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Bone morphogenetic proteins (BMP) are phylogenetically conserved signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily of proteins, involved in developmental and (patho)physiological processes, including cancer. BMP signaling has been regarded as tumor-suppressive in colorectal cancer (CRC) by reducing cancer cell proliferation and invasion, and by impairing epithelial-to-mesenchymal transition (EMT). Here, we mined existing proteomic repositories to explore the expression of BMPs in CRC. We found that the BMP antagonist gremlin-1 (GREM1) is secreted from heterotypic tumor-host cell interactions. We then sought to investigate whether GREM1 is contextually and mechanistically associated with EMT in CRC. Using immunohistochemistry, we showed that GREM1-expressing stromal cells harbor prominent features of myofibroblasts (i.e., cancer-associated fibroblasts), such as expression of α-smooth muscle actin and laminin-beta-1, and were in contextual proximity to invasion fronts with loss of the tight junction protein occludin and parallel nuclear accumulation of β-catenin, two prominent EMT hallmarks. Furthermore, in vitro assays demonstrated that GREM1-dependent suppression of BMP signaling results in EMT induction, characterized by cadherin switching (loss of E-cadherin-upregulation of N-cadherin) and overexpression of Snail. Collectively, our data support that GREM1 promotes the loss of cancer cell differentiation at the cancer invasion front, a mechanism that may facilitate tumor progression.

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Myocarditis is a rare cause of sudden death in childhood. We describe the sudden death of a child from viral myocarditis, which we demonstrate was likely caused by an uncontrolled inflammatory response to a disseminated adenovirus serotype 3 infection originating in the tonsil. CASE REPORTAn 11-year old boy collapsed suddenly at home. He was transferred to a hospital by ambulance. Cardiopulmonary resuscitation was unsuccessful, and he was pronounced dead. He had visited his general practitioner (GP) 1 day earlier with a sore throat and was treated with antibiotics for tonsillitis. No investigations were carried out by his GP or on arrival at the hospital due to his sudden death. He had no past medical history of note, and there was no family history of cardiac illness or sudden death. No recent foreign travel was reported, nor was there contact with persons from abroad. A postmortem was carried out at the direction of the coroner.Much of the postmortem examination was normal. His tonsils were mildly enlarged and showed a surface purulent exudate. However, on postmortem examination, his heart was enlarged (weight, 214.2 g; expected weight, 124 g). On sectioning, the myocardium appeared diffusely abnormal with areas of petechiae and pallor. There was no evidence of myocardial hypertrophy. Microscopically, there was a severe myocardial infiltrate diffusely present composed of lymphocytes, histiocytes, and plasma cells with occasional eosinophils and neutrophils (Fig. 1). There were admixed areas of necrosis and hemorrhage. There was no evidence of fibrosis or myofiber hypertrophy. Immunohistochemical staining revealed that the infiltrate was predominantly lymphohistiocytic (CD45 positive). CD3 staining confirmed that this was a T-lymphocytemediated response (Fig. 2).All routine investigations, including swabs for bacterial culture, blood cultures, meningococcal PCR, and pneumococcal PCR, were negative. Toxicology testing for alcohol and drugs was negative. Target-specific immunoglobulin M assays were performed for Mycoplasma pneumoniae, cytomegalovirus, Epstein-Barr virus, parvovirus B19, and rubella virus, along with complement fixation testing for total antibodies to Mycoplasma pneumoniae, Chlamydia group, and adenovirus and latex agglutination testing for Toxoplasma gondii. All serological investigations were negative. In addition, no viruses were observed in the lung or myocardial tissue by electron microscopy. Cerebrospinal fluid Gram staining and culture were negative.The most common viral etiologies of myocarditis are Coxsackie group B viruses and members of the adenovirus genus (3, 5). Therefore, molecular methods were employed to investigate the presence of these viruses. Total viral RNA/DNA was extracted from serum using the Qiagen QIAmp viral RNA mini kit, and total viral DNA was extracted from myocardial and pulmonary tissue using the QIAamp DNA mini kit (Qiagen) in accordance with the manufacturer's instructions. Enterovirus RNA was not detected in lung or myocardial tissue using a nested reverse trans...