß-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, α-smooth muscle actin (α-SMA), and extracellular matrix proteins, including collagen-Iα1 and collagen-IV. Treating GSD-Ia mice with a CBP/ß-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active ß-catenin and reduced renal levels of renin, Snail1, α-SMA, and collagen-IV. The results suggest that inhibition of Wnt/ß-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy.


Asunto(s)
Lesión Renal Aguda , beta Catenina , Ratones , Animales , beta Catenina/genética , beta Catenina/metabolismo , Fibrosis , Colágeno
12.
Res Sq ; 2023 Dec 02.
Artículo en Inglés | MEDLINE | ID: mdl-38076992

RESUMEN

Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how N-glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.

13.
Curr Oncol ; 30(11): 9530-9541, 2023 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-37999110

RESUMEN

Those with cirrhosis who develop colorectal cancer (CRC) are an understudied group who may tolerate treatments poorly and are at risk of worse outcomes. This is a retrospective cohort study of 842 individuals from Ontario, Canada, with a pre-existing diagnosis of cirrhosis who underwent surgery for CRC between 2009 and 2017. Practice patterns, overall survival, and short-term morbidity and mortality were assessed. The most common cirrhosis etiology was non-alcoholic fatty liver disease (NAFLD) (52%) and alcohol-associated liver disease (29%). The model for end-stage liver disease score (MELD-Na) was available in 42% (median score of 9, IQR7-11). Preoperative radiation was used in 62% of Stage II/III rectal cancer patients, while postoperative chemotherapy was used in 42% of Stage III colon cancer patients and 38% of Stage II/III rectal cancer patients. Ninety-day mortality following surgery was 12%. Five-year overall survival was 53% (by Stages I-IV, 66%, 55%, 50%, and 11%, respectively). Those with alcohol-associated cirrhosis (HR 1.8, 95% CI 1.5-2.2) had lower survival than those with NAFLD. Those with a MELD-Na of 10+ did worse than those with a lower MELD-Na score (HR 1.9, 95% CI 1.4-2.6). This study reports poor survival in those with cirrhosis who undergo treatment for CRC. Caution should be taken when considering aggressive treatment.


Asunto(s)
Neoplasias del Colon , Enfermedad Hepática en Estado Terminal , Enfermedad del Hígado Graso no Alcohólico , Neoplasias del Recto , Humanos , Enfermedad Hepática en Estado Terminal/complicaciones , Estudios Retrospectivos , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Índice de Severidad de la Enfermedad , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Ontario/epidemiología
14.
Thyroid ; 33(10): 1201-1214, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37675898

RESUMEN

Background: Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic/additive activity. Thus, we hypothesized that the combination of BRAFV600E inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in BRAFV600E-mutant ATC. We evaluated the effect of BRAFV600E inhibitors in combination with the MTKI axitinib and its mechanism(s) of action. Methods: We evaluated the effects of BRAFV600E inhibitors and axitinib alone and in combination in in vitro and in vivo models of BRAFV600E-mutant and wild-type ATC. Results: The combination of axitinib and BRAFV600E inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou-Talalay algorithm in BRAFV600E-mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (p < 0.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0/G1 phase. Axitinib arrested ATC cells in the G2/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model. Conclusions: The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.


Asunto(s)
Carcinoma Anaplásico de Tiroides , Neoplasias de la Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/patología , Axitinib/farmacología , Axitinib/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/uso terapéutico , Mutación , Línea Celular Tumoral
15.
Wellcome Open Res ; 8: 308, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37593567

RESUMEN

Background: The Behaviour Change Technique Taxonomy v1 (BCTTv1) specifies the potentially active content of behaviour change interventions. Evaluation of BCTTv1 showed the need to extend it into a formal ontology, improve its labels and definitions, add BCTs and subdivide existing BCTs. We aimed to develop a Behaviour Change Technique Ontology (BCTO) that would meet these needs. Methods: The BCTO was developed by: (1) collating and synthesising feedback from multiple sources; (2) extracting information from published studies and classification systems; (3) multiple iterations of reviewing and refining entities, and their labels, definitions and relationships; (4) refining the ontology via expert stakeholder review of its comprehensiveness and clarity; (5) testing whether researchers could reliably apply the ontology to identify BCTs in intervention reports; and (6) making it available online and creating a machine-readable version. Results: Initially there were 282 proposed changes to BCTTv1. Following first-round review, 19 BCTs were split into two or more BCTs, 27 new BCTs were added and 26 BCTs were moved into a different group, giving 161 BCTs hierarchically organised into 12 logically defined higher-level groups in up to five hierarchical levels. Following expert stakeholder review, the refined ontology had 247 BCTs hierarchically organised into 20 higher-level groups. Independent annotations of intervention evaluation reports by researchers familiar and unfamiliar with the ontology resulted in good levels of inter-rater reliability (0.82 and 0.79, respectively). Following revision informed by this exercise, 34 BCTs were added, resulting in a final version of the BCTO containing 281 BCTs organised into 20 higher-level groups over five hierarchical levels. Discussion: The BCT Ontology provides a standard terminology and comprehensive classification system for the content of behaviour change interventions that can be reliably used to describe interventions.

16.
J Vis Exp ; (196)2023 06 16.
Artículo en Inglés | MEDLINE | ID: mdl-37395575

RESUMEN

Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide that plays a putative role in the pathophysiology of migraine headaches and may be a candidate for biomarker status. CGRP is released from neuronal fibers upon activation and induces sterile neurogenic inflammation and arterial vasodilation in the vasculature that receives trigeminal efferent innervation. The presence of CGRP in the peripheral vasculature has spurred investigations to detect and quantify this neuropeptide in human plasma using proteomic assays, such as the enzyme-linked immunosorbent assay (ELISA). However, its half-life of 6.9 min and the variability in technical details of assay protocols, which are often not fully described, have yielded inconsistent CGRP ELISA data in the literature. Here, a modified ELISA protocol for the purification and quantification of CGRP in human plasma is presented. The procedural steps involve sample collection and preparation, extraction using a polar sorbent as a means of purification, additional steps to block non-specific binding, and quantification via ELISA. Further, the protocol has been validated with spike and recovery and linearity of dilution experiments. This validated protocol can theoretically be used to quantify CGRP concentrations in the plasma of individuals not only with migraine, but also with other diseases in which CGRP may play a role.


Asunto(s)
Trastornos Migrañosos , Neuropéptidos , Humanos , Péptido Relacionado con Gen de Calcitonina/metabolismo , Proteómica , Trastornos Migrañosos/metabolismo , Neuropéptidos/metabolismo , Neuronas/metabolismo , Ensayo de Inmunoadsorción Enzimática
17.
Hematol Oncol Clin North Am ; 37(5): 877-892, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37330345

RESUMEN

The incidence of renal cancer has increased over the past several decades, but mortality has declined. This is thought to be related in part to earlier detection of renal masses which portend excellent 5-year survival rates. Management of small renal masses and localized disease include both nonsurgical and surgical options. The choice of intervention is ultimately based on comprehensive evaluation and shared decision-making. This article provides a comprehensive review of the current surgical management options for localized renal cancer.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Nefrectomía , Riñón , Neoplasias Renales/cirugía , Neoplasias Renales/diagnóstico , Carcinoma de Células Renales/cirugía , Tasa de Supervivencia
18.
Oral Oncol ; 141: 106402, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37094500

RESUMEN

OBJECTIVES: This study investigates the impact of immediate resection of positive margins on local control of oral tongue cancer. MATERIALS AND METHODS: We analyzed 273 consecutive oral tongue cancers resected from 2013 to 2018. Additional resection was performed in cases during the initial operation based on surgeon inspection of the specimen and/or frozen margins. Positive margins were defined as invasive carcinoma/high-grade dysplasia < 1 mm from the inked edge. Patients were grouped as follows: negative margin (Group 1); positive margin with immediate additional tissue resection (Group 2); and positive margin without additional tissue resection (Group 3). RESULTS: Overall, the rate of local recurrence was 7.7 % (21/273), and the rate of positive main specimen margin was 17.9 %. Of these patients, 38.8 % (19/49) underwent immediate additional resection of the presumed positive margin. Group 3 had higher local recurrence rates than Group 1 after adjustment for T-stage (aHR 2.8 [95 % CI 1.0-7.7], p = 0.04). Group 2 had similar rates of local recurrence (aHR 0.45 [95 % CI 0.06-3.6], p = 0.45). Three year local recurrence free survival for Groups 1, 2, and 3 were 91 %, 92 % and 73 %, respectively. Compared to the main specimen margin, sensitivity of intraoperative frozen tumor bed margins was 17.4 %, and specificity was 95 %. CONCLUSION: In patients with positive main specimen margins, anticipation and detection in real-time with immediate additional tissue resection reduced local recurrence to rates similar to those with negative main specimen margins. These findings support the use of technology to provide real-time intraoperative margin data and guide additional resection for improved local control.


Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de la Boca , Neoplasias de la Lengua , Humanos , Neoplasias de la Lengua/cirugía , Neoplasias de la Lengua/patología , Pronóstico , Carcinoma de Células Escamosas/patología , Estudios Retrospectivos , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/prevención & control , Recurrencia Local de Neoplasia/patología , Neoplasias de la Boca/patología , Márgenes de Escisión
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