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Objectives: We aim to characterize the serial quantitative apparent diffusion coefficient (ADC) changes of the target disease volume using diffusion-weighted imaging (DWI) acquired weekly during radiation therapy (RT) on a 1.5T MR-Linac and correlate these changes with tumor response and oncologic outcomes for head and neck squamous cell carcinoma (HNSCC) patients as part of a programmatic R-IDEAL biomarker characterization effort. Methods: Thirty patients with pathologically confirmed HNSCC who received curative-intent RT at the University of Texas MD Anderson Cancer Center, were included in this prospective study. Baseline and weekly Magnetic resonance imaging (MRI) (weeks 1-6) were obtained, and various ADC parameters (mean, 5 th , 10 th , 20 th , 30 th , 40 th , 50 th , 60 th , 70 th , 80 th , 90 th and 95 th percentile) were extracted from the target regions of interest (ROIs). Baseline and weekly ADC parameters were correlated with response during RT, loco-regional control, and the development of recurrence using the Mann-Whitney U test. The Wilcoxon signed-rank test was used to compare the weekly ADC versus baseline values. Weekly volumetric changes (Δvolume) for each ROI were correlated with ΔADC using Spearman's Rho test. Recursive partitioning analysis (RPA) was performed to identify the optimal ΔADC threshold associated with different oncologic outcomes. Results: There was an overall significant rise in all ADC parameters during different time points of RT compared to baseline values for both gross primary disease volume (GTV-P) and gross nodal disease volumes (GTV-N). The increased ADC values for GTV-P were statistically significant only for primary tumors achieving complete remission (CR) during RT. RPA identified GTV-P ΔADC 5 th percentile >13% at the 3 rd week of RT as the most significant parameter associated with CR for primary tumor during RT (p <0.001). Baseline ADC parameters for GTV-P and GTV-N didn't significantly correlate with response to RT or other oncologic outcomes. There was a significant decrease in residual volume of both GTV-P & GTV-N throughout the course of RT. Additionally, a significant negative correlation between mean ΔADC and Δvolume for GTV-P at the 3 rd and 4 th week of RT was detected (r = -0.39, p = 0.044 & r = -0.45, p = 0.019, respectively). Conclusion: Assessment of ADC kinetics at regular intervals throughout RT seems to be correlated with RT response. Further studies with larger cohorts and multi-institutional data are needed for validation of ΔADC as a model for prediction of response to RT.
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BACKGROUND AND PURPOSE: GABAA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate. EXPERIMENTAL APPROACH: New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABAA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations. KEY RESULTS: All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABAA receptor, are the most likely cause of the distinctive functional profiles. CONCLUSIONS AND IMPLICATIONS: Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABAA receptor drug design and development.
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Pregnenolona , Receptores de GABA-A , Receptores de GABA-A/metabolismo , Pregnenolona/farmacologia , Pregnenolona/metabolismo , Ácido gama-Aminobutírico/farmacologiaRESUMO
Detection of methylation patterns in circulating tumor DNA (ctDNA) can offer a novel approach for cancer diagnostics given the unique signature for each tumor type. We developed a next-generation sequencing (NGS)-based assay targeting 32 CpG sites to detect colorectal cancer-specific ctDNA. NGS was performed on bisulfite-converted libraries and status dichotomization was done using median methylation ratios at all targets. We included plasma samples from patients with metastatic colorectal (nâ =â 20) and non-colorectal cancers (nâ =â 8); and healthy volunteers (nâ =â 4). Median methylation ratio was higher in colorectal cancer compared with non-colorectal cancers (Pâ =â .001) and normal donors (Pâ =â .005). The assay detected ctDNA in 85% of patients with colorectal cancer at a specificity of 92%. Notably, we were able to detect methylated ctDNA in 75% of patients in whom ctDNA was not detected by other methods. Detection of methylated ctDNA was associated with shorter median progression-free survival compared to non-detection (8 weeks versus 54 weeks; Pâ =â .027).
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DNA Tumoral Circulante , Neoplasias Colorretais , Neoplasias , Humanos , Metilação , DNA Tumoral Circulante/genética , Biópsia Líquida , Mutação , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genéticaRESUMO
Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα) is a brain-relevant kinase and an emerging drug target for ischemic stroke and neurodegenerative disorders. Despite reported CaMKIIα inhibitors, their usefulness is limited by low subtype selectivity and brain permeability. (E)-2-(5-Hydroxy-5,7,8,9-tetrahydro-6H-benzo[7]annulen-6-ylidene)acetic acid (NCS-382) is structurally related to the proposed neuromodulator, γ-hydroxybutyric acid, and is a brain-penetrating high nanomolar-affinity ligand selective for the CaMKIIα hub domain. Herein, we report the first series of NCS-382 analogs displaying improved affinity and preserved brain permeability. Specifically, we present Ph-HTBA (1i) with enhanced mid-nanomolar affinity for the CaMKIIα binding site and a marked hub thermal stabilization effect along with a distinct CaMKIIα Trp403 flip upon binding. Moreover, Ph-HTBA has good cellular permeability and low microsomal clearance and shows brain permeability after systemic administration to mice, signified by a high Kp, uu value (0.85). Altogether, our study highlights Ph-HTBA as a promising candidate for CaMKIIα-associated pharmacological interventions and future clinical development.
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Benzocicloeptenos , Encéfalo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Animais , Camundongos , Benzocicloeptenos/farmacologia , Sítios de Ligação , Encéfalo/metabolismo , Ligação Proteica , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidoresRESUMO
The Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac (3). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3. The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Diclofenaco , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diclofenaco/análogos & derivados , Ligantes , Potenciação de Longa DuraçãoRESUMO
PURPOSE: To evaluate laparoscopic management of hydroceles in pediatrics, with evaluation of the internal inguinal ring (IIR) and the PPV (patent processus vaginalis) in different types of hydroceles, and the incidence of the contralateral PPV. METHODS: The IIR and the type of hydrocele on the same side of 93 patients with 106 infantile hydroceles were evaluated and managed, in addition to contralateral side. RESULTS: The IIR on same side was closed in 8.5% (Type I) and patent in 91.5% (Type II and III) with different shapes. Contralateral IIR was open in 88.7% of cases. The operative time was 30.99 ± 7.23 min, with no intra-operative complication. The vas deferens and testicular vessels were secured and there were no injuries or bleeding. The conversion rate was zero, and all procedures (Type II and II) were completed totally laparoscopic. No post-operative complications except a case of tense hydrocele developed scrotal edema that managed conservatively. CONCLUSION: Laparoscopic hydrocelectomy is safe, applicable and feasible for management of different types of hydroceles in pediatrics. The IIR is patent in nearly all cases with/out communication to the hydrocele. The contralateral IIR can be managed in the same session. Laparoscopic hydrocelectomy with/out hydrocelectomy and IIR closure is essential in preventing recurrence.
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Hérnia Inguinal , Laparoscopia , Pediatria , Hidrocele Testicular , Criança , Hérnia Inguinal/cirurgia , Humanos , Lactente , Canal Inguinal , Laparoscopia/métodos , Masculino , Hidrocele Testicular/cirurgiaRESUMO
PURPOSE: The aim of this study was to compare the effect of antral resection versus antral preservation sleeve gastrectomy on the post-operative GLP-1, glycemic control, and weight loss in adolescents suffering from severe obesity and type 2 diabetes (T2D). MATERIALS AND METHODS: This study included 36 adolescents. Patients were randomly divided into 2 groups: group (A) and group (B). Each group included 18 patients who underwent LSG, starting transection at 2 cm or 5 cm from the pyloric ring in group (A) and group (B), respectively. They were followed up at 1, 3, 6, 12, and 24 months post-operatively. The outcomes were the post-operative GLP-1 response, glycemic control, weight loss, and safety. RESULTS: The improvements in the body mass index and the percentage of excess weight loss (%EWL) were statistically significant within each group. The mean GLP-1 levels showed significant increase at the 1, 3, and 6 months but not in the 12 and 24 months in all the studied samples within each group. The mean HbA1c levels and post-prandial serum C-peptide significantly improved within each group (P < 0.05). No statistical differences in the weight loss, %EWL, GLP-1, HbA1c, C-peptide changes, and complication rates were observed between both groups. Diabetic remission was significantly higher (88.9%) in group (A). CONCLUSIONS: LSG resulted in generalized significant GLP-1 initial response that decreased over time. The reduced antrum size did not influence the GLP-1 response, glycemic control, or insulin resistance, but resulted in significantly better T2D remission. Since the study examines a small number of patients, further studies are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04388059.
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Diabetes Mellitus Tipo 2 , Laparoscopia , Obesidade Mórbida , Obesidade Infantil , Adolescente , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/cirurgia , Gastrectomia , Peptídeo 1 Semelhante ao Glucagon , Controle Glicêmico , Humanos , Obesidade Mórbida/cirurgia , Obesidade Infantil/cirurgia , Resultado do Tratamento , Redução de PesoRESUMO
Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Oxibato de Sódio/metabolismo , Sítios de Ligação , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Ciclopentanos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Neuroproteção , Ligação Proteica , Domínios Proteicos , Transdução de SinaisRESUMO
Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when ≥75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.
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In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.
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Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Países em Desenvolvimento/economia , Detecção Precoce de Câncer/normas , Conhecimentos, Atitudes e Prática em Saúde , Guias de Prática Clínica como Assunto/normas , Comportamento de Redução do Risco , África do Norte/epidemiologia , Neoplasias da Mama/economia , Neoplasias da Mama/epidemiologia , Autoexame de Mama , Congressos como Assunto , Feminino , Humanos , Renda , Mamografia , Oriente Médio/epidemiologiaRESUMO
GPR139 is an orphan G protein-coupled receptor (GPCR) that is primarily expressed in the brain in regions known to regulate motor control and metabolism. Here, we screened a diverse 4,000 compound library in order to identify GPR139 agonists. We identified 11 initial hits in a calcium mobilization screen, including one compound, AC4, which contains a different chemical scaffold to what has previously been described for GPR139 agonists. Our mutagenesis data shows that AC4 interacts with the same hotspots in the binding site of GPR139 as those reported to interact with the reference agonists 1a and 7c. We additionally tested and validated 160 analogs in a calcium mobilization assay and found 5 compounds with improved potency compared to AC4. In total, we identified 36 GPR139 agonists with potencies in the nanomolar range (90-990 nM). The most potent compounds were confirmed as GPR139 agonists using an orthogonal ERK phosphorylation assay where they displayed a similar rank order of potency. Accordingly, we herein introduce multiple novel GPR139 agonists, including one with a novel chemical scaffold, which can be used as tools for future pharmacological and medicinal chemistry exploration of GPR139.
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Proteínas do Tecido Nervoso/agonistas , Receptores Acoplados a Proteínas G/agonistas , Animais , Sítios de Ligação , Células CHO , CricetulusRESUMO
INTRODUCTION: Urinary schistosomiasis caused by Schistosoma haematobium is common in some parts of Lusaka Province, Zambia, where water contact activity is high and sanitation is poor. We conducted a longitudinal study in Ng'ombe Compound of Lusaka, between 2007 and 2015, to observe the prevalence and intensity of S. haematobium infection among community primary school children, before and after receiving a single dose of praziquantel. MATERIALS AND METHODS: A total of 975 (445 females and 530 males) pupils, aged 9-16 years, were tested for S. haematobium at baseline. After mass treatment with praziquantel in 2010, 1570 pupils (785 females and 785 males), aged 9-15 years, were examined for S. haematobium eggs, from 2011 to 2015. RESULTS: At baseline, 279 out of 975 of the children were infected, with light infections constituting 84.9% and 15.1% classified as heavy infection. After mass treatment with praziquantel, the prevalence rate dropped, slightly, to 20.3% (63 out of 310) in 2011. However, it increased the following years up to 38% (133 out of 350) in 2015, with prevalence rates higher in males than females. The average number of heavy infection cases increased to 24.3% (120 out of 494) after treatment, reducing cases of light infections to 75.7% (374 out of 494). CONCLUSION: This study revealed that mass treatment with a single dose of praziquantel was not sufficient to significantly reduce the transmission of schistosomiasis. Further studies will need to evaluate whether multiple praziquantel treatments will be more therapeutically effective in limiting future incidences.
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GPR139 is an orphan G protein-coupled receptor expressed in the brain, in particular in the habenula, hypothalamus and striatum. It has therefore been suggested that GPR139 is a possible target for metabolic disorders and Parkinson's disease. Several surrogate agonist series have been published for GPR139. Two series published by Shi et al. and Dvorak et al. included agonists 1a and 7c respectively, with potencies in the ten-nanomolar range. Furthermore, Isberg et al. and Liu et al. have previously shown that tryptophan (Trp) and phenylalanine (Phe) can activate GPR139 in the hundred-micromolar range. In this study, we produced a mutagenesis-guided model of the GPR139 binding site to form a foundation for future structure-based ligand optimization. Receptor mutants studied in a Ca2+ assay demonstrated that residues F1093×33, H1875×43, W2416×48 and N2717×38, but not E1083×32, are highly important for the activation of GPR139 as predicted by the receptor model. The initial ligand-receptor complex was optimized through free energy perturbation simulations, generating a refined GPR139 model in agreement with experimental data. In summary, the GPR139 reference surrogate agonists 1a and 7c, and the endogenous amino acids L-Trp and L-Phe share a common binding site, as demonstrated by mutagenesis, ligand docking and free energy calculations.
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Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/química , Fenilalanina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Triptofano/metabolismo , Sítios de Ligação , Análise Mutacional de DNA , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Proteínas do Tecido Nervoso/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
GPR139 is an orphan G protein-coupled receptor that is expressed primarily in the brain. Not much is known regarding the function of GPR139. Recently we have shown that GPR139 is activated by the amino acids l-tryptophan and l-phenylalanine (EC50 values of 220 µM and 320 µM, respectively), as well as di-peptides comprised of aromatic amino acids. This led us to hypothesize that GPR139 may be activated by peptides. Sequence alignment of the binding cavities of all class A GPCRs, revealed that the binding pocket of the melanocortin 4 receptor is similar to that of GPR139. Based on the chemogenomics principle "similar targets bind similar ligands", we tested three known endogenous melanocortin 4 receptor agonists; adrenocorticotropic hormone (ACTH) and α- and ß-melanocyte stimulating hormone (α-MSH and ß-MSH) on CHO-k1 cells stably expressing the human GPR139 in a Fluo-4 Ca2+-assay. All three peptides, as well as their conserved core motif HFRW, were found to activate GPR139 in the low micromolar range. Moreover, we found that peptides consisting of nine or ten N-terminal residues of α-MSH activate GPR139 in the submicromolar range. α-MSH1-9 was found to correspond to the product of a predicted cleavage site in the pre-pro-protein pro-opiomelanocortin (POMC). Our results demonstrate that GPR139 is a peptide receptor, activated by ACTH, α-MSH, ß-MSH, the conserved core motif HFRW as well as a potential endogenous peptide α-MSH1-9. Further studies are needed to determine the functional relevance of GPR139 mediated signaling by these peptides.
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Hormônio Adrenocorticotrópico/metabolismo , Melanócitos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , alfa-MSH/metabolismo , beta-MSH/metabolismo , Motivos de Aminoácidos , Animais , Células CHO , Cricetulus , Hormônios Estimuladores de Melanócitos/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismoRESUMO
GPR139 is an orphan class A G protein-coupled receptor found mainly in the central nervous system. It has its highest expression levels in the hypothalamus and striatum, regions regulating metabolism and locomotion, respectively, and has therefore been suggested as a potential target for obesity and Parkinson's disease. The two aromatic amino acids L-Trp and L-Phe have been proposed as putative endogenous agonists, and three structurally related benzohydrazide, glycine benzamide, and benzotriazine surrogate agonist series have been published. Herein, we assayed 158 new analogues selected from a pharmacophore model, and identified 12 new GPR139 agonists, containing previously untested bioisosteres. Furthermore, we present the first combined structure-activity relationships, and a refined pharmacophore model to serve as a rationale for future ligand identification and optimization.
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Hidrazinas/química , Modelos Químicos , Modelos Moleculares , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/química , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/química , Triazinas/química , Animais , Células CHO , Cricetulus , Humanos , Proteínas do Tecido Nervoso/genética , Receptores Acoplados a Proteínas G/genética , Relação Estrutura-AtividadeRESUMO
Carbonic anhydrase IX (CAIX) is an enzyme whose expression is very limited in normal tissues and it is highly expressed in various cancers. Therefore, inhibition of CAIX is considered as a promising therapeutic target for the treatment of solid tumors where hypoxic environment has developed. The aim of the current work is to evaluate the immunohistochemical (IHC) expression of CAIX in breast cancer (BC) of Egyptian patients and to investigate the associations of CAIX expression with the standard clinicopathologic features, IHC subtypes of BC, and overall survival. This retrospective study was conducted on 56 archival cases of Egyptian BC patients. Fifty-one of 56 cases (91.1%) showed positive expression of CAIX with cytoplasmic localization, whereas 5 cases (8.9%) showed negative expression. CAIX IHC overexpression is significantly associated with advanced stage and presence of coagulative tumor cell necrosis (P=0.03 and 0.02, respectively). Multivariate analysis revealed Ki67 labeling index and CAIX H-score grouping (P=0.03 and 0.02, respectively) as independent prognostic factors affecting BC patients' overall survival. We concluded that CAIX could play a role in the progression of the studied BC cases. CAIX is a good candidate for target therapy.
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Neoplasias da Mama/enzimologia , Anidrase Carbônica IX/metabolismo , Adulto , Neoplasias da Mama/patologia , Egito , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
The immunohistochemical (IHC) subtyping of breast cancer can be a useful substitute for gene expression analysis. The aim of this study was to investigate the relationship of CK8/18 to the biology of breast carcinoma (BC) represented by its IHC subtypes. The IHC expression of CK8/18 was correlated with IHC subtypes of BC using ER, PR, HER2/neu, and Ki67 LI (with cutoff 14%). All cases showed CK 8/18 expression in tumour cells with varying degree of intensities; 49/70 cases (70%) showed diffuse cytoplasmic expression (loss of membranous pattern), while 21/70 cases (30%) showed membrano-cytoplasmic pattern. Adjacent non-neoplastic breast lobules showed membrano-cytoplasmic pattern in 58% of cases, which was significantly different from the pattern in invasive cancer (P = 0.002). A loss of membranous pattern in malignant tumours was significantly associated with higher tumour grade (P = 0.02), higher mitotic count (P = 0.03), and negative HER2/neu status (P = 0.04). CK 8/18 H score ranged between 1 and 290 with mean ± SD was 181 ± 70.54. Tumours with lower CK 8/18 H score were in the advanced stage group (P = 0.04). Low CK8/18 H score and loss of membranous pattern were significantly associated with triple negative (TN) subtype as compared with luminal subtype (P = 0.006 and P = 0.026, respectively). In addition, CK8/18 with lost membranous pattern was significantly associated with TN subtype compared with HER2/neu positive subtype (P = 0.001). However, there was no significant difference between luminal A and B subtypes regarding CK8/18 H score or pattern of expression. This study concluded that low CK8/18 H score and loss of membranous pattern of CK8/18 are associated with worse prognostic features and TN subtype.