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1.
Clin Ophthalmol ; 18: 2907-2915, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39429439

RESUMO

Purpose: Distinguishing an iris melanoma from an iris nevus can be challenging as few clinical features other than documented growth are helpful in making the diagnosis. In this study, we compared the presenting intraocular pressure (IOP) and cup-to-disc ratio (CDR) between affected and unaffected eyes in patients with iris melanoma and iris nevus. Patients and methods: This was a single-institution retrospective case series of patients treated for iris melanoma and iris nevus from January 2013 to October 2022. Thirty-nine subjects with iris melanoma and forty age-matched patients with iris nevus were included. We analyzed the difference in IOP, CDR, and diagnosis of glaucoma between affected and unaffected eyes in patients with iris melanoma and control iris nevus cohort. Results: The average IOP for eyes with iris melanoma and iris nevus was 18.8±6.1 mmHg and 14.6±3.5 mmHg (P<0.001), respectively. The average CDR was 0.36±0.27 and 0.24±0.14 (P=0.02), respectively. The average IOP of the contralateral unaffected eye in iris melanoma patients was 16.3±3.5 mmHg, significantly less than the affected eye (P=0.03). The average CDR of the contralateral unaffected eye in iris melanoma was 0.25±0.15, which was trending towards being less than the affected eye (P=0.05). There was no difference in the average IOP (P=0.89) or average CDR (P=0.49) between the affected and unaffected eye in patients with iris nevus. Conclusion: We demonstrate that patients with iris melanoma are more likely to have greater IOP and CDR in the affected eye compared to the unaffected eye, and a diagnosis of unilateral glaucoma than eyes with iris nevus. Patients with iris melanoma had greater IOP asymmetry between the affected and unaffected eye. Therefore, IOP and CDR asymmetry may suggest a diagnosis of iris melanoma.

2.
Artigo em Inglês | MEDLINE | ID: mdl-39231107

RESUMO

A 69-year-old white woman with a history of vitreomacular traction (VMT) presented with a 2-week history of visual loss in the right eye. Visual acuity, with correction, measured 20/200 in the right eye. Examination revealed a partial posterior vitreous detachment and a stage 2 full-thickness macular hole (FTMH). Spectral-domain optical coherence tomography (SD-OCT) testing confirmed a stage 2 FTMH with VMT. Pars plana vitrectomy without internal limiting membrane peeling was planned and the patient was sent for preoperative clearance, where she was diagnosed with atrial fibrillation and wanted to delay surgery. Two months later, the patient returned for follow-up with a visual acuity of 20/80, a closed macular hole, and an incomplete posterior vitreous detachment in her right eye. Four months later, the patient exhibited a completely closed FTMH with a visual acuity of 20/30. Spontaneous resolution of FTMHs (stages 2 to 4) in the adult population is an extremely rare event, occurring in less than 4% of affected eyes. We describe a patient with a stage 2 FTMH who exhibited spontaneous resolution due to the resolution of VMT while awaiting preoperative clearance. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

3.
J Neurol Surg B Skull Base ; 85(3): 221-226, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38721367

RESUMO

Objective We completed a prospective human cadaveric study to determine the ability of a ball bearing (BB) pellet to penetrate the orbit and/or surrounding structures. Methods A single trained sergeant officer discharged an alloy steel air rifle to eight cadaver orbits from four adult human cadaver heads. Five BB pellets each were aimed at three locations (caruncle, upper eyelid, or lower eyelid) at 10 cm and 1 m, and then less specifically, at the orbital region for 3- and 5-m distances. Computed tomography (CT) of the cadaver heads was performed. Final locations of BB pellets are divided into three categories: intracranial, surrounding orbital structures including the pterygopalatine fossa and infratemporal fossa, and orbit. Results Of 40 BB pellets, 37 penetrated soft tissue and were visualized on CT: 19 (51%) rested in the intracranial space, 17 (46%) in surrounding orbital structures, and 1 (3%) within the orbit. The deepest position of a pellet was in the parietal lobe, and most superficial location anterior to the frontal bone. Pellets discharged from 1 m were more likely to rest in the intracranial space compared with those from 10 cm ( p < 0.001), 3 m ( p = 0.011), and 5 m ( p = 0.004). The distance of discharge was associated with final pellet location ( p = 0.001). Conclusion BB guns should be considered dangerous and potentially deadly when aimed at the orbit. Although the thick calvarium can protect the intracranial space from BB penetration, the orbit may be a vulnerable entry point with relatively low resistance, allowing penetration of the intracranial and periorbital spaces.

5.
Orbit ; : 1-5, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374584

RESUMO

An 8-year-old female presented to the oculoplastics clinic with 3 months of left upper eyelid fullness and edema. Examination showed a mass in the left anterior superior orbit with erythema. Imaging demonstrated a well-circumscribed superolateral orbital mass that was T1 hypointense and T2 hypo-to-iso intense with contrast enhancement. An incisional biopsy was performed via an upper lid crease incision. Histopathology showed aggregates of histiocytic cells with fibrosis and infiltration of eosinophils. Immunohistochemistry revealed positive CD68 and CD163 staining and negative langerin staining, confirming the diagnosis of indeterminate cell histiocytosis. There was no systemic involvement or associated dermatologic findings. Repeat exam 3 months later showed no change in the size of the lesion and the patient was referred to hematology-oncology for treatment. On most recent exam, the patient had no new symptoms or side effects following 3 months of oral hydroxyurea (25 mg/kg/day). Repeat orbital imaging showed no progression of the lesion and the patient will be monitored closely. Here, we report a rare case of isolated orbital indeterminate cell histiocytosis in a young child.

6.
Ophthalmic Plast Reconstr Surg ; 40(4): 399-402, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38285960

RESUMO

PURPOSE: To determine the prevalence, clinical features, and radiographic findings of superior ophthalmic vein periphlebitis (SOVP) in thyroid eye disease (TED). METHODS: Patients with a clinical diagnosis of thyroid eye disease and contrast-enhanced imaging were included. Imaging was reviewed for the presence of SOVP, and patients with SOVP were compared to those without. A random eye was determined to be the affected eye in patients without SOVP. RESULTS: A total of 212 patients met the inclusion criteria. Unilateral SOVP was identified in 4.7% of cases. There was no significant difference in age ( p = 0.22), gender ( p = 0.09), or disease duration ( p = 0.14) between patients with and without SOVP. There was a significant ( p < 0.05) difference in stage classification and clinical activity core between the groups. The affected eye in patients with SOVP had significantly ( p < 0.05) greater margin reflex distance 1, degree of relative proptosis, horizontal motility restriction, and vertical motility restriction than in patients without SOVP. There was no significant difference in horizontal strabismus ( p = 1.0), vertical strabismus ( p = 0.87), or relative intraocular pressure ( p = 0.77). On imaging, the maximal diameter of the SR and IR were found to be significantly ( p < 0.05) larger in the affected eye of patients with periphlebitis; however, there was no difference in measured diameter of the medial rectus and ( p = 0.30) or lateral rectus ( p = 0.78). CONCLUSIONS: SOVP is an under-reported imaging finding of thyroid eye disease. It is associated with significantly greater margin reflex distance 1, relative proptosis, and motility restriction on exam as well as larger superior rectus and inferior rectus diameter on imaging. These patients tend to present in the active stage of disease with greater clinical activity score.


Assuntos
Oftalmopatia de Graves , Flebite , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Oftalmopatia de Graves/diagnóstico , Oftalmopatia de Graves/epidemiologia , Oftalmopatia de Graves/complicações , Prevalência , Adulto , Idoso , Flebite/diagnóstico , Flebite/epidemiologia , Flebite/etiologia , Estudos Retrospectivos , Veias/diagnóstico por imagem , Idoso de 80 Anos ou mais , Tomografia Computadorizada por Raios X
7.
Am J Ophthalmol Case Rep ; 33: 101980, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38261879

RESUMO

Purpose: To present a rare case of dedifferentiated liposarcoma of the orbit. Observations: A 61-year-old male complained of left-sided proptosis, diplopia, and limited ocular motility for two years. Biopsy results at that time were suggestive of an atypical lipomatous neoplasm. Ten years later, he presented with increase in size of the mass and worsening of his symptoms. Imaging showed a multi-lobulated mass in the left orbit involving the intraconal, medial, and anterior orbit. Decompression and orbitotomy with biopsy were performed to debulk the mass. Pathology showed a low-grade well-differentiated liposarcoma and the patient was monitored thereafter annually. Eight years later, he complained of persistent proptosis and mass effect from the tumor resulting in ptosis and diplopia and underwent orbital exenteration. Histopathological analysis of the exenterated orbit revealed a focal area of dedifferentiated liposarcoma. Conclusions and importance: Dedifferentiation of an orbital mass can occur as a late complication years after the diagnosis of well-differentiated liposarcoma. Compared to the previously published cases of orbital liposarcoma, this presentation shows a prolonged timeline prior to dedifferentiation (18 years after initial diagnosis). Symptoms of growth or invasive features could indicate dedifferentiation and should warrant a biopsy.

8.
Artigo em Inglês | MEDLINE | ID: mdl-37972973

RESUMO

PURPOSE: The goal of this study is to understand the dynamic trends of 20 cosmetic procedures in the United States using Google Trends. METHODS: This was a descriptive cross-sectional study using Google Trends to measure changes in search volumes for 20 cosmetic procedures from a 5-year period (2018 to 2023) in the United States. Outcome measures included total and weekly changes in relative search volumes and variance levels for the following 20 search terms related to cosmetic surgeries: blepharoplasty, botox, breast augmentation, breast lift, brow lift, buccal fat removal, chemical peel, dermal filler, face lift, hair removal, hair transplant, lip filler, liposuction, masseter botox, microneedling, otoplasty, photofacial, rhinoplasty, tear trough filler, and tummy tuck. Search terms were divided into 3 categories, a) those with a change of public interest over a single week of 25% or less, b) 26%-50%, and c) greater than 50%. RESULTS: There was an overall 5-year increase of public interest in all but 5 search terms: breast augmentation, breast lift, liposuction, photofacial, and tummy tuck. Within a single week, lip filler, masseter botox, buccal fat removal, and tear trough filler exhibited greater than 50% change in public interest, while public interest in microneedling, hair removal, rhinoplasty, tummy tuck, liposuction, breast lift, and augmentation were more stable with less than 26% change. CONCLUSIONS: While certain procedures may experience rapid accelerations in public interest, not all procedures will consistently increase in popularity. Physicians must recognize the shifting popularity of cosmetic procedures to provide informed cosmetic care to patients.

9.
ACS Med Chem Lett ; 14(9): 1179-1187, 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37736184

RESUMO

Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle and are frequently altered in cancer cells, thereby leading to uncontrolled proliferation. In this context, CDK2 has emerged as an appealing target for anticancer drug development. Herein, we describe the discovery of a series of selective small molecule inhibitors of CDK2 beginning with historical compounds from our ERK2 program (e.g., compound 6). Structure-based drug design led to the potent and selective tool compound 32, where excellent selectivity against ERK2 and CDK4 was achieved by filling the lipophilic DFG-1 pocket and targeting interactions with CDK2-specific lower hinge binding residues, respectively. Compound 32 demonstrated 112% tumor growth inhibition in mice bearing OVCAR3 tumors with 50 mg/kg bis in die (BID) oral dosing.

10.
Cureus ; 15(3): e36819, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36998920

RESUMO

Frosted branch angiitis (FBA) is an uncommon form of retinal vasculitis and is typically associated with vision loss. We report a unique case of FBA that manifested in the setting of an active COVID-19 infection in a patient with Mixed Connective Tissue Disease (MCTD). A 34-year-old female with a history of MCTD, including overlapping findings of dermatomyositis, systemic lupus erythematosus, and rheumatoid arthritis, on immunosuppressive medications, presented for left-sided vision loss. She was also found to have an active COVID-19 infection with symptoms including sore throat and dry cough. The patient's visual acuity was counting fingers in her affected eye with a fundus exam revealing diffuse retinal hemorrhages, retinal whitening, cystoid macular edema, and perivascular sheathing of tertiary arterioles and venules, characteristic of FBA. Labs showed mildly elevated inflammatory markers. She exhibited no other signs or symptoms concerning systemic rheumatologic flare. There was no evidence of COVID-19 on viral PCR testing of intraocular fluid but given her positive nasopharyngeal PCR, COVID-induced retinal vasculitis with FBA remained high on the differential. The patient's retinal vasculitis later improved with heightened immunosuppressive therapy including high-dose intravenous corticosteroids. Clinicians should be aware of the possibility of COVID-related FBA, particularly in patients with an underlying predisposition to autoimmune inflammation. Our experience with this patient highlights the utility of high-dose systemic immunosuppressive therapy in treating such inflammatory occlusive retinal vasculitis. Further studies are needed to characterize retinal manifestations of COVID-19 in the setting of autoimmune disease.

11.
Ocul Oncol Pathol ; 9(1-2): 48-55, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38376097

RESUMO

Introduction: The aim of this study was to report the nearly ubiquitous prevalence of melanocytic hyperplasia in benign pterygia/pingueculae and establish that the entity is insufficiently recognized. Methods: This is a retrospective immunohistochemical pathology case series of 30 consecutive pterygia/pingueculae samples selected from an ophthalmic pathology database at a single institution. Histopathologic and immunohistochemistry analyses with anti-SOX-10 and anti-MART-1 antibodies were used for identifying melanocytes. The number of squamous cells intervening between melanocytes was determined. Results: The frequency of dendritic melanocytes was found to meet the criteria for dendritic melanocytic hyperplasia in 29 of 30 pterygia/pingueculae samples using specific antibodies. Melanocytes were found in several patterns: diffuse (28%), multifocal (28%), and focal (44%). In each case, the melanocytes were distributed as single melanocytes at the base; clusters of melanocytes were seen in 17% of samples. There were an average of about two intervening epithelial cells between melanocytes at the base. Conclusion: When diagnosed with immunohistochemistry, dendritic melanocytic hyperplasia is nearly ubiquitous in pterygia and pingueculae. Melanocytic hyperplasia may have a distribution that includes nests and single melanocytes above the basal layer, which can be confused with forms of primary acquired melanosis. It is important for pathologists to recognize these lesions as a distinct benign clinicopathologic entity.

12.
Orbit ; : 1-5, 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36437749

RESUMO

A 70-year-old male presented with diplopia and painless proptosis of the left eye for 5 months. Examination showed 6 mm of axial proptosis and restriction of supraduction, abduction and adduction, and mild limitation of infraduction of the left eye. Magnetic resonance imaging demonstrated a large, moderately well-circumscribed intraconal mass in the left lateral orbit, and excisional biopsy was performed. Histopathologic features of mixed fibrous and myxoid areas in a whorl-like pattern and immunohistochemical staining for MUC4 confirmed the diagnosis of low-grade fibromyxoid sarcoma (LGFMS). Next-generation sequencing revealed genetic fusion of EWSR1-CREB3L1. LGFMS is an extremely rare neoplasm with only two prior documented cases of orbital involvement. Here, we report the third case of orbital LGFMS.

13.
Anal Chem ; 94(37): 12927-12933, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36083155

RESUMO

KRAS is one of the most frequently mutated oncogenes, with KRAS G12C recently becoming an actionable target for small molecule intervention. GDC-6036 is an investigational KRAS G12C inhibitor that acts by irreversibly binding to the switch II pocket of KRAS G12C when in the inactive GDP-bound state, thereby blocking GTP binding and activation. Assessing target engagement is an essential component of clinical drug development, helping to demonstrate mechanistic activity, guide dose selection, understand pharmacodynamics as it relates to clinical response, and explore resistance. Here, we report the development of an ultra-sensitive approach for assessing KRAS G12C engagement. Immunoaffinity enrichment with a commercially available anti-RAS antibody was combined with a targeted 2D-LC-MS/MS technique to quantify both free and GDC-6036-bound KRAS G12C proteins. A KRAS G12C-positive non-small cell lung cancer xenograft model was dosed with GDC-6036 to assess the feasibility of this assay for analyzing small core needle biopsies. As predicted, dose-dependent KRAS G12C engagement was observed. To date, a sensitivity of 0.08 fmol/µg of total protein has been achieved for both free and GDC-6036-bound KRAS G12C with as little as 4 µg of total protein extracted from human tumor samples. This sub-fmol/µg level of sensitivity provides a powerful potential approach to assess covalent inhibitor target engagement at the site of action using core needle tumor biopsies from clinical studies.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Antineoplásicos/química , Biópsia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida , Guanosina Trifosfato , Humanos , Neoplasias Pulmonares/patologia , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Espectrometria de Massas em Tandem
14.
Nat Biotechnol ; 40(5): 769-778, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34992247

RESUMO

Small molecules that stabilize inactive protein conformations are an underutilized strategy for drugging dynamic or otherwise intractable proteins. To facilitate the discovery and characterization of such inhibitors, we created a screening platform to identify conformation-locking antibodies for molecular probes (CLAMPs) that distinguish and induce rare protein conformational states. Applying the approach to KRAS, we discovered CLAMPs that recognize the open conformation of KRASG12C stabilized by covalent inhibitors. One CLAMP enables the visualization of KRASG12C covalent modification in vivo and can be used to investigate response heterogeneity to KRASG12C inhibitors in patient tumors. A second CLAMP enhances the affinity of weak ligands binding to the KRASG12C switch II region (SWII) by stabilizing a specific conformation of KRASG12C, thereby enabling the discovery of such ligands that could serve as leads for the development of drugs in a high-throughput screen. We show that combining the complementary properties of antibodies and small molecules facilitates the study and drugging of dynamic proteins.


Assuntos
Anticorpos , Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Anticorpos/química , Humanos , Ligantes , Mutação , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores
15.
Public Health Nutr ; 24(1): 62-74, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33019950

RESUMO

OBJECTIVE: To examine the impact of front-of-package (FOP) labels on perceived healthfulness, purchasing intentions and understanding of common FOP systems. DESIGN: A parallel, open-label design randomised participants to different FOP labelling conditions: 'high in' warning labels (WL), multiple traffic light labelling (TLL), health star ratings (HSR) (all displayed per serving) or control with no interpretive FOP labelling. Participants completed a brief educational session via a smartphone application and two experimental tasks. In Task 1, participants viewed healthy or unhealthy versions of four products and rated healthiness and purchasing intention on a seven-point Likert-type scale. In Task 2, participants ranked three sets of five products from healthiest to least healthy. SETTING: Online commercial panel. PARTICIPANTS: Canadian residents ≥ 18 years who were involved in household grocery shopping, owned a smartphone and met minimum screen requirements. RESULTS: Data from 1997 participants (n 500/condition) were analysed. Task 1: across most product categories, the TLL and HSR increased perceived healthiness of healthier products. All FOP systems decreased perceived healthiness of less healthy products. Similar, albeit dampened, effects were seen regarding purchasing intentions. Task 2: participants performed best in the HSR, followed by the TLL, WL and control conditions. Lower health literacy was associated with higher perceived healthiness and purchasing intentions and poorer ranking task performance across all conditions. CONCLUSIONS: All FOP labelling systems, after a brief educational session, improved task performance across a wide spectrum of foods. This effect differed depending on the nutritional quality of the products and the information communicated on labels.Trial Registration: NCT03290118.


Assuntos
Rotulagem de Alimentos , Comportamentos Relacionados com a Saúde , Canadá , Comportamento de Escolha , Comportamento do Consumidor , Preferências Alimentares , Humanos , Valor Nutritivo
16.
ACS Med Chem Lett ; 11(4): 541-549, 2020 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-32292562

RESUMO

A class of imidazoisoindole (III) heme-binding indoleamine-2,3-dioxygenase (IDO1) inhibitors were optimized via structure-based drug design into a series of tryptophan-2,3-dioxygenase (TDO)-selective inhibitors. Kynurenine pathway modulation was demonstrated in vivo, which enabled evaluation of TDO as a potential cancer immunotherapy target. As means of mitigating the risk of drug-drug interactions arising from cytochrome P450 inhibition, a novel property-based drug design parameter, herein referred to as the CYP Index, was implemented for the design of inhibitors with appreciable selectivity for TDO over CYP3A4. We anticipate the CYP Index will be a valuable design parameter for optimizing CYP inhibition of any small molecule inhibitor containing a Lewis basic motif capable of binding heme.

17.
Appetite ; 149: 104629, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32061707

RESUMO

Mandatory front-of-pack (FOP) labelling was proposed in Canada to highlight foods with high contents of sugars, sodium and/or saturated fats, which would be displayed on labels along with the mandatory Nutrition Facts table and voluntary nutrition claims. In an online survey, participants (n = 1997) were randomized to one of four FOP labelling conditions: 1) control, 2) warning label, 3) health star rating or 4) traffic light labelling. Participants were shown four drinks (a healthier drink with or without a disease risk reduction claim, a healthier drink with or without a nutrient content claim, a less healthy drink with or without a disease risk reduction claim and a less healthy drink with or without a nutrient content claim) in random order and one at a time. Participants rated perceived product healthfulness and purchase intentions using a 7-point Likert scale. Participants could access the Nutrition Facts table while viewing labels. Results showed less healthy drinks displaying any FOP labelling were perceived as less healthy compared to the control. In healthier drinks, health star rating and traffic light labelling created a 'halo' effect, which was not observed with warning labels. Similar results were observed with purchase intentions. Drinks displaying a disease risk reduction claim were perceived as healthier than those without (p < 0.001) regardless of product's healthfulness. The effect of a nutrient content claim was not significantly different. The effect of FOP labelling and claims was mitigated for those who used the Nutrition Facts table. FOP labelling was likely helpful for consumers with different levels of health literacy. Overall, FOP labelling had significantly stronger influence than nutrition claims on consumers' perceptions; however, the effect of each FOP label varied on healthier and less healthy drinks.


Assuntos
Comportamento do Consumidor , Dieta Saudável/psicologia , Rotulagem de Alimentos/métodos , Preferências Alimentares/psicologia , Comportamentos Relacionados com a Saúde , Adolescente , Adulto , Idoso , Canadá , Comportamento de Escolha , Feminino , Rotulagem de Alimentos/legislação & jurisprudência , Humanos , Intenção , Masculino , Pessoa de Meia-Idade , Política Nutricional/legislação & jurisprudência , Valor Nutritivo , Adulto Jovem
18.
J Neurol Surg B Skull Base ; 79(3): 314-318, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29765831

RESUMO

Objectives/Hypotheses To assess quality of life (QOL) after transnasal, endoscopic pituitary surgery using the 36-item short form (SF-36) instrument. Design Retrospective review was used for this study. Setting The study was conducted in a tertiary academic medical center. Participants Patients who underwent endoscopic, transnasal, transsphenoidal surgery for pituitary adenomas between January 1, 2007 and July 1, 2016 and completed preoperative and postoperative SF-36 surveys. Main Outcome Measures SF-36 survey data as measured by its eight domains (physical functioning, physical role functioning, emotional role functioning, energy/fatigue, emotional well-being, social functioning, pain, and general health). Results There were 18 preoperative, 13 short-term (2 weeks or less after surgery) postoperative, and 14 longer term (>2 weeks after surgery) postoperative surveys. There was no significant difference between preoperative and long-term postoperative SF-36 scores across domains ( p > 0.05). In comparing short-term postoperative and preoperative scores, tumor size was positively associated with emotional well-being ( p = 0.049) and general health scores ( p = 0.031), while visual changes preoperatively were positively associated with general health scores ( p = 0.046). Compared with standard U.S. general population summary data, these patients scored lower preoperatively in all domains except for emotional role functioning and pain ( p < 0.05). Postoperatively, patients improved to baseline general population data scores with the exception of the physical role functioning domain ( p < 0.0001). Conclusion Patients undergoing endoscopic, transnasal, transsphenoidal surgery for pituitary adenomas had lower QOL in six of eight domains preoperatively, but improved to baseline values on the long run after surgery in seven of eight domains. This suggests that minimally invasive pituitary surgery has a restorative role in general QOL as measured by the SF-36.

19.
J Med Chem ; 59(11): 5520-41, 2016 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-27167326

RESUMO

p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinases Ativadas por p21/antagonistas & inibidores , Doença Aguda , Animais , Relação Dose-Resposta a Droga , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Piridonas , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Quinases Ativadas por p21/metabolismo
20.
ACS Med Chem Lett ; 6(12): 1241-6, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26713112

RESUMO

Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

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