Assessment of anti-inflammatory tumor treatment efficacy by longitudinal monitoring employing sonographic micro morphology in a preclinical mouse model

<p>Abstract</p> <p>Background</p> <p>With the development of increasingly sophisticated three-dimensional volumetric imaging methods, tumor volume can serve as a robust and reproducible measurement of drug efficacy. Since the use of molecularly targeted agents in the clinic will almost certainly involve combinations with other therapeutic modalities, the use of volumetric determination can help to identify a dosing schedule of sequential combinations of cytostatic drugs resulting in long term control of tumor growth with minimal toxicity. The aim of this study is to assess high resolution sonography imaging for the in vivo monitoring of efficacy of Infliximab in pancreatic tumor.</p> <p>Methods</p> <p>In the first experiment, primary orthotopic pancreatic tumor growth was measured with Infliximab treatment. In the second experiment, orthotopic tumors were resected ten days after inoculation of tumor cells and tumor recurrence was measured following Infliximab treatment. Tumor progression was evaluated using 3D high resolution sonography.</p> <p>Results</p> <p>Sonography measurement of tumor volume in vivo showed inhibitory effect of Infliximab on primary tumor growth in both non-resected and resected models. Measurement of the dynamics of tumor growth by sonography revealed that in the primary tumor Infliximab is effective against established tumors while in the resection model, Infliximab is more effective at an early stage following tumor resection. Infliximab treatment is also effective in inhibiting tumor growth growth as a result of tumor cell contamination of the surgical field.</p> <p>Conclusions</p> <p>Clinical application of Infliximab is feasible in both the neoadjuvant and adjuvant setting. Infliximab is also effective in slowing the growth of tumor growth under the peritoneum and may have application in treating peritoneal carcinomatosis. Finally the study demonstrates that high resolution sonography is a sensitive imaging modality for the measurement of pancreatic tumor growth.</p

Expression and Temperature-Dependent Regulation of the Beta2-Microglobulin (Cyca-B2m) Gene in a Cold-Blooded Vertebrate, the Common Carp (Cyprinus carpio L.)

Expression of beta2-microglobulin (β 2m) in the common carp was studied using a polyclonal antibody raised against a recombinant protein obtained from eukaryotic expression of the Cyca-B2m gene. β 2m is expressed on peripheral blood Ig+ and Ig- lymphocytes, but not on erythrocytes and thrombocytes. In spleen and pronephros, dull- and bright-positive populations could be identified correlating with the presence of erythrocytes, thrombocytes, and mature leucocytes or immature and mature cells from the lympho-myeloid lineage, respectively. Thymocytes were shown to be comprised of a single bright-positive population. The Cyca-B2m polyclonal antiserum was used in conjunction with a similarly produced polyclonal antiserum to an MHC class I (Cyca-UA) α chain to investigate the expression of class I molecules on peripheral blood leucocytes (PBL) at different permissive temperatures. At 12℃, a temporary downregulation of class I molecules was demonstrated, which recovered to normal levels within 3 days. However, at 6℃, a lasting absence of class I cell-surface expression was observed, which could be restored slowly by transfer to 12C. The expression of immunoglobulin molecules on B cells was unaffected by temperature changes. The absence of the class cell-surface expression was shown to be the result of a lack of sufficient Cyca-B2m gene transcription, although Cyca-UA mRNA was present at comparable levels at all temperatures. This suggests that class I expression is regulated by a temperature-sensitive transcription of the Cyca-B2m gene

Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine

Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC

Породы песчаники – редкие материалы высокой крепости – уникальные фрикционные материалы

Розглядаються питання при підготовці до відпрацювання пологих вугільних пластів на великих глибинах в умовах шахти «Довжанська Капітальна» ТОВ "ДТЕК Свердловантрацит". Проведено дослідження вміщуючих підготовчу виробку порід. Запропоновано можливості проектування комплексного видобутку супутніх корисних компонентів при підготовці Антрацитівського пластів до видобутку.The questions in preparation for mining of shallow coal seams at great depths in the mine "Dolzhanskaya Capital" LLC "DTEK Sverdlovantratsit." Investigations of host rocks of underground working. Suggested the possibility of designing an integrated co-production of useful components in preparation Antratsitovskogo of flat seam to production

Adverse events related to biologicals used for patients with multiple sclerosis: a comparison between information originating from regulators and information originating from the scientific community

Publisher's version (útgefin grein)Background and purpose: Clinical decision making is facilitated by healthcare professionals’ and patients’ adequate knowledge of the adverse events. This is especially important for biologicals used for treating multiple sclerosis (MS). So far, little is known about whether different information sources report adverse events consistently. Methods: Biologicals authorized by the European Medicines Agency for the treatment of MS were included in this study. Information on adverse events derived from phase 3 clinical trials from European Public Assessment Reports (EPARs) and from scientific publications was compared. Results: In the study, eight biologicals used for the treatment of MS were included for which the EPAR and/or scientific publication reported a total of 707 adverse events. Approximately one-third of the adverse events was reported in both the EPAR and scientific publication, one-third was only reported in the EPAR and one-third only in the scientific publication. Serious adverse events and adverse events that regulators classified as ‘important identified risk’ were significantly more often reported in both sources compared to adverse events not classified as such (respectively, 38% vs. 30% and 49% vs. 30%). Adverse events only reported in the EPAR or in the scientific publication were, in general, not described in the benefit–risk section or abstract, which were considered to be the most important sections of the documents. Conclusions: This study showed that there is substantial discordance in the reporting of adverse events on the same phase 3 trials between EPARs and scientific publications. To support optimal clinical decision making, both documents should be considered.It is confirmed that no specific funding was receivedfor this study.Peer Reviewe

COVID-19 unmasked global collaboration protocol:Longitudinal cohort study examining mental health of young children and caregivers during the pandemic

Background: Early empirical data shows that school-aged children, adolescents and adults are experiencing elevated levels of anxiety and depression during the COVID-19 pandemic. Currently, there is very little research on mental health outcomes for young children. Objectives: To describe the formation of a global collaboration entitled, 'COVID-19 Unmasked'. The collaborating researchers aim to (1) describe and compare the COVID-19 related experiences within and across countries; (2) examine mental health outcomes for young children (1 to 5 years) and caregivers over a 12-month period during the COVID-19 pandemic; (3) explore the trajectories/time course of psychological outcomes of the children and parents over this period and (4) identify the risk and protective factors for different mental health trajectories. Data will be combined from all participating countries into one large open access cross-cultural dataset to facilitate further international collaborations and joint publications. Methods: COVID-19 Unmasked is an online prospective longitudinal cohort study. An international steering committee was formed with the aim of starting a global collaboration. Currently, partnerships have been formed with 9 countries (Australia, Cyprus, Greece, the Netherlands, Poland, Spain, Turkey, the UK, and the United States of America). Research partners have started to start data collection with caregivers of young children aged 1-5 years old at baseline, 3-months, 6-months, and 12-months. Caregivers are invited to complete an online survey about COVID-19 related exposure and experiences, child's wellbeing, their own mental health, and parenting. Data analysis: Primary study outcomes will be child mental health as assessed by scales from the Patient-Reported Outcomes Measurement Information System - Early Childhood (PROMIS-EC) and caregiver mental health as assessed by the Depression Anxiety Stress Scale (DASS-21). The trajectories/time course of mental health difficulties and the impact of risk and protective factors will be analysed using hierarchical linear models, accounting for nested effects (e.g. country) and repeated measures

Anti‐cN‐1A autoantibodies are absent in juvenile dermatomyositis

Objectives: To assess anti‐cytosolic 5′‐nucleotidase 1A (cN‐1A/NTC51A) autoantibodies in children with juvenile dermatomyositis (JDM) and healthy controls, using three different methods of antibody detection, as well as verification of the results in an independent cohort. / Methods: Anti‐cN‐1A reactivity was assessed in 34 Dutch JDM patients and 20 healthy juvenile controls by a commercially available full‐length cN‐1A ELISA, a synthetic peptide ELISA and by immunoblotting using a lysate from cN‐1A expressing HEK‐293 cells. Sera from JDM patients with active disease and in remission were analysed. An independent British cohort of 110 JDM patients and 43 healthy juvenile controls was assessed by an in‐house full‐length cN‐1A ELISA. / Results: Anti‐cN‐1A reactivity was not present in JDM patients’ sera or in healthy controls when tested with the commercially available full‐length cN‐1A ELISA or by immunoblotting, both in active disease and in remission. Also, in the British JDM cohort anti‐cN‐1A reactivity was not detected. Three Dutch JDM patients tested weakly positive for one of the three synthetic cN‐1A peptides measured by ELISA. / Conclusion: JDM patients and young healthy individuals do not show anti‐cN‐1A reactivity as assessed by different antibody detection techniques

Use of Dipeptidyl Peptidase-4 Inhibitors and the Reporting of Infections: A Disproportionality Analysis in the World Health Organization VigiBase

OBJECTIVE - Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antidiabetic drugs. They inactivate incretin hormones but also have many other effects throughout the body, among which are effects on the immune system. This might result in an increased infection risk. This study assessed the association between use of DPP-4 inhibitors and the reporting of infections. RESEARCH DESIGN AND METHODS - A nested case-control was conducted using VigiBase, the World Health Organization-Adverse Drug Reactions (WHO-ADR) database. The base cohort consisted of ADRs for antidiabetic drugs (Anatomical Therapeutic Chemical code A10). Cases were defined as ADRs of infection according to the Medical Dictionary for Regulatory Activities (MedDRA) classification system. All other ADRs were considered controls. Reporting odds ratios (RORs) were calculated to estimate the strength of the association between different classes of antidiabetic drugs and the reporting of infections. RESULTS - We identified 305,415 suspected ADRs involving antidiabetic drugs in 106,469 case reports, of which 8,083 involved DPP-4 inhibitors monotherapy. Overall, the reporting of infections was higher for patients using DPP-4 inhibitors compared with users of biguanides (ROR 2.3 [95% CI 1.9-2.7]). Reporting of upper respiratory tract infections (ROR 12.3 [95% CI 8.6-17.5]) was significantly associated with use of DPP-4 inhibitors. CONCLUSIONS - This study indicates an increased reporting of infections, in particular upper respiratory tract infections, for users of DPP-4 inhibitors compared with users of other antidiabetic drugs. However, the limitations of spontaneous reporting systems (e.g., underreporting, the Weber-effect, reporting bias) should be taken into account. Therefore, further research is needed to evaluate this suspicion and the underlying mechanism