Dietary interventions and tumor response to chemotherapy in breast cancer: A comprehensive review of preclinical and clinical data.

Background & Aims: Optimizing treatment efficacy is still a critical part in advancing the treatment of breast cancer. Dietary interventions have drawn significant attention for their potential to increase tumor sensitivity, with a plethora of strategies evaluated both preclinically and clinically. The aim of this paper is to explore these strategies, ranging from entire dietary programs to specific supplements, for their potential to directly enhance tumor sensitivity and chemotherapy adherence.

Determining Plasma Tacrolimus Concentrations Using High-Performance LC-MS/MS in Renal Transplant Recipients.

Background: Whole-blood therapeutic drug monitoring of tacrolimus is conducted to maintain tacrolimus concentrations within a safe and effective range. Changes in hematocrit cause variability in blood concentrations of tacrolimus because it is highly bound to erythrocytes. Measuring plasma concentrations may eliminate this variability; however, current methods have limitations owing to the use of cross-reactive immunoassays, plasma separation at nonbiological temperatures, and lack of clinical validation.

The Association between the Gut Microbiome and Development and Progression of Cancer Treatment Adverse Effects.

Adverse effects are a common consequence of cytotoxic cancer treatments. Over the last two decades there have been significant advances in exploring the relationship between the gut microbiome and these adverse effects. Changes in the gut microbiome were shown in multiple clinical studies to be associated with the development of acute gastrointestinal adverse effects, including diarrhoea and mucositis.

Structural insight and analysis of TLR4 interactions with IAXO-102, TAK-242 and SN-38: an in silico approach.

Introduction: Toll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract.

Methods: In silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4.

Effects of a novel toll-like receptor 4 antagonist IAXO-102 in a murine model of chemotherapy-induced gastrointestinal toxicity.

Introduction: Gastrointestinal mucositis (GIM) is a side effect of high-dose irinotecan (CPT-11), causing debilitating symptoms that are often poorly managed. The role of TLR4 in the development of GIM has been clearly demonstrated. We, therefore, aimed to investigate the potential of the TLR4 antagonist, IAXO-102, to attenuate gastrointestinal inflammation as well as supress tumour activity in a colorectal-tumour-bearing mouse model of GIM induced by CPT-11.

Investigation of TLR4 Antagonists for Prevention of Intestinal Inflammation.

Activation of toll-like receptor 4 (TLR4) has been shown to be a major influence on the inflammatory signalling pathways in intestinal mucositis (IM), as demonstrated by TLR4 knock-out mice. Pharmacological TLR4 inhibition has thus been postulated as a potential new therapeutic approach for the treatment of IM but specific TLR4 inhibitors have yet to be investigated. As such, we aimed to determine whether direct TLR4 antagonism prevents inflammation in pre-clinical experimental models of IM.

Contribution of TLR4 to colorectal tumor microenvironment, etiology and prognosis.

Purpose: Toll-like receptor 4 (TLR4) is increasingly recognized for its ability to govern the etiology and prognostic outcomes of colorectal cancer (CRC) due to its profound immunomodulatory capacity. Despite widespread interest in TLR4 and CRC, no clear analysis of current literature and data exists. Therefore, translational advances have failed to move beyond conceptual ideas and suggestions.

Epithelial-Specific TLR4 Knockout Challenges Current Evidence of TLR4 Homeostatic Control of Gut Permeability.

Introduction: Toll-like receptor 4 (TLR4) is a highly conserved immunosurveillance protein of innate immunity, displaying well-established roles in homeostasis and intestinal inflammation. Current evidence shows complex relationships between TLR4 activation, maintenance of health, and disease progression; however, it commonly overlooks the importance of site-specific TLR4 expression. This omission has the potential to influence translation of results as previous evidence shows the differing and distinct roles that TLR4 exhibits are dependent on its spatiotemporal expression.

Intestinal toll-like receptor 4 knockout alters the functional capacity of the gut microbiome following irinotecan treatment.

Purpose: Irinotecan can cause high levels of diarrhea caused by toxic injury to the gastrointestinal microenvironment. Toll-like receptor 4 (TLR4) and the gut microbiome have previously been implicated in gastrointestinal toxicity and diarrhea; however, the link between these two factors has not been definitively determined. We used a tumor-bearing, intestinal epithelial cell (IEC) TLR4 knockout model (Tlr4) to assess microbiome changes following irinotecan treatment.

Associations of Immune Genetic Variability with Gulf War Illness in 1990-1991 Gulf War Veterans from the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key.

Brain-Immune Interactions as the Basis of Gulf War Illness: Clinical Assessment and Deployment Profile of 1990-1991 Gulf War Veterans in the Gulf War Illness Consortium (GWIC) Multisite Case-Control Study.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990-1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S.

Toll-like receptor 4 (TLR4) antagonists as potential therapeutics for intestinal inflammation.

Gastrointestinal inflammation is a hallmark of highly prevalent disorders, including cancer treatment-induced mucositis and ulcerative colitis. These disorders cause debilitating symptoms, have a significant impact on quality of life, and are poorly managed. The activation of toll-like receptor 4 (TLR4) has been proposed to have a major influence on the inflammatory signalling pathways of the intestinal tract.

Tacrolimus dose, blood concentrations and acute nephrotoxicity, but not CYP3A5/ABCB1 genetics, are associated with allograft tacrolimus concentrations in renal transplant recipients.

Aims: Long-term use of the immunosuppressant tacrolimus is limited by nephrotoxicity. Following renal transplantation, the risk of nephrotoxicity may be determined more by allograft than by blood tacrolimus concentrations, and thus may be affected by donor CYP3A5 and ABCB1 genetics. Little is known regarding factors that determine tacrolimus intrarenal exposure.

Site-specific contribution of Toll-like receptor 4 to intestinal homeostasis and inflammatory disease.

Toll-like receptor 4 (TLR4) is a highly conserved protein of innate immunity, responsible for the regulation and maintenance of homeostasis, as well as immune recognition of external and internal ligands. TLR4 is expressed on a variety of cell types throughout the gastrointestinal tract, including on epithelial and immune cell populations. In a healthy state, epithelial cell expression of TLR4 greatly assists in homeostasis by shaping the host microbiome, promoting immunoglobulin A production, and regulating follicle-associated epithelium permeability.

Diarrhea Induced by Small Molecule Tyrosine Kinase Inhibitors Compared With Chemotherapy: Potential Role of the Microbiome.

Small molecule receptor tyrosine kinase inhibitors (SM-TKIs) are among a group of targeted cancer therapies, intended to be more specific to cancer cells compared with treatments, such as chemotherapy, hence reducing adverse events. Unfortunately, many patients report high levels of diarrhea, the pathogenesis of which remains under investigation. In this article, we compare the current state of knowledge of the pathogenesis of chemotherapy-induced diarrhea (CID) in comparison to SM-TKI-induced diarrhea, and investigate how a similar research approach in both areas may be beneficial.

No Major Effect of Innate Immune Genetics on Acute Kidney Rejection in the First 2 Weeks Post-Transplantation.

Background: Innate immunity contributes to acute rejection after kidney transplantation. Genetic polymorphisms affecting innate immunity may therefore influence patients' risk of rejection. -330T > G, -1082G > A, -819C > T, and -592C > A, and -308G > A are not associated with acute rejection incidence in Caucasian kidney transplant recipients receiving a calcineurin inhibitor, ciclosporin or tacrolimus (TAC).

Intestinal accumulation of silica particles in a rat model of dextran sulfate sodium-induced colitis.

Background: Ulcerative colitis (UC) is a lifelong inflammatory bowel disease characterized by periods of intense colonic inflammation leading to debilitating symptoms. Delivery methods of current UC treatments are suboptimal and associated with side effects. Silica particles are a potential alternative delivery method for UC therapeutics, given their promising drug-loading and safety profiles.

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (C ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and C and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere-Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on C .

Relationship between allograft cyclosporin concentrations and P-glycoprotein expression in the 1st month following renal transplantation.

The immunosuppressant cyclosporin is a P-glycoprotein (P-gp) substrate whose impaired function has been associated with an increased risk of cyclosporin-induced nephrotoxicity following renal transplantation. This study investigated the relationship between blood and allograft cyclosporin concentration, and the effect of P-gp expression. Fifty biopsy samples were obtained from 39 renal transplant recipients who received cyclosporin as part of maintenance immunosuppression.

Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation.

Background: CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression.

Toll-like receptor/interleukin-1 domain innate immune signalling pathway genetic variants are candidate predictors for severe gastrointestinal toxicity risk following 5-fluorouracil-based chemotherapy.

Purpose: Severe gastrointestinal (GI) toxicity is a common adverse effect following 5-fluorouracil (5-FU)-based chemotherapy treatment. The presence of severe GI toxicity leads to treatment revisions, sub-optimal therapy outcomes, and decreases to patients' quality of life. There are no adequate predictors for 5-FU-induced severe GI toxicity risk.