Lumacaftor/ivacaftor improves liver cholesterol metabolism but does not influence hypocholesterolemia in patients with cystic fibrosis

BackgroundCystic fibrosis (CF) patients have reduced intestinal absorption of sterols and, despite enhanced endogenous synthesis, low plasma cholesterol. Lumacaftor/ivacaftor CFTR protein modulator therapy is used to improve the clinical outcome of CF patients homozygous for F508del mutation (homo-deltaF508). Aim of the study is to evaluate the cholesterol metabolism and hepatobiliary injury/function in adult homo-deltaF508 patients, before and after lumacaftor/ivacaftor treatment. Baseline parameters in homo-deltaF508 patients were compared to those in CF patients compound heterozygous for F508del mutation and another severe mutation (hetero-deltaF508).MethodsCholesterol metabolism was evaluated measuring plasma phytosterols and cholestanol, as intestinal absorption markers, and lathosterol, as liver biosynthesis marker. We quantified serum vitamin E, as nutritional marker. We evaluated liver injury by aspartate aminotransferase (AST) and alanine transaminase (ALT), biliary injury by γ-glutamyltransferase (γGT) and AP, and the liver function by bilirubin and albumin.ResultsBefore the treatment, homo-deltaF508 patients (n = 20) had significantly lower cholesterol and vitamin E compared to hetero-deltaF508 (n = 20). Lumacaftor/ivacaftor treatment caused: 1) further reduction of cholesterol; 2) lathosterol reduction, suggesting a normalization of endogenous synthesis; 3) cholestanol and vitamin E increment, indicating an improvement of lipid digestion/absorption. Vitamin E difference (after-before treatment) was positively associated to treatment months. Alkaline phosphatase was also reduced.ConclusionsThese data suggest an effect of lumacaftor/ivacaftor on cholesterol metabolism and enterohepatic flux in CF patients. However, lumacaftor/ivacaftor does not promote the increase of cholesterol serum concentration that on the contrary declines. Further studies are needed to research the real mechanism causing this reduction.     

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.

PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response.     

Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.

Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.     

Gallic Acid-Functionalized,TiO2-Based Nanomaterial—Preparation,Physicochemical and Biological Properties

Wound healing and skin tissue regeneration remain the most critical challenges faced by medical professionals. Titanium(IV) oxide-based materials were proposed as components of pharmaceutical formulations for the treatment of difficult-to-heal wounds and unsightly scarring. A gallic acid-functionalized TiO₂ nanomaterial (TiO₂-GA) was obtained using the self-assembly technique and characterized using the following methods: scanning electron microscopy (SEM), transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), X-ray powder diffraction (XRPD), infrared spectroscopy (IR), Raman spectroscopy and thermogravimetry (TG). Additionally, physicochemical and biological tests (DPPH assay, Microtox^® acute toxicity test, MTT assay) were performed to assess antioxidant properties as well as to determine the cytotoxicity of the novel material against eukaryotic (MRC-5 pd19 fibroblasts) and prokaryotic (Staphylococcus aureus, Escherichia coli, Candida albicans, Aliivibrio fischeri) cells. To determine the photocytotoxicity of the material, specific tests were carried out with and without exposure to visible light lamps (425 nm). Following the results, the TiO₂-GA material could be considered an additive to dressings and rinsing suspensions for the treatment of difficult-to-heal wounds that are at risk of bacterial infections.     

Risk factors for domestic sporadic campylobacteriosis among young children in Sweden

A case-control study was conducted in Sweden to study risk factors for domestically acquired Campylobacter jejuni/coli infections among children aged less than 6 y. A total of 126 cases, reported to the national surveillance system were recruited over 1 y. Controls, selected from the population register, were matched to the cases by age, gender, place of residence and time of infection of the case. Information was gathered by posted questionnaires. Two separate conditional regression models were developed including and excluding 'protective' factors. Two of the factors significantly associated with Campylobacter infection were water-related: having a well in the household (OR=2.6) and drinking water from a lake/river (OR=7.4; 6.0). Other exposures associated with increased risk were: having a dog (OR=8.4; 3.8) and eating grilled meat (OR=5.5; 2.1). Drinking unpasteurized milk was borderline significant in 1 model (OR=3.7). Eating sausage was protective (OR=0.05). Eating chicken was not a significant risk. Exposures such as eating grilled meat and drinking water from a lake or a river were more common in the warm months, a factor that may partly explain the observed seasonality. The authors suggest that differences between risk factors across studies may reflect geographical and age-specific differences in the sources of infection.     

Rheumatic and Musculoskeletal Diseases (RMDs) Public Awareness Program of Georgia 2019–2020

Clinical Rheumatology - The program’s goal is to launch the platform of positive perspectives for people who are suffering from/working in rheumatic and musculoskeletal diseases through the...     

Effects of gas-filled temporary breast tissue expanders on radiation dose from modulated rotational photon beams

Gas-filled temporary tissue expanders (TTEs), implanted to assist in post mastectomy breast reconstructions, are expected to produce increased dosimetric uncertainty in breast radiotherapy treatments, due to their containing both a substantial metallic component and a comparatively large volume of gas. This study therefore builds on previous investigations of the dosimetric effects of gas-filled TTEs in static photon and electron beams, by examining the effects of these implants on dose distributions from common modulated rotational treatment techniques; volumetric modulated arc therapy (VMAT) and helical tomotherapy (HT). Radiochromic film measurements were used to evaluate the accuracy of VMAT and HT dose calculations, for a humanoid phantom augmented with a sample Aeroform CO₂-filled TTE (AirXpanders Inc, San Jose, USA) as well as purpose-designed and 3D printed “breast tissue.” Results showed that the TomoTherapy Hi-Art VoLO convolution-superposition algorithm (Accuray Inc, Sunnyvale, USA) produced comparatively accurate calculations of treatment dose within this complex phantom, including immediately anterior and posterior to the TTE. The Varian Eclipse Acuros (AXB) algorithm generally showed better agreement with the film measurement than the Varian Eclipse AAA algorithm (Varian Medical Systems, Palo Alto, USA), although the film measurements showed regions of 5% to 10% disagreement with both AAA and AXB in the dosimetrically-challenging region on the anterior side of the implant. Although the Aeroform CO₂-filled TTE has substantial and obvious effects on the downstream dose from a static photon beam, the results of this study showed how inverse-planning of modulated rotational radiotherapy treatments can produce modulated fluence distributions that compensate for the dramatic density heterogeneities in the implant. Despite some disagreements with the planned dose, all film measurements showed that the use of inverse-planned modulated rotational photon beams resulted in comparatively homogeneous coverage of the radiotherapy target, in the complex patient-like phantom with a gas-filled TTE. Due to the importance of matching each planned fluence distribution to the density distribution within each TTE, careful use of available 3D imaging techniques is advisable, when modulated rotational radiotherapy treatments are delivered to patients with gas-filled TTEs.