RESUMEN

In this study, the effect of carrot fiber and certain gums on the physicochemical, textural, microbiological, and sensory properties of block-type melting cheese, which holds a significant place in our daily food consumption, was investigated. The study also aimed to determine the impact of carrot fiber and other gums on cheese properties, as well as on yield and meltability. Carrot fiber was used at levels of 2.5% and 5.0% by weight, while carrageenan and xanthan gum were each used at levels of 0.25% and 0.50%. The cheeses were analyzed on days 1, 15, and 30. At the end of the study, it was determined that the highest total dry matter, fat, and protein values were found in the control sample due to the addition of water when preparing the cheeses with fiber and gum. The highest dry matter, fat, salt, and protein ratios were 59.65%, 29.40%, 1.48%, and 24.48%, respectively, in the control sample. The lowest fat, salt, and protein ratios were 25.00%, 1.31%, and 22.07%, respectively, in the 5.0% carrot fiber sample. The lowest dry matter value was found in the 0.5% xanthan sample, namely 53.62%. The highest L* value was measured in the control sample at 86.89, while the lowest was measured in the 5.0% carrot fiber sample at 81.86. The lowest a* and b* values were 2.82 and 29.42, respectively, in the control sample, while the highest values were 6.20 and 37.37, respectively, in the 5.0% carrot fiber sample. It was observed that the use of carrot fiber imparted an orangish color to the cheese. It was observed that the pH values of the samples were similar. According to the sensory evaluation results, the most liked sample was the control sample with 8.5 points, followed by the 0.25% xanthan sample with 8.0 points. The 5.0% carrot fiber sample received the lowest sensory appreciation with 6.1 points. It was understood that the use of carrot fiber gave the cheese an orangish color. Although the meltability varied according to the amount of gum and fiber used, it was measured at 6.92 cm in the 0.25% carrageenan sample on the first day and at 6.79 cm in the control sample on the last day of storage. It was observed that the use of fiber decreased the total bacterial count, while the use of gum increased it.

RESUMEN

Under normal physiological conditions, the kynurenine pathway (KP) plays a critical role in generating cellular energy and catabolizing tryptophan. Under inflammatory conditions, however, there is an upregulation of the KP enzymes, particularly kynurenine 3-monooxygenase (KMO). KMO has garnered much attention due to its production of toxic metabolites that have been implicated in many diseases and disorders. With many of these illnesses having an inadequate or modest treatment, there exists a need to develop KMO inhibitors that reduce the production of these toxic metabolites. Though prior efforts to find an appropriate KMO inhibitor were unpromising, the development of a KMO crystal structure has provided the opportunity for a rational structure-based design in the development of inhibitors. Therefore, the purpose of this review is to describe the kynurenine pathway, the kynurenine 3-monooxygenase enzyme, and KMO inhibitors and their potential candidacy for clinical use.

Asunto(s)

Diseño de Fármacos , Inhibidores Enzimáticos , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Quinurenina 3-Monooxigenasa , Quinurenina , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Inflamación/enzimología , Quinurenina/química , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Quinurenina 3-Monooxigenasa/biosíntesis , Quinurenina 3-Monooxigenasa/química , Relación Estructura-Actividad

RESUMEN

BACKGROUND: In rectal cancer, extramural vascular invasion (EMVI) is the presence of tumour cells in blood vessels outside the muscular layer, which is associated with poor prognosis. Regression of EMVI on MRI following neoadjuvant chemoradiotherapy or its persistence may have prognostic implications. METHODS: This retrospective study included 52 patients with rectal cancer who underwent total mesorectal excision following long-course neoadjuvant chemoradiotherapy (CRT). EMVI assessments were done on previous pelvic MRIs obtained before neoadjuvant CRT and eight weeks after the completion of neoadjuvant chemoradiotherapy in initially EMVI positive cases. RESULTS: Persistently EMVI positive patients had worse overall survival and disease-free survival compared to initially EMVI negative patients and patients who returned to negative (p < 0.001 for both). Multivariate analysis identified persistent EMVI positivity after neoadjuvant treatment (HR, 102.9; p = 0.003) as significant independent predictor of worse overall survival; and persistent EMVI positivity (HR, 17.0; p = 0.002), mesorectal fascia involvement after neoadjuvant treatment (HR, 8.0; p = 0.017), and poor differentiation (HR, 10.3, p = 0.012) as significant independent predictors of worse disease-free survival. CONCLUSION: Persistent EMVI positivity after neoadjuvant therapy appears to be an independent factor for poor overall survival; and persistent EMVI positivity as well as mesorectal fascia involvement on post neoadjuvant therapy MRI and poor differentiation appears to be important predictors of poor disease-free survival in rectal cancer patients.

Asunto(s)

Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Imagen por Resonancia Magnética , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Estudios Retrospectivos

RESUMEN

PURPOSE: Totally implantable venous access devices (TIVADs) currently have an important place in medical oncology practice; however, their long-term availability deserves further investigation, since they are usually required by patients for prolonged periods. This study aimed to evaluate long-term availability of TIVADs in adult cancer patients, in conjunction with complication/removal rates over time and associated risk factors during 7-year follow-up. METHODS: A total of 204 adult cancer patients who underwent TIVAD placement via subclavian vein using the Seldinger technique were included in this study. Medical data and catheter follow-up records were investigated retrospectively. Complications and port removals due to complications were evaluated over time. RESULTS: During median 21.9 (range, 0.7-82.9) months of follow-up, great majority of the patients did not require catheter removal due to complications (91.7%). During a total follow-up of 183,328 catheter days, 20 (9.8%) patients had complications with an incidence of 0.109 cases per 1000 catheter days and 18 (8.8%) of them required TIVAD removal (0.098 cases per 1000 catheter days). Most device removals due to complications (15/18, 83.3%) occurred within the first 24 months. Multivariate analysis identified left-sided device location as the only significant independent predictor of short device availability (OR, 3.5 [95% CI, 1.1-11.1], p = 0.036). CONCLUSION: TIVADs in cancer patients appear to be safe and their availability appears to be high in the long term. A decision for early removal might be revisited. Opting for the accustomed side (right side in the present study) for implantations seems to be associated with better outcomes.

Asunto(s)

Neoplasias/terapia , Prótesis e Implantes/normas , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos

RESUMEN

BACKGROUND: This study aimed to compare the standard one-stage coloanal anastomosis (CAA) technique plus diverting ileostomy and the Turnbull-Cutait (T-C) technique with delayed CAA in terms of early post-operative morbidity in patients with low rectal cancer. METHODS: A total of 33 patients with non-metastatic distal rectal cancer who were operated with one of the two different reconstruction methods (one-stage CAA plus diverting ileostomy or two-stage T-C technique with delayed CAA) after total mesorectal excision were included in this retrospective study. The two groups were compared for early post-operative morbidity within 30 post-operative days using complication frequency, Clavien-Dindo classification and Comprehensive Complication Index scores. RESULTS: The two groups did not differ in terms of morbidity parameters, including frequency of any morbidity, presence of grade 3b morbidity requiring management under general anaesthesia, as well as Comprehensive Complication Index score (P > 0.05 for all). CONCLUSION: Our findings suggest that the two techniques did not differ in terms of early post-operative morbidity. Owing to its comparable morbidity and safety to CAA plus concomitant ileostomy performed at the same session, the T-C technique may be considered in distal rectal cancer patients refusing to have a temporary stoma and in patients in whom CAA poses technical difficulties during the initial operation.

Asunto(s)

Ileostomía , Neoplasias del Recto , Anastomosis Quirúrgica/efectos adversos , Colon/cirugía , Humanos , Ileostomía/efectos adversos , Morbilidad , Complicaciones Posoperatorias/epidemiología , Neoplasias del Recto/cirugía , Estudios Retrospectivos

RESUMEN

ABSTRACT Background Current threshold for minimum lymph node harvest may not be adequate for appropriate staging in colon cancer and newer surgical techniques may allow more lymph nodes to be harvested. The aim of this study was to examine the prognostic role of harvesting and examining lymph nodes higher in number than the recommended threshold (≥12), in patients with colon cancer. Methods This retrospective study included 179 patients that underwent open colon resection for adenocarcinoma of the colon. A D3 resection with high vascular ligation was made so that large number of lymph nodes was removed in most patients. Differences in overall survival between below and above three cutoff points (≥18, ≥24, ≥40) were estimated. Results During median 33 months of follow-up, 45 patients died and mean overall survival was 108.7 ± 5.6 months (95% CI, 97.7-119.7). The mean number of lymph nodes harvested and examined was 44.0 ± 25.7 (median 38; range, 7-150). No significant effect was found for three different cut-off values (≥18, ≥24, or ≥40 nodes) on mean overall survival (p > 0.05 for all comparisons). The same was true for the whole study population as well as for N0 (N negative) and N1-2 (N positive) patient subgroups, when they are analyzed separately. Conclusions Our findings do not support the survival benefit of substantially higher number of lymph nodes harvested in colon cancer.

---

RESUMO Fundamento: O limite atual para a coleta mínima de linfonodos pode não ser adequado para o estadiamento adequado no câncer de cólon e novas técnicas cirúrgicas podem permitir que um número maior de linfonodos seja coletado. O objetivo deste estudo foi examinar o papel prognóstico da coleta e exame de linfonodos em número maior do que o limite recomendado (≥ 12), em pacientes com câncer de cólon. Método: Este estudo retrospectivo incluiu 179 pacientes submetidos à ressecção aberta de cólon para adenocarcinoma de cólon. A ressecção D3 com ligadura vascular alta foi realizada para que um grande número de linfonodos fosse removido na maioria dos pacientes. As diferenças na sobrevida global entre abaixo e acima de três pontos de corte (≥ 18, ≥ 24, ≥ 40) foram estimadas. Resultados: Durante a mediana de 33 meses de seguimento, 45 pacientes morreram e a sobrevida global média foi de 108,7 ± 5,6 meses (IC 95%: 97,7-119,7). O número médio de linfonodos coletados e examinados foi de 44,0 ± 25,7 (mediana = 38; variação: 7-150). Nenhum efeito significativo foi encontrado para três valores de corte diferentes (≥ 18, ≥ 24 ou ≥ 40 linfonodos) na sobrevida global média (p >0,05 para todas as comparações). O mesmo foi verdadeiro para toda a população do estudo, bem como para os subgrupos de pacientes N0 (N negativos) e N1-2 (N positivos), quando analisados separadamente. Conclusões: Nossos achados não apoiam o benefício na sobrevida de um número substancialmente maior de linfonodos coletados no câncer de cólon.

Asunto(s)

Humanos , Masculino , Femenino , Adenocarcinoma/diagnóstico , Neoplasias del Colon/diagnóstico , Neoplasias del Colon/mortalidad , Escisión del Ganglio Linfático/métodos , Pronóstico , Análisis de Supervivencia

RESUMEN

BACKGROUND: This study aimed to evaluate clinicopathological characteristics and long-term oncological outcome with respect to mucinous histology of tumor in colorectal cancer (CRC) patients. METHODS: A total of 372 patients who underwent resection surgery due to CRC between March 2006 and March 2019 were included in this retrospective study. Patients were divided into two groups according to degree of mucinous component including mucinous carcinoma group (n=48, ≥50% mucinous component) and non-mucinous carcinoma (n=324, <50% mucinous component) group. Data on patient demographics, tumor characteristics, treatment characteristics, metastasis and recurrence rates, disease free survival (DFS), and overall survival (OS) times were recorded. RESULTS: Mucinous vs. non-mucinous carcinoma was associated with higher rate of T4 stage (p=0.036) and high grade tumors (p=0.001) with extranodal invasion (p=0.019) Both the OS time (75.9±13.1 vs. 110.8±5.6 months, p=0.019) and DFS time (98.5±15.6 vs. 140.5±5.1 months, p=0.003) were significantly shorter in colon cancer patients with vs. without mucinous carcinoma despite their higher likelihood of receiving chemotherapy (89.6 vs. 71.9%, p=0.009). Multivariate analysis revealed presence of perineural invasion (HR 1.865, p=0.002), extranodal invasion (HR 1.869, p=0.009), T4 stage (HR 1.617, p=0.019), and M1 stage tumors (HR 3.643, p<0.001) but not mucinous carcinoma to significantly predict poor survival in CRC patients. CONCLUSION: In conclusion, our findings indicate colorectal tumors with mucinous carcinoma histology to have a more aggressive tumor characteristics and advanced disease stage on admission in CRC patients as well as shorter OS time and DFS time specifically in colon cancer patients despite receiving chemotherapy. KEY WORDS: Chemotherapy, Colorectal cancer, Long-term follow up, Mucinous histology, Survival.

Asunto(s)

Adenocarcinoma Mucinoso/patología , Neoplasias Colorrectales , Adenocarcinoma Mucinoso/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Humanos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia

RESUMEN

PURPOSE: To evaluate utility and prognostic value of serum CA 19-9 levels in relation to serum CEA levels in the longterm follow up of patients with colorectal cancer (CRC) METHODS: A total of 315 patients with CRC who were treated over a 13-year period were included in this retrospective study. Data on tumor characteristics, CEA and CA 19-9 levels were recorded. Survival analysis was performed with respect to marker status, while receiver operating characteristics (ROC) curve was plotted to determine the performance of CEA in predicting survival during follow up with calculation of area under curve (AUC) and cut-off value via ROC analysis. RESULTS: Advanced T stage (T3-4, p<0.001), presence of intramural invasion (p=0.019), lymphatic invasion (p=0.003) and larger tumor volume (p=0.02) were associated only with high CEA levels on admission, while poor histological differentiation (p=0.036) was only associated with high CA 19-9 levels on admission. Presence of normal CEA and CA 19-9 levels was associated with the longest survival time (131.6 and 46.8 months, respectively, p<0.001 for each) and 5-year OS rate of 90.5%, while ROC analysis revealed CEA levels >11 (AUC (95% CI): 0.636 (0.580-0.690), p<0.001) to be a potential marker of poor survival with a sensitivity of 75.0% and specificity of 45.9%. CONCLUSION: In conclusion, our findings seem to indicate a weaker poor prognostic value of high CA 19-9 levels when used alone and strongly suggest combined use of CEA and CA 19-9 markers in prognostic assessment and risk-adapted follow-up surveillance in CRC patients. KEY WORDS: CEA, CA 19-9, Colorectal cancer, Prognosis, Survival.

Asunto(s)

Biomarcadores de Tumor/sangre , Antígeno CA-19-9/sangre , Antígeno Carcinoembrionario/sangre , Neoplasias Colorrectales , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/patología , Estudios de Seguimiento , Humanos , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos

RESUMEN

Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.

Asunto(s)

Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Antineoplásicos/farmacología , Bencilaminas/química , Bencilaminas/farmacología , Línea Celular Tumoral , Diaminas/química , Diaminas/farmacología , Diseño de Fármacos , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfolípidos/química , Piperazinas/química , Piperazinas/farmacología , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Transducción de Señal , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Tiadiazoles/química , Tiadiazoles/farmacología , Tiofenos/química , Tiofenos/farmacología

RESUMEN

BACKGROUND/AIM: The P13K/Akt signaling pathway is a growth-regulating cellular pathway that is constitutively activated in a variety of human cancers. In previous studies, we reported that a solenopsin analog, compound B (MU-06-SC-608-7), shows inhibitory effects on Akt phosphorylation at a key activation site, as well as on proliferation of tumorigenic cells at sub-micromolar concentrations. The purpose of this study was to evaluate the effect of compound B on downstream effectors of Akt kinase, phosphorylation of Akt at a second activation site, Akt kinase activity in vitro, tumorigenic cell viability and other signaling pathways. MATERIALS AND METHODS: Western blot analyses were performed using WBras1 epithelial and H2009 human carcinoma cells and cell viability assays were performed on H2009 cells. In vitro Akt kinase assays were performed using a commercially available kit. RESULTS: Compound B decreased the phosphorylation of Akt at the Thr308 activation site and key downstream effectors of Akt kinase, but did not directly inhibit Akt kinase. Substantial decreases in cell viability were observed at concentrations above 5 µM. No effect was seen on ERK or JNK pathways. CONCLUSION: The results earmark this compound for further studies as a potential targeted cancer therapy.

Asunto(s)

Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos

RESUMEN

There is increasing support for the potential clinical use of compounds that interact with serotonin 2A (5-HT2A) receptors. It is therefore of interest to discover novel compounds that interact with 5-HT2A receptors. In the present study, we used computational chemistry to identify critical ligand structural features of 5-HT2A receptor binding and function. Query of compound databases using those ligand features revealed the adrenergic receptor antagonist carvedilol as a high priority match. As carvedilol is used clinically for cardiovascular diseases, we conducted experiments to assess whether it has any interactions with 5-HT2A receptors. In vitro experiments demonstrated that carvedilol has high nanomolar affinity for 5-HT2A receptors. In vivo experiments demonstrated that carvedilol increases the ethanol-induced loss of the righting reflex and suppresses operant responding in mice, and that these effects are attenuated by pretreatment with the selective 5-HT2A receptor antagonist M100907. Moreover, carvedilol did not induce the head-twitch response in mice, suggesting a lack of psychedelic effects. However, carvedilol did not activate canonical 5-HT2A receptor signaling pathways and antagonized serotonin-mediated signaling. It also reduced the head-twitch response induced by 2,5-Dimethoxy-4-iodoamphetamine, suggesting potential in vivo antagonism, allosteric modulation, or functional bias. These data suggest that carvedilol has functionally relevant interactions with 5-HT2A receptors, providing a novel mechanism of action for a clinically used compound. However, our findings do not clearly delineate the precise mechanism of action of carvedilol at 5-HT2A receptors, and additional experiments are needed to elucidate the role of 5-HT2A receptors in the behavioral and clinical effects of carvedilol.

Asunto(s)

Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacología , Carvedilol/química , Carvedilol/farmacología , Química Computacional/métodos , Descubrimiento de Drogas/métodos , Receptor de Serotonina 5-HT2A/química , Antagonistas Adrenérgicos/administración & dosificación , Antagonistas Adrenérgicos/metabolismo , Anfetaminas/administración & dosificación , Anfetaminas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Sitios de Unión , Carvedilol/administración & dosificación , Carvedilol/metabolismo , Fluorobencenos/farmacología , Células HEK293 , Humanos , Dietilamida del Ácido Lisérgico/química , Masculino , Ratones , Modelos Animales , Modelos Moleculares , Piperidinas/farmacología , Unión Proteica , Receptor de Serotonina 5-HT2A/genética , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacología , Transfección

RESUMEN

The P13K/Akt pathway is a growth-regulating cellular signaling pathway that is over-activated in numerous human cancers. A novel series of Akt pathway inhibitors were identified using iterative pharmacophore modeling, energy-based calculations, and property predictions of known Akt inhibitors. Inhibitory effects on activation of Akt and growth of human neoplastic cells are reported. Results show variable inhibitory effects of three selected compounds on Akt phosphorylation at a key activation site, and on proliferation of tumorigenic cells. We identify one lead compound with potent inhibitory activity on both human carcinoma cell proliferation and Akt activation.

Asunto(s)

Diseño de Fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Alcaloides/química , Alcaloides/farmacología , Línea Celular Tumoral , Activación Enzimática , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/patología , Modelos Moleculares , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal

RESUMEN

NADPH oxidases (Nox enzymes) are critical mediators of both physiologic and pathophysiologic processes. Nox enzymes catalyze NADPH-dependent generation of reactive oxygen species (ROS), including superoxide and hydrogen peroxide. Until recently, Nox4 was proposed to be involved exclusively in normal physiologic functions. Compelling evidence, however, suggests that Nox4 plays a critical role in fibrosis, as well as a host of pathologies and diseases. These considerations led to a search for novel, small molecule inhibitors of this important enzyme. Ultimately, a series of novel tertiary sulfonylureas (23-25) was designed using pharmacophore modeling, synthesized, and evaluated for inhibition of Nox4-dependent signaling.

Asunto(s)

Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , NADPH Oxidasa 4/antagonistas & inhibidores , Compuestos de Sulfonilurea/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , NADPH Oxidasa 4/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfonilurea/síntesis química , Compuestos de Sulfonilurea/farmacología

RESUMEN

Lymphangioleiomyomatosis (LAM) is a rare and fatal disease which occurs almost exclusively in young women. The disease often affects lungs and most of the patients die from respiratory failure. It is often initially misdiagnosed as asthma or chronic obstructive pulmonary disease. The most common presentations of pulmonary LAM (P-LAM) include dyspnea and coughing. Chylothorax and spontaneous pneumothorax may be seen in advanced cases. Although rare, it may present with extrapulmonary LAM (E-LAM). Renal angiomyolipomas and abdominal lymphadenopathies (LAPs) are common in E-LAM cases. Pelvic retroperitoneal masses are very rare and often require exploratory laparotomy. Herein, we report a 36-year-old female case of a rare extrapulmonary manifestation of LAM who was treated with abdominal and thoracic surgery, radiotherapy and finally sirolimus.

RESUMEN

Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of kcat and kcat/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with KI values lower than the Km for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a KI value of 1.5µM. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The KI for this compound was found to be 34µM, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO.

Asunto(s)

Cytophaga/enzimología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Quinurenina/análogos & derivados , Quinurenina/farmacología , Inhibidores Enzimáticos/metabolismo , Halogenación , Humanos , Cinética , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Modelos Moleculares , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/enzimología , Enfermedades Neurodegenerativas/metabolismo , Especificidad por Sustrato

RESUMEN

BACKGROUND: The deregulation and localization of the Annexins is consistently reported to have close relation to tumor cell malignancy, invasion, and metastasis as well as clinical progression of tumors. This study aimed to evaluate serum Annexin A2 (Anx A2) levels in patients with colon cancer in comparison to healthy controls and in relation to demographics and tumor pathology. MATERIAL AND METHODS: A total of 100 patients (mean (SD) age: 58 (5.8) years, 55.0% females) with colon cancer and 70 controls (mean (SD) age: 59 (5.4) years, 50.0% females) were included. Serum levels for Anx A2 were evaluated in relation to study group, demographics, and tumor pathology. RESULTS: Serum levels for Anx A2 were significantly lower in patients with colon cancer than in controls (13.1 (4.5) vs. 22.8 (2.1) ng/mL, p<0.001) and significantly decreased with increase in tumor size (p=0.003), and at higher stages of TNM (p=0.004), tumor invasion (p=0.005), lymph node metastasis (p=0.003), and distant metastasis (p=0.005). CONCLUSIONS: Our findings indicate a significant decrease in Anx A2 expression in colon cancer patients compared to healthy controls and in parallel with tumor progression.

Asunto(s)

Anexina A2/sangre , Neoplasias del Colon/sangre , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias del Colon/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad

RESUMEN

For over a century since the early 1900s, Paul Ehrlich was credited with originating the concept of pharmacophores. This was challenged by John Van Drie in 2007 due to the fact that Ehrlich did not use the word "pharmacophore" in his writings. Van Drie claimed that the attribution of the pharmacophore concept to Ehrlich was due to an erroneous citation made by Ariëns in a 1966 paper, and instead he claimed, Lemont B. Kier developed the pharmacophore concept (in the modern sense, as defined by the IUPAC) during 1967-1971. There are two separate issues that may have triggered this conflict. The first one is the shift in the meaning of pharmacophore from "chemical groups" to patterns of "abstract features" of a molecule that are responsible for a biological effect. Indeed, the original use of the term is different than the current definition proposed by the IUPAC. The term was redefined in 1960 by Schueler, and this modification formed the basis of IUPAC's modern definition. The second issue is the origin of the "concept" of pharmacophore. While Ehrlich's contemporaries have consistently attributed the origin of the concept to him, the issue is further complicated by the fact that Ehrlich did not use the term pharmacophore in his papers. He, instead, referred to the features of a molecule that are responsible for biological effects as toxophores, while his contemporaries were using the term pharmacophore for the same features. In this paper, we resolve any doubts about the origins of the pharmacophore concept. Our research points to Paul Ehrlich's 1898 paper for originating the concept, which identifies peripheral chemical groups in molecules responsible for binding that leads to the subsequent biological effect, and to Schueler's 1960 book that extends the concept to the modern definition where spatial patterns of abstract features of a molecule define the pharmacophore and are ultimately responsible for the biological effect.

Asunto(s)

Descubrimiento de Drogas , Terminología como Asunto , Modelos Moleculares , Conformación Molecular

RESUMEN

Understanding the molecular basis of drug action has been an important objective for pharmaceutical scientists. With the increasing speed of computers and the implementation of quantum chemistry methodologies, pharmacodynamic and pharmacokinetic problems have become more computationally tractable. Historically the former has been the focus of drug design, but within the last two decades efforts to understand the latter have increased. It takes about fifteen years and over $1 billion dollars for a drug to go from laboratory hit, through lead optimization, to final approval by the U.S. Food and Drug Administration. While the costs have increased substantially, the overall clinical success rate for a compound to emerge from clinical trials is approximately 10%. Most of the attrition rate can be traced to ADMET (absorption, distribution, metabolism, excretion, and toxicity) problems, which is a powerful impetus to study these issues at an earlier stage in drug discovery. Quantum mechanics offers pharmaceutical scientists the opportunity to investigate pharmacokinetic problems at the molecular level prior to laboratory preparation and testing. This review will provide a perspective on the use of quantum mechanics or a combination of quantum mechanics coupled with other classical methods in the pharmacokinetic phase of drug discovery. A brief overview of the essential features of theory will be discussed, and a few carefully selected examples will be given to highlight the computational methods.

Asunto(s)

Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos/métodos , Drogas en Investigación/farmacocinética , Teoría Cuántica , Disponibilidad Biológica , Aprobación de Drogas , Diseño de Fármacos , Drogas en Investigación/farmacología , Humanos , Simulación de Dinámica Molecular , Relación Estructura-Actividad

RESUMEN

One of the major reasons for late-stage failure of drug candidates is due to problems uncovered in pharmacokinetics during clinical trials. There is now a general consensus for earlier consideration of these effects in the drug discovery process. Computer-aided design technology provides us with tools to develop predictive models for such pharmacokinetic properties. Among these tools, we focus on pharmacophore modeling techniques in this article. Pharmacophore models that are reported for various cytochrome P450 (CYP) enzymes are reviewed for the isoenzymes CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In addition pharmacophore models for related metabolic processes through CYP19 (aromatase), CYP51 (14.α-lanosterol demethylase), PXR (pregnane X-receptor), and finally for human intrinsic clearance are also reviewed. The models reported by various scientists are schematically represented in the figures in order to visually demonstrate their similarities and differences. The models developed by different researchers or sometimes even by the same research group for different sets of ligands, provide a clear picture of the challenges in coming up with a single model with good predictive values. One of the main reasons for this challenge is related to relatively large size of the active sites and flexibility of the CYP isoenzymes, which results in multiple binding sites. We propose development of multiple- diverse pharmacophore models for each binding mode (as opposed to a single predictive model for each CYP isoenzyme). After scoring and prioritization of the models, we propose the use of a battery of pharmacophore models for each CYP isoenzyme binding mode to computationally obtain a P450 interaction profile for drug candidates early in the drug development cycle, when decisions on their fate can be made before incurring the costs of synthesis and testing.

Asunto(s)

Diseño Asistido por Computadora , Sistema Enzimático del Citocromo P-450/química , Evaluación Preclínica de Medicamentos/métodos , Drogas en Investigación/química , Drogas en Investigación/metabolismo , Receptores de Esteroides/química , Sitios de Unión , Sistema Enzimático del Citocromo P-450/metabolismo , Diseño de Fármacos , Interacciones Farmacológicas , Drogas en Investigación/farmacocinética , Pruebas de Enzimas , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Isoenzimas/química , Isoenzimas/metabolismo , Modelos Moleculares , Receptor X de Pregnano , Relación Estructura-Actividad Cuantitativa , Receptores de Esteroides/metabolismo , Electricidad Estática

RESUMEN

A lymphangioma is a benign proliferation of lymph vessels, producing fluid-filled cysts that result from a blockage of the lymphatic system. The incidence of abdominal lymphangiomas is unknown; however they account for from 3% to 9.2% of all pediatric lymphangiomas, with retroperitoneal lymphangioma representing less than 1% of abdominal lymphangiomas. Due to rarity, preoperative diagnosis is often difficult.