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BACKGROUND: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. PATIENTS AND METHODS: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. RESULTS: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. CONCLUSIONS: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
In this paper, we bridged faculty research expertise with concept-based learning pedagogy to design and implement a unique laboratory experience for biomedical engineering undergraduate students enrolled in the biomechanics of tissues course at the University of Calgary. This laboratory aimed to increase student engagement, facilitate deeper understanding of course content, and provide an opportunity for accelerated undergraduate research through "hands-on," "minds-on," and "science-up" learning components, respectively. The laboratory exercise involves testing aortic tissues using a novel miniaturized planar biaxial machine. This type of machine is normally reserved for use in the context of research. The relevance of the proposed laboratory as a teaching tool was assessed using student feedback. Results indicate an overall valuable and positive learning experience for students.
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Engenharia Biomédica , Laboratórios , Estudantes , PaladarRESUMO
A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
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Nitroimidazóis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Tripanossomíase Africana/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Nitroimidazóis/administração & dosagem , Nitroimidazóis/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Trypanothione reductase (TR) is an enzyme critical to the maintenance of the thiol redox balance in trypanosomatids, including the genera Trypanosoma and Leishmania that are parasites responsible for several serious diseases. Analogs of clomipramine were prepared since clomipramine is reported to inhibit TR and cure mice infected with trypanosomes, however its psychotropic activity precludes its use as an anti-trypanosomal therapeutic. The clomipramine analogs contained a tricyclic dibenzosuberyl moiety. Additionally a series of polyamines with N-dibenzosuberyl substituents were prepared. All compounds studied were competitive inhibitors of TR and showed trypanocidal activities against Trypanosoma brucei in vitro. The analogs of clomipramine were poor inhibitors of TR, whereas the polyamine derivatives were effective TR inhibitors with the most potent compound, N(4),N(8)-bis(dibenzosuberyl)spermine (7), having a Ki value of 0.26µM. However, compound (7) did not prolong the lives of mice infected with trypanosomes. Analysis of docking studies indicated: the tricyclic groups of inhibitors bind at four distinct hydrophobic regions in the active site of TR; the importance of the chlorine substituent of clomipramine in binding to TR; and binding of the dibenzosuberyl groups of (7) occur at separate and distinct hydrophobic regions within the active site of TR.
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Clomipramina/análogos & derivados , Inibidores Enzimáticos/farmacologia , NADH NADPH Oxirredutases/antagonistas & inibidores , Poliaminas/farmacologia , Tripanossomicidas/farmacologia , Animais , Clomipramina/química , Inibidores Enzimáticos/química , Camundongos , Simulação de Acoplamento Molecular , Poliaminas/química , Trypanosoma brucei brucei/efeitos dos fármacos , Trypanosoma brucei brucei/enzimologiaRESUMO
BACKGROUND: Prostate cancer is the most-diagnosed non-skin cancer among males in the US, and the second leading cause of cancer-related death. Current methods of treatment and diagnosis are not specific for the disease. This work identified an antibody fragment that binds selectively to a molecule on the surface of androgen-dependent prostate cancer cells but not benign prostatic cells. RESULTS: Antibody fragment identification was achieved using a library screening and enrichment strategy. A library of 109 yeast-displayed human non-immune antibody fragments was enriched for those that bind to androgen-dependent prostate cancer cells, but not to benign prostatic cells or purified prostate-specific membrane antigen (PSMA). Seven rounds of panning and fluorescence-activated cell sorting (FACS) screening yielded one antibody fragment identified from the enriched library. This molecule, termed HiR7.8, has a low-nanomolar equilibrium dissociation constant (Kd) and high specificity for androgen-dependent prostate cancer cells. CONCLUSIONS: Antibody fragment screening from a yeast-displayed library has yielded one molecule with high affinity and specificity. With further pre-clinical development, it is hoped that the antibody fragment identified using this screening strategy will be useful in the specific detection of prostate cancer and in targeted delivery of therapeutic agents for increased efficacy and reduced side effects.
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Especificidade de Anticorpos , Fragmentos de Imunoglobulinas/química , Neoplasias da Próstata/diagnóstico , Afinidade de Anticorpos , Linhagem Celular Tumoral , Humanos , MasculinoRESUMO
Reproductive behaviors differ across species, but the mechanisms that control variation in mating and parental care systems remain unclear. In many animal species, pheromones guide mating and parental care. However, it is not well understood how vertebrate pheromone signaling evolution can lead to new reproductive behavior strategies. In fishes, prostaglandin F2α (PGF2α) drives mating and reproductive pheromone signaling in fertile females, but this pheromonal activity appears restricted to specific lineages, and it remains unknown how a female fertility pheromone is sensed for most fish species. Here, we utilize single-cell transcriptomics and CRISPR gene editing in a cichlid fish model to identify and test the roles of key genes involved in olfactory sensing of reproductive cues. We find that a pheromone receptor, Or113a, detects fertile cichlid females and thereby promotes male attraction and mating behavior, sensing a ligand other than PGF2α. Furthermore, while cichlid fishes exhibit extensive parental care, for most species, care is provided solely by females. We find that males initiate mouthbrooding parental care if they have disrupted signaling in ciliated sensory neurons due to cnga2b mutation or if or113a is inactivated. Together, these results show that distinct mechanisms of pheromonal signaling drive reproductive behaviors across taxa. Additionally, these findings indicate that a single pheromone receptor has gained a novel role in behavior regulation, driving avoidance of paternal care among haplochromine cichlid fishes. Lastly, a sexually dimorphic, evolutionarily derived parental behavior is controlled by central circuits present in both sexes, while olfactory signals gate this behavior in a sex-specific manner.
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Ciclídeos , Comportamento Sexual Animal , Animais , Feminino , Masculino , Ciclídeos/fisiologia , Ciclídeos/genética , Comportamento Sexual Animal/fisiologia , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Receptores de Feromônios/genética , Receptores de Feromônios/metabolismo , Comportamento Paterno/fisiologiaRESUMO
Metallo-polyelectrolytes are versatile materials for applications like filtration, biomedical devices, and sensors, due to their metal-organic synergy. Their dynamic and reversible electrostatic interactions offer high ionic conductivity, self-healing, and tunable mechanical properties. However, the knowledge gap between molecular-level dynamic bonds and continuum-level material properties persists, largely due to limited fabrication methods and a lack of theoretical design frameworks. To address this critical gap, we present a framework, combining theoretical and experimental insights, highlighting the interplay of molecular parameters in governing material properties. Using stereolithography-based additive manufacturing, we produce durable metallo-polyelectrolytes gels with tunable mechanical properties based on metal ion valency and polymer charge sparsity. Our approach unveils mechanistic insights into how these interactions propagate to macroscale properties, where higher valency ions yield stiffer, tougher materials, and lower charge sparsity alters material phase behavior. This work enhances understanding of metallo-polyelectrolytes behavior, providing a foundation for designing advanced functional materials.
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INTRODUCTION: Dissection or rupture of the aorta is accompanied by high mortality rates, and there is a pressing need for better prediction of these events for improved patient management and clinical outcomes. Biomechanically, these events represent a situation wherein the locally acting wall stress exceed the local tissue strength. Based on recent reports for polymers, we hypothesized that aortic tissue failure strength and stiffness are directly associated with tissue mass density. The objective of this work was to test this novel hypothesis for porcine thoracic aorta. METHODS: Three tissue specimens from freshly harvested porcine thoracic aorta were treated with either collagenase or elastase to selectively degrade structural proteins in the tissue, or with phosphate buffer saline (control). The tissue mass and volume of each specimen were measured before and after treatment to allow for density calculation, then mechanically tested to failure under uniaxial extension. RESULTS: Protease treatments resulted in statistically significant tissue density reduction (sham vs. collagenase p = 0.02 and sham vs elastase p = 0.003), which in turn was significantly and directly correlated with both ultimate tensile strength (sham vs. collagenase p = 0.02 and sham vs elastase p = 0.03) and tangent modulus (sham vs. collagenase p = 0.007 and sham vs elastase p = 0.03). CONCLUSIONS: This work demonstrates for the first time that tissue stiffness and tensile strength are directly correlated with tissue density in proteolytically-treated aorta. These findings constitute an important step towards understanding aortic tissue failure mechanisms and could potentially be leveraged for non-invasive aortic strength assessment through density measurements, which could have implications to clinical care.
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Aorta Torácica , Resistência à Tração , Animais , Suínos , Aorta Torácica/fisiologia , Elastase Pancreática/metabolismo , Colagenases , Proteólise , Rigidez Vascular/fisiologia , Estresse MecânicoRESUMO
CONTEXT.: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. OBJECTIVE.: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. DESIGN.: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. RESULTS.: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively). CONCLUSIONS.: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies.
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Background Arthroscopic repair of glenohumeral instability is becoming an increasingly common procedure. These repairs can be undertaken using knot-tying and knotless suture anchors; there is currently no clear consensus in the literature about what type of repair is most cost-effective and provides superior outcomes. The purpose of this study is to examine postoperative outcomes of patients undergoing arthroscopic anteroinferior labral repair (AALR) with either knot-tying or knotless anchors. Methods A single institution retrospective observational cohort study of 122 patients undergoing AALR from January 2014 to June 2021 was conducted. Univariate statistics were used to assess differences in demographics, operative characteristics, and postoperative outcomes between repair types; multivariate analysis was used to evaluate risk factors for recurrent instability and reoperation. Results Patients undergoing AALR with knotless anchors had a shorter case duration than those with knot-tying anchors (112.64 vs. 89.86 minutes, p<0.001). There were no significant differences between groups in the size of labral tear, presence of a glenoid bone defect, or Hill-Sachs lesion. After controlling for age, BMI, sex, glenoid bone defect, number of preoperative dislocations, and fixation type, only age (OR=0.896, p=0.010) and female sex (OR=5.341, p=0.008) were independent risk factors for recurrent instability and no factors were independent predictors of reoperation. Conclusion Patients undergoing AALR experienced similar rates of reoperation and recurrent instability regardless of whether a knot-tying or knotless repair was performed. The use of knotless suture anchors may improve cost-effectiveness due to decreased surgical time without diminishing postoperative outcomes.
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Objective: Evaluate the mechanical and matrix effects on abdominal aortic aneurysms (AAA) during the initial aortic dilation and after prolonged exposure to beta-aminopropionitrile (BAPN) in a topical elastase AAA model. Methods: Abdominal aortae of C57/BL6 mice were exposed to topical elastase with or without BAPN in the drinking water starting 4 days before elastase exposure. For the standard AAA model, animals were harvested at 2 weeks after active elastase (STD2) or heat-inactivated elastase (SHAM2). For the enhanced elastase model, BAPN treatment continued for either 4 days (ENH2b) or until harvest (ENH2) at 2 weeks; BAPN was continued until harvest at 8 weeks in one group (ENH8). Each group underwent assessment of aortic diameter, mechanical testing (tangent modulus and ultimate tensile strength [UTS]), and quantification of insoluble elastin and bulk collagen in both the elastase exposed aorta as well as the descending thoracic aorta. Results: BAPN treatment did not increase aortic dilation compared with the standard model after 2 weeks (ENH2, 1.65 ± 0.23 mm; ENH2b, 1.49 ± 0.39 mm; STD2, 1.67 ± 0.29 mm; and SHAM2, 0.73 ± 0.10 mm), but did result in increased dilation after 8 weeks (4.3 ± 2.0 mm; P = .005). After 2 weeks, compared with the standard model, continuous therapy with BAPN did not have an effect on UTS (24.84 ± 7.62 N/cm2; 18.05 ± 4.95 N/cm2), tangent modulus (32.60 ± 9.83 N/cm2; 26.13 ± 9.10 N/cm2), elastin (7.41 ± 2.43%; 7.37 ± 4.00%), or collagen (4.25 ± 0.79%; 5.86 ± 1.19%) content. The brief treatment, EHN2b, resulted in increased aortic collagen content compared with STD2 (7.55 ± 2.48%; P = .006) and an increase in UTS compared with ENH2 (35.18 ± 18.60 N/cm2; P = .03). The ENH8 group had the lowest tangent modulus (3.71 ± 3.10 N/cm2; P = .005) compared with all aortas harvested at 2 weeks and a lower UTS (2.18 ± 2.18 N/cm2) compared with both the STD2 (24.84 ± 7.62 N/cm2; P = .008) and ENH2b (35.18 ± 18.60 N/cm2; P = .001) groups. No differences in the mechanical properties or matrix protein concentrations were associated with abdominal elastase exposure or BAPN treatment for the thoracic aorta. The tangent modulus was higher in the STD2 group (32.60 ± 9.83 N/cm2; P = .0456) vs the SHAM2 group (17.99 ± 5.76 N/cm2), and the UTS was lower in the ENH2 group (18.05 ± 4.95 N/cm2; P = .0292) compared with the ENH2b group (35.18 ± 18.60 N/cm2). The ENH8 group had the lowest tangent modulus (3.71 ± 3.10 N/cm2; P = .005) compared with all aortas harvested at 2 weeks and a lower UTS (2.18 ± 2.18 N/cm2) compared with both the STD2 (24.84 ± 7.62 N/cm2; P = .008) and ENH2b (35.18 ± 18.60 N/cm2; P = .001) groups. Abdominal aortic elastin in the STD2 group (7.41 ± 2.43%; P = .035) was lower compared with the SHAM2 group (15.29 ± 7.66%). Aortic collagen was lower in the STD2 group (4.25 ± 0.79%; P = .007) compared with the SHAM2 group (12.44 ± 6.02%) and higher for the ENH2b (7.55 ± 2.48%; P = .006) compared with the STD2 group. Conclusions: Enhancing an elastase AAA model with BAPN does not affect the initial (2-week) dilation phase substantially, either mechanically or by altering the matrix content. Late mechanical and matrix effects of prolonged BAPN treatment are limited to the elastase-exposed segment of the aorta. Clinical Relevance: This paper explores the use of short- and long-term exposure to beta-aminopropionitrile to create an enhanced topical elastase abdominal aortic aneurysm model in mice. Readouts of aneurysm severity included loss of mechanical stability and vascular extracellular matrix composition reminiscent of what is seen in the course of human disease. Additionally, we show that the thoracic aorta, unlike the findings below the renal arteries, is not damaged in our animal model.
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Introduction: Soft tissue sarcomas (STS) are rare, heterogenous malignancies with an unmet need for novel immunotherapies. Tumor infiltrating lymphocytes (TILs) have been linked with favorable outcomes in STS patients, though the contribution of natural killer (NK) cells and spatial relationships of TILs with MHC-I expressing cells lacks detailed characterization. Experimental design: Using archived and prospectively collected specimens, we evaluated intratumoral NK cells by immunohistochemistry (IHC), flow cytometry, and immunofluorescence (IF). We assessed spatial localization of NK and T cells by multiplex IF, analyzing the effects of MHC-I expression status on NK and T cell clustering. Results: Both intratumoral NKp46 and CD56dim expression were associated with significantly improved overall survival (P=0.05), while higher infiltrates of CD56bright NK cells predicted a worse prognosis (P=0.05). The presence of intratumoral NK cells was inversely proportional to CD3+ T cells. Spatial analyses showed NK cells preferentially clustering close to other NK cells with sparse CD3+ T and CD8+ T cells in range (P<0.0001). Additionally, CD3+ T and CD8+ T cells showed significantly greater co-localization with MHC-I+ cells, compared to NK cells (P<0.0001). After neoadjuvant radiotherapy, there was greater CD8 clustering, while after neoadjuvant chemotherapy, there was overall lower TIL clustering. Conclusion: Intratumoral NK cells are prognostic in STS and localize closer to MHC-I- cells than T cells. Although both NK and T cells are associated with improved survival in STS, their differential distribution in the TME based on MHC-I expression status may serve as a biomarker for improved immunotherapy treatment selection.
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Linfócitos T CD8-Positivos , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Linfócitos T CD8-Positivos/imunologia , Células Matadoras Naturais/imunologia , Prognóstico , Sarcoma/imunologia , Sarcoma/terapia , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/terapiaRESUMO
This work aimed at evaluating patients' swallowing functions by a newly validated swallow-specific questionnaire, the Sydney Swallow Questionnaire (SSQ), in a cohort of oral and oropharyngeal cancer patients. Mean/median SSQ scores were calculated and compared with study variables using the Mann-Whitney U test and Kruskal-Wallis test. The mean composite SSQ scores (SD) for the base of tongue, oral tongue, and tonsillar cancer patients were 663.8 (382.8), 456.2 (407.6), and 283.0 (243.1), respectively (p = 0.005); for advanced vs. early T stage disease they were 918.1 (319.5) vs. 344.8 (292.1) (p ≤ 0.001); for patients <60 years vs. ≥60 years they were 549.3 (415.1) vs. 314.0 (247.3) (p = 0.02); and for patients with reconstruction vs. without reconstruction they were 676.5 (410.5) vs. 331.9 (286.5) (p = 0.002). SSQ is a useful tool for evaluation of swallowing in head and neck cancer patients. Site of cancer, T stage, patient's age, and reconstruction directly affect post-treatment swallow outcome.
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Transtornos de Deglutição/fisiopatologia , Deglutição/fisiologia , Neoplasias Orofaríngeas/fisiopatologia , Inquéritos e Questionários , Estudos Transversais , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/complicações , Neoplasias Orofaríngeas/cirurgia , Complicações Pós-Operatórias , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Reino Unido/epidemiologiaRESUMO
There are insufficient data on swallowing and the consequences of its dysfunction in patients with cancers of the oral cavity (OC) and oropharynx (OP) that are treated with primary surgery. The study attempts to explore the effect of important clinico-demographic variables on post-treatment swallowing and related quality of life (QOL) in post-surgical OC and OP cancer patients. Sixty-two consecutive OC and OP cancer patients completed the MD Anderson Dysphagia Inventory (MDADI) questionnaire. Mean scores were computed. Comparison of scores based on mean ranks were performed using Mann-Whitney U test or Kruskal-Wallis test. Level of significance was set at P ≤ 0.02. Adjustments were made for multiple comparisons. Significantly worse mean (SD) QOL scores were observed in late T-stage (T3/T4) versus early T-stage (T1/T2) patients for global domain, physical domain, functional domain and emotional domains [44.4 (21.9) vs. 78.7 (22.7) (P < 0.001); 50.0 (9.4) vs. 75.9 (16.3), (P < 0.0001); 57.8 (20.6) vs. 84.1 (16.7), (P < 0.001) and 55.2 (18.0) vs. 78.5 (16.3), (P < 0.001)], respectively. Patients undergoing reconstruction versus without reconstruction had worse QOL scores; 58.8 (26.9) versus 79.5 (22.8), (P < 0.01); 61.2 (15.1) versus 76.4 (17.5), (P = 0.002); 65.4 (20.5) versus 86.3 (15.9), (P < 0.0001) and 63.3 (18.8) versus 79.8 (16.3), (P < 0.01), respectively, for global, physical, functional and emotional domains. Advanced T-stage, reconstruction, younger age and base of tongue tumours have a negative impact on post-treatment swallow function and related QOL in these patients.
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Deglutição/fisiologia , Neoplasias Bucais/fisiopatologia , Procedimentos Cirúrgicos Bucais/métodos , Neoplasias Orofaríngeas/fisiopatologia , Qualidade de Vida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/psicologia , Neoplasias Bucais/cirurgia , Neoplasias Orofaríngeas/psicologia , Neoplasias Orofaríngeas/cirurgia , Inquéritos e QuestionáriosRESUMO
The aim was to explore the impact of important clinico-demographic factors on the post-treatment quality of life (QOL) in surgically treated oral and oropharyngeal cancer patients. 63 consecutive follow-up oral and oropharyngeal cancer patients treated primarily with surgery were recruited. 55 patients sent the completed questionnaires and finally included in this study. QOL and important sub-domains of the QOL were assessed. Mean QOL scores (SD) were computed, level of significance was set at P < 0.05. The mean composite QOL score and standard deviation (SD) for oral and oropharyngeal cancer patients were 76.6 (15.2) and 73.4 (13.9), respectively. Patients with higher T-stage (T3 and T4) and higher overall-stage (III and IV) had lower mean QOL scores as against early T (T1 and T2) and overall early-stage (I and II); mean scores (SD) 64.3 (13.6) and 72.3 (13.8), and 76.6 (13.6) and 81.7 (14.1), respectively. Younger patients had lower mean scores (SD) than older patients; mean QOL scores (SD) 69.7 (14.0) and 79.6 (SD), respectively. Patients with reconstruction had lower mean QOL scores as compared to those without reconstruction; mean scores (SD) 67.6 (16.0) and 77.4 (12.5), respectively. In conclusion, tumor-stage, overall-stage, age of patients, and reconstruction had a significant direct effect on the post-treatment QOL of oral and oropharyngeal cancer patients.
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Neoplasias Bucais/psicologia , Neoplasias Bucais/cirurgia , Neoplasias Orofaríngeas/psicologia , Neoplasias Orofaríngeas/cirurgia , Complicações Pós-Operatórias/psicologia , Qualidade de Vida/psicologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia Adjuvante/psicologia , Terapia Combinada/psicologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Inquéritos e QuestionáriosRESUMO
Background: Rotator cuff repairs (RCRs) are one of the most commonly performed shoulder surgeries in the United States. Psychological health has been shown to influence postoperative outcomes in orthopedic procedures. The purpose of this study is to evaluate the relationship between depression and anxiety (DA) and psychotropic medication and postoperative outcomes following RCR. Methods: A single institution retrospective observational cohort study of 816 patients undergoing arthroscopic RCR from January 2014 to October 2020 was conducted. Univariate statistics were used to assess differences in demographics, operative characteristics, and postoperative outcomes; multivariate analysis was used to evaluate risk factors for postoperative complications. Results: Patients with DA were more likely to have a higher first (3.60 vs. 3.00, P = .004) and last (1.23 vs. 0.96, P = .042) postoperative pain scores, lower first (18.67 vs. 21.85, P = .008) and last (61.87 vs. 64.71, P = .014) Upper Extremity Functional Score (UEFS), more likely to experience an emergency department visit postoperatively (9.1 vs. 5.0%, P = .028), have a symptomatic recurrent tear (8.2 vs. 3.3%, P = .003), and persistent pain (4.3 vs. 1.2%, P = .011). After controlling for age, sex, body mass index, American Society of Anesthesiologists score, diabetes, smoking, coronary artery disease, asthma, hypertension, psychotropic medication and DA, having DA at the time of surgery was independently predictive of any complication (odds ratio, 2.033; P = .028) and persistent pain (odds ratio, 8.232; P ≤ .001). Patients with and without DA showed significant improvement in postoperative pain and UEFS from the first to the last measurement (P < .001). Conclusion: DA is not a deterrent for RCR but targeted interventions may be needed to decrease the occurrence of complications.
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BACKGROUND: There is limited information on the need for bone augmentation in the context of delayed implant placement whether alveolar ridge preservation (ARP) is previously performed or not. The primary aim of this retrospective cohort study was to evaluate the efficacy of ARP therapy after tooth extraction compared with unassisted socket healing (USH) in reducing the need for ancillary bone augmentation before or at the time of implant placement. METHODS: Adult subjects that underwent non-molar single tooth extraction with or without simultaneous ARP therapy were included in this study. Cone beam computed tomography scans obtained before tooth extraction and after a variable healing period were used to record the baseline facial bone thickness and to virtually plan implant placement according to a standard method. A logistic regression model was used to evaluate the effect of facial alveolar bone thickness upon tooth extraction and baseline therapy (USH or ARP) on the need for additional bone augmentation, adjusting for several covariates (i.e., age, sex, baseline KMW, and tooth type). RESULTS: One hundred and forty subjects that were equally distributed between both baseline therapy groups constituted the study population. Implant placement was deemed virtually feasible in all study sites. Simultaneous bone augmentation was considered necessary in 60% and 11.4% of the sites in the USH and ARP group, respectively. Most of these sites (64.2% in the USH group and 87.5% in the ARP group) exhibited a thin facial bone phenotype (<1 mm) at baseline. Logistic regression revealed that the odds of not needing ancillary bone augmentation were 17.8 times higher in sites that received ARP therapy. Furthermore, the need for additional bone augmentation was reduced 7.7 times for every 1 mm increase in facial bone thickness, regardless of baseline therapy. CONCLUSIONS: Based on a digital analysis, ARP therapy, compared with USH, and thick facial alveolar bone largely reduce the need for ancillary bone augmentation at the time of implant placement in non-molar sites.
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Perda do Osso Alveolar , Aumento do Rebordo Alveolar , Adulto , Perda do Osso Alveolar/diagnóstico por imagem , Perda do Osso Alveolar/prevenção & controle , Perda do Osso Alveolar/cirurgia , Processo Alveolar/diagnóstico por imagem , Processo Alveolar/cirurgia , Aumento do Rebordo Alveolar/métodos , Tomografia Computadorizada de Feixe Cônico , Feminino , Humanos , Masculino , Estudos Retrospectivos , Extração Dentária , Alvéolo Dental/diagnóstico por imagem , Alvéolo Dental/cirurgiaRESUMO
Purpose: Clinical successes using current T-cell based immunotherapies have been limited in soft tissue sarcomas (STS), while pre-clinical studies have shown evidence of natural killer (NK) cell activity. Since tumor immune infiltration, especially tumor-infiltrating lymphocytes, is associated with improved survival in most solid tumors, we sought to evaluate the gene expression profile of tumor and blood NK and T cells, as well as tumor cells, with the goal of identifying potential novel immune targets in STS. Experimental Design: Using fluorescence-activated cell sorting, we isolated blood and tumor-infiltrating CD3-CD56+ NK and CD3+ T cells and CD45- viable tumor cells from STS patients undergoing surgery. We then evaluated differential gene expression (DGE) of these purified populations with RNA sequencing analysis. To evaluate survival differences and validate primary DGE results, we also queried The Cancer Genome Atlas (TCGA) database to compare outcomes stratified by bulk gene expression. Results: Sorted intra-tumoral CD3+ T cells showed significant upregulation of established activating (CD137) and inhibitory genes (TIM-3) compared to circulating T cells. In contrast, intra-tumoral NK cells did not exhibit upregulation of canonical cytotoxic genes (IFNG, GZMB), but rather significant DGE in mitogen signaling (DUSP4) and metabolic function (SMPD3, SLC7A5). Tumors with higher NK and T cell infiltration exhibited significantly increased expression of the pro-inflammatory receptor TLR4 in sorted CD45- tumor cells. TCGA analysis revealed that tumors with high TLR4 expression (P = 0.03) and low expression of STMN1 involved in microtubule polymerization (P < 0.001) were associated with significantly improved survival. Conclusions: Unlike T cells, which demonstrate significant DGE consistent with upregulation of both activating and inhibiting receptors in tumor-infiltrating subsets, NK cells appear to have more stable gene expression between blood and tumor subsets, with alterations restricted primarily to metabolic pathways. Increased immune cell infiltration and improved survival were positively correlated with TLR4 expression and inversely correlated with STMN1 expression within tumors, suggesting possible novel therapeutic targets for immunotherapy in STS.
Assuntos
Células Matadoras Naturais , Linfócitos do Interstício Tumoral , Sarcoma , Neoplasias de Tecidos Moles , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Receptor 4 Toll-Like/metabolismo , TranscriptomaRESUMO
OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus. DESIGN: The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance. METHODS: MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method. RESULTS: Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3. CONCLUSIONS: MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.
Assuntos
COVID-19 , Viroses , COVID-19/prevenção & controle , Descontaminação/métodos , Reutilização de Equipamento , Humanos , Máscaras , Azul de Metileno/farmacologia , Respiradores N95 , Equipamento de Proteção Individual , SARS-CoV-2RESUMO
A series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against Trypanosoma brucei in an acute mouse model. However, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. Consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability.