RESUMEN
This study aimed to investigate the impact of ambient lead (Pb) exposure on progesterone (P4) and pregnancy-associated glycoprotein 1 (PAG1) and their relationship with abortion in Egyptian Zaraibi goats (C. hircus). To achieve this, 40 female goats (does) were mated with highly fertile male goats, resulting in a total of 28 pregnant goats. Eight of them aborted, and each of the 12 pregnant goats gave birth to one kid, whereas the remaining eight gave birth to twins. The levels of PAG1, P4, and Pb in serum were estimated by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), and inductively coupled plasma mass spectrometry (ICP-MS) respectively. Statistically, the repeated measure two-way ANOVA, regression analysis, correlation coefficient, and receiver operating characteristic (ROC) curves were applied. The current data demonstrated that the levels of blood Pb in aborted goats were significantly higher than those in non-aborted goats at the early, mid, and late gestations, and this was followed by significant decreases in serum PAG1 and P4. Furthermore, there were substantial inverse associations between blood Pb concentration and levels of PAG1 and P4, with markedly negative correlation coefficients of - 0.88 and - 0.77, respectively, in aborted goats. The threshold level of Pb required to cause abortion was ≥ 32.08 µg/dl, but for PAG1 and P4 were respectively ≤ 0.95 ng/ml and ≤ 0.48 ng/ml. Additionally, threshold levels of ≥ 12.34 ng/ml and ≥ 31.52 ng/ml for P4 and PAG1, respectively, were needed to deliver twins. In conclusion, pollution-induced increases in Pb bioavailability resulted in dramatic decreases in P4 and PAG1 levels, leading to abortions. PAG1 and P4 levels are also key factors in determining whether Zaraibi goats will give birth to twins.
Asunto(s)
Ácido Aspártico Endopeptidasas , Proteínas Gestacionales , Progesterona , Animales , Femenino , Embarazo , Cabras , PlomoRESUMEN
OBJECTIVE: This report presents the results of a randomized prospective study comparing synchronous transurethral cystolitholapaxy and transurethral resection of the prostate (TURP) with transurethral cystolitholapaxy plus medical treatment for benign prostatic hyperplasia (BPH) in patients with concomitant vesical stone(s) and BPH. PATIENTS AND METHODS: The study included 100 patients with bladder stone(s) < 2.5 cm associated with BPH. Eligible patients were divided randomly into two groups: group I (n = 50 patients) underwent simultaneous transurethral cystolitholapaxy and TURP, and group II (n = 50 patients) underwent transurethral cystolitholapaxy and received postoperative tamsulosin plus finasteride. RESULTS: The mean follow-up was 20.1 ± 5.3 months. No statistically significant differences were found between the 2 groups regarding the preoperative parameters (age, prostatic volume, bladder stone characteristics, prostate-specific antigen level, International Prostate Symptom Score, peak urinary flow rate, and post-void residual urine volume). Both groups experienced statistically significant postoperative improvement in IPSS, post-void residual (PVR) urine volume, and peak flow rate compared with the preoperative parameters (P < 0.001 for all parameters). However, patients in group 1 had a more pronounced improvement (P < 0.001 for all parameters). Thus, 15 patients in group 2 underwent TURP during follow-up. PVR urine and prostate volume predicted the failure of medical therapy and the need for TURP. CONCLUSION: Synchronous transurethral cystolitholapaxy and TURP revealed better results than transurethral cytolitholapaxy plus medical therapy. Cystolitholapaxy without TURP should not be indicated especially in patients with significant PVR urine volumes and larger prostates.
Asunto(s)
Hiperplasia Prostática , Resección Transuretral de la Próstata , Cálculos de la Vejiga Urinaria , Humanos , Masculino , Estudios Prospectivos , Próstata/cirugía , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/cirugía , Resección Transuretral de la Próstata/métodos , Resultado del Tratamiento , Cálculos de la Vejiga Urinaria/complicaciones , Cálculos de la Vejiga Urinaria/cirugíaRESUMEN
This study aimed to assess the predictive factors of successful sperm retrieval in non-obstructive azoospermia with a history of bilateral cryptorchidism. This retrospective study included 103 patients with azoospermia who had micro-dissection testicular sperm extraction between January 2010 and January 2020. The median (range) age of the patients and their wives in the study group was 33 (21-44) and 24 (19-33) years, respectively. The patients with low testosterone level (<3 ng/dl) were prescribed with human chorionic gonadotropin 5,000 IU injection every 3 days for 3 months. Those with persistent low testosterone even after hormonal stimulation were excluded. Sperms were retrieved from 64 (62%) patients, whilst failed in 39 (38%) patients. On univariate analysis, the median testicular volume was significantly larger in the successful group versus the failed group (p < .001), serum FSH and serum LH were significantly lower in the successful group (p = .001), serum testosterone was significantly higher in the successful group compared to the failed group (p < .001) and the age of orchidopexy was lower in the successful group versus the failed group (p = .016). On multivariate analysis, the average testicular volume and the serum testosterone levels were independent factors for successful sperm retrieval.
Asunto(s)
Azoospermia , Criptorquidismo , Criptorquidismo/complicaciones , Criptorquidismo/cirugía , Humanos , Masculino , Estudios Retrospectivos , Recuperación de la Esperma , Espermatozoides , Testículo/cirugía , TestosteronaRESUMEN
Neuropathy is considered a critical complication of diabetes mellitus (DM). Scientific studies are needed to relieve these painful complications. The current study aims to estimate the ameliorative role of Physalis juice (PJ) against neurological impairment in streptozotocin (STZ)-induced diabetic rats. Type 1 DM was induced after one week of injecting rats with 55 mg STZ/kg body weight. PJ-treated rats were orally administered 5 ml PJ/kg body weight per day for 28 days after induction of diabetes. A small piece of the cerebral cortex of rats was fixed and used for histopathological investigations. The remaining portion of the cerebral cortex was homogenized for biochemical and molecular analyses. As compared to the controls, STZ-injected rats showed significant elevations in the levels of blood glucose, tumor necrosis factor alfa, interleukin-1ß, malondialdehyde, nitric oxide, and expression levels of caspase-3 and B-cell lymphoma-2 associated X-protein. Additionally, remarkable declines in the levels of brain-derived neurotrophic factor, monoamines, B-cell lymphoma-2, glutathione, as well as the activities and gene expression levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase in STZ-treated rats were reported. Moreover, some histopathological alterations were observed in the brain cortex of the STZ-treated rats. On the other hand, the administration of PJ substantially reduced the blood glucose and alleviated the above-mentioned alterations in all the studied parameters of the cerebral cortex. In conclusion, an oral administration of 5 ml PJ/kg revealed a neuroprotective action against neurodegenerative diabetes-induced complications in rats, which might be due to the reported antioxidative and anti-inflammatory actions of PJ. Thus, further therapeutic studies are recommended to apply PJ in the treatment regimen of diabetes.
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Antibióticos Antineoplásicos/farmacología , Diabetes Mellitus Experimental/tratamiento farmacológico , Physalis/efectos de los fármacos , Estreptozocina/farmacología , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Experimental/inducido químicamente , Hipoglucemiantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Physalis/metabolismo , Extractos Vegetales/farmacología , RatasRESUMEN
This study aimed to assess the effectiveness of low-intensity extracorporeal shockwave therapy (Li-ESWT) in the management of erectile dysfunction in diabetic patients with mixed vasculogenic and neurogenic causes as confirmed by nerve conduction and Doppler studies. This randomised controlled trial included 42 patients 41-55 years of age with a confirmed diagnosis of erectile dysfunction and diabetic polyneuropathy. They were randomly allocated to one of two groups: shock wave group (n = 21) treated with Li-ESWT plus pelvic floor muscle training and control Group (n = 21) treated with pelvic floor muscle exercise and sham therapy by a shock wave. The erectile function was scored according to the five-item version of the International Index of Erectile Function (IIEF-5). Colour-coded duplex sonography was used for the evaluation of penile perfusion of the two cavernous arteries. The assessment was done before and three months after treatment. IIEF-EF increased significantly in the study group (p < .001), but not in the control group (p = .194). Peak systolic velocity increased significantly in the two groups; however, the post-treatment peak systolic velocity was significantly higher in the study group compared to the control group (p < .001, for both arteries).
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Diabetes Mellitus , Disfunción Eréctil , Tratamiento con Ondas de Choque Extracorpóreas , Disfunción Eréctil/etiología , Disfunción Eréctil/terapia , Humanos , Masculino , Erección Peniana , Pene/diagnóstico por imagenRESUMEN
The present study was conducted to investigate the effect of incorporating Cicer arietinum in the diet on the testicular functions of the male mice. Seventy-two mice were divided equally into four groups that were daily fed a diet containing 0, 20, 30 and 50% of C. arietinum seeds, respectively. After 7, 14 and 21 days of starting the experiments, the mice were anesthetized and euthanized to collect the blood, testes, epididymis and seminal vesicles. The present results showed that the increased percentage of C. arietinum in the diet caused significant elevations in the serum levels of testosterone and luteinizing hormone (LH), sperm concentration, sperm motility as well as the testicular levels of antioxidants including glutathione (GSH), glutathione peroxidase (GPx) and catalase (CAT), in comparison to the controls. On the other hand, marked reductions in the sperm abnormality, testicular levels of malondialdehyde (MDA), the percentage of DNA damage in tail and tail moment (TM) were observed in the mice that received a diet containing C. arietinum as compared to the controls. Both the sperms and testes of the mice fed a diet containing C. arietinum in the diet showed a normal intact appearance of the electrophoresed genomic DNA on agarose, as those of the controls. In conclusion, C. arietinum is not only a safe ingredient in the fast-food but also an enhancer of the testicular functions.
Asunto(s)
Cicer/química , Fármacos para la Fertilidad/farmacología , Fertilidad/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Espermatozoides/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Catalasa/metabolismo , Ensayo Cometa , ADN/química , ADN/metabolismo , Epidídimo/efectos de los fármacos , Epidídimo/metabolismo , Fertilidad/fisiología , Glutatión/agonistas , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Hormona Luteinizante/sangre , Masculino , Malondialdehído/antagonistas & inhibidores , Malondialdehído/metabolismo , Ratones , Semillas/química , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/metabolismo , Recuento de Espermatozoides , Motilidad Espermática/efectos de los fármacos , Motilidad Espermática/fisiología , Espermatogénesis/fisiología , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/sangreRESUMEN
BACKGROUND: This study aims to investigate the detailed computed tomography (CT) measurement of the nasopharynx (NP) in normal adult detecting mean of its dimension and relation of that measurement to that of the sphenoid sinus. METHODOLOGY/PRINCIPAL: A normal paranasal CT scan and a straight nasal septum of 128 individuals (256 sphenoid sinuses) were included in the study. Axial images were acquired with multiplanar reformates to obtain delicate details in coronal and sagittal planes for all subjects. Measurement of the width, length, and anteroposterior dimensions of the NP and sphenoid sinuses were taken separately. RESULTS: In 128 studied CT of adult subjects, the mean height of the NP was 19.4619â±â4.52661 and mean depth was 21.80714â±â4.62324 while the mean width was 25.31951â±â3.80521. No significant relations between diameters of NP and sphenoid sinuses were found. CONCLUSION: The detailed CT measurement of the NP in normal adult is an easy and reliable measurement. This study put the base of CT measurement of NP for further work to describe changes in such measures in patients with nasal and paranasal sinus anomalies.
Asunto(s)
Seno Esfenoidal/anatomía & histología , Seno Esfenoidal/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Femenino , Humanos , Masculino , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
The work aimed to evaluate the nanoalumina toxicity on the histological architecture, some haematological and biochemical aspects in male albino rats, during acute and sublethal experiments. Rats, in acute experiments, were injected with a single-acute dose of 3.9 g or 6.4 g or 8.5 g of aluminium oxide (Al2O3) kg(-) (1), whereas those of sublethal were injected with 1.3 g of Al2O3 kg(-) (1)2 days(-) (1) One-way analysis of variance indicated that injected doses and the experimental periods were significantly affected by haemoglobin (Hb) content; haematocrit value (Hct); white blood cell (WBC) count; blood platelet (Plt) count; mean corpuscular volume (MCV); mean corpuscular Hb (MCH) and MCH concentration (MCHC). In acute experiments, Hct, WBC count, MCV and Plt were significantly higher than the corresponding controls, whereas Hb, MCH and MCHC markedly decreased. In comparison with the related controls after 1, 3 and 7 days post-injection, red blood cell count, Hb, Hct, WBC count, Plt and MCV were significantly increased, but begun to decrease after 14 or/and 28 days and were associated with a marked decrease in MCH and MCHC. In serum of rats injected with acute or sublethal dose, the concentrations of total protein (TP) and total lipid (TL) were significantly lesser than the corresponding controls, whereas the levels of urea, uric acid, creatinine and the activities of aspartate aminotransferase and alanine aminotransferase were markedly increased. The injected doses were directly proportional with all the studied biochemical parameter, except the TL and TP that exhibited a negative correlation. Histologically, the highest acute and sublethal doses of nanoalumina caused hepatic irregular disarray, necrosis to the hepatic and Kupffer cells that are associated with congested blood sinusoids. The renal tissues characterized by the appearance of inter-tubular congestion that is accompanied by the dilation of the vascular glomeruli that completely occupied Bowman's capsule and accompanied with partial disappearance of the renal tubule's brush border. The brain showed a progressive degeneration of neurons in both the experiments.
Asunto(s)
Óxido de Aluminio/toxicidad , Nanopartículas del Metal/toxicidad , Óxido de Aluminio/química , Animales , Recuento de Células Sanguíneas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Nanopartículas del Metal/química , RatasRESUMEN
The present work aimed to evaluate the oxidative stress of nanoalumina (aluminium oxide nanoparticles, Al2O3-NPs) with a diameter <13 nm (9.83 ± 1.61 nm) as assessed by the perturbations in the enzymatic and non-enzymatic antioxidants as well as lipid peroxidation (LPO) in the brain, liver and kidney of male albino rats, after 2 days of single acute dose (3.9 or 6.4 or 8.5 g/kg) injection and a sublethal dose of 1.3 g/kg once in 2 days for a period of 28 days. According to two-way analysis of variance, superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities as well as the levels of glutathione (GSH) and LPO were significantly affected by the injected doses, organs and their interactions. On the other hand, in sublethal experiments, these parameters were affected by the experimental periods, organs and their interactions. Regression analysis confirmed that the activities of SOD, CAT, GPx and GSH levels in the brain, liver and kidney were inversely proportional with the acute doses, the experimental periods, and aluminium accumulated in these tissues, whereas the levels of LPO exhibited a positive relationship. Correlation coefficient indicated that oxidative stress mainly depends on aluminium accumulated in the studied organs, followed by injected doses and the experimental periods. In comparison with the corresponding controls, the acute and sublethal doses of Al2O3-NPs caused significant inhibition of the brain, hepatic and renal SOD, CAT, GPx activities and a severe marked reduction in the concentrations of GSH that were associated with a significant elevation in the levels of malondialdehyde (an indicator of LPO). In conclusion, our data indicated that rats injected with nanoalumina suffered from the oxidative stresses that were dose and time dependent. In addition, Al2O3-NPs released into the biospheres could be potentiating a risk to the environment and causing hazard effects on living organisms, including mammals.
Asunto(s)
Óxido de Aluminio/toxicidad , Encéfalo/efectos de los fármacos , Riñón/efectos de los fármacos , Hígado/efectos de los fármacos , Nanopartículas/química , Estrés Oxidativo/efectos de los fármacos , Óxido de Aluminio/química , Animales , Antioxidantes/farmacología , Encéfalo/metabolismo , Catalasa/metabolismo , Relación Dosis-Respuesta a Droga , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Riñón/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
The purpose of this study is to follow-up the distribution, lethality percentile doses (LDs) and bioaccumulation of aluminium oxide nanoparticles (Al2O3-NPs, average diameter 9.83 ± 1.61 nm) in some tissues of male albino rats, and to evaluate its genotoxicity to the brain tissues, during acute and sublethal experiments. The LDs of Al2O3-NPs, including median lethal dose (LD50), were estimated after intraperitoneal injection. The computed LD50 at 24 and 48 h were 15.10 and 12.88 g/kg body weight (b.w.), respectively. For acute experiments, the bioaccumulation of aluminium (Al) in the brain, liver, kidneys, intestine and spleen was estimated after 48 h of injection with a single acute dose (3.9, 6.4 and 8.5 g/kg b.w.), while for sublethal experiments it was after 1, 3, 7, 14 and 28 days of injection with 1.3 g/kg b.w. once in 2 days. Multi-way analysis of variance affirmed that Al uptake, in acute experiments, was significantly affected by the injected doses, organs (brain, liver, kidneys, intestine and spleen) and their interactions, while for sublethal experiments an altogether effect based on time (1, 3, 7, 14, 28 days), doses (0 and 1.3 g), organs and their interactions was reported. In addition, Al accumulated in the brain, liver, kidney, intestine and spleen of rats administered with Al2O3-NPs were significantly higher than the corresponding controls, during acute and sublethal experiments. The uptake of Al by the spleen of rats injected with acute doses was greater than that accumulated by kidney>brain>intestine>liver, whereas the brain of rats injected with sublethal dose accumulated lesser amount of Al followed by the kidneyAsunto(s)
Óxido de Aluminio/toxicidad
, Daño del ADN/efectos de los fármacos
, Nanopartículas/toxicidad
, Óxido de Aluminio/farmacocinética
, Animales
, Encéfalo/efectos de los fármacos
, Encéfalo/metabolismo
, Ensayo Cometa
, Inyecciones Intraperitoneales
, Mucosa Intestinal/metabolismo
, Intestinos/efectos de los fármacos
, Riñón/efectos de los fármacos
, Riñón/metabolismo
, Hígado/efectos de los fármacos
, Hígado/metabolismo
, Masculino
, Ratas
, Bazo/efectos de los fármacos
, Bazo/metabolismo
, Distribución Tisular
RESUMEN
Resistance to androgen-deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform into emergent aggressive variant prostate cancer (AVPC), which has neuroendocrine (NE)-like features. In this work, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflect and retain key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. We compared 15 NE versus 33 AdCa samples, which included six different PDX tumors for each group in biological replicates, and identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of concordance from PDX tumor-matched protein and mRNA revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa. IMPLICATIONS: Overall, our study highlights the importance of protein-based identification when compared with RNA and provides a rich resource of new and feasible targets for clinical assay development and in understanding the underlying biology of these tumors.
Asunto(s)
Fosfoproteínas , Proteoma , Humanos , Masculino , Proteoma/metabolismo , Animales , Ratones , Fosfoproteínas/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Xenoinjertos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Ensayos Antitumor por Modelo de Xenoinjerto , Proteómica/métodosRESUMEN
Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.
Asunto(s)
Carcinoma de Células Renales , Epigenómica , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Epigenómica/métodos , Metilación de ADN/genética , Diferenciación Celular , Regulación Neoplásica de la Expresión Génica , Masculino , Femenino , Epigénesis Genética , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-fosRESUMEN
Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
RESUMEN
Gene behavior is governed by activity of other genes in an ecosystem as well as context-specific cues including cell type, microenvironment, and prior exposure to therapy. Here, we developed the Algorithm for Linking Activity Networks (ALAN) to compare gene behavior purely based on patient -omic data. The types of gene behaviors identifiable by ALAN include co-regulators of a signaling pathway, protein-protein interactions, or any set of genes that function similarly. ALAN identified direct protein-protein interactions in prostate cancer (AR, HOXB13, and FOXA1). We found differential and complex ALAN networks associated with the proto-oncogene MYC as prostate tumors develop and become metastatic, between different cancer types, and within cancer subtypes. We discovered that resistant genes in prostate cancer shared an ALAN ecosystem and activated similar oncogenic signaling pathways. Altogether, ALAN represents an informatics approach for developing gene signatures, identifying gene targets, and interpreting mechanisms of progression or therapy resistance.
Asunto(s)
Ecosistema , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/patología , Genes myc , Genómica , Transducción de Señal/genética , Microambiente Tumoral/genéticaRESUMEN
PURPOSE: In patients with metastatic prostate cancer (mPC), ATM and BRCA2 mutations dictate differences in PARPi inhibitor response and other therapies. We interrogated the molecular features of ATM- and BRCA2-mutated mPC to explain the divergent clinical outcomes and inform future treatment decisions. EXPERIMENTAL DESIGN: We examined a novel set of 1,187 mPCs after excluding microsatellite-instable (MSI) tumors. We stratified these based on ATM (n = 88) or BRCA2 (n = 98) mutations. As control groups, mPCs with mutations in 12 other homologous recombination repair (HRR) genes were considered non-BRCA2/ATM HRR-deficient (HRDother, n = 193), whereas lack of any HRR mutations were considered HRR-proficient (HRP; n = 808). Gene expression analyses were performed using Limma. Real-world overall survival was determined from insurance claims data. RESULTS: In noncastrate mPCs, only BRCA2-mutated mPCs exhibited worse clinical outcomes to AR-targeted therapies. In castrate mPCs, both ATM and BRCA2 mutations exhibited worse clinical outcomes to AR-targeted therapies. ATM-mutated mPCs had reduced TP53 mutations and harbored coamplification of 11q13 genes, including CCND1 and genes in the FGF family. BRCA2-mutated tumors showed elevated genomic loss-of-heterozygosity scores and were often tumor mutational burden high. BRCA2-mutated mPCs had upregulation of cell-cycle genes and were enriched in cell-cycle signaling programs. This was distinct from ATM-mutated tumors. CONCLUSIONS: Tumoral ATM and BRCA2 mutations are associated with differential clinical outcomes when patients are stratified by treatments, including hormonal or taxane therapies. ATM- and BRCA2-mutated tumors exhibited differences in co-occurring molecular features. These unique molecular features may inform therapeutic decisions and development of novel therapies.
Asunto(s)
Genes BRCA2 , Neoplasias de la Próstata , Masculino , Humanos , Mutación , Proteína BRCA2/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Biomarcadores de Tumor/genética , Proteínas de la Ataxia Telangiectasia Mutada/genéticaRESUMEN
OBJECTIVE: Allergic rhinitis (AR) is regulated by the local production and release of several cytokines. Allergen specific immunotherapy (IT) has been widely used for many years as a specific treatment of allergic diseases. This study aimed to investigate the changes in clinical and immunological markers before and after Phoenix dactylifera IT in AR patients. MATERIALS AND METHODS: Total symptom score and levels of total immunoglobulin E (IgE), albumin, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-10, IL-4, and IL-13 were measured in the serum and nasal samples of thirty non-atopic healthy controls and thirty patients with allergic rhinitis before and after 15 months of IT. RESULTS: We found significantly higher concentrations of serum TNF-α and nasal TNF-α and IL-13, and significantly lower concentration of nasal IL-10, in allergic patients than in non-allergic. Moreover, serum and nasal IL-10 increased significantly after IT. However, there was neither a significant reduction in total IgE nor a significant increase in IFN-γ at the end of IT. CONCLUSIONS: Our data show a clinical improvement associated with a decline in some inflammation parameters after IT. Moreover, date palm IT induced a significant increase in serum and nasal IL-10 levels.
Asunto(s)
Arecaceae/inmunología , Polen/inmunología , Rinitis Alérgica Estacional/terapia , Adolescente , Adulto , Albúminas/inmunología , Alérgenos/inmunología , Citocinas/sangre , Citocinas/inmunología , Desensibilización Inmunológica , Femenino , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Masculino , Mucosa Nasal/inmunología , Extractos Vegetales/inmunología , Rinitis Alérgica Estacional/sangre , Rinitis Alérgica Estacional/inmunología , Pruebas Cutáneas , Adulto JovenRESUMEN
Testicular impairment is a serious complication of diabetes that is mediated by oxidative stress and inflammation. Physalis has antioxidative and anti-inflammatory actions. Thus, the present study investigated the ameliorative role of Physalis juice (PJ) prepared from the fruits against testicular damages in streptozotocin (STZ)-induced diabetic rats. Adult male Wistar rats were divided randomly into five groups (n=6): control, orally administered 5 mL PJ/kg daily (PJ), injected intraperitoneally with a single dose of 55 mg STZ/kg without treatment (STZ), or treated daily with PJ (STZ+PJ) or with 500 mg metformin/kg (STZ+Met), for 28 days. The STZ group showed a marked elevation in the blood glucose level by 230%, whereas remarkable declines in the serum levels of testosterone (44%), follicle-stimulating hormone (FSH) (48%), and luteinizing hormone (LH) (36%), as compared to controls. In comparison to controls, the testis of the STZ group showed remarkable declines in the testis weight (15%), the glutathione (GSH) content (45%), mRNA and protein levels of B-cell lymphoma-2 (Bcl-2) (48 and 35%), mRNA and activities of superoxide dismutase (SOD) (63 and 40%), catalase (CAT) (56 and 31%), glutathione peroxidase (GPx) (51 and 44%), and glutathione reductase (GR) (62 and 43%), whereas marked elevations in the levels of interleukin-1 beta (IL-1ß (169%), tumor necrosis factor-alfa (TNFα) (85%), nitric oxide (NO) (96%), malondialdehyde (MDA) (83%), mRNA and protein levels of Bcl-2-associated X protein (Bax) (400 and 61%), and mRNA level of caspase-3 (Cas-3) (370%). Some histopathological alterations were observed in the testicular tissue of the STZ group. In contrast, PJ markedly alleviated all the abovementioned disturbances. In conclusion, PJ at a dose of 5 mL/kg attenuated the diabetes-associated testicular impairments, which may be due to its antioxidative, anti-inflammatory, and antiapoptotic actions.
Asunto(s)
Diabetes Mellitus Experimental , Physalis , Animales , Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Estrés Oxidativo , Ratas , Ratas Wistar , Estreptozocina/metabolismo , Testículo/metabolismoRESUMEN
Nickel oxide nanoparticles (NiONPs) are involved in several applications but still have some adverse effects. Apigenin (APG) is a widespread natural product with antioxidative, anticancer, and anti-inflammatory properties. The present work aimed to study the protective role of APG against the NiONP-induced toxicity in male Wistar rats. Rats were randomly distributed to one control group and three treated groups. The treated groups were orally administered NiONPs (100 mg/kg) alone, APG (25 mg/kg) alone, or APG 1 h before NiONPs, once daily for 28 days. Blood, liver, and kidney were collected after 7, 14, and 28 days of administration for Ni accumulation, hematological, biochemical, histological, and transmission electron microscopy (TEM) investigations. As compared to the controls, the administration of NiONPs alone significantly elevated the levels of Ni, malondialdehyde, total cholesterol, low-density lipoprotein cholesterol, creatinine, urea, blood urea nitrogen, and the activity of alanine and aspartate aminotransferases as well as the count of white blood cells. Besides, marked reductions in the activity of superoxide dismutase, and the levels of glutathione, high-density lipoprotein cholesterol, total proteins, albumin, globulin, hemoglobin, packed cell volume, and red blood cell count were reported. Histologically, the liver and kidney of rats administered NiONPs alone showed remarkable disturbances. According to TEM, subcellular alterations were observed in the liver and kidney of rats administered NiONPs alone. In contrast, APG administering before NiONPs substantially alleviated all the studied parameters. In conclusion, APG can ameliorate the NiONP-induced hepatotoxicity and nephrotoxicity in male Wistar rats.
Asunto(s)
Apigenina , Nanopartículas , Animales , Antioxidantes/metabolismo , Apigenina/metabolismo , Glutatión/metabolismo , Riñón/metabolismo , Hígado/metabolismo , Masculino , Malondialdehído/metabolismo , Níquel , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
INTRODUCTION: The rapid worldwide spread of COVID-19 motivated medical professionals to pursue and authenticate appropriate remedies and treatment protocols. This article aims to analyze the potential benefits of one treatment protocol developed by a group of care providers caring for severe COVID-19 patients. METHODS: The clinical findings of COVID-19 patients who were transferred to a specialized care hospital after unsuccessful treatment in previous institutions, were analyzed. The specialized care hospital used a treatment protocol including hydroxyurea, a medication commonly used for sickle cell treatment, to improve respiratory distress in the COVID-19 patients. None of the COVID-19 patients included in the analyzed data were diagnosed with sickle cell, and none had previously taken hydroxyurea for any other conditions. RESULTS: In all presented cases, patients reverted to their baseline respiratory health after treatment with the hydroxyurea protocol. There was no significant difference in the correlation between COVID-19 and hydroxyurea. However, deaths were extremely low for those taking hydroxyurea. CONCLUSIONS: Fatality numbers were extremely low for those taking hydroxyurea; death could be attributed to other underlying issues.
RESUMEN
The consumption of inadequately thermally treated fish is a public health risk due to the possible propagation of Anisakis larvae. The present study demonstrated the physiological and histopathological changes that accompanied an oral inoculation of crude extracts from fresh and thermally treated Anisakis Type II (L3) in rats. Worms were isolated from a marine fish and examined and identified using light and scanning electron microscopy. The study was performed in 6 rat groups: control (I), garlic oil (GO) inoculated (II), fresh L3 inoculated (III), thermally treated L3 inoculated (IV), fresh L3 + GO inoculated (V), and a thermally treated L3 + GO inoculated (VI) groups. Rats inoculated with fresh and thermally treated L3 showed abnormal liver and kidney functions associated with the destruction of normal architecture. GO produced a protective effect in rat groups inoculated with L3 extracts + GO via the amelioration of liver and kidney functions, which was confirmed by the marked normal structure on histology. Cooking of L3-infected fish induced severe alterations compared to uncooked fish. The administration of garlic before and after fish eating is recommended to avoid the dangerous effect of anisakids, even if they are cooked.