Effects of Composite Restorations on the Periodontal Membrane in Monkeys

We evaluated the histopathological response of the periodontal membrane to intentionolly-replanted teeth carrying composite (experimental) and silver amalgam (control) restorations in the middle third of each root. The study revealed that the amalgam produced, in the periodontal tissues, an initial localized inflammation that subsided with the subsequent formation of a fibrous capsule. However, the periodontal membrane adjacent to the composite resin restorations demonstrated chronic inflammation. It was concluded that the composite evoked chronic inflammatory responses of the periodontal tissues in monkeys.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67994/2/10.1177_00220345830620011801.pd

The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy‐induced gastrointestinal toxicity

Online 28 Aug 2018Chemotherapy‐induced gastrointestinal toxicity (CIGT) occurs in up to 80% of all patients undergoing cancer treatment, and leads to symptoms such as diarrhoea, abdominal bleeding and pain. There is currently limited understanding of how to predict an individual patient's risk of CIGT. It is believed the gut microbiome and its interactions with the host's innate immune system plays a key role in the development of this toxicity and potentially other toxicities, however comprehensive bioinformatics modelling has not been rigorously performed. The innate immune system is strongly influenced by the microbial environment and vice‐versa. Ways this may occur include the immune system controlling composition and compartmentalisation of the microbiome, the microbiome affecting development of antigen‐presenting cells, and finally, the NLRP6 inflammasome orchestrating the colonic host‐microbiome interface. This evidence calls into question the role of pre‐treatment risk factors in the development of gastrointestinal toxicity after chemotherapy. This review aims to examine evidence of a bidirectional interaction between the gut microbiome and innate immunity, and how these interactions occur in CIGT. In the future, knowledge of these interactions may lead to improved personalised cancer medicine, predictive risk stratification methods and the development of targeted interventions to reduce, or even prevent, CIGT severity.Kate R. Secombe, Janet K. Coller, Rachel J. Gibson, Hannah R. Wardill and Joanne M. Bowe

Selective MMP inhibition, using AZD3342, to reduce gastrointestinal toxicity and enhance chemoefficacy in a rat model

BACKGROUND:The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. OBJECTIVES:The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. METHODS:Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. RESULTS:AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. CONCLUSIONS:This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling.Rachel J. Gibson, Ysabella Z.A. van Sebille, Hannah R. Wardill, Anthony Wignall, Joseph Shirren, Imogen A. Ball, Nicole Williams, Kiara Wanner, Joanne M. Bowe

Guidelines for reporting on animal fecal transplantation (GRAFT) studies: recommendations from a systematic review of murine transplantation protocols

Fecal microbiota transplant (FMT) is a powerful tool used to connect changes in gut microbial composition with a variety of disease states and pathologies. While FMT enables potential causal relationships to be identified, the experimental details reported in preclinical FMT protocols are highly inconsistent and/or incomplete. This limitation reflects a current lack of authoritative guidance on reporting standards that would facilitate replication efforts and ultimately reproducible science. We therefore systematically reviewed all FMT protocols used in mouse models with the goal of formulating recommendations on the reporting of preclinical FMT protocols. Search strategies were applied across three databases (PubMed, EMBASE, and Ovid Medline) until June 30, 2020. Data related to donor attributes, stool collection, processing/storage, recipient preparation, administration, and quality control were extracted. A total of 1753 papers were identified, with 241 identified for data extraction and analysis. Of the papers included, 92.5% reported a positive outcome with FMT intervention. However, the vast majority of studies failed to address core methodological aspects including the use of anaerobic conditions (91.7% of papers lacked information), storage (49.4%), homogenization (33.6%), concentration (31.5%), volume (19.9%) and administration route (5.3%). To address these reporting limitations, we developed theGuidelines for Reporting Animal Fecal Transplant (GRAFT) that guide reporting standards for preclinical FMT. The GRAFT recommendations will enable robust reporting of preclinical FMT design, and facilitate high-quality peer review, improving the rigor and translation of knowledge gained through preclinical FMT studies.Kate R. Secombe, Ghanyah H. Al-Qadami, Courtney B. Subramaniam, Joanne M. Bowen, Jacqui Scott, Ysabella Z.A. Van Sebille ... et a

Whey-based diet containing medium chain triglycerides modulates the gut microbiota and protects the intestinal mucosa from chemotherapy while maintaining therapy efficacy.

Cytotoxicity (i.e. cell death) is the core mechanism by which chemotherapy induces its anti-cancer effects. Unfortunately, this same mechanism underpins the collateral damage it causes to healthy tissues. The gastrointestinal tract is highly susceptible to chemotherapy’s cytotoxicity, resulting in ulcerative lesions (termed gastrointestinal mucositis, GI-M) that impair the functional capacity of the gut leading to diarrhea, anorexia, malnutrition and weight loss, which negatively impact physical/psychological wellbeing and treatment adherence. Preventing these side effects has proven challenging given the overlapping mechanisms that dictate chemotherapy efficacy and toxicity. Here, we report on a novel dietary intervention that, due to its localized gastrointestinal effects, is able to protect the intestinal mucosal from unwanted toxicity without impairing the anti-tumor effects of chemotherapy. The test diet (containing extensively hydrolyzed whey protein and medium chain triglycerides (MCTs)), was investigated in both tumor-naïve and tumor-bearing models to evaluate its effect on GI-M and chemo-efficacy, respectively. In both models, methotrexate was used as the representative chemotherapeutic agent and the diet was provided ad libitum for 14 days prior to treatment. GI-M was measured using the validated biomarker plasma citrulline, and chemo-efficacy defined by tumor burden (cm3 /g body weight). The test diet significantly attenuated GI-M (P = 0.03), with associated reductions in diarrhea (P < 0.0001), weight loss (P < 0.05), daily activity (P < 0.02) and maintenance of body composition (P < 0.02). Moreover, the test diet showed significant impact on gut microbiota by increasing diversity and resilience, whilst also altering microbial composition and function (indicated by cecal short and brained chain fatty acids). The test diet did not impair the efficacy of methotrexate against mammary adenocarcinoma (tumor) cells. In line with the first model, the test diet minimized intestinal injury (P = 0.001) and diarrhea (P < 0.0001). These data support translational initiatives to determine the clinical feasibility, utility and efficacy of this diet to improve chemotherapy treatment outcomes.Hannah R. Wardill, Ana Rita Da Silva Ferreira, Himanshu Kumar, Emma H. Bateman, Courtney B. Cross, Joanne M. Bowen, Rick Havinga, Hermie J. M. Harmsen, Jan Knol, Bram Dorresteijn, Miriam van Dijk, Jeroen van Bergenhenegouwen, and Wim J. E. Tissin

Proposal to study multiparticle-peripheral hadron physics at NAL

We propose to build a large wire chamber magnetic spectrometer at NAL to measure multi-body forward-going hadronic systems produced by {pi}'s, K's and protons up to 80 GeV/c. Specific reactions will be isolated in order to study the s and t dependencies of the cross sections for peripheral processes, search for new resonant states and attempt to measure {pi}{pi} and K{pi} inelastic scattering. We propose a physics program for the spectrometer which is initially limited to those processes easiest to measure and which nevertheless spans a large range of strong interaction problems. Technically, the proposed spectrometer is a relatively modest extension of presently operating systems in the 10-20 GeV/c region, and does not present a challenge of uncertain magnitude to construct

Search for leptophobic Z ' bosons decaying into four-lepton final states in proton-proton collisions at root s=8 TeV

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