The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation.

The potential involvement of cytokines in acute graft-versus-host disease led us to analyze interleukin-6 in serial serum sets from 22 allogeneic marrow recipients who developed either grade 3 or 4 GVHD (n = 10), grade 2 GVHD (n = 6), or grade 1 or no diagnosed GVHD (n = 6). A total of 279 serial serum samples taken three times weekly before day 35 were analyzed. Maximum IL-6 levels were greater than 40 U/ml (range, 40-1536 U/ml), 11-40 U/ml, and less than or equal to 10 U/ml for six, eleven, and five patients, respectively. Serum IL-6 peaks were temporally related to onset of GVHD, onset of a syndrome of hepatorenal dysfunction (HRD), or bilateral lung infiltration. Eight of ten patients who developed grade 3 or 4 GVHD overall had IL-6 maxima of greater than 10 U/ml an average of 1.5 +/- 1.8 days before the clinical onset. Fifteen of 17 patients with peak IL-6 levels greater than 10 U/ml developed symptoms of hepatic and renal dysfunction within three days of the peak, while none of five patients with less than or equal to 10 U/ml of Il-6 developed HRD. Regression analysis demonstrated a linkage between the log magnitudes of the serum IL-6 peaks and onset of either GVHD or HRD within three days (P = 0.001). Furthermore, IL-6 peaks tended to precede GVHD onset for the 10 patients whose GVHD onset and IL-6 peak were within three days of each other (P = 0.02). These results, confirmed by both specific bioassay and by IL-6 ELISA, support the idea that acute GVHD in humans involves a cytokine cascade that includes production of IL-6 in addition to the previously reported involvement of tumor necrosis factor alpha and interferon-gamma.     

Karapandzic flap for reconstruction of lip defects.

PURPOSE: Systematic evaluation of the Karapandzic flap in the reconstruction of lip defects after ablative surgery. PATIENTS AND METHODS: Patients who had a Karapandzic flap to reconstruct lip defects were analyzed with reference to demographic details, histology and location of the tumor, and dimensions of resection. The functional aspects of the reconstruction were assessed in terms of the size of the oral stoma, preservation of oral competence, and facial expression, in addition to speech, diet and ease of cutlery, and denture usage. The esthetic outcome was assessed with a 4-point scale and in addition the symmetry of the commissure at rest and function, preservation of the philtrum, and lip projection also were assessed. The complications were noted. RESULTS: Seven patients underwent Karapandzic flap reconstruction (4 males, 3 females) with an age range of 43 to 98 years. Three tumors were located in the upper lip, 4 in the lower lip, and there were 5 squamous and 2 basal cell carcinomas. The lip defects ranged from 40% to 75% of the lip circumference. The oral stoma was of a reduced circumference in all cases but did not lead to any functional compromise in terms of oral competence, facial expression, speech, diet, denture and cutlery usage, and sensation. There were no wound complications in our series. The esthetic outcome was considered excellent/good in 85% of cases. The commissure was symmetrical in all except 1 patient, the philtrum was preserved in all cases of lower lip reconstruction, and the projection of the lip was reduced in edentulous patients. CONCLUSIONS: The Karapandzic flap is a reliable technique that offers consistently good functional and esthetic outcomes after reconstruction of lip defects.     

Identification of N-(deoxyguanosin-8-yl)-4-azobiphenyl by (32)P-postlabeling analyses of DNA in human uroepithelial cells exposed to proximate metabolites of the environmental carcinogen 4-aminobiphenyl

DNA adducts formed in human uroepithelial cells (HUC) following exposure to N-hydroxy-4-aminobiphenyl (N-OH-ABP), the proximate metabolite of the human bladder carcinogen 4-aminobiphenyl (ABP), were analyzed by the (32)P-postlabeling method. Two adducts detected by (32)P-postlabeling were previously identified as the 3',5'-bisphospho derivatives of N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) and N-(deoxyadenosin-8-yl)-4-aminobiphenyl (dA-C8-ABP) (Frederickson S et al. [1992] Carcinogenesis 13: 955-961; Hatcher and Swaminathan [1995b] Carcinogenesis 16: 295-301). In contrast to the dG-C8-ABP adduct, which was 3'-dephosphorylated by nuclease P1, dA-C8-ABP was resistant to nuclease P1, thus providing an enrichment step before postlabeling. Autoradiography of the two-dimensional thin-layer chromatogram of the postlabeled products obtained following nuclease P1 digestion revealed several minor adducts, one of which has been identified in the present study. Postlabeling analyses following nuclease P1 digestion of the products obtained from the reaction of N-acetoxy-4-aminobiphenyl with deoxyguanosine-3'-monophosphate (dGp) demonstrated the presence of this minor adduct. The 3'-monophosphate derivative of the adduct was subsequently chromatographically purified and subjected to spectroscopic analyses. Based on proton NMR and mass spectroscopic analyses of the synthetic product, the chemical structure of the adduct has been identified as N-(deoxyguanosin-N(2)-yl)-4-azobiphenyl (dG-N==N-ABP). (32)P-Postlabeling analysis of the nuclease P1-enriched DNA hydrolysate of HUCs treated with N-OH-ABP or N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) showed the presence of the dG-N==N-ABP adduct. It was also detected in calf thymus DNA incubated with HUC cytosol and N-OH-ABP in the presence of acetyl-CoA, or incubated with HUC microsomes and N-OH-AABP. These results demonstrate that in the target cells for ABP carcinogenesis in vivo, N-OH-ABP and N-OH-AABP are bioactivated by acyltransferases to reactive arylnitrenium ions that covalently interact at the N2 position of deoxyguanosine in DNA.     

Role of 18F‐FDOPA PET/CT imaging in endocrinology

¹⁸F‐FDOPA (6‐[18F]‐L‐fluoro‐L‐3, 4‐dihydroxyphenylalanine)‐based PET/CT imaging can be a useful tool for the detection of different neuroendocrine tumours (NETs). ¹⁸F‐FDOPA is taken up into the cells via the neutral amino acid transporter (LAT1/4F2hc). This transporter is also coupled to the mammalian target of rapamycin (mTOR) signalling pathway. ¹⁸F‐FDOPA PET/CT may be performed for confirmation of diagnosis of pheochromocytoma/paraganglioma, staging at initial presentation, restaging and follow‐up of patients. In SDHx‐related syndromes, ¹⁸F‐FDG PET/CT should be performed in addition to ¹⁸F‐FDOPA PET/CT. ¹⁸F‐FDOPA PET/CT is also invaluable in the detection staging/restaging of carcinoid tumours and has greater sensitivity as compared to somatostatin receptor scintigraphy. ¹⁸F‐FDOPA PET/CT can also distinguish between focal vs diffuse CHI. It is not as useful in adult hyperinsulinism due to increased background uptake, but the problem may be overcome with the help of premedication with carbidopa. It has limited use in pancreatic NETs. ¹⁸F‐FDOPA PET/CT is a good modality for detection of persistent and residual medullary thyroid cancer (MTC), but ¹⁸F‐FDG PET/CT may be needed in aggressive tumours. In summary, F‐DOPA PET/CT has widespread utility in the diagnosis of different neuroendocrine tumours.     

Persistence of parasite antigenemia following diethylcarbamazine therapy of bancroftian filariasis

This study was designed to reexamine the efficacy of diethylcarbamazine for bancroftian filariasis with special reference to changes in serum parasite antigen levels and antifilarial antibody titers after treatment. Patients with asymptomatic microfilaremia were treated with 6 mg/kg diethylcarbamazine daily for 12 days. Microfilaria counts fell dramatically after treatment, as expected. IgG antibody titers to adult and microfilarial antigens of B. malayi were increased 1 month after treatment in most patients. Titers fell slowly to or below pretreatment levels, but remained positive during subsequent months. Parasite antigen levels, measured by monoclonal antibody-based enzyme immunoassay, decreased to 72%, 58%, 53%, and 48% of pretreatment values 1, 3, 6, and 12 months after diethylcarbamazine treatment, respectively. Parasite antigen levels decreased similarly in subjects with and without residual microfilaremia after treatment. These results suggest that diethylcarbamazine has only partial macrofilaricidal activity against W. bancrofti with this dosage schedule. The sustained, impressive reductions in microfilaria counts after treatment despite significant persistence of parasite antigenemia may be explained by sublethal effects of the drug on adult worms. We believe that parasite antigen detection represents a valuable new approach for monitoring the efficacy of antifilarial drug therapy which we hope will lead to improved use of existing drugs and aid in the evaluation of new drugs for filariasis.     

MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response

MicroRNAs (miRNAs) are small noncoding RNAs, 19-24 nucleotides in length, that regulate gene expression and are expressed aberrantly in most types of cancer. MiRNAs also have been detected in the blood of cancer patients and can serve as circulating biomarkers. It has been shown that secreted miRNAs within exosomes can be transferred from cell to cell and can regulate gene expression in the receiving cells by canonical binding to their target messenger RNAs. Here we show that tumor-secreted miR-21 and miR-29a also can function by another mechanism, by binding as ligands to receptors of the Toll-like receptor (TLR) family, murine TLR7 and human TLR8, in immune cells, triggering a TLR-mediated prometastatic inflammatory response that ultimately may lead to tumor growth and metastasis. Thus, by acting as paracrine agonists of TLRs, secreted miRNAs are key regulators of the tumor microenvironment. This mechanism of action of miRNAs is implicated in tumor-immune system communication and is important in tumor growth and spread, thus representing a possible target for cancer treatment.