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PURPOSE: Biallelic pathogenic variants in the mismatch repair (MMR) genes cause a recessive childhood cancer predisposition syndrome known as constitutional mismatch repair deficiency (CMMRD). Family members with a heterozygous MMR variant have Lynch syndrome. We aimed at estimating cancer risk in these heterozygous carriers as a novel approach to avoid complicated statistical methods to correct for ascertainment bias. METHODS: Cumulative colorectal cancer incidence was estimated in a cohort of PMS2- and MSH6-associated families, ascertained by the CMMRD phenotype of the index, by using mutation probabilities based on kinship coefficients as analytical weights in a proportional hazard regression on the cause-specific hazards. Confidence intervals (CIs) were obtained by bootstrapping at the family level. RESULTS: The estimated cumulative colorectal cancer risk at age 70 years for heterozygous PMS2 variant carriers was 8.7% (95% CI 4.3-12.7%) for both sexes combined, and 9.9% (95% CI 4.9-15.3%) for men and 5.9% (95% CI 1.6-11.1%) for women separately. For heterozygous MSH6 variant carriers these estimates are 11.8% (95% CI 4.5-22.7%) for both sexes combined, 10.0% (95% CI 1.83-24.5%) for men and 11.7% (95% CI 2.10-26.5%) for women. CONCLUSION: Our findings are consistent with previous reports that used more complex statistical methods to correct for ascertainment bias. These results underline the need for MMR gene-specific surveillance protocols for Lynch syndrome.

Destabilization of the genome seems to be an important step in the generation of drug resistance. Since malignant melanoma is extremely resistant to chemotherapy, we used human melanoma cell lines as a model to investigate the putative role of genomic instability in the appearance of drug resistance. Drug-resistant variants were obtained with MNNG, BiCNU, doxorubicin and 6-thioguanine selection of melanoma cell lines. Genomic alterations in variant cells were detected by arbitrarily primed PCR of Alu-I digested DNA (Alu-I-AP-PCR). Two differential DNA bands from 6-TG-resistant cell variants were sequenced. One is homologous to intron 25 of the neural cell adhesion molecule L1 and the second to endogenous retroviral LTR sequences. We have shown that drug-resistant melanoma cell lines accumulate genomic alterations that are efficiently detected by Alu I-AP-PCR and that drug-resistant variants show genomic instability, including variations in LTR sequences, which may be associated with the appearance of the drug resistance phenotype.

Experiments with two models of intestinal ischemia were performed in order to examine the protective effect of dimethyl sulfoxide (DMSO). Segmental ischemia of the small intestine for 150 minutes caused necrosis of the affected bowel in 90% of the animals. Intravenous administration of DMSO or impregnation of the peritoneum with this substance prevented the development of gangrene in 28 of 29 rats. 30 or 60 minutes of complete ischemia of the small intestine, produced by clamping of the superior mesenteric artery, resulted in partial or complete necrosis of bowel segments with a high incidence of perforation and peritonitis and a high mortality rate within the first 24 hours. Intravenous DMSO, given upon declamping of the artery, effectively protected the bowel from the ischemic damage. There were no deaths among DMSO-treated animals and at 24 h there was no evidence of ischemic damage to the intestine. Through the exact mechanism of action of DMSO is unknown, the results of these and other experiments may warrant clinical trials especially in cases of mesenteric thrombosis., This article is from 'Conference on Biological Actions and Medical Applications of Dimethyl Sulfoxide (DMSO), 15-17 September 1982,' AD-A133 175. p100-104.

Renal ischemia was produced in rats by clamping of the renal artery for 1 h. Upon termination of the ischemic period a 20% solution of DMSO (5 g/kg b.w.) was given intravenously to 33 rats. Eighteen control animals received normal saline. All DMSO-treated animals survived while all control animals died within the subsequent seven days. At 24 h following the experiment, the mean blood urea of the control rats was 254 mg/100 m1 and the mean plasma creatinine 7.2 mg/100 m1. By contrast, the DMSO-treated rats had a mean blood urea of 69 mg/100 m1 and plasma creatinine of 1.6 mg/100 m1. In 17 animals the kidney was perfused with DMSO prior to the closure of the renal artery. All these rats survived the procedure and showed near normal kidney function at 24 h. The renal artery was clamped for 60 min in ten dogs. Five dogs received DMSO (3 g/kg b.w.) and the other five received an equivalent dose of normal saline. Three weeks later a contralateral nephrectomy was performed. Renal function was normal in the DMSO-treated dogs. One control dog died of uremia, in the remaining four a transient renal failure was observed. These experiments in two different animals highlight the protective effect of DMSO on the ischemic kidney when the drug is administered after the ischemic period., This article is from 'Conference on Biological Actions and Medical Applications of Dimethyl Sulfoxide (DMSO), 15-17 September 1982,' AD-A133 175. p131-134.