Abstract Decline in skeletal muscle cell size (myofiber atrophy) is a key feature of cancer-induced wasting (cachexia). In particular, atrophy of the diaphragm, the major muscle responsible for breathing, is an important determinant of cancer-associated mortality. However, therapeutic options are limited. Here, we have used Drosophila transgenic screening to identify muscle-secreted factors (myokines) that act as paracrine regulators of myofiber growth. Subsequent testing in mouse myotubes revealed that mouse Fibcd1 is an evolutionary-conserved myokine that preserves myofiber size via ERK signaling. Local administration of recombinant Fibcd1 (rFibcd1) ameliorates cachexia-induced myofiber atrophy in the diaphragm of mice bearing patient-derived melanoma xenografts and LLC carcinomas. Moreover, rFibcd1 impedes cachexia-associated transcriptional changes in the diaphragm. Fibcd1-induced signaling appears to be muscle selective because rFibcd1 increases ERK activity in myotubes but not in several cancer cell lines tested. We propose that rFibcd1 may help reinstate myofiber size in the diaphragm of patients with cancer cachexia. 

https://www.nature.com/articles/s41467-022-30120-1.pdf

The myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy

Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen’s Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.

/pdf/experimental-chemotherapy-induced-mucositis-a-scoping-review-2t3az4x8.pdf

Experimental Chemotherapy-Induced Mucositis: A Scoping Review Guiding the Design of Suitable Preclinical Models

Introduction: Chemotherapy-induced gastrointestinal toxicity (CIGT) is a frequent, severe and dose-limiting side effect. Few treatments have proven effective for CIGT. CIGT is characterized by activation of the nuclear factor kappa B pathway which, leads to upregulation of proinflammatory cytokines. The innate immune protein peptidoglycan recognition peptide 2 (PGLYRP2) binds to and hydrolyzes microbial peptidoglycan. Expression of PGLYRP2 is upregulated in the intestine of chemotherapy-treated piglets. In this experimental study, we investigated the role of Pglyrp2 in the development and severity of murine CIGT.

Methods: Pglyrp2 wildtype and Pglyrp2 knockout mice received intraperitoneal injections of chemotherapy (Doxorubicin 20 mg/kg) to induce CIGT. Weight was monitored daily, and animals were euthanized after 2 or 7 days. Expression of proinflammatory cytokines in the jejunum was measured by quantitative real-time polymerase-chain reaction and enzyme-linked immunosorbent assay. Villus height, crypt depth, and histologic inflammation were evaluated on haematoxylin and eosin stained tissue specimens.

Results: Chemotherapeutic treatment induced weight loss (p < 0.05), shortening of the small intestine (p < 0.05), elongation of villus height (p < 0.05), increased crypt depth (p < 0.05), and led to elevated mRNA levels of II1β (p < 0.05), II6 (p < 0.05), and Tnf (p < 0.001) at day 2. Protein levels of IL1β, IL6, and TNFα did not change after exposure to chemotherapy. Doxorubicin treated wildtype mice had a more pronounced weight loss compared to knockout mice from day 3 to day 7 (D3-D6: p < 0.05 and D7: p < 0.01). No other phenotypic differences were detected.

Conclusion: Pglyrp2 aggravates chemotherapy-induced weight loss but does not induce a specific pattern of inflammation and morphological changes in the small intestine.

/pdf/peptidoglycan-recognition-peptide-2-aggravates-weight-loss-54pfioze03.pdf

Peptidoglycan Recognition Peptide 2 Aggravates Weight Loss in a Murine Model of Chemotherapy-Induced Gastrointestinal Toxicity.

Introduction A severe side effect of cancer chemotherapy is the development of gastrointestinal mucositis, characterised by mucosal inflammation. We investigated if 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography combined with computed tomography (2-[18F]FDG-PET/CT) could visualise gastrointestinal mucositis in mice treated with the chemotherapeutic agent doxorubicin. Methods In this study, gastrointestinal inflammation was longitudinally evaluated by 2-[18F]FDG-PET/CT scans before and 1, 3, 6, and 10 days after treatment with doxorubicin. Doxorubicin-treated mice were compared to saline-treated littermates using the abdominal standard uptake value of 2-[18F]FDG corrected for body weight (SUVBW). Results Abdominal SUVBW was significantly increased on day 1 (p < 0.0001), day 3 (p < 0.0001), and day 6 (p < 0.05) in the doxorubicin-treated group compared to controls. Abdominal SUVBW returned to baseline levels on day 10. In the doxorubicin group, the largest weight loss was observed on day 3 (control vs doxorubicin, mean percent of baseline weight: (98.5 ± 3.2% vs 87.9 ± 4.6%, p < 0.0001). Moreover, in the doxorubicin-treated group, villus lengths were decreased by 23-28% on days 1 and 3 in the small intestine (p < 0.05), and jejunal levels of tumour necrosis factor and interleukin-1β were significantly increased on day 3 (p < 0.05). Discussion Together, these findings indicate that sequential 2-[18F]FDG-PET/CT scans can objectively quantify and evaluate the development and resolution of intestinal inflammation over time in a mouse model of doxorubicin-induced mucositis.

/pdf/pet-ct-imaging-detects-intestinal-inflammation-in-a-mouse-35j2sxny.pdf

PET/CT imaging detects intestinal inflammation in a mouse model of doxorubicin-induced mucositis

Nutrition support use and clinical outcomes in patients with multiple myeloma undergoing autologous stem cell transplant

Chemotherapy-induced gastrointestinal toxicity is a common adverse event during chemotherapeutic treatment. No uniformly applicable strategies exist to predict, prevent, or treat gastrointestinal toxicity. Thus, a goal of mucositis research is to identify targets for therapeutic interventions and individualized risk prediction. Fibrinogen C domain containing 1 (FIBCD1) is a transmembrane protein expressed in human intestinal epithelial cells with functions in the innate immune system. Previous observations have shown that FIBCD1 ameliorates dextran sulfate sodium (DSS)–induced intestinal inflammation in vivo. We evaluated the effect of FIBCD1 in a murine model of chemotherapy-induced gastrointestinal toxicity and inflammation. Transgenic (Tg) mice overexpressing FIBCD1 in the intestinal epithelium (Fibcd1Tg) and wild-type (WT) littermates (C57BL/6N) were randomized to receive an intraperitoneal injection of doxorubicin 20 mg/kg or saline and were terminated 2 or 7 days after the injection. Gastrointestinal toxicity was evaluated by weight change, intestinal length, villus height/crypt depth, and histological mucositis score. Expression of inflammatory markers (IL-6, IL-1β, and Tnfα) was measured by quantitative real-time PCR in intestinal tissue samples. Following doxorubicin treatment, WT mice exhibited an increased weight loss compared with Tg littermates (p < 0.001). No differences between genotypes were seen in mucositis score, intestinal length, villus height/crypt depth, or IL-6, IL-1β, and Tnfα expression. Our findings suggest that FIBCD1 could ameliorate chemotherapy-induced gastrointestinal toxicity by reducing weight loss; however, the mechanism of this possible protective effect remains to be defined warranting additional investigations.

FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis

Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified.Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA.We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa.Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation. 

/pdf/pediatric-celiac-disease-and-selective-iga-deficiency-11fin8cc.pdf

Maria C E Andersen

Papers

FIBCD1 ameliorates weight loss in chemotherapy-induced murine mucositis

Pediatric Celiac Disease and Selective IgA Deficiency: Unexpected Sequence of Events