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1.
J Ayurveda Integr Med ; 15(2): 100903, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38574518

RESUMEN

BACKGROUND: The pathogenesis of COVID-19 includes an integrated immune-inflammatory response. Modulation of host immune responses against the SARS-CoV-2 virus might be effective therapeutic management. Various Unani formulations have an immunomodulatory effect. OBJECTIVE: To explore the immunomodulatory effect and safety of Unani polyherbal drug (Tiryaq Wabai) in COVID-19 patients. MATERIALS AND METHODS: The current study was a randomized placebo-controlled clinical trial that included 92 mild to moderate COVID-19 patients randomized into two groups. The Unani formulation Tiryaq Wabai (2 gm orally once a day) was used as an intervention for 45 days, while the control group received a placebo. Both groups received standard care treatment. The primary outcome was 50% increment in absolute lymphocyte count (ALC). The secondary outcome was 50% increment in mean lymphocyte percentage, CD4 cells, and CD8 cell count. The mean increase in all the above parameters has also been studied. Relevant statistical tests were used to analyze the effect. RESULTS: A statistically significant improvement in a 50% increase in ALC (p-value, 0.004), lymphocyte percentage (p-value, 0.056), CD4 (p-value, 0.005), and CD8 cell count (p-value, 0.050) was reported. Also, a significant improvement in the mean value of the lymphocyte percentage (p-value 0.0007), ALC (p-value 0.0022), CD4 cell count (p-value 0.0025), and CD8 cell count (p-value 0.0093) was observed after the treatment. One adverse event of mild grade was reported in the placebo group. The analysis of safety parameters (LFT and KFT) was normal for both groups. CONCLUSION: In mild to moderate COVID-19 patients, Tiryaq Wabai effectively showed immunomodulatory activity by improving ALC count, lymphocyte percentage, CD4, and CD8 cell count.

2.
Opt Express ; 31(16): 26451-26462, 2023 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-37710506

RESUMEN

Photonic integrated circuits require photodetectors that operate at room temperature with sensitivity at telecom wavelengths and are suitable for integration with planar complementary-metal-oxide-semiconductor (CMOS) technology. Silicon hyperdoped with deep-level impurities is a promising material for silicon infrared detectors because of its strong room-temperature photoresponse in the short-wavelength infrared region caused by the creation of an impurity band within the silicon band gap. In this work, we present the first experimental demonstration of lateral Te-hyperdoped Si PIN photodetectors operating at room temperature in the optical telecom bands. We provide a detailed description of the fabrication process, working principle, and performance of the photodiodes, including their key figure of merits. Our results are promising for the integration of active and passive photonic elements on a single Si chip, leveraging the advantages of planar CMOS technology.

3.
Sci Rep ; 13(1): 9865, 2023 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-37332070

RESUMEN

The landscape of current cancer immunotherapy is dominated by antibodies targeting PD-1/PD-L1 and CTLA-4 that have transformed cancer therapy, yet their efficacy is limited by primary and acquired resistance. The blockade of additional immune checkpoints, especially TIGIT and LAG-3, has been extensively explored, but so far only a LAG-3 antibody has been approved for combination with nivolumab to treat unresectable or metastatic melanoma. Here we report the development of a PDL1 × TIGIT bi-specific antibody (bsAb) GB265, a PDL1 × LAG3 bsAb GB266, and a PDL1 × TIGIT × LAG3 tri-specific antibody (tsAb) GB266T, all with intact Fc function. In in vitro cell-based assays, these antibodies promote greater T cell expansion and tumor cell killing than benchmark antibodies and antibody combinations in an Fc-dependent manner, likely by facilitating T cell interactions (bridging) with cancer cells and monocytes, in addition to blocking immune checkpoints. In animal models, GB265 and GB266T antibodies outperformed benchmarks in tumor suppression. This study demonstrates the potential of a new generation of multispecific checkpoint inhibitors to overcome resistance to current monospecific checkpoint antibodies or their combinations for the treatment of human cancers.


Asunto(s)
Melanoma , Neoplasias , Animales , Humanos , Neoplasias/terapia , Nivolumab , Receptores Inmunológicos , Inmunoterapia , Linfocitos T
4.
Nat Commun ; 13(1): 7641, 2022 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-36496453

RESUMEN

Eps15-homology domain containing proteins (EHDs) are eukaryotic, dynamin-related ATPases involved in cellular membrane trafficking. They oligomerize on membranes into filaments that induce membrane tubulation. While EHD crystal structures in open and closed conformations were previously reported, little structural information is available for the membrane-bound oligomeric form. Consequently, mechanistic insights into the membrane remodeling mechanism have remained sparse. Here, by using cryo-electron tomography and subtomogram averaging, we determined structures of nucleotide-bound EHD4 filaments on membrane tubes of various diameters at an average resolution of 7.6 Å. Assembly of EHD4 is mediated via interfaces in the G-domain and the helical domain. The oligomerized EHD4 structure resembles the closed conformation, where the tips of the helical domains protrude into the membrane. The variation in filament geometry and tube radius suggests a spontaneous filament curvature of approximately 1/70 nm-1. Combining the available structural and functional data, we suggest a model for EHD-mediated membrane remodeling.


Asunto(s)
Dinaminas , Tomografía con Microscopio Electrónico , Dinaminas/metabolismo , Adenosina Trifosfatasas/metabolismo , Membrana Celular/metabolismo , Membranas/metabolismo , Microscopía por Crioelectrón
5.
Adv Ther (Weinh) ; : 2200159, 2022 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-36246300

RESUMEN

Inosine pranobex (IP), an immunomodulatory agent, is used in the treatment of various viral infections. The results of a phase 3 randomized controlled trial are reported, evaluating the efficacy and safety of IP in the treatment of mild to moderate COVID-19. It includes 416 symptomatic patients with confirmed SARS-CoV-2 infection. In addition to a defined standard of care, patients  randomly (1:1) receive either IP 500 mg tablet (IP group) or a matching placebo (placebo group) at 50 mg kg-1 body weight/day rounded to the nearest 500 mg dose (maximum 4 g day-1) administered in 3-4 divided doses for 10 days. Compared to the placebo group, IP group shows significantly higher rates of clinical response (CR) and clinical cure (CC) on Day-6 for both non-hospitalized patients and the total population. IP group shows significantly earlier CR and CC with fewer adverse events and no mortality. Based on these findings and the fact that IP increases natural killer cell-mediated cytotoxicity of virus-infected cells as an early immune response to viral infection and enhances NKG2D ligand expression, it is concluded that IP should be started early to maximize the benefit in mild to moderate COVID-19 patients. (Trial registration number: CTRI/2021/02/030892).

6.
ACS Nano ; 16(8): 12777-12785, 2022 Aug 23.
Artículo en Inglés | MEDLINE | ID: mdl-35900823

RESUMEN

Highly sensitive short-wave infrared (SWIR) detectors, compatible with the silicon-based complementary metal oxide semiconductor (CMOS) process, are regarded as the key enabling components in the miniaturized system for weak signal detection. To date, the high photogain devices are greatly limited by a large bias voltage, low-temperature refrigeration, narrow response band, and complex fabrication processes. Here, we demonstrate high photogain detectors working in the SWIR region at room temperature, which use graphene for charge transport and Te-hyperdoped silicon (Te-Si) for infrared absorption. The prolonged lifetime of carriers, combined with the built-in potential generated at the interface between the graphene and the Te-Si, leads to an ultrahigh photogain of 109 at room temperature (300 K) for 1.55 µm light. The gain can be improved to 1012, accompanied by a noise equivalent power (NEP) of 0.08 pW Hz-1/2 at 80 K. Moreover, the proposed device exhibits a NEP of 4.36 pW Hz-1/2 at 300 K at the wavelength of 2.7 µm, which is exceeding the working region of InGaAs detectors. This research shows that graphene can be used as an efficient platform for silicon-based SWIR detection and provides a strategy for the low-power, uncooled, high-gain infrared detectors compatible with the CMOS process.

7.
Indian J Crit Care Med ; 26(5): 596-603, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35719441

RESUMEN

Background: Coronavirus disease-2019 (COVID-19) is prone to acute hypoxemic respiratory failure (AHRF). Because tracheal intubation is associated with a higher risk of death in these patients, AHRF employs high-flow nasal oxygen therapy (HFNOT). The goal of this study was to assess the effect of HFNOT on oxygenation status as well as different predictors of HFNOT failure. Methods: A prospective observational cohort study was conducted in COVID-positive critically ill adult patients (age >18 years) with AHRF, who were unable to maintain SpO2 >90% on a non-rebreathing face mask at an oxygen flow ≥15 L/minute. Respiratory variables (PaO2/FiO2, SpO2, and RR) before HFNOT (baseline) and then at 1 hour, 6 hours, 7th day, and 14th day after HFNOT application were recorded. Borg CR10 scale and visual analogue scale were used to evaluate the subjective sensation of dyspnea and comfort level, respectively. As needed, Student's t, Mann-Whitney U, or Wilcoxon signed-rank tests were performed. To find parameters linked to HFNOT failure, multivariate logistic regression and receiver operating characteristic (ROC) analysis were employed. Results: A total of 114 patients were enrolled in the study, with an HFNOT failure rate of 29%. The median PaO2/FiO2 ratio at baseline (before the initiation of HFNOT) was 99.5 (80-110) which significantly increased at various time points (1 hour, 6 hours, 7th day, and 14th day) after HFNOT initiation in the successful group. Patients reported significant improvement in sensation of breathlessness [9 (8-10), 3 (2-4); p <0.001] as well as in comfort level [2 (1-2), 8 (4-9); p <0.001]. Multivariate logistic regression analysis, sequential organ failure assessment (SOFA) score >7, acute physiology and chronic health evaluation (APACHE) II score >20, admission P/F ratio <100, D-dimer >2 mg/L, IL-6 >40 pg/mL, random blood sugar (RBS) >250 mg/dL, and 6 hours ROX Index <3.5 were independent prognostic factors of HFNOT failure. Conclusion: The use of HFNOT significantly increased the oxygenation levels in COVID-19 patients with AHRF at various time periods after HFNOT beginning. Age, SOFA score, APACHE II score, ROX score, admission P/F ratio, IL-6, D-dimer, and RBS were independent prognostic factors of HFNOT failure in this cohort. How to cite this article: Khan MS, Prakash J, Banerjee S, Bhattacharya PK, Kumar R, Nirala DK. High-flow Nasal Oxygen Therapy in COVID-19 Critically Ill Patients with Acute Hypoxemic Respiratory Failure: A Prospective Observational Cohort Study. Indian J Crit Care Med 2022;26(5):596-603.

8.
Intensive Care Med ; 48(5): 580-589, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35359168

RESUMEN

PURPOSE: We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. METHODS: We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. RESULTS: We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference - 4.3%; 99% confidence interval (CI) - 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI - 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (- 3 to 10; P = 0.22). CONCLUSION: Among patients with COVID-19 and severe hypoxaemia, dexamethasone 12 mg compared with 6 mg did not result in statistically significant improvements in mortality or HRQoL at 180 days, but the results were most compatible with benefit from the higher dose.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Dexametasona , Hipoxia , Adulto , COVID-19/complicaciones , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Humanos , Hipoxia/complicaciones , Hipoxia/tratamiento farmacológico , Gravedad del Paciente , Calidad de Vida , Encuestas y Cuestionarios , Resultado del Tratamiento
9.
Nanoscale ; 14(7): 2826-2836, 2022 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-35133384

RESUMEN

Plasmonic sensing in the infrared region employs the direct interaction of the vibrational fingerprints of molecules with the plasmonic resonances, creating surface-enhanced sensing platforms that are superior to traditional spectroscopy. However, the standard noble metals used for plasmonic resonances suffer from high radiative losses as well as fabrication challenges, such as tuning the spectral resonance positions into mid- to far-infrared regions, and the compatibility issue with the existing complementary metal-oxide-semiconductor (CMOS) manufacturing platform. Here, we demonstrate the occurrence of mid-infrared localized surface plasmon resonances (LSPR) in thin Si films hyperdoped with the known deep-level impurity tellurium. We show that the mid-infrared LSPR can be further enhanced and spectrally extended to the far-infrared range by fabricating two-dimensional arrays of micrometer-sized antennas in a Te-hyperdoped Si chip. Since Te-hyperdoped Si can also work as an infrared photodetector, we believe that our results will unlock the route toward the direct integration of plasmonic sensors with the on-chip CMOS platform, greatly advancing the possibility of mass manufacturing of high-performance plasmonic sensing systems.

10.
J Tradit Complement Med ; 12(1): 100-113, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-35036347

RESUMEN

BACKGROUND AND AIM: The management of the worldwide spreading COVID-19 consists of amelioration of its symptoms but no cure is yet available. Herbal medicines supplemented with the Western medicine have been applied for COVID-19 treatment in India, China, Iran, and other countries. This systematic review and meta-analysis of RCTs evaluates the effect and safety of herbal intervention in the management of COVID-19. EXPERIMENTAL PROCEDURE: RCTs from databases like PubMed, Cochrane Library, ScienceDirect, Google Scholar, Science Direct, CTRI, AYUSH Research Portal, India, were reviewed and the data were extracted for study sample demographics, intervention details, clinical effect, inflammatory markers and safety monitoring. Outcomes were expressed as Risk-ratio (RR) with 95% CI for dichotomous data, and Mean-Difference (MD) with 95% CI for continuous data. RESULT AND CONCLUSION: From the 32 eligible studies, a total of 3177 COVID-19 patients were included in the review. Herbal intervention as an adjuvant to Western medicine causes significantly higher improvement compared to Western medicine alone [Fever (RR = 1.09 CI 1.03, 1.15), Cough (Risk-Ratio = 1.22 CI 1.08, 1.37), Fatigue (Risk-Ratio = 1.27 CI 1.11, 1.44), Chest CT Improvement (Risk-Ratio = 1.15 CI 1.08, 1.23)]. The laboratory parameters were also better in the herbal medicine group compared to standard care group only WBC (MD = 0.36 CI 0.16, 0.55), Lymphocyte percentage (MD = 5.48 CI 3.05, 7.92), Absolute lymphocyte count (MD = 0.23 CI 0.07, 0.39), CRP (MD = -5.66 CI -7.96, -3.37). However, duration of hospital stays (MD = -1.82 CI -3.84, 0.21); IL-6 (MD = -3.67 CI -8.76, 1.43), ESR Level (MD = -10.38 CI -25.96, 5.21) were statistically insignificant. No significant adverse events for herbal medications were noted in the included RCTs, during the time of the studies. (n = 665, RR 0.93; 95% CI 0.76, 1.14).

11.
Intensive Care Med ; 48(1): 45-55, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34757439

RESUMEN

PURPOSE: We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. METHODS: We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. RESULTS: The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI -0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. CONCLUSION: We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Teorema de Bayes , Dexametasona , Humanos , Hipoxia , SARS-CoV-2 , Esteroides
12.
Indian J Crit Care Med ; 26(11): 1184-1191, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36873595

RESUMEN

Background: Emergency authorization and approval were given for the coronavirus disease-19 (COVID-19) vaccines. The efficacy reported after phase III trials were 70.4% and 78% for Covishield and Covaxin, respectively.In this study, we aim to analyze the risk factors, which were associated with mortality in critically ill COVID-19-vaccinated patients admitted into intensive care unit (ICU). Materials and methods: This study was conducted from April 1, 2021 to December 31, 2021 across five centers in India. Patients who had received either one or two doses of any of the COVID vaccines and developed COVID-19 were included. The ICU mortality was a primary outcome. Results: A total of 174 patients with COVID-19 illness were included in the study. The mean age was 57 years standard deviation (SD 15). Acute physiology, age and chronic health evaluation (APACHE II) score and the sequential organ failure assessment (SOFA) score were 14 (8-24.5) and 6 (4-8), respectively. Multiple variable logistic regression showed patients who have received a single dose [odds ratio (OR): 2.89, confidence interval (CI): 1.18, 7.08], neutrophil:lymphocyte (NL) ratio (OR: 1.07, CI: 1.02,1.11), and SOFA score (OR: 1.18, CI: 1.03,1.36) were associated with higher mortality. Conclusion: The mortality in the vaccinated patients admitted to the ICU was 43.68% due to COVID illness. The mortality was lower in patients who had received two doses. How to cite this article: Havaldar AA, Prakash J, Kumar S, Sheshala K, Chennabasappa A, Thomas RR et al. Demographics and Clinical Characteristics of COVID-19-vaccinated Patients Admitted to ICU: A Multicenter Cohort Study from India (PostCoVac Study-COVID Group). Indian J Crit Care Med 2022;26(11):1184-1191.

14.
Acta Anaesthesiol Scand ; 65(5): 702-710, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33583027

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID-19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID-19 and severe hypoxia. METHODS: This protocol outlines the rationale and statistical methods for a secondary, pre-planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle-negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre-defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. DISCUSSION: This secondary, pre-planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04509973; EudraCT: 2020-003363-25.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Dexametasona/administración & dosificación , Hipoxia/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , SARS-CoV-2 , Teorema de Bayes , Humanos
15.
J Cell Sci ; 132(3)2019 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-30709970

RESUMEN

Compartmentalization of membrane transport and signaling processes is of pivotal importance to eukaryotic cell function. While plasma membrane compartmentalization and dynamics are well known to depend on the scaffolding function of septin GTPases, the roles of septins at intracellular membranes have remained largely elusive. Here, we show that the structural and functional integrity of the Golgi depends on its association with a septin 1 (SEPT1)-based scaffold, which promotes local microtubule nucleation and positioning of the Golgi. SEPT1 function depends on the Golgi matrix protein GM130 (also known as GOLGA2) and on centrosomal proteins, including CEP170 and components of γ-tubulin ring complex (γ-Turc), to facilitate the perinuclear concentration of Golgi membranes. Accordingly, SEPT1 depletion triggers a massive fragmentation of the Golgi ribbon, thereby compromising anterograde membrane traffic at the level of the Golgi.


Asunto(s)
Autoantígenos/genética , Centrosoma/metabolismo , Aparato de Golgi/metabolismo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos/metabolismo , Septinas/genética , Células 3T3-L1 , Animales , Autoantígenos/metabolismo , Transporte Biológico , Compartimento Celular , Línea Celular , Centrosoma/ultraestructura , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Regulación de la Expresión Génica , Aparato de Golgi/ultraestructura , Células HEK293 , Células HeLa , Humanos , Células Jurkat/metabolismo , Células Jurkat/ultraestructura , Proteínas de la Membrana/metabolismo , Ratones , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/ultraestructura , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/metabolismo , Septinas/antagonistas & inhibidores , Septinas/metabolismo , Transducción de Señal
18.
Clin Cancer Res ; 19(1): 73-84, 2013 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-23147995

RESUMEN

PURPOSE: miRNAs can act as oncomirs or tumor-suppressor miRs in cancer. This study was undertaken to investigate the status and role of miR-34b in prostate cancer. EXPERIMENTAL DESIGN: Profiling of miR-34b was carried out in human prostate cancer cell lines and clinical samples by quantitative real-time PCR and in situ hybridization. Statistical analyses were done to assess diagnostic/prognostic potential. Biological significance was elucidated by carrying out a series of experiments in vitro and in vivo. RESULTS: We report that miR-34b is silenced in human prostate cancer and the mechanism is through CpG hypermethylation. miR-34b directly targeted methyltransferases and deacetylases resulting in a positive feedback loop inducing partial demethylation and active chromatin modifications. miR-34b expression could predict overall and recurrence-free survival such that patients with high miR-34b levels had longer survival. Functionally, miR-34b inhibited cell proliferation, colony formation, migration/invasion, and triggered G(0)/G(1) cell-cycle arrest and apoptosis by directly targeting the Akt and its downstream proliferative genes. miR-34b caused a decline in the mesenchymal markers vimentin, ZO1, N-cadherin, and Snail with an increase in E-cadherin expression, thus inhibiting epithelial-to-mesenchymal transition. Finally we showed the antitumor effect of miR-34b in vivo. MiR-34b caused a dramatic decrease in tumor growth in nude mice compared with cont-miR. CONCLUSION: These findings offer new insight into the role of miR-34b in the inhibition of prostate cancer through demethylation, active chromatin modification, and Akt pathways and may provide a rationale for the development of new strategies targeting epigenetic regulation of miRNAs for the treatment of prostate cancer.


Asunto(s)
Cromatina/genética , Cromatina/metabolismo , MicroARNs/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Regiones no Traducidas 5' , Animales , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Transformación Celular Neoplásica/genética , Islas de CpG , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , Epigénesis Genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Masculino , Ratones , MicroARNs/metabolismo , Invasividad Neoplásica/genética , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología
19.
J Ovarian Res ; 5(1): 44, 2012 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-23237306

RESUMEN

Ovarian cancer is the fifth most common cancer among women and causes more deaths than any other type of female reproductive cancer. Currently, treatment of ovarian cancer is based on the combination of surgery and chemotherapy. While recurrent ovarian cancer responds to additional chemotherapy treatments, the progression-free interval becomes shorter after each cycle, as chemo-resistance increases until the disease becomes incurable. There is, therefore, a strong need for prognostic and predictive markers to help optimize and personalize treatment in order to improve the outcome of ovarian cancer. An increasing number of studies indicate an essential role for microRNAs in ovarian cancer progression and chemo-resistance. MicroRNAs (miRNAs) are small endogenous non-coding RNAs (~22bp) which are frequently dysregulated in cancer. Typically, miRNAs are involved in crucial biological processes, including development, differentiation, apoptosis and proliferation. Two families of miRNAs, miR-200 and let-7, are frequently dysregulated in ovarian cancer and have been associated with poor prognosis. Both have been implicated in the regulation of epithelial-to-mesenchymal transition, a cellular transition associated with tumor aggressiveness, tumor invasion and chemo-resistance. Moreover, miRNAs also have possible implications for improving cancer diagnosis; for example miR-200 family, let-7 family, miR-21 and miR-214 may be useful in diagnostic tests to help detect ovarian cancer at an early stage. Additionally, the use of multiple target O-modified antagomirs (MTG-AMO) to inhibit oncogenic miRNAs and miRNA replacement therapy for tumor suppressor miRNAs are essential tools for miRNA based cancer therapeutics. In this review we describe the current status of the role miRNAs play in ovarian cancer and focus on the possibilities of microRNA-based therapies and the use of microRNAs as diagnostic tools.

20.
PLoS One ; 7(11): e50203, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23189187

RESUMEN

BACKGROUND: miR-23b is located on chromosome number 9 and plays different roles in different organs especially with regards to cancer development. However, the functional significance of miR-23b-3p in renal cell carcinoma (RCC) has not been reported. METHODS AND RESULTS: We measured miR-23b-3p levels in 29 pairs of renal cell carcinoma and their normal matched tissues using real-time PCR. The expression level of miR-23b-3p was correlated with the 5 year survival rate of renal cancer patients. In 15 cases (52%), miR-23b-3p expression was found to be high. All patients with moderate to low miR-23b-3p expression survived 5 years, while those with high miR-23b-3p expression, only 50% survived. After knocking down miRNA-23b-3p expression in RCC cell lines, there was an induction of apoptosis and reduced invasive capabilities. MiR-23b-3p was shown to directly target PTEN gene through 3'UTR reporter assays. Inhibition of miR-23b-3p induces PTEN gene expression with a concomitant reduction in PI3-kinase, total Akt and IL-32. Immunohistochemistry showed the lack of PTEN protein expression in cancerous regions of tissue samples where the expression of miR-23b-3p was high. We studied the in vitro effects of the dietary chemo preventive agent genistein on miR-23b-3p expression and found that it inhibited expression of miR-23b-3p in RCC cell lines. CONCLUSIONS: The current study shows that miR-23b-3p is an oncogenic miRNA and inhibits PTEN tumor suppressor gene in RCC. Therefore, inhibition of miR-23b-3p may be a useful therapeutic target for the treatment of renal cell carcinoma.


Asunto(s)
Carcinoma de Células Renales/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales/genética , MicroARNs/genética , Fosfohidrolasa PTEN/genética , Apoptosis/genética , Secuencia de Bases , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Genisteína/metabolismo , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , MicroARNs/metabolismo , Fosfohidrolasa PTEN/metabolismo , Interferencia de ARN
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