Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial.

BACKGROUND: Pembrolizumab plus lenvatinib has shown antitumor activity and acceptable safety in patients with platinum-refractory urothelial carcinoma (UC). OBJECTIVE: To evaluate pembrolizumab plus either lenvatinib or placebo as first-line therapy for advanced UC in the phase 3 LEAP-011 study. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced UC who were ineligible for cisplatin-based therapy or any platinum-based chemotherapy were enrolled. INTERVENTION: Patients were randomly assigned (1:1) to pembrolizumab 200 mg intravenously every 3 wk plus either lenvatinib 20 mg or placebo orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). An external data monitoring committee (DMC) regularly reviewed safety and efficacy data every 3 mo. RESULTS AND LIMITATIONS: Between June 25, 2019 and July 21, 2021, 487 patients were allocated to receive lenvatinib plus pembrolizumab (n = 245) or placebo plus pembrolizumab (n = 242). The median time from randomization to the data cutoff date (July 26, 2021) was 12.8 mo (interquartile range, 6.9-19.3). The median PFS was 4.5 mo in the combination arm and 4.0 mo in the pembrolizumab arm (hazard ratio [HR] 0.90 [95% confidence interval {CI} 0.72-1.14]). The median OS was 11.8 mo for the combination arm and 12.9 mo for the pembrolizumab arm (HR 1.14 [95% CI 0.87-1.48]). Grade 3-5 adverse events attributed to trial treatment occurred in 123 of 241 patients (51%) treated with lenvatinib plus pembrolizumab and in 66 of 242 patients (27%) treated with placebo plus pembrolizumab. This trial was terminated earlier than initially planned based on recommendation from the DMC. CONCLUSIONS: The benefit-to-risk ratio for first-line lenvatinib plus pembrolizumab was not considered favorable versus pembrolizumab plus placebo as first-line therapy in patients with advanced UC. PATIENT SUMMARY: Lenvatinib plus pembrolizumab was not more effective than pembrolizumab plus placebo in patients with advanced urothelial carcinoma.

Potentially inappropriate prescriptions in geriatric patients hospitalized in the internal medicine department of a referral hospital in Mexico.

BACKGROUND: Potentially inappropriate prescription (PIP) constitutes a risk for the development of adverse effects of a drug that outweigh its benefits, which can be considered inappropriate medication use. OBJECTIVE: To describe the prevalence of PIP in geriatric patients hospitalized at the internal medicine department of a referral hospital in Mexico. MATERIAL AND METHODS: Cross-sectional, descriptive design, with simple allocation of medical records from patients older than 65 years hospitalized between January 2016 and August 2017. The STOPP/START criteria were applied to identify the number of PIPs, the number of prescribed medications, number and type of comorbidities, as well as days of hospital stay. RESULTS: A prevalence of PIP of 73.3% was identified, with main comorbidities being hypertension and type 2 diabetes mellitus. A total of 1,885 prescribed medications were quantified; mean hospital stay was 6.3 days. CONCLUSIONS: A high prevalence of PIP was identified in hospitalized geriatric patients, hence the importance of applying the STOPP/START criteria and of the role of the pharmacist for validating the prescription prior to drug administration.

ANTECEDENTES: Una prescripción potencialmente inapropiada (PPI) constituye un riesgo de presentar efectos adversos por un fármaco que superan los beneficios de este, pudiendo considerarse como uso inadecuado de medicamentos. OBJETIVO: Describir la prevalencia de prescripciones potencialmente inapropiadas en pacientes geriátricos hospitalizados en el servicio de medicina interna de un hospital de referencia en México. MATERIAL Y MÉTODOS: Diseño descriptivo transversal, con asignación simple de expedientes clínicos de pacientes hospitalizados mayores de 65 años, entre enero de 2016 y agosto de 2017. Se aplicaron los criterios STOPP y START para identificar el número de PPI, cantidad de medicamentos prescritos, presencia, cantidad y tipo de comorbilidades, así como días de estancia hospitalaria. RESULTADOS: Se encontró una prevalencia de 73.3 % de PPI y las principales comorbilidades fueron hipertensión arterial y diabetes mellitus tipo 2. Se cuantificaron 1885 medicamentos prescritos; la estancia hospitalaria media fue de 6.3 días. CONCLUSIONES: Se identificó alta prevalencia de PPI en los pacientes geriátricos hospitalizados, de ahí la importancia de aplicar los criterios STOPP y START y del papel del farmacéutico en la validación de la prescripción antes de la administración de medicamentos.

Prescripciones potencialmente inapropiadas en pacientes geriátricos hospitalizados en el servicio de medicina interna en un hospital de referencia en México / Potentially inappropriate prescriptions in geriatric patients hospitalized in the internal medicine department of a referral hospital in Mexico

Resumen Antecedentes: Una prescripción potencialmente inapropiada (PPI) constituye un riesgo de presentar efectos adversos por un fármaco que superan los beneficios de este, pudiendo considerarse como uso inadecuado de medicamentos. Objetivo: Describir la prevalencia de prescripciones potencialmente inapropiadas en pacientes geriátricos hospitalizados en el servicio de medicina interna de un hospital de referencia en México. Material y métodos: Diseño descriptivo transversal, con asignación simple de expedientes clínicos de pacientes hospitalizados mayores de 65 años, entre enero de 2016 y agosto de 2017. Se aplicaron los criterios STOPP y START para identificar el número de PPI, cantidad de medicamentos prescritos, presencia, cantidad y tipo de comorbilidades, así como días de estancia hospitalaria. Resultados: Se encontró una prevalencia de 73.3 % de PPI y las principales comorbilidades fueron hipertensión arterial y diabetes mellitus tipo 2. Se cuantificaron 1885 medicamentos prescritos; la estancia hospitalaria media fue de 6.3 días. Conclusiones: Se identificó alta prevalencia de PPI en los pacientes geriátricos hospitalizados, de ahí la importancia de aplicar los criterios STOPP y START y del papel del farmacéutico en la validación de la prescripción antes de la administración de medicamentos.

Abstract Background: Potentially inappropriate prescription (PIP) constitutes a risk for the development of adverse effects of a drug that outweigh its benefits, which can be considered inappropriate medication use. Objective: To describe the prevalence of PIP in geriatric patients hospitalized at the internal medicine department of a referral hospital in Mexico. Material and methods: Cross-sectional, descriptive design, with simple allocation of medical records from patients older than 65 years hospitalized between January 2016 and August 2017. The STOPP/START criteria were applied to identify the number of PIPs, the number of prescribed medications, number and type of comorbidities, as well as days of hospital stay. Results: A prevalence of PIP of 73.3% was identified, with main comorbidities being hypertension and type 2 diabetes mellitus. A total of 1,885 prescribed medications were quantified; mean hospital stay was 6.3 days. Conclusions: A high prevalence of PIP was identified in hospitalized geriatric patients, hence the importance of applying the STOPP/START criteria and of the role of the pharmacist for validating the prescription prior to drug administration.

Herpetic Anterior Uveitis Multicentre Longitudinal Study (The UVHER Project). Baseline Characteristics.

PURPOSE: The aim of the UVHER project is to evaluate the risk of development of optic nerve damage in patients with herpetic anterior uveitis (AU) prospectively followed over 2 years. Herein, we described the baseline characteristics. METHODS: This is a multicentre, prospective study. An aqueous humour tap was performed. Only patients with a positive PCR were included. Clinical characteristics, optical coherence tomography (OCT) parameters and visual field (VF) abnormalities were registered. RESULTS: 27 patients were included: 18 Herpes Simplex (HSV), one Varicella Zoster (VVZ), and 8Cytomegalovirus (CMV). Patients with HSV-AU had severe inflammation, iris atrophy and corneal involvement. In patients with CMV-AU, less inflammation and medium-to-large keratic precipitates were observed. OCT showed a thinner RNFL and GCL in CMV-AU patients in comparison to HSV patients. VF showed abnormalities in six cases. CONCLUSIONS: Patients in the UVHER cohort showed the typical clinical manifestations of herpetic AU. In CMV patients, optic nerve damage was observed at baseline, and in HSV patients, inflammation was more severe.

Impact of Pharmaceutical Education on Medication Adherence and Its Clinical Efficacy in Patients with Type 2 Diabetes and Systemic Arterial Hypertension.

Purpose: To evaluate the impact of pharmaceutical education on medication adherence in patients with Type 2 Diabetes and Systemic Arterial Hypertension. Patients and Methods: This randomized clinical trial enrolled patients with a diagnosis of Type 2 Diabetes Mellitus and Systemic Arterial Hypertension treated in an internal medicine outpatient clinic of a teaching hospital. One hundred and three patients were randomly assigned to the study groups; 51 to the control group and 52 to the intervention group with a 6 months follow-up. Medication adherence was assessed using the Morisky 8-item medication adherence scale. To improve patient adherence to treatment, a wallet card was provided with an up-to-date list of prescribed medications along with recommendations for follow-up care. Results: One hundred and seventy-nine patients were screened for eligibility, of which 103 (57.5%) participated in the study. The intervention group showed a statistically significant decrease in capillary glucose levels, glycated hemoglobin, systolic and diastolic blood pressure, total cholesterol and triglycerides compared to the control group. The frequencies on medication adherence levels at 3 and 6 months in the control group remained similar to baseline, while in the intervention group the frequency of high adherence increased significantly at 6 months (8.7% to 43.5%). Conclusion: A high percentage of patients are not achieving optimal control of their diabetes. Medication adherence rates were between 45-50% in patients at the baseline of the study, but after receiving education and support from a pharmacist, the intervened group showed a significant increase in their adherence.

Antioxidant and Anti-Inflammatory Effects of Coenzyme Q10 Supplementation on Infectious Diseases.

With the appearance of new viruses and infectious diseases (ID) such as COVID-19 in 2019, as well as the lack of specific pharmacological tools for the management of patients with severe complications or comorbidities, it is important to search for adjuvant treatments that help improve the prognosis of infectious disease patients. It is also important that these treatments limit the oxidative and hyperinflammatory damage caused as a response to pathogenic agents, since, in some cases, an inflammatory syndrome may develop that worsens the patient's prognosis. The potential benefits of complementary nutrients and dietary interventions in the treatment of pathological processes in which oxidative stress and inflammation play a fundamental role have been widely evaluated. Coenzyme Q10 (CoQ10) is a supplement that has been shown to protect cells and be effective in cardiovascular diseases and obesity. Additionally, some studies have proposed it as a possible adjuvant treatment in viral infections. Preclinical and clinical studies have shown that CoQ10 has anti-inflammatory and antioxidant effects, and effects on mitochondrial dysfunction, which have been linked to the inflammatory response.

Ischemic Optic Neuropathy After Administration of a SARS-CoV-2 Vaccine: A Report of 2 Cases.

BACKGROUND Since the start of vaccination efforts against COVID-19, several presumed secondary ocular events have been described. We present 2 cases of non-arteritic anterior ischemic optic neuropathy (NA-AION) in patients whose symptoms appeared in the first 2 weeks after administration of the Pfizer-BioNTech COVID-19 mRNA BNT162b2/Cominarty vaccine. CASE REPORT The first patient was a 53-year-old man who presented visual field disturbance in the right eye 7 days after the first vaccine dose, and who consulted a physician 10 days after the second dose, when he experienced loss of vision in the left eye. After a full examination, bilateral anterior optic disc neuropathy was diagnosed. The second patient was a 65-year-old man who presented anterior optic disc neuropathy 12 days after his first vaccination. In both cases, arteritic origin was ruled out due to absence of systemic symptoms and because of normal levels of C-reactive protein and erythrocyte sedimentation rates. CONCLUSIONS Ischemic optic neuropathy is a rare adverse ocular secondary effect of COVID-19 vaccines. Further basic and clinical research is needed to elucidate the pathogenic mechanisms and better characterize the clinical picture of this entity.

Factors Possibly Associated with Mortality in Intubated COVID-19 Patients: A Retrospective Study.

In Mexico, there is a high mortality rate among patients intubated because of COVID-19. The objective of this study was to investigate the associations of age, comorbidities, and biochemical parameters with the in-hospital mortality of COVID-19 patients. A retrospective study of 79 intubated patients admitted to one hospital in Jalisco, Mexico, between July 2020 and January 2021 was performed. Demographic and clinical characteristics were collected. The mean age was 57.7 (±12.8) years, with 83.5% non-survivors and 16.5% survivors. Age, lactate dehydrogenase (LDH) and D-dimer levels were found to be significantly higher in the non-survivor group (p = 0.011, p = 0.026, p = 0.007, respectively). Patients ≥58 years had a high risk of mortality (OR = 7.017). Significant correlations were also found in some of the study variables: LDH levels and leukocyte count (r = 0.388, p = 0.034) and CRP levels and fibrinogen (r = 0.692, p ˂ 0.001) in the patients ˂58 years. Leukocyte count with LDH levels (r = 0.381, p = 0.024) were significant in the group ≥58 years. No significant difference was observed in the presence of diabetes mellitus (DM) and hypertension. In conclusion, according to logistic regression analysis, age over 58 years represents the main factor associated with mortality in these patients.

Multisystem Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Role of Oxidative Stress.

With the appearance of the SARS-CoV-2 virus in December 2019, all countries in the world have implemented different strategies to prevent its spread and to intensively search for effective treatments. Initially, severe cases of the disease were considered in adult patients; however, cases of older school-age children and adolescents who presented fever, hypotension, severe abdominal pain and cardiac dysfunction, positive for SARS-CoV-2 infection, have been reported, with increased pro-inflammatory cytokines and tissue damage, condition denominated multisystemic inflammatory syndrome (MIS-C); The emerging data from patients with MIS-C have suggested unique characteristics in the immunological response and also clinical similarities with other inflammatory syndromes, which can support as a reference in the search for molecular mechanisms involved in MIS-C. We here in propose that oxidative stress (OE) may play a very important role in the pathophysiology of MIS-C, such as occurs in Kawasaki disease (KD), severe COVID-19 in adults and other processes with characteristics of vascular damage similar to MIS- C, for which we review the available information that can be correlated with possible redox mechanisms.

Human Forebrain Organoids from Induced Pluripotent Stem Cells: A Novel Approach to Model Repair of Ionizing Radiation-Induced DNA Damage in Human Neurons.

Human induced pluripotent stem cells (iPSCs) can generate virtually any cell type and therefore are applied to studies of organ development, disease modeling, drug screening and cell replacement therapy. Under proper culture conditions in vitro induced pluripotent stem cells (iPSCs) can be differentiated to form organ-like tissues, also known as "organoids", which resemble organs more closely than cells, in vivo. We hypothesized that human brain organoids can be used as an experimental model to study mechanisms underlying DNA repair in human neurons and their progenitors after radiation-induced DNA double-strand breaks (DSBs), the most severe form of DNA damage. To this end, we customized a protocol for brain organoid generation that is time efficient. These organoids recapitulate key features of human cortical neuron development, including a subventricular zone containing neural progenitors that mature to postmitotic cortical neurons. Using immunofluorescence to measure DNA DSB markers, such as γ-H2AX and 53BP1, we quantified the kinetics of DSB repair in neural progenitors within the subventricular zone for up to 24 h after a single 2 Gy dose of ionizing radiation. Our data on DNA repair in progenitor versus mature neurons indicate a similar timeline: both repair DNA DSBs which is mostly resolved by 18 h postirradiation. However, repair kinetics are more acute in progenitors than mature neurons in the mature organoid. Overall, this study supports the use of 3D organoid culture technology as a novel platform to study DNA damage responses in developing or mature neurons, which has been previously difficult to study.

Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy.

PURPOSE: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy.Experimental Design: Isogenic ARID1A-/- and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A-/- tumors. RESULTS: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of non-homologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A-/- cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1A-deficient tumors. CONCLUSIONS: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1A-deficient malignancies.

Effect of statins on oxidative DNA damage in diabetic polyneuropathy.

Oxidative stress induces nerve damage in type 2 diabetes mellitus and leads to diabetic polyneuropathy (DPN) and can affect the DNA and antioxidant status. Statins have pleiotropic, protective effects on the peripheral nerves of patients with diabetes. The aim of this study was to determine the effects of ezetimibe/simvastatin and rosuvastatin on DNA damage in patients with DPN. This randomized, double-blind, placebo-controlled, clinical trial comprised outpatients from Guadalajara, Mexico. The inclusion criteria were either gender, age 35-80 years, type 2 diabetes, glycated hemoglobin ≤10%, diabetic polyneuropathy stage 1/2, and signed informed consent. Patients who were taking antioxidant therapy or statins, had hypersensitivity to drugs, experienced organ failure, were pregnant or breastfeeding, or had other types of neuropathy were excluded. We assigned patients to placebo, ezetimibe/simvastatin 10/20 mg, or rosuvastatin 20 mg, and the primary outcomes were 8-hydroxy-2'-deoxyguanosine (8-OHdG) for DNA damage, 8-oxoguanine-DNA-N-glycosilase (hOGG1) for DNA repair, and superoxide dismutase (SOD). Seventy-four patients were recruited. Nine patients were included as negative controls. There were no differences in 8-OHdG between the healthy subjects (4.68 [3.53-6.38] ng/mL) and the DPN patients (4.51 [1.22-9.84] ng/mL), whereas the hOGG1 level was 0.39 (0.37-0.42) ng/mL in the healthy subjects and 0.41 (0.38-0.54) ng/mL in patients with DPN at baseline (p = 0.01). SOD decreased significantly in patients with DPN (5.35 [0.01-17.90] U/mL) compared with the healthy subjects (9.81 [8.66-12.61] U/mL) at baseline (p < 0.001). No significant changes in DNA biomarkers were observed in any group between baseline and final levels. We noted a rise in hOGG1 in patients with DPN, without modifications after treatment. There was a slight, albeit insignificant, increase in SOD in patients who were on statins.

The Role for the DSB Response Pathway in Regulating Chromosome Translocations.

In response to DNA double strand breaks (DSB), mammalian cells activate the DNA Damage Response (DDR), a network of factors that coordinate their detection, signaling and repair. Central to this network is the ATM kinase and its substrates at chromatin surrounding DSBs H2AX, MDC1 and 53BP1. In humans, germline inactivation of ATM causes Ataxia Telangiectasia (A-T), an autosomal recessive syndrome of increased proneness to hematological malignancies driven by clonal chromosomal translocations. Studies of cancers arising in A-T patients and in genetically engineered mouse models (GEMM) deficient for ATM and its substrates have revealed complex, multilayered roles for ATM in translocation suppression and identified functional redundancies between ATM and its substrates in this context. "Programmed" DSBs at antigen receptor loci in developing lymphocytes employ ubiquitous DDR factors for signaling and repair and have been particularly useful for mechanistic studies because they are region-specific and can be monitored in vitro and in vivo. In this context, murine thymocytes deficient for ATM recapitulate the molecular events that lead to transformation in T cells from A-T patients and provide a widely used model to study the mechanisms that suppress RAG recombinase-dependent translocations. Similarly, analyses of the fate of Activation induced Cytidine Deaminase (AID)-dependent DSBs during mature B cell Class Switch Recombination (CSR) have defined the genetic requirements for end-joining and translocation suppression in this setting. Moreover, a unique role for 53BP1 in the promotion of synapsis of distant DSBs has emerged from these studies.

Oxidative Stress, Apoptosis, and Mitochondrial Function in Diabetic Nephropathy.

Diabetic nephropathy (DN) is the second most frequent and prevalent complication of diabetes mellitus (DM). The increase in the production of oxidative stress (OS) is induced by the persistent hyperglycemic state capable of producing oxidative damage to the macromolecules (lipids, carbohydrates, proteins, and nucleic acids). OS favors the production of oxidative damage to the histones of the double-chain DNA and affects expression of the DNA repairer enzyme which leads to cell death from apoptosis. The chronic hyperglycemic state unchains an increase in advanced glycation end-products (AGE) that interact through the cellular receptors to favor activation of the transcription factor NF-κB and the protein kinase C (PKC) system, leading to the appearance of inflammation, growth, and augmentation of synthesis of the extracellular matrix (ECM) in DN. The reactive oxygen species (ROS) play an important role in the pathogenesis of diabetic complications because the production of ROS increases during the persistent hyperglycemia. The primary source of the excessive production of ROS is the mitochondria with the capacity to exceed production of endogenous antioxidants. Due to the fact that the mechanisms involved in the development of DN have not been fully clarified, there are different approaches to specific therapeutic targets or adjuvant management alternatives in the control of glycemia in DN.

PARP1 depletion induces RIG-I-dependent signaling in human cancer cells.

DNA Damage Response (DDR) and DNA repair pathways are emerging as potent, ubiquitous suppressors of innate immune signaling in human cells. Here, we show that human cells surviving depletion of the Single Strand Break (SSB) repair protein PARP1 undergo p21-dependent senescence or cell cycle checkpoint activation in the context of activation of innate immune signaling, or viral mimicry. Specifically, we observe induction of a large number of interferon-stimulated genes (ISGs) and multiple pattern recognition receptors (PRRs; including RIG-I, MDA-5, MAVS, TLR3 and STING) and increased nuclear IRF3 staining. Mechanistically, depletion of the double-stranded RNA (dsRNA) helicase RIG-I or its downstream effector MAVS specifically rescues ISG induction in PARP1-depleted cells, suggesting that the RIG-I/MAVS pathway is required for sustained ISG expression in this context. Experiments with conditioned media or a neutralizing antibody to the α/ß-IFN receptor revealed that persistent ISG expression additionally requires an autocrine/paracrine loop. Finally, loss of PARP1 and radiation-induced DNA damage strongly synergize in the induction of p21 and ISGs. Overall, these findings increase our understanding of how PARP1 may suppress deleterious phenotypes associated to aging, inflammation and cancer in humans.

The Role of Oxidative Stress, Mitochondrial Function, and Autophagy in Diabetic Polyneuropathy.

Diabetic polyneuropathy (DPN) is the most frequent and prevalent chronic complication of diabetes mellitus (DM). The state of persistent hyperglycemia leads to an increase in the production of cytosolic and mitochondrial reactive oxygen species (ROS) and favors deregulation of the antioxidant defenses that are capable of activating diverse metabolic pathways which trigger the presence of nitro-oxidative stress (NOS) and endoplasmic reticulum stress. Hyperglycemia provokes the appearance of micro- and macrovascular complications and favors oxidative damage to the macromolecules (lipids, carbohydrates, and proteins) with an increase in products that damage the DNA. Hyperglycemia produces mitochondrial dysfunction with deregulation between mitochondrial fission/fusion and regulatory factors. Mitochondrial fission appears early in diabetic neuropathy with the ability to facilitate mitochondrial fragmentation. Autophagy is a catabolic process induced by oxidative stress that involves the formation of vesicles by the lysosomes. Autophagy protects cells from diverse stress factors and routine deterioration. Clarification of the mechanisms involved in the appearance of complications in DM will facilitate the selection of specific therapeutic options based on the mechanisms involved in the metabolic pathways affected. Nowadays, the antioxidant agents consumed exogenously form an adjuvant therapeutic alternative in chronic degenerative metabolic diseases, such as DM.

Markers of Oxidative Stress and Inflammation in Ascites and Plasma in Patients with Platinum-Sensitive, Platinum-Resistant, and Platinum-Refractory Epithelial Ovarian Cancer.

Diverse proinflammatory biomarkers and oxidative stress are strongly associated with advanced epithelial ovarian cancer (EOC). Objective. To determine the behavior of markers of oxidative stress and inflammation in plasma and ascites fluid in patients with platinum-sensitive, platinum-resistant, and platinum-refractory EOC. Methods. A prospective cohort study. The colorimetric method was used to determine levels of the markers 8-isoprostanes (8-IP), lipid peroxidation products (LPO), and total antioxidant capacity (TAC) in plasma and ascites fluid; and with ELISA, the levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were determined in patients with EOC. Results. In ascites fluid, a significant increase in 8-IP versus baseline plasma levels was found (p = 0.002). There was an important leakage of the TAC levels in ascites fluid versus baseline plasma levels (p < 0.001). The IL-6 was elevated in ascites fluid versus baseline plasma levels (p = 0.003), and there were diminished levels of TNF-α in ascites fluid versus baseline plasma levels (p = 0.001). Discussion. We hypothesize that the ascites fluid influences the behavior and dissemination of the tumor. Deregulation between oxidants, antioxidants, and the proinflammatory cytokines was found to vary among platinum-sensitive, platinum-resistant, and platinum-refractory patients.

The Oxidative and Inflammatory State in Patients with Acute Renal Graft Dysfunction Treated with Tacrolimus.

Objective. To determine the oxidative stress/inflammation behavior in patients with/without acute graft dysfunction (AGD) with Tacrolimus. Methods. Cross-sectional study, in renal transplant (RT) recipients (1-yr follow-up). Patients with AGD and without AGD were included. Serum IL-6, TNF-α, 8-isoprostanes (8-IP), and Nitric Oxide (NO) were determined by ELISA; C-reactive protein (CRP) was determined by nephelometry; lipid peroxidation products (LPO) and superoxide dismutase (SOD) were determined by colorimetry. Results. The AGD presentation was at 5.09 ± 3.07 versus 8.27 ± 3.78 months (p < 0.001); CRP >3.19 mg/L was found in 21 versus 19 in the N-AGD group (p = 0.83); TNF-α 145.53 ± 18.87 pg/mL versus 125.54 ± 15.92 pg/mL in N-AGD (p = 0.64); IL-6 2110.69 ± 350.97 pg/mL versus 1933.42 ± 235.38 pg/mL in N-AGD (p = 0.13). The LPO were higher in AGD (p = 0.014): 4.10 ± 0.69 µM versus 2.41 ± 0.29 µM; also levels of 8-IP were higher in AGD 27.47 ± 9.28 pg/mL versus 8.64 ± 1.54 pg/mL (p = 0.01). Serum levels of NO in AGD were lower 138.44 ± 19.20 µmol/L versus 190.57 ± 22.04 µmol/L in N-AGD (p = 0.042); antioxidant enzyme SOD activity was significantly diminished in AGD with 9.75 ± 0.52 U/mL versus 11.69 ± 0.55 U/mL in N-AGD (p = 0.012). Discussion. Patients with RT present with a similar state of the proinflammatory cytokines whether or not they have AGD. The patients with AGD showed deregulation of the oxidative state with increased LPO and 8-IP and decreased NO and SOD.

Integration-free erythroblast-derived human induced pluripotent stem cells (iPSCs) from an individual with Ataxia-Telangiectasia (A-T).

Peripheral blood was obtained from a 12-year old male carrying bialleleic inactivating mutations at the ATM locus, causing Ataxia-Telangiectasia (A-T). Blood erythroid cells were briefly expanded in vitro and induced pluripotent stem cells (iPSCs) were generated via transfection with episomal vectors carrying hOCT4, hSOX2, hKLF4, hMYC and hBCL2L1. SF-003 iPSCs were free of genomically integrated reprogramming genes, had the specific compound heterozygous mutations, stable karyotype, expressed pluripotency markers and formed teratomas in immunodeficient (NOD scid gamma; NGS) mice. The SF-003 iPSC line may be a useful resource for in vitro modeling of A-T.

Robust reprogramming of Ataxia-Telangiectasia patient and carrier erythroid cells to induced pluripotent stem cells.

Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse.