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PURPOSE: To evaluate demographics, academic backgrounds, and scholarly activities of Program Directors (PDs) in Abdominal Imaging Fellowships in the United States (US), emphasizing gender representation, international origins, and academic milestones. METHODS: A list of Fellowships in Abdominal Imaging programs in the US was obtained from the Society of Abdominal Radiology. The search was expanded using the Fellowship and Residency Electronic Interactive Database. Data for PDs were sourced from program websites, Healthgrades, Doximity, and Elsevier's Scopus. Metrics such as age, gender, education, academic rank, additional qualifications, prior leadership roles, publications, and h-indices were analyzed using R software. A two-tailed unpaired t-test was used to calculate the difference in means of scholarly activity between male and female PDs. RESULTS: 113 programs were identified: South (36.28%), Northeast (25.66%), Mid-West (20.35%), West (17.69%). Of 107 PDs, 54% male, 41% female, and average age 48 ± 9.4 years. 66.6% were US graduates, 29.2% were international graduates. Most were Assistant Professors (36.28%). 19.46% had degrees like M.P.H. or M.B.A. 45% had prior leadership roles. Average year of residency graduation was 2007. Mean publication count was 54.16, and mean h-index was 14.663. Male PDs had higher publication counts and h-indices than female PDs (p= 0.009 and p= 0.0019 respectively). CONCLUSION: In Abdominal Imaging Fellowship programs in the US, there is an increasing representation of females in Program Director roles. However, research led by female PDs remains less prevalent. The field of Abdominal Imaging values contributions from international graduates and insights from Assistant Professors.
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Becas , Internado y Residencia , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Demografía , Escolaridad , Docentes Médicos , Estados UnidosRESUMEN
Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4-6 months and 18-21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments.
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Envejecimiento , Bencimidazoles , Fibras Musculares de Contracción Rápida , Fibras Musculares de Contracción Lenta , Oxadiazoles , Ratas Sprague-Dawley , Sarcopenia , Animales , Sarcopenia/prevención & control , Sarcopenia/metabolismo , Sarcopenia/tratamiento farmacológico , Sarcopenia/patología , Masculino , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Envejecimiento/efectos de los fármacos , Ratas , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Miostatina/metabolismo , Antioxidantes/farmacologíaRESUMEN
RATIONALE AND OBJECTIVES: The objective of this study was to assess diversity among radiology residents relative to other specialties and compare it with historical trends. MATERIALS AND METHODS: The Graduate Medical Education results from 2010-2011 to 2020-2021 were accessed for demographic information for major medical specialties (number of residents > 500 as of the 2020-2021 report). Subspecialties and fellowship programs were not included in this analysis. The racial and ethnicity breakdowns were extracted, including Black, White/Caucasian, Asian, Hispanic, and others. The changes in racial and ethnicity composition of residents in radiology was compared to other specialties using the Chi Squared test using a significance level of p < 0.05. RESULTS: In 2020-2021, radiology ranked ninth in total resident enrollment among the 21 largest ACGME training programs, unchanged when compared to 2010-2011. Amongst all specialties, Radiology ranked 10th for Black and 9th for Hispanic representation in 2020-2021.The percentage of Black residents increased from 3.07% in 2010-2011 to 3.83% in 2020-2021. The percentage of Hispanic Radiology residents increased from 4.83% to 7.35%, constituting the third largest increase amongst all specialties. CONCLUSION: The representation of Blacks and Hispanics in Radiology has improved relative to other medical specialties in the last decade.
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Diabetes accelerates muscle atrophy, leading to the deterioration of skeletal muscles. This study aimed to assess the potential of the ß2-adrenoceptor agonist, salbutamol (SLB), to alleviate muscle atrophy in streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were randomized into four groups (n=6): control, SLB, STZ (55 mg/kg, single i.p.), and STZ + SLB (6 mg/kg, orally for 4 weeks). After the final SLB dose, animals underwent tests to evaluate muscle strength and coordination, including forelimb grip strength, wire-hanging, actophotometer, rotarod, and footprint assessments. Rats were then sacrificed, and serum and gastrocnemius (GN) muscles were collected for further analysis. Serum evaluations included proinflammatory markers (tumor necrosis factor α, interleukin-1ß, interleukin-6), muscle markers (creatine kinase, myostatin), testosterone, and lipidemic markers. Muscle oxidative stress (malonaldehyde, protein carbonyl), antioxidants (glutathione, catalase, superoxide dismutase), and histology were also performed. Additionally, 1H nuclear magnetic resonance serum profiling was conducted. SLB notably enhanced muscle grip strength, coordination, and antioxidant levels, while reduced proinflammatory markers and oxidative stress in STZ-induced diabetic rats. Reduced serum muscle biomarkers, increased testosterone, restored lipidemic levels, and improved muscle cellular architecture indicated SLB's positive effect on muscle condition in diabetic rats. Metabolomics profiling revealed that the STZ group significantly increased the phenylalanine-to-tyrosine ratio (PTR), lactate-to-pyruvate ratio (LPR), acetate, succinate, isobutyrate, and histidine. SLB administration restored these perturbed serum metabolites in the STZ-induced diabetic group. In conclusion, salbutamol significantly protected against skeletal muscle wasting in STZ-induced diabetic rats.
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Diabetes Mellitus Experimental , Ratas , Masculino , Animales , Ratas Sprague-Dawley , Estreptozocina , Diabetes Mellitus Experimental/metabolismo , Antioxidantes/farmacología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Estrés Oxidativo , Músculo Esquelético/patología , Testosterona/metabolismoRESUMEN
Cucumis callosus (Kachri) is an under-exploited fruit of the Cucurbitaceae family, distributed majorly in the arid regions of India in the states of Haryana, Rajasthan, and Gujarat. The fruit is traditionally used by the native people at a small scale by home-level processing. It is a perennial herb that has been shown to possess therapeutic potential in certain disorders. In several studies, the antioxidant, anti-hyperlipidaemic, anti-diabetic, anti-cancerous, anti-microbial, and cardioprotective properties of Kachri have been reported. The fruit has a good nutritional value in terms of high percentages of protein, carbohydrates, essential fatty acids, phenols, and various phytochemicals. Also, gamma radiation treatment has been used on this crop to reduce total bacterial counts (TBC), ensuring safety from pathogens during the storage period of the fruit and its products. These facts lay down a foundation for the development of functional food formulations and nutraceuticals of medicinal value from this functionally rich crop. Processing of traditionally valuable arid region foods into functional foods and products can potentially increase the livelihood and nutritional security of people globally. Therefore, this review focuses on the therapeutic and pharmacological potentials of the Kachri fruit in the management of non-communicable diseases (NCDs) namely, diabetes, cancer, and hyperlipidemia. Graphical abstract of the review.
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Cucumis , Enfermedades no Transmisibles , Humanos , Enfermedades no Transmisibles/tratamiento farmacológico , India , Frutas/química , Extractos Vegetales/farmacología , Extractos Vegetales/química , Fitoquímicos/análisisRESUMEN
Type 2 diabetes is a metabolic disorder that leads to accelerated skeletal muscle atrophy. In this study, we aimed to evaluate the effect of salbutamol (SLB) on skeletal muscle atrophy in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were divided into four groups (n = 6): control, SLB, HFD/STZ, and HFD/STZ + SLB (6 mg/kg orally for four weeks). After the last dose of SLB, rats were assessed for muscle grip strength and muscle coordination (wire-hanging, rotarod, footprint, and actophotometer tests). Body composition was analyzed in live rats. After that, animals were sacrificed, and serum and gastrocnemius (GN) muscles were collected. Endpoints include myofibrillar protein content, muscle oxidative stress and antioxidants, serum pro-inflammatory cytokines (interleukin-1ß, interleukin-2, and interleukin-6), serum muscle markers (myostatin, creatine kinase, and testosterone), histopathology, and muscle 1H NMR metabolomics. Findings showed that SLB treatment significantly improved muscle strength and muscle coordination, as well as increased lean muscle mass in diabetic rats. Increased pro-inflammatory cytokines and muscle markers (myostatin, creatine kinase) indicate muscle deterioration in diabetic rats, while SLB intervention restored the same. Also, Feret's diameter and cross-sectional area of GN muscle were increased by SLB treatment, indicating the amelioration in diabetic rat muscle. Results of muscle metabolomics exhibit that SLB treatment resulted in the restoration of perturbed metabolites, including histidine-to-tyrosine, phenylalanine-to-tyrosine, and glutamate-to-glutamine ratios and succinate, sarcosine, and 3-hydroxybutyrate (3HB) in diabetic rats. These metabolites showed a pertinent role in muscle inflammation and oxidative stress in diabetic rats. In conclusion, findings showed that salbutamol could be explored as an intervention in diabetic-associated skeletal muscle atrophy.
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(1) Background: Skeletal muscle atrophy is a common and debilitating condition associated with disease, bed rest, and inactivity. We aimed to investigate the effect of atenolol (ATN) on cast immobilization (IM)-induced skeletal muscle loss. (2) Methods: Eighteen male albino Wistar rats were divided into three groups: a control group, an IM group (14 days), and an IM+ATN group (10 mg/kg, orally for 14 days). After the last dose of atenolol, forced swimming test, rotarod test, and footprint analysis were performed, and skeletal muscle loss was determined. Animals were then sacrificed. Serum and gastrocnemius (GN) muscles were then collected, serum creatinine, GN muscle antioxidant, and oxidative stress levels were determined, and histopathology and 1H NMR profiling of serum metabolites were performed. (3) Results: Atenolol significantly prevented immobilization-induced changes in creatinine, antioxidant, and oxidative stress levels. Furthermore, GN muscle histology results showed that atenolol significantly increased cross-sectional muscle area and Feret's diameter. Metabolomics profiling showed that glutamine-to-glucose ratio and pyruvate, succinate, valine, citrate, leucine, isoleucine, phenylalanine, acetone, serine, and 3-hydroxybutyrate levels were significantly higher, that alanine and proline levels were significantly lower in the IM group than in the control group, and that atenolol administration suppressed these metabolite changes. (4) Conclusions: Atenolol reduced immobilization-induced skeletal muscle wasting and might protect against the deleterious effects of prolonged bed rest.
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Major depressive disorder (MDD) is a multimodal neuropsychiatric and neurodegenerative illness characterized by anhedonia, continued melancholy, dysfunctional circadian rhythm and many other behavioral infirmities. Depression is also associated with somatic ailments such as cardiometabolic diseases. The existing and upcoming hypotheses have succeeded in explaining the pathophysiology of depression. Only a few of the most validated theories, such as hyperactivity of the HPA axis, activated inflammatory-immune response, and monoaminergic and GABAergic deficit hypotheses, have been discussed in this review. So, an effective and safer alternative approach beyond symptomatic relief has been desired. Therefore, botanical products have steadily been probed to strengthen the modern medicinal system as a promising medicament. In this line, Asparagus racemosus Willd. belongs to Asparagaceace family is the well-documented adaptogen cited in the ancient texts namely, Ayurvedic, Greek, and Chinese medicine system. The whole plant possesses pleiotropic therapeutic activity, antioxidant, anti-inflammatory, immunomodulatory, neuroprotective, nootropic, antidepressant, etc., without showing any remarkable side effects. The literature review has also suggested that A. racemosus administration at varied levels alleviates depression by modulating the HPA axis, increasing BDNF levels, and monoaminergic and GABAergic neurotransmission. Alongside, spikes the level of antioxidant enzymes, SOD, GSH peroxidase, GSH, and catalase in distinct brain regions (i.e., hippocampus, prefrontal cortex, amygdala, and hypothalamus) and promote neurogenesis and neuroplasticity. Thus, it could be a new generation antidepressant that provides relief from both behavioral and somatic illness. The review first describes the plant characteristics, then discusses the hypotheses associated with the pathogenesis of depression, and gives an insight into A. racemosus antidepressant properties and the underlying mechanism.
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An association between the loss of skeletal muscle mass and obesity in the geriatric population has been identified as a disease known as sarcopenic obesity. Therefore, therapeutic/preventive interventions are needed to ameliorate sarcopenia. The present study investigates the effect of azilsartan (AZL) on skeletal muscle loss in High-Fat Diet (HFD)-induced sarcopenic obese (SO) rats. Four- and fourteen-months male Sprague Dawley rats were used and randomized in control and azilsartan treatment. 14 months animals were fed with HFD for four months and labeled as HFD-fed SO rats. Young & old rats received 0.5% carboxymethyl cellulose as a vehicle/AZL (8 mg/kg, per oral) treatment for six weeks. Grip strength and body composition analysis were performed after the last dose of AZL. Serum and gastrocnemius (GN)muscles were collected after animal sacrifice. AZL treatment significantly increased lean muscle mass, grip strength, myofibrillar protein, and antioxidant (superoxide dismutase & nitric oxide) levels in SO rats. AZL also restored the muscle biomarkers (creatine kinase, myostatin & testosterone), and insulin levels. AZL improves cellular, and ultracellular muscle structure and prevents type I to type II myofiber transitions in SO rats. Further, immunohistochemistry results showed increased expressions of pAkt and reduced expression of MuRF-1 and TNF-α exhibiting that AZL intervention could decrease protein degradation in SO rats. In conclusion, present results showed that AZL significantly increased lean mass, and restored muscle biomarkers, and muscle architecture. Taken together, the aforementioned findings suggest that azilsartan could be a possible therapeutic approach to reduce muscle wasting in sarcopenic obesity.
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Resistencia a la Insulina , Sarcopenia , Anciano , Ratas , Masculino , Humanos , Animales , Sarcopenia/tratamiento farmacológico , Sarcopenia/etiología , Sarcopenia/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratas Sprague-Dawley , Músculo Esquelético/metabolismo , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Resistencia a la Insulina/fisiologíaRESUMEN
In this article, we aim to highlight the utility of dual-energy computed tomography (DECT) in demonstrating imaging changes due to hypoxic pulmonary vasoconstriction (HPV). DECT allows detailed image reconstructions that have been shown to better characterize cardiothoracic pathologies, as compared to conventional CT techniques. DECT simultaneously detects two different X-ray energies, which enables generation of iodine density maps, virtual monoenergetic images, and effective atomic number maps (Zeff), among others. DECT has been shown to have utility in the assessment of benign versus malignant pulmonary nodules, pulmonary embolism, myocardial perfusion defects, and other conditions. Herein, we describe four cases of indeterminate pulmonary pathology when imaged with conventional CT in which subsequent use of DECT-derived image reconstructions demonstrated HPV as the underlying pathophysiological mechanism. The goal of this article is to understand the imaging appearance of HPV on DECT and discuss how HPV may mimic other causes of perfusion defects.
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Allium cepa L. is an important medicinal and food plant enormously affected by salinity in terms of its growth and quality. This experiment investigates ameliorative potential of NO donor sodium nitroprusside (SNP) on chromosomal aberrations and physiological parameters in A. cepa L. roots exposed to salinity stress. Roots with different concentrations of NaCl (25, 50, and 100 mM) alone, and in combination with 100 µM SNP were analyzed for mitotic aberrations, DNA damage, proline, malondialdehyde (MDA) content, and ascorbate-glutathione (AsA-GSH) cycle after 120 h of salinity treatments. Results revealed that salinity stress increased chromosomal aberrations, MDA, proline accumulation, and severely hampered the AsA-GSH cycle function. The comet assay revealed a significant (p ≤ 0.05) enhancement in tail length (4.35 ± 0.05 µm) and olive tail moment (3.19 ± 0.04 µm) at 100 mM NaCl exposure. However, SNP supplementation decreased total percent abnormalities, while increased the prophase, metaphase, anaphase, and telophase indexes. Moreover, ascorbate peroxidase and glutathione reductase activities increased with AsA/DHA and GSH/GSSG ratios, respectively. Results suggest that SNP supplementation alleviates salinity stress responses by improving AsA-GSH cycle and proline accumulation. Based on present findings, NO supplementation could be recommended as a promising approach for sustainable crop production under salinity stress.
Allium cepa L. response to salt stress has been investigated but its role on chromosomal changes and DNA damage are less investigated therefore, our focus is to explore NO supplementation effects on cytological aberrations and biochemical responses in A. cepa L. roots under salinity stress.
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Óxido Nítrico , Cebollas , Óxido Nítrico/metabolismo , Cebollas/metabolismo , Cloruro de Sodio/metabolismo , Plantones , Biodegradación Ambiental , Ácido Ascórbico/metabolismo , Antioxidantes/metabolismo , Glutatión/metabolismo , Estrés Salino , Daño del ADN , Prolina/metabolismo , Aberraciones Cromosómicas , Estrés OxidativoRESUMEN
Progesterone and prostaglandin E1 are postulated to trigger the human sperm acrosome reaction (AR). However, their reported efficacy is very variable which likely, in part, reflects the plethora of experimental conditions and methodologies used to detect this physiologically relevant event. The purpose of this study was to develop an assay for the robust induction and objective measurement of the complete AR. Sperm from healthy volunteers or patients undertaking IVF were treated with a variety of ligands (progesterone, prostaglandin E1 or NH4Cl, alone or in combinations). AR, motility and intracellular calcium measurements were measured using flow cytometry, computer-assisted sperm analysis (CASA) and fluorimetry, respectively. The AR was significantly increased by the simultaneous application of progesterone, prostaglandin E1 and NH4Cl, following an elevated and sustained intracellular calcium concentration. However, we observed notable inter- and intra-donor sample heterogeneity of the AR induction. When studying the patient samples, we found no relationship between the IVF fertilization rate and the AR. We conclude that progesterone and prostaglandin E1 alone do not significantly increase the percentage of live acrosome-reacted sperm. This assay has utility for drug discovery and sperm toxicology studies but is not predictive for IVF success.
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Reacción Acrosómica , Calcio , Acrosoma , Alprostadil , Calcio de la Dieta , Humanos , Masculino , Progesterona/farmacología , Semen , Motilidad Espermática , Espermatozoides/fisiologíaRESUMEN
Since endophytic fungi are pivotal sources of various bioactive natural compounds, the present study is aimed to investigate the antioxidant compounds of the endophytic fungus Nigrospora sphaerica isolated from a pantropical weed, Euphorbia hirta L. The fungus was fermented in four different media and each filtered broth was sequentially extracted in various solvents. Crude extracts collected from different solvents were subjected to phytochemical analysis and antioxidant activity. The total phenolic content (TPC) and total flavonoid content (TFC) were maximal in ethyl acetate crude extract (EtOAcE) of endophyte fermented in potato dextrose broth (PDB) medium (77.74 ± 0.046mgGAE/g and 230.59 ± 2.0 mgRE/g) with the highest 96.80% antioxidant activity. However, TPC and TFC were absent in hexane extract of Czapek Dox broth (CDB) medium exhibiting the lowest 4.63 ± 2.75% activity. The EtOAcE (PDB) showed a positive correlation between TFC and antiradical activity (R2 = 0.762; P < 0.05), whereas a high positive correlation was noticed between TPC and antioxidant activity (R2 = 0.989; P < 0.05). Furthermore, to determine the antioxidant activity, EtOAcE (PDB) was subjected to TLC bioautography-based partial purification, while GC/MS analysis of the partial purified extract was done to confirm the presence of phenolics along with antioxidant compounds that resulted in the detection of 2,4-Di-tert-butylphenol (13.83%), a phenolic compound accountable for the antioxidant potential. Conclusively, N. sphaerica is a potential candidate for natural antioxidant.
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Ascomicetos , Euphorbia , Plantas Medicinales , Antioxidantes , Flavonoides , Extractos VegetalesRESUMEN
Natamycin is a natural antimicrobial peptide produced by the strains of Streptomyces natalensis. It effectively acts as an antifungal preservative on various food products like yogurt, khoa, sausages, juices, wines, etc. Additionally, it has been used as a bio preservative and is listed as generally recognized as a safe ingredient for various food applications. In this review, natamycin properties, production methods, toxicity, and application as a natural preservative in different foods are emphasized. This review also focuses on optimal condition and process control required in natamycin production. The mode of action and inhibitory effect of natamycin on yeast and molds inhibition and its formulation and dosage to preserve various food products, coating, and hurdle applications are summarized. Understanding the scientific factors in natamycin's production process, its toxicity, and its efficiency as a preservative will open its practical application in various food products. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10068-021-00981-1.
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The endophytic fungus Diaporthe longicolla was isolated from the stem of Saraca asoca (Roxb.) Willd., commonly known as Ashok plant in India and Sri Lanka. Since no reports are available regarding epigenetic modulations by BRD4770 in microbial entities, D. longicolla was treated with different concentrations of BRD4770 for this purpose and evaluated for its antioxidant and antibacterial potential against five human pathogenic bacteria, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Shigella boydii, Klebsiella pneumoniae, and Escherichia coli. The crude extract obtained from cultures treated with 100 nM concentration of BRD4770 showed increased antioxidant activity and inhibition zone against S. aureus and MRSA, compared to the non-treated control. The composition of the non-treated and treated crude extract was analyzed, and induced compounds were identified with the help of Gas chromatography-mass spectrometry (GC-MS) and LC-ESI-MS/MS. LC-ESI-MS/MS analysis showed that berberine (antibacterial)-, caffeine-, and theobromine (antioxidant)-like compounds were induced in the BRD4770-treated crude extract. The presence of particular absorbance at a wavelength of 346.5 nm for berberine, 259.4 nm for caffeine, and 278.4 nm for theobromine in the reverse-phase high-performance liquid chromatography (HPLC) analysis of both BRD4770-treated crude metabolites and standard solution of the above compounds strongly supported the increased antibacterial and antioxidant activities that may be due to inducing the alterations in bioactivities of the BRD4770-treated culture.
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One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer. Cancer Immunol Res; 6(5); 509-16. ©2018 AACR.
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Neoplasias Colorrectales/terapia , Citotoxicidad Inmunológica , Inmunoterapia Adoptiva/métodos , Neoplasias Pulmonares/prevención & control , Receptores Quiméricos de Antígenos/metabolismo , Receptores de Enterotoxina , Linfocitos T/trasplante , Animales , Células Cultivadas , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/secundario , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Metástasis de la Neoplasia , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Quiméricos de Antígenos/genética , Receptores de Enterotoxina/genética , Receptores de Enterotoxina/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The dissemination of cancer cells to local and distant sites depends on a complex and poorly understood interplay between malignant cells and the cellular and non-cellular components surrounding them, collectively termed the tumour microenvironment. One of the most abundant cell types of the tumour microenvironment is the fibroblast, which becomes corrupted by locally derived cues such as TGF-ß1 and acquires an altered, heterogeneous phenotype (cancer-associated fibroblasts, CAF) supportive of tumour cell invasion and metastasis. Efforts to develop new treatments targeting the tumour mesenchyme are hampered by a poor understanding of the mechanisms underlying the development of CAF. Here, we examine the contribution of microRNA to the development of experimentally-derived CAF and correlate this with changes observed in CAF derived from tumours. Exposure of primary normal human fibroblasts to TGF-ß1 resulted in the acquisition of a myofibroblastic CAF-like phenotype. This was associated with increased expression of miR-145, a miRNA predicted in silico to target multiple components of the TGF-ß signalling pathway. miR-145 was also overexpressed in CAF derived from oral cancers. Overexpression of miR-145 blocked TGF-ß1-induced myofibroblastic differentiation and reverted CAF towards a normal fibroblast phenotype. We conclude that miR-145 is a key regulator of the CAF phenotype, acting in a negative feedback loop to dampen acquisition of myofibroblastic traits, a key feature of CAF associated with poor disease outcome.