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1.
Proc Natl Acad Sci U S A ; 121(26): e2319971121, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38885375

RESUMO

Many bird species commonly aggregate in flocks for reasons ranging from predator defense to navigation. Available evidence suggests that certain types of flocks-the V and echelon formations of large birds-may provide a benefit that reduces the aerodynamic cost of flight, whereas cluster flocks typical of smaller birds may increase flight costs. However, metabolic flight costs have not been directly measured in any of these group flight contexts [Zhang and Lauder, J. Exp. Biol. 226, jeb245617 (2023)]. Here, we measured the energetic benefits of flight in small groups of two or three birds and the requirements for realizing those benefits, using metabolic energy expenditure and flight position measurements from European Starlings flying in a wind tunnel. The starlings continuously varied their relative position during flights but adopted a V formation motif on average, with a modal spanwise and streamwise spacing of [0.81, 0.91] wingspans. As measured via CO2 production, flight costs for follower birds were significantly reduced compared to their individual solo flight benchmarks. However, followers with more positional variability with respect to leaders did less well, even increasing their costs above solo flight. Thus, we directly demonstrate energetic costs and benefits for group flight followers in an experimental context amenable to further investigation of the underlying aerodynamics, wake interactions, and bird characteristics that produce these metabolic effects.


Assuntos
Metabolismo Energético , Voo Animal , Estorninhos , Animais , Voo Animal/fisiologia , Metabolismo Energético/fisiologia , Estorninhos/fisiologia , Estorninhos/metabolismo , Aves/fisiologia
2.
Crit Care ; 26(1): 101, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35395943

RESUMO

BACKGROUND: Calcium release-activated calcium (CRAC) channel inhibitors block proinflammatory cytokine release, preserve endothelial integrity and may effectively treat patients with severe COVID-19 pneumonia. METHODS: CARDEA was a phase 2, randomized, double-blind, placebo-controlled trial evaluating the addition of Auxora, a CRAC channel inhibitor, to corticosteroids and standard of care in adults with severe COVID-19 pneumonia. Eligible patients were adults with ≥ 1 symptom consistent with COVID-19 infection, a diagnosis of COVID-19 confirmed by laboratory testing using polymerase chain reaction or other assay, and pneumonia documented by chest imaging. Patients were also required to be receiving oxygen therapy using either a high flow or low flow nasal cannula at the time of enrolment and have at the time of enrollment a baseline imputed PaO2/FiO2 ratio > 75 and ≤ 300. The PaO2/FiO2 was imputed from a SpO2/FiO2 determine by pulse oximetry using a non-linear equation. Patients could not be receiving either non-invasive or invasive mechanical ventilation at the time of enrolment. The primary endpoint was time to recovery through Day 60, with secondary endpoints of all-cause mortality at Day 60 and Day 30. Due to declining rates of COVID-19 hospitalizations and utilization of standard of care medications prohibited by regulatory guidance, the trial was stopped early. RESULTS: The pre-specified efficacy set consisted of the 261 patients with a baseline imputed PaO2/FiO2≤ 200 with 130 and 131 in the Auxora and placebo groups, respectively. Time to recovery was 7 vs. 10 days (P = 0.0979) for patients who received Auxora vs. placebo, respectively. The all-cause mortality rate at Day 60 was 13.8% with Auxora vs. 20.6% with placebo (P = 0.1449); Day 30 all-cause mortality was 7.7% and 17.6%, respectively (P = 0.0165). Similar trends were noted in all randomized patients, patients on high flow nasal cannula at baseline or those with a baseline imputed PaO2/FiO2 ≤ 100. Serious adverse events (SAEs) were less frequent in patients treated with Auxora vs. placebo and occurred in 34 patients (24.1%) receiving Auxora and 49 (35.0%) receiving placebo (P = 0.0616). The most common SAEs were respiratory failure, acute respiratory distress syndrome, and pneumonia. CONCLUSIONS: Auxora was safe and well tolerated with strong signals in both time to recovery and all-cause mortality through Day 60 in patients with severe COVID-19 pneumonia. Further studies of Auxora in patients with severe COVID-19 pneumonia are warranted. Trial registration NCT04345614.


Assuntos
Benzamidas , Tratamento Farmacológico da COVID-19 , Canais de Cálcio Ativados pela Liberação de Cálcio , Pirazinas , Síndrome do Desconforto Respiratório , Adulto , Benzamidas/uso terapêutico , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Humanos , Pirazinas/uso terapêutico , Respiração Artificial , SARS-CoV-2 , Resultado do Tratamento
3.
Breast Cancer Res ; 22(1): 89, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32795346

RESUMO

BACKGROUND: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. METHODS: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. RESULTS: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models. CONCLUSIONS: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Receptor alfa de Estrogênio/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Camundongos Nus , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Gravidez , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Investig Med High Impact Case Rep ; 11: 23247096231184760, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37421300

RESUMO

Anti-glomerular basement membrane (GBM) antibody nephritis is defined by linear immunofluorescence staining of GBM by immunoglobulin G (IgG), typically associated with GBM rupture, fibrinoid necrosis, and crescent formation. Clinically, the patients present with rapidly worsening renal function, often with hematuria. Typical renal pathologic findings include necrotizing and crescentic glomerulonephritis. In contrast, thrombotic microangiopathy (TMA) is characterized by microvascular thrombosis, which can also lead to acute kidney injury. Thrombotic microangiopathy is associated with some systemic diseases and has characteristic clinical features of microangiopathic hemolytic anemia, platelet consumption, and multiple organ failure. Anti-GBM nephritis associated with TMA has rarely been reported. We describe an unusual case of atypical anti-GBM disease without crescent formation or necrosis but with light microscopic and ultrastructural features consistent with endothelial cell injury and glomerular-limited TMA.


Assuntos
Glomerulonefrite , Nefrite , Púrpura Trombocitopênica Trombótica , Humanos , Glomerulonefrite/complicações , Glomerulonefrite/patologia , Necrose , Membrana Basal/patologia
5.
bioRxiv ; 2023 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-37333286

RESUMO

Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here we show that a macropinocytosis activator, the tumor promoter Phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the Xenopus embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.

6.
Elife ; 122023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37902809

RESUMO

Activation of the Wnt pathway lies at the core of many human cancers. Wnt and macropinocytosis are often active in the same processes, and understanding how Wnt signaling and membrane trafficking cooperate should improve our understanding of embryonic development and cancer. Here, we show that a macropinocytosis activator, the tumor promoter phorbol 12-myristate 13-acetate (PMA), enhances Wnt signaling. Experiments using the Xenopus embryo as an in vivo model showed marked cooperation between the PMA phorbol ester and Wnt signaling, which was blocked by inhibitors of macropinocytosis, Rac1 activity, and lysosome acidification. Human colorectal cancer tissue arrays and xenografts in mice showed a correlation of cancer progression with increased macropinocytosis/multivesicular body/lysosome markers and decreased GSK3 levels. The crosstalk between canonical Wnt, focal adhesions, lysosomes, and macropinocytosis suggests possible therapeutic targets for cancer progression in Wnt-driven cancers.


Assuntos
Carcinógenos , Neoplasias , Feminino , Gravidez , Humanos , Animais , Camundongos , Via de Sinalização Wnt , Quinase 3 da Glicogênio Sintase , Ésteres de Forbol , Ésteres
7.
Mol Cancer Ther ; 22(12): 1365-1375, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37788341

RESUMO

Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.


Assuntos
Imunoconjugados , Neoplasias , Humanos , Camundongos , Animais , Anticorpos Monoclonais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoconjugados/química , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Modelos Animais de Doenças , Neoplasias/tratamento farmacológico , Claudinas , Neoplasias Pancreáticas
8.
J Med Cases ; 13(7): 322-329, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35949945

RESUMO

Acute interstitial nephritis (AIN) classically presents as acute kidney injury most often induced by offending drugs. Less frequently it is secondary to infections, autoimmune disorders, or idiopathic conditions. Development of drug-related AIN is not dose dependent and a recurrence can occur with re-exposure to the drug. We present a 50-year-old male with treatment resistant schizoaffective disorder who developed clozapine-induced AIN, confirmed with kidney biopsy within 2 months of taking this medication. His kidney function improved with removal of the drug and treatment with steroids. However, his kidney function was again significantly impaired when rechallenged with even a lower dose of clozapine a year later. Kidney function returned to baseline after stopping clozapine. Monitoring of kidney function during clozapine therapy is essential to therapy. Prompt diagnosis is imperative as discontinuation of offending agent can prevent acute kidney injury.

9.
Mol Cancer Ther ; 21(5): 751-761, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417017

RESUMO

Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the mAb, trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small-molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small-molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Oxazóis , Fosfatidilinositol 3-Quinases/uso terapêutico , Piridinas , Quinazolinas , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/uso terapêutico , Trastuzumab
10.
Cureus ; 13(12): e20661, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35103212

RESUMO

Peritonitis can be a lethal outcome of peritoneal dialysis (PD), often leading to significant morbidity and mortality. It is caused mostly by gram-positive organisms. Neisseria cinerea is a gram-negative nasal and oropharyngeal commensal, rarely reported as an etiology of peritonitis in PD patients. Our patient was a 37-year-old female on continuous ambulatory peritoneal dialysis for the last seven years, who developed peritonitis found to be from Neisseria cinerea. She didn't respond to broad-spectrum antibiotics well and had to be switched to intermittent hemodialysis. We highlight this important microorganism that can lead to significant morbidity and an unfortunate change in dialysis modality.

11.
Eur J Case Rep Intern Med ; 8(12): 003046, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35059342

RESUMO

Anion gap metabolic acidosis is a laboratory finding commonly encountered in patients with sepsis, diabetic ketoacidosis, acute kidney injury and toxic alcohol ingestion. Serum blood chemistry assessment detects this abnormality. However, this can be falsely low in situations of high triglyceride levels due to lipid interference with measurement of the bicarbonate levels and through volume displacement by these large molecules. Arterial blood gas analysis and a lipid panel are required to confirm accurate bicarbonate levels. Clinicians handling acid-base disorders in hospitalized patients need to be aware of this spurious laboratory value to avoid unnecessary tests and to determine accurate total bicarbonate levels. LEARNING POINTS: Elevated triglycerides can cause spurious low blood bicarbonate levels.High anion gap metabolic acidosis is associated with serious clinical illness which can lead to a battery of diagnoses and therapeutics.Accurate knowledge of this condition with falsely low bicarbonate levels will prevent unnecessary medical work-up and guide prompt treatment.

12.
Cancer Metab ; 9(1): 38, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34742347

RESUMO

BACKGROUND: Excessive lactate production, a hallmark of cancer, is largely formed by the reduction of pyruvate via lactate dehydrogenase (LDH) to L-lactate. Although D-lactate can also be produced from glucose via the methylglyoxal pathway in small amounts, less is known about the amount of D-lactate produced in cancer cells. Since the stereoisomers of lactate cannot be distinguished by conventional 1H NMR spectroscopy, a chiral NMR shift reagent was used to fully resolve the 1H NMR resonances of D- and L-lactate. METHODS: The production of L-lactate from glucose and D-lactate from methylglyoxal was first demonstrated in freshly isolated red blood cells using the chiral NMR shift reagent, YbDO3A-trisamide. Then, two different cell lines with high GLO1 expression (H1648 and H 1395) were selected from a panel of over 80 well-characterized human NSCLC cell lines, grown to confluence in standard tissue culture media, washed with phosphate-buffered saline, and exposed to glucose in a buffer for 4 h. After 4 h, a small volume of extracellular fluid was collected and mixed with YbDO3A-trisamide for analysis by 1H NMR spectroscopy. RESULTS: A suspension of freshly isolated red blood cells exposed to 5mM glucose produced L-lactate as expected but very little D-lactate. To evaluate the utility of the chiral NMR shift reagent, methylglyoxal was then added to red cells along with glucose to stimulate the production of D-lactate via the glyoxalate pathway. In this case, both D-lactate and L-lactate were produced and their NMR chemical shifts assigned. NSCLC cell lines with different expression levels of GLO1 produced both L- and D-lactate after incubation with glucose and glutamine alone. A GLO1-deleted parental cell line (3553T3) showed no production of D-lactate from glucose while re-expression of GLO1 resulted in higher production of D-lactate. CONCLUSIONS: The shift-reagent-aided NMR technique demonstrates that D-lactate is produced from glucose in NSCLC cells via the methylglyoxal pathway. The biological role of D-lactate is uncertain but a convenient method for monitoring D-lactate production could provide new insights into the biological roles of D- versus L-lactate in cancer metabolism.

13.
Cancer Res ; 66(22): 10778-85, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17108114

RESUMO

Mitogen-activated protein kinases (MAPK) play important roles in malignancy. The ability to detect and quantitate MAPKs in live animal models of cancer will facilitate an understanding of disease progression. We have developed a gene expression-based imaging system that detects and quantifies MAPK activity in prostate cancer tumors implanted into severe combined immunodeficient mice. The imaging technology uses a modified version of two-step transcriptional amplification (TSTA). The tissue specificity of gene expression is imparted by an enhanced version of the prostate-specific antigen regulatory region that expresses GAL4-ELK1. GAL4-ELK1 confers MAPK specificity by activating a firefly luciferase (FLuc) reporter gene when the Ets-like transcription factor (ELK) 1 activation domain is phosphorylated by MAPK. FLuc activity in live animals was detected using the Xenogen In vivo Imaging System. We validated the TSTA-ELK1 system by analyzing its response to epidermal growth factor treatment in transfected tissue culture cells and in adenovirus (AdTSTA-ELK1)-injected prostate cancer xenograft tumors. We measured MAPK activity in two well-characterized xenograft models, CWR22 and LAPC9. Although no significant differences in MAPK levels were detected between androgen-dependent and androgen-independent xenografts, the CWR22 models display significantly higher levels of AdTSTA-ELK1 activity versus LAPC9. Western blots of tumor extracts showed that the elevated imaging signal in CWR22 xenografts correlated with elevated levels of phosphorylated extracellular signal-regulated kinase 1/2 but not p38 or c-Jun NH(2)-terminal kinase. We conclude that a gene expression-based optical imaging system can accurately detect and quantify MAPK activity in live animals.


Assuntos
Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Hormônio-Dependentes/enzimologia , Neoplasias da Próstata/enzimologia , Androgênios/fisiologia , Animais , Modelos Animais de Doenças , Fator de Crescimento Epidérmico/metabolismo , Humanos , Immunoblotting , Masculino , Camundongos , Camundongos SCID , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Neoplasias Hormônio-Dependentes/genética , Neoplasias da Próstata/genética , Transplante Heterólogo , Proteínas Elk-1 do Domínio ets/genética , Proteínas Elk-1 do Domínio ets/metabolismo
14.
Cancer Res ; 63(1): 196-206, 2003 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-12517798

RESUMO

To determine how AKT2 might contribute to tumor cell progression, a full-length, wild-type, human AKT2/protein kinase B (PKB)beta cDNA was transfected into a panel of eight human breast and ovarian cancer cells. AKT2 transfectants demonstrated increased adhesion and invasion through collagen IV because of up-regulation of beta1 integrins. In addition, AKT2 cells were more metastatic than control cells in vivo. Increased invasion by AKT2 was blocked by preincubation with an anti-beta1 integrin function blocking antibody, exposure to wortmannin, and by expression of phosphatase and tensin homologue tumor suppressor (PTEN). Confocal microscopy performed on transfected human breast cancer cells showed that unlike AKT1, AKT2 protein predominantly localized adjacent to the collagen IV matrix during cellular attachment. Overexpression of AKT2, but not AKT1 or AKT3, was sufficient to duplicate the invasive effects of phosphoinositide 3-OH kinase (PI3-K) transfected in breast cancer cells. Furthermore, expression of kinase dead AKT2(181 amino acid methionine [M]), and not kinase dead AKT1(179M) or AKT3(177M), was capable of blocking invasion induced by either human epidermal growth factor receptor-2 (HER-2) overexpression or by activation of PI3-K. Taken together, these data indicate that AKT2 mediates PI3-K-dependent effects on adhesion, motility, invasion, and metastasis in vivo.


Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Integrina beta1/genética , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/genética , Neoplasias da Mama/genética , Primers do DNA , Feminino , Humanos , Invasividade Neoplásica , Neoplasias Ovarianas/genética , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-akt , Células Tumorais Cultivadas
15.
J Ovarian Res ; 9(1): 41, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27388275

RESUMO

BACKGROUND: Serum levels of CA125 measured before any treatment have been evaluated in epithelial ovarian cancer (EOC) as a predictor of patient survival; however, results in survival index are controversial, as CA125 levels are influenced by several variables. Taking this into consideration, the present study evaluated the association of pretreatment levels of CA125 serum with the clinical stage, histology and differentiation grade of the tumor and the survival rate in a group of patients from an oncology referral center in Mexico, all of them diagnosed with ovarian carcinoma. This retrospective study consisted of 1009 patients with EOC, diagnosed between 2006 and 2013 at the National Cancerology Institute (Instituto Nacional de Cancerología-INCan), considering only those with CA125 measurements before any chemotherapy or surgical cytoreduction. Patients with three years of medical follow-up having pretreatment CA125 value and simultaneous diagnoses of histological subtype, clinical stage and differentiation grade of the tumor (n = 656) were studied in order to determine their survival rate. RESULTS: The abnormal level (>35 U/mL) of CA125 was observed in 99 % of serous carcinoma cases rated I to IV in the FIGO stages. Abnormal CA125 proportions were 89 % in endometrioid subtype and 69 % in mucinous tumors, with the highest absolute value of CA125 observed in serous carcinoma surpassing any other histological subtype. Clinical stages III and IV displayed increased CA125 values compared to stages I and II. Undifferentiated carcinomas show the highest level of this indicator compared with those of low and moderate differentiated grade. Survival evaluation by Kaplan-Meier analysis including only high grade serous carcinoma at FIGO stage III (n = 57) demonstrated 57.1 % chances of survival in patients with CA125 pretreatment levels higher than 500 U/mL. Survival was 26.7 % in patients with CA125 lower than 500 U/mL and the hazard ratio for CA125 ≤ 500 U/mL was 2.28, 95 % CI 1.08-4.84, P = 0.032. CONCLUSIONS: Clinical stage associated with pretreatment absolute values of CA125 should be considered as prognostic factor in EOC patients. Values of CA125 higher than 500 U/mL in high grade serous carcinoma with FIGO stage III resulted in an enhanced survival rate of the patients.


Assuntos
Biomarcadores Tumorais , Antígeno Ca-125/sangue , Cistadenocarcinoma Seroso/sangue , Cistadenocarcinoma Seroso/mortalidade , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Adulto Jovem
16.
Rev. Fac. Med. Hum ; 19(1): 105-107, Jan.-Mar. 2019.
Artigo em Inglês, Espanhol | LILACS-Express | LILACS | ID: biblio-1049857

RESUMO

El condiloma acuminado es una enfermedad de transmisión sexual causada por el virus del papiloma (VPH). Se encuentra con frecuencia en la región ano-genital y es poco frecuente en la cavidad bucal. Sin embargo, el aumento de la actividad sexual oral ha favorecido aún más la aparición de PVH en la mucosa oral. Este informe describe un condiloma en la cavidad oral (lengua) de un hombre de 43 años con antecedentes de práctica sexual oral, cuyo diagnóstico se confirmó mediante una biopsia.


The acuminated condyloma is a sexually transmissible disease caused by the Papilomavirus (HPV). It is frequently found in the anus-genital region and rare in the mouth cavity. However, the increase of the oral-sexual activity has even more favored the occurrence of the PVH in the oral mucous. This report describes a condyloma I the oral cavity (tongue) of a 43 year old man with a history of oral sex practice, which diagnostic was confirmed by a biopsy.

17.
Mol Cancer Ther ; 12(4): 509-19, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23395886

RESUMO

HSP90 enables the activation of many client proteins of which the most clinically validated is HER2. NVP-AUY922, a potent HSP90 inhibitor, is currently in phase II clinical trials. To explore its potential clinical use in HER2-amplified breast and gastric cancers, we evaluated the effect of AUY922 alone and in combination with trastuzumab in both trastuzumab-sensitive and -resistant models. A panel of 16 human gastric and 45 breast cancer cell lines, including 16 HER2-amplified (3 and 13, respectively) cells, was treated with AUY922 over various concentrations. In both breast and gastric cancer, we used cell lines and xenograft models with conditioned trastuzumab-resistance to investigate the efficacy of AUY922 alongside trastuzumab. Effects of this combination on downstream markers were analyzed via Western blot analysis. AUY922 exhibited potent antiproliferative activity in the low nanomolar range (<40 nmol/L) for 59 of 61 cell lines. In both histologies, HER2-amplified cells expressed greater sensitivity to AUY than HER2-negative cells. In conditioned trastuzumab-resistant models, AUY922 showed a synergistic effect with trastuzumab. In vitro, the combination induced greater decreases in HER2, a G2 cell-cycle arrest, and increased apoptosis. In a trastuzumab-resistant gastric cancer xenograft model, the combination of AUY922 and trastuzumab showed greater antitumor efficacy than either drug alone. These data suggest that AUY922 in combination with trastuzumab has unique efficacy in trastuzumab-resistant models. The combination of HSP90 inhibition and direct HER2 blockade represents a novel approach to the treatment of HER2-amplified cancers and clinical trials based on the above data are ongoing.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Isoxazóis/farmacologia , Receptor ErbB-2/genética , Resorcinóis/farmacologia , Neoplasias Gástricas/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Amplificação de Genes , Humanos , Concentração Inibidora 50 , Isoxazóis/química , Camundongos , Resorcinóis/química , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Trastuzumab
18.
Mol Cancer Ther ; 12(5): 632-42, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23443805

RESUMO

The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection.


Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Neoplasias do Endométrio/metabolismo , Compostos de Fenilureia/farmacologia , Pirimidinas/farmacologia , Quinolonas/farmacologia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Humanos , Concentração Inibidora 50 , Camundongos , Mutação , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Quinolonas/administração & dosagem , Quinolonas/química , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Clin Cancer Res ; 16(5): 1509-19, 2010 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-20179222

RESUMO

PURPOSE: HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. Lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts. EXPERIMENTAL DESIGN: EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells, the combination of trastuzumab and lapatinib was evaluated using the median effects principal. The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models. RESULTS: Lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone. CONCLUSION: Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/biossíntese , Quinazolinas/farmacologia , Receptor ErbB-2/biossíntese , Neoplasias Gástricas/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Receptores ErbB/genética , Cloridrato de Erlotinib , Humanos , Imunoprecipitação , Hibridização in Situ Fluorescente , Lapatinib , Camundongos , Camundongos Nus , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Acta méd. peru ; 27(2): 127-128, abr.-jun. 2010. ilus
Artigo em Espanhol | LILACS, LIPECS | ID: lil-580161

RESUMO

La endometriosis es una condición en que el tejido endometrial es localizado fuera de la cavidad uterina. Esta puede ser pélvica o extra pélvica, y de esta última, la afectación del tracto gastrointestinal representa de 3-15% y de localización más frecuente en el rectosigmoides, siendo el compromiso apendicular raro con 3-5% de todas las endometriosis, motivo por el cual se presenta este caso, diagnosticado incidentalmente en una paciente admitida en emergencia por cuadro de apendicitis aguda.


Endometriosis is a condition in which uterine mucosal tissue is located outside the uterus. Endometriosis may be pelvic or extrapelvic, and in this latter case, gastrointestinal tract involvement represents 3-15% of cases, being most frequently located in the rectal-sigmoid region. Appendix involvement in endometriosis is rare, accounting 3-5% of all endometriosis cases. For this reason we present this case of appendicular endometriosis, which was incidentally diagnosed in a patient admitted in the emergency service with a condition resembling acute appendicitis.


Assuntos
Humanos , Feminino , Adulto , Apendicite , Endometriose
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