Acupuncture in chemotherapy-induced dysgeusia (AcuDysg): study protocol of a randomised controlled trial

Introduction: Dysgeusia is a common side effect of chemotherapy in patients with cancer, but to date, there is no effective treatment. Many patients with cancer request complementary medicine treatment in addition to their cancer treatments, and acupuncture is highly accepted for patients with cancer; however, evidence regarding the effectiveness of acupuncture for dysgeusia is scarce.The study investigates the effectiveness of an additional dysgeusia-specific acupuncture plus self-acupressure intervention compared with supportive acupuncture plus self-acupressure intervention alone for chemotherapy-induced dysgeusia in patients with cancer. Methods and analysis: This is a multicentre, randomised, controlled and two-armed parallel-group, single-blind trial involving 130 patients. Both groups will receive eight sessions of acupuncture treatment over a period of 8 weeks and will be trained to perform self-acupressure (eLearning combined with therapist instruction) at predefined acupressure points once a day during the whole treatment period. Patients in the control group will receive supportive routine care acupuncture and self-acupressure treatment only; in addition to this treatment, the intervention group will receive the dysgeusia-specific acupuncture and acupressure within the same treatment session. The primary outcome is the perceived dysgeusia over 8 weeks, measured weekly after the acupuncture treatment. Secondary outcomes include the indices from the objective taste and smell test, weight loss, perceived dysgeusia, fatigue, distress, nausea and vomiting, odynophagia, xerostomia and polyneuropathy, as well as quality of life at the different time points. Ethics and dissemination: The study has been approved by the Cantonal Ethics Committee (CEC) (Kanton Zürich Kantonale Ethikkommission) (approval no. KEK-ZH-Nr. 2020-01900). The results will be submitted to a peer-reviewed journal for publication

Catalytic inhibition of topoisomerase II by a novel rationally designed ATP-competitive purine analogue

ABSTRACT: BACKGROUND: Topoisomerase II poisons are in clinical use as anti-cancer therapy for decades and work by stabilizing the enzyme-induced DNA breaks. In contrast, catalytic inhibitors block the enzyme before DNA scission. Although several catalytic inhibitors of topoisomerase II have been described, preclinical concepts for exploiting their anti-proliferative activity based on molecular characteristics of the tumor cell have only recently started to emerge. Topoisomerase II is an ATPase and uses the energy derived from ATP hydrolysis to orchestrate the movement of the DNA double strands along the enzyme. Thus, interfering with ATPase function with low molecular weight inhibitors that target the nucleotide binding pocket should profoundly affect cells that are committed to undergo mitosis. RESULTS: Here we describe the discovery and characterization of a novel purine diamine analogue as a potent ATP-competitive catalytic inhibitor of topoisomerase II. Quinoline aminopurine compound 1 (QAP 1) inhibited topoisomerase II ATPase activity and decatenation reaction at sub-micromolar concentrations, targeted both topoisomerase II alpha and beta in cell free assays and, using a quantitative cell-based assay and a chromosome segregation assay, displayed catalytic enzyme inhibition in cells. In agreement with recent hypothesis, we show that BRCA1 mutant breast cancer cells have increased sensitivity to QAP 1. CONCLUSION: The results obtained with QAP 1 demonstrate that potent and selective catalytic inhibition of human topoisomerase II function with an ATP-competitive inhibitor is feasible. Our data suggest that further drug discovery efforts on ATP-competitive catalytic inhibitors are warranted and that such drugs could potentially be developed as anti-cancer therapy for tumors that bear the appropriate combination of molecular alterations

A symbiotic footprint in the plant root microbiome

BACKGROUND: A major aim in plant microbiome research is determining the drivers of plant-associated microbial communities. While soil characteristics and host plant identity present key drivers of root microbiome composition, it is still unresolved whether the presence or absence of important plant root symbionts also determines overall microbiome composition. Arbuscular mycorrhizal fungi (AMF) and N-fixing rhizobia bacteria are widespread, beneficial root symbionts that significantly enhance plant nutrition, plant health, and root structure. Thus, we hypothesized that symbiont types define the root microbiome structure. RESULTS: We grew 17 plant species from five families differing in their symbiotic associations (no symbioses, AMF only, rhizobia only, or AMF and rhizobia) in a greenhouse and used bacterial and fungal amplicon sequencing to characterize their root microbiomes. Although plant phylogeny and species identity were the most important factors determining root microbiome composition, we discovered that the type of symbioses also presented a significant driver of diversity and community composition. We found consistent responses of bacterial phyla, including members of the Acidobacteria, Chlamydiae, Firmicutes, and Verrucomicrobia, to the presence or absence of AMF and rhizobia and identified communities of OTUs specifically enriched in the different symbiotic groups. A total of 80, 75 and 57 bacterial OTUs were specific for plant species without symbiosis, plant species forming associations with AMF or plant species associating with both AMF and rhizobia, respectively. Similarly, 9, 14 and 4 fungal OTUs were specific for these plant symbiont groups. Importantly, these generic symbiosis footprints in microbial community composition were also apparent in absence of the primary symbionts. CONCLUSION: Our results reveal that symbiotic associations of the host plant leaves an imprint on the wider root microbiome - which we term the symbiotype. These findings suggest the existence of a fundamental assembly principle of root microbiomes, dependent on the symbiotic associations of the host plant

The price of tumor control

Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects

Role of integrins and evidence for two distinct mechanisms mediating human colorectal carcinoma cell interaction with peritoneal mesothelial cells and extracellular matrix

Ficha de fotocolecta de Pecari tajacu (Linnaeus, 1758) en Bosque Mesofilo de Montana de Jalisc

Early developability screen of therapeutic antibody candidates using Taylor dispersion analysis and UV area imaging detection

Therapeutic antibodies represent one of the fastest growing segments in the pharmaceutical market. They are used in a whole range of disease fields, such as autoimmune diseases, cancer, inflammation and infectious diseases. These developments called for new analytical platforms for faster and better antibody selection and characterization. Early quality control and risk assessment of biophysical parameters help to prevent late stage failure in antibody development thus reducing costs and time. Critical parameters such as aggregation, conformational stability, colloidal stability and hydrophilicity, are measured during the early phase of antibody generation and guide the selection process of the best lead candidates in terms of technical developability. We report on the use of a novel instrument (Actipix/Viscosizer) for measuring both the hydrodynamic radius and the absolute viscosity of antibodies based on Taylor dispersion analysis and UV area imaging. The looped microcapillary-based method combines low sample consumption, fast throughput and high precision as compared to other conventional methods. From a random panel of 130 mAbs in the early selection process, we identified a few antibodies with larger hydrodynamic radius outside the normal distribution and a few others with non-Gaussian Taylor dispersion profiles. These antibodies with such abnormal properties were confirmed later in the selection process to show poor developability profiles. Moreover, combining these results with the viscosity measurements at high antibody concentrations as usually required for sub-cutaneous injection, allows screening with limited amounts of materials, candidates with potential issues in pre-formulation development

Early developability screen of therapeutic antibody candidates using Taylor dispersion analysis and UV area imaging detection

Therapeutic antibodies represent one of the fastest growing segments in the pharmaceutical market. They are used in a broad range of disease fields, such as autoimmune diseases, cancer, inflammation and infectious diseases. The growth of the segment has necessitated development of new analytical platforms for faster and better antibody selection and characterization. Early quality control and risk assessment of biophysical parameters help prevent failure in later stages of antibody development, and thus can reduce costs and save time. Critical parameters such as aggregation, conformational stability, colloidal stability and hydrophilicity, are measured during the early phase of antibody generation and guide the selection process of the best lead candidates in terms of technical developability. We report on the use of a novel instrument (ActiPix/Viscosizer) for measuring both the hydrodynamic radius and the absolute viscosity of antibodies based on Taylor dispersion analysis and UV area imaging. The looped microcapillary-based method combines low sample consumption, fast throughput and high precision compared to other conventional methods. From a random panel of 130 antibodies in the early selection process, we identified some with large hydrodynamic radius outside the normal distribution and others with non-Gaussian Taylor dispersion profiles. The antibodies with such abnormal properties were confirmed later in the selection process to show poor developability profiles. Moreover, combining these results with those of the viscosity measurements at high antibody concentrations allows screening, with limited amounts of materials, candidates with potential issues in pre-formulation development