Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-ß or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.

Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: A Phase 3, Randomized Clinical Trial.

BACKGROUND: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy. METHODS: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2. RESULTS: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups. CONCLUSIONS: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose. CLINICAL TRIALS REGISTRATION: NCT02058589.

Autohemotherapy with ozone as a possible effective treatment for Fibromyalgia.

OBJECTIVE: The objective of this study is to evaluate the effectiveness of autohemotherapy with ozone in the management of fibromyalgia (FM). DESIGN: 20 FM patients (according to the criteria of the American College of Rheumatology), were treated with 10 sessions of ozone hemotherapy (2 sessions per week) with a concentration of 30-60 mcgr/ml. The health condition of the patients was evaluated before and after treatment, through the Fibromyalgia Impact Questionnaire (FIQ). Blood samples were obtained from all patients by venous puncture for biochemical routine analysis and serotonin levels in serum and the following peripheral blood mononuclear cells (BMCs) were isolated for oxidative stress quantification: reactive oxygen species (ROS) generation, and lipid peroxidation (LP) and protein carbonyl (PC) content, as these are signs of oxidative cell damage. RESULTS: All patients treated with ozone reported an improvement in sleep and mental alertness, a marked decrease of asthenia accompanied by a decrease of FIQ as well as tender points, and a moderate increase of serotonin levels. Also, an important decrease of LP and PC was observed; ROS also decreased, although less obvious, which indicates a reduction in oxidative stress levels. CONCLUSIONS: The autohemotherapy with ozone in patients with FM showed an important decline of tender points and FIQ score, as well as a decrease of oxidative stress levels. This treatment allows patients to face life with greater vitality and less drug use, diminishing harmful side effects. Further investigation should be carried out, including groups with more patients and clinical trials, to elucidate the effect of ozone therapy in patients suffering from FM.

Gastrointestinal lesions in chronic kidney disease patients with anaemia. / Lesiones gastrointestinales en pacientes con enfermedad renal crónica y anemia.

INTRODUCTION: Despite the frequency with which anaemia is present in patients with chronic kidney disease (CKD), its relationship with gastrointestinal lesions has not been studied. METHOD: A cross-sectional, analytical, observational study involving one year of recruitment was carried out to determine the prevalence of endoscopic gastrointestinal lesions and associated risk factors in asymptomatic patients with chronic kidney disease stages 1-5 and anaemia who had a positive qualitative immunochemical faecal occult blood test. RESULTS: A total of 9,658 patients with CKD were analysed, of which 286 (2.9%) had anaemia; 198 had a positive faecal occult blood test (47% male, 71.1±11.8 years). The endoscopic study revealed 255 lesions, with at least one lesion in 68.2% of patients, with the most prevalent being: adenomatous colorectal polyps (39.6%), acute lesions of the gastric mucosa (22.6%), neoplastic lesions 15.1%), angiodysplasia (14.4%), oesophagitis (8.4%), inflammatory bowel disease (4.8%) and ischaemic colitis (3.1%). Uraemia and acetylsalicylic acid were identified as risk factors for acute gastric mucosal lesions. Angiodysplasia was associated with alcoholism, a more advanced stage of chronic kidney disease, anaemia, and lack of response to erythropoiesis-stimulating agents. Age and refractory anaemia were risk factors for adenomatous polyps and colorectal cancer. CONCLUSION: Renal patients with anaemia could benefit from an endoscopic study due to their high prevalence of gastrointestinal lesions, particularly adenomatous polyps and colorectal cancer, which are more common in those over 50 years of age with CKD stages 3-5.

Amitriptyline down-regulates coenzyme Q10 biosynthesis in lung cancer cells.

Amitriptyline, a tricyclic antidepressant, has been proposed as an antitumoral drug in oxidative therapy. Its pro-apoptotic effects, mediated by high reactive oxygen species generation, have been already described. In this study we analysed the effect of amitriptyline on the biosynthesis of coenzyme Q10 (CoQ), an essential component for electron transport and a potent membrane antioxidant involved in redox signaling. We treated H460 cells, a non-small-cell lung cancer cell line, with amitriptyline and we analysed CoQ levels by HPLC and CoQ biosynthesis rate, as well as the enzymes involved in CoQ biosynthesis by real-time PCR and Western blot. Amitriptyline treatment induced a dose-dependent decrease in CoQ levels in tumor cells. CoQ decreased levels were associated with down-regulation of the expression of COQ4 gene, as well as decreased Coq4 and Coq6 protein levels. Our findings suggest that the effect of amitriptyline on CoQ biosynthesis highlights the potential of this drug for antitumoral oxidative therapy.

Fibromyalgia syndrome and temporomandibular disorders with muscular pain. A review.

OBJECTIVES: Temporomandibular disorders (TMD) refer to a group of clinical picture affecting the masticatory muscles and temporomandibular joint that are characterized by muscular or joint pain, dysfunction (limited or altered functions) and joint noises, as well as other associated symptoms, such as tension headaches, otalgia, dizziness, tinnitus, and others. Fibromyalgia (FM) is a syndrome of unknown etiology involving generalized chronic pain accompanied, in a high percentage of cases, by other symptoms such as asthenia, anxiety, depression, sleep disturbances, and other less frequent symptoms, such as temporomandibular disorders (TMD). DATA: Data were compiled by two experienced examiners following a specific form. SOURCES: An electronic search was carried out in the Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, and SCOPUS electronic databases (up to April 2016, unrestricted by date or language). STUDY SELECTION: Comparative clinical studies with patients with both clinical pictures involving the study of pathogenic processes. CONCLUSIONS: Fibromyalgia and temporomandibular disorders with muscle pain both have profiles that affect the muscular system and therefore share many epidemiological, clinical, and physiopathological symptoms. Because of this, we are led to think that there is, if not a common etiology, at least a common pathogenesis. This article revises the physiopathological processes of both clinical pictures in an attempt to determine their similarities and likenesses. This would undoubtedly help in providing a better therapeutic approach.

Clinical symptoms in fibromyalgia are associated to overweight and lipid profile.

In order to analyze the association between body mass index (BMI), lipid profile and clinical symptoms in patients with fibromyalgia, we assessed BMI levels, lipid profile and its association with clinical symptoms in 183 patients with fibromyalgia. The patients were evaluated using tender points, FIQ and Visual Analogue Scales of pain (VAS). Serum lipid profile analysis (total cholesterol, triglyceride, HDL, LDL and VLDL), and biochemical parameters were measured in the biochemistry laboratory. The BMI distribution of the nonobese, overweight and obese patients' groups were relatively even with 37.7, 35.5 and 26.8%, respectively, with a mean BMI of 27.3 ± 4.9. The number of tender points showed significantly positive correlation with higher BMI (P < 0.05). A total of 57.9% of patients showed increased levels of total cholesterol, 63.4 % increased levels of LDL cholesterol and 19.9% high levels of triglycerides. BMI, total cholesterol and triglycerides showed high association with some clinical parameters. Overweight and lipid profile could be associated with fibromyalgia symptoms. A treatment program with weight loss strategies, and control in diet and increased physical activity is advised to patients.

Can coenzyme q10 improve clinical and molecular parameters in fibromyalgia?

Fibromyalgia (FM) is a complex disorder that affects up to 5% of the general population worldwide. Its pathophysiological mechanisms are difficult to identify and current drug therapies demonstrate limited effectiveness. Both mitochondrial dysfunction and coenzyme Q10 (CoQ10) deficiency have been implicated in FM pathophysiology. We have investigated the effect of CoQ10 supplementation. We carried out a randomized, double-blind, placebo-controlled trial to evaluate clinical and gene expression effects of forty days of CoQ10 supplementation (300 mg/day) on 20 FM patients. This study was registered with controlled-trials.com (ISRCTN 21164124). An important clinical improvement was evident after CoQ10 versus placebo treatment showing a reduction of FIQ (p<0.001), and a most prominent reduction in pain (p<0.001), fatigue, and morning tiredness (p<0.01) subscales from FIQ. Furthermore, we observed an important reduction in the pain visual scale (p<0.01) and a reduction in tender points (p<0.01), including recovery of inflammation, antioxidant enzymes, mitochondrial biogenesis, and AMPK gene expression levels, associated with phosphorylation of the AMPK activity. These results lead to the hypothesis that CoQ10 have a potential therapeutic effect in FM, and indicate new potential molecular targets for the therapy of this disease. AMPK could be implicated in the pathophysiology of FM.

Are low levels of 25-hydroxyvitamin D a risk factor for cardiovascular diseases or malignancies in renal transplantation?

BACKGROUND: Observational studies in healthy people suggest an inverse relationship between 25-hydroxy-vitamin D (25(OH)D levels) and cardiovascular diseases and malignancies. We performed an observational prospective study in renal transplant recipients to investigate the effects of vitamin D deficiency on cardiovascular and malignancy risks. METHODS: From 389 renal transplant recipients, 331 with a functioning graft at 12 months were included in the study. Mineral metabolism parameters were measured at 1, 3, 4 and 12 months. Information regarding the cardiovascular events and malignancies were collected from an electronic database. RESULTS: According to the 1-year mean of 25(OH)D levels, 75 recipients (22.7%) had a normal vitamin D status, 161 (48.6%) had insufficiency and 95 (28.7%) had deficiency in vitamin D levels. During the follow-up, 80 recipients presented at least one cardiovascular event. The total cardiovascular diseases included: 27 patients with coronary diseases, 25 with cardiac failure, 18 with arrhythmia, 11 with acute cerebrovascular events and 19 with peripheral vascular disease. Cardiovascular events were not associated with 25(OH)D levels or vitamin D status, and the 10-year cumulative incidence was 29.3% for normal vitamin D status and 31.6% for insufficiency and 51.9% for deficiency (P = 0.216). Furthermore, Cox univariate analysis showed no association between cardiovascular events and vitamin D levels or vitamin D status. In addition, 53 recipients presented at least one malignancy: 33 non-melanoma skin malignancies and 20 non-skin malignancies (5 prostate, 3 kidney and urinary tract, 2 colon, 2 lung, 2 lymphoma, 2 breast and 4 from other locations). The cumulative incidence of malignancies was 21.3% for normal vitamin D status, 22.7% for insufficiency and 16.7% for deficiency (P = 0.818). CONCLUSIONS: Our data suggested that low vitamin D levels were not associated with an increased risk of cardiovascular diseases or malignancies. However, due to the small number of patients and events, the results should not be considered as definitive. Additional studies with a higher number of patients are required to elucidate the true impact of vitamin D status on cardiovascular and malignancy risks.