Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, was identified as a specific keratinocyte mitogen after isolation from a lung fibroblast line. Recently, recombinant (r)KGF was found to influence proliferation and differentiation patterns of multiple epithelial cell lineages within skin, lung, and the reproductive tract. In the present study, we designed experiments to identify additional target tissues, and focused on the rat gastrointestinal (GI) system, since a putative receptor, K-sam, was originally identified in a gastric carcinoma. Expression of KGF receptor and KGF mRNA was detected within the entire GI tract, suggesting the gut both synthesized and responded to KGF. Therefore, rKGF was administered to adult rats and was found to induce markedly increased proliferation of epithelial cells from the foregut to the colon, and of hepatocytes, one day after systemic treatment. Daily treatment resulted in the marked selective induction of mucin-producing cell lineages throughout the GI tract in a dose-dependent fashion. Other cell lineages were either unaffected (e.g., Paneth cells), or relatively decreased (e.g., parietal cells, enterocytes) in rKGF-treated rats. The direct effect of rKGF was confirmed by demonstrating markedly increased carcinoembryonic antigen production in a human colon carcinoma cell line, LIM1899. Serum levels of albumin were specifically and significantly elevated after daily treatment. These results demonstrate rKIGF can induce epithelial cell activation throughout the GI tract and liver. Further, endogenous KGF may be a normal paracrine mediator of growth within the gut. (J. Clin. Iptvqst. 1994Iptvqst. . 94:1764Iptvqst. -1777

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Tumors deficient in the urea cycle enzymes argininosuccinate synthase-1 (ASS1) and ornithine transcarbamylase (OTC) are unable to synthesize arginine and can be targeted using arginine-deprivation therapy. Here, we show that colorectal cancers (CRCs) display negligible expression of OTC and, in subset of cases, ASS1 proteins. CRC cells fail to grow in arginine-free medium and dietary arginine deprivation slows growth of cancer cells implanted into immunocompromised mice. Moreover, we report that clinically-formulated arginine-degrading enzymes are effective anticancer drugs in CRC. Pegylated arginine deiminase (ADI-PEG20), which degrades arginine to citrulline and ammonia, affects growth of ASS1-negative cells, whereas recombinant human arginase-1 (rhArg1peg5000), which degrades arginine into urea and ornithine, is effective against a broad spectrum of OTC-negative CRC cell lines. This reflects the inability of CRC cells to recycle citrulline and ornithine into the urea cycle. Finally, we show that arginase antagonizes chemotherapeutic drugs oxaliplatin and 5-fluorouracil (5-FU), whereas ADI-PEG20 synergizes with oxaliplatin in ASS1-negative cell lines and appears to interact with 5-fluorouracil independently of ASS1 status. Overall, we conclude that CRC is amenable to arginine-deprivation therapy, but we warrant caution when combining arginine deprivation with standard chemotherapy.

Monocytes from HIV-seronegative persons were analyzed for CD4 expression and susceptibility to infection with HIV-1 on the day of isolation and following 1, 2, and 7 days in culture. Although surface CD4 was readily detected on freshly isolated monocytes, these cells were relatively resistant to infection. After 1 to 2 days in culture, when surface expression of CD4 had decreased over 90% to near background levels, cells became susceptible to infection with HIV-1. CD4 expression on monocytes cultured for 7 days was more than four times higher than that on freshly isolated cells, and the cultured cells were fully permissive to infection. These observations suggest that the differing susceptibility of monocytes and monocyte-derived macrophages to infection with HIV-1 is not simply proportional to the level of surface CD4 expression.

Introduction Uterine sarcomas are a group of rare tumours with heterogeneous morphological and genetic features. Recent advances in the molecular characterisation of these tumours have identified a novel clinicopathological category underpinned by NTRK gene fusions. Case report We present the case of a 42-year-old woman with a polypoid cervical lesion formed of densely cellular, short, haphazard fascicles of monomorphic spindle cells that lacked coagulative necrosis and which showed high mitotic activity. On immunohistochemistry, the tumour was diffusely positive for pan-Trk and weakly positive for CD34 but was negative for a range of other markers, including cytokeratins, smooth muscle markers, hormone receptors and S100. FISH analysis using a NTRK1 break-apart probe was above the threshold for translocation positivity and subsequent next-generation sequencing (NGS) identified a TPM3-NTRK1 fusion. Discussion NTRK-rearranged uterine sarcomas are a novel subset of gynaecological mesenchymal neoplasms characterised by cytological isomorphism and fibrosarcoma-like morphology. Although distinction from more common mesenchymal neoplasms is possible on the basis of morphology and immunohistochemistry, exclusion of rare differential diagnoses, such as malignant peripheral nerve sheath tumour or the recently described COL1A1-PDGFB fusion sarcoma, requires molecular work-up with FISH or NGS. Identification of these rare tumours is clinically relevant because of their cervical location and the possible role for tropomyosin receptor kinase inhibitors in their treatment.