Breast cancers in monoallelic MUTYH germline mutation carriers have clinicopathological features overlapping with those in BRCA1 germline mutation carriers.

PURPOSE: Breast cancer patients referred to genetic counseling often undergo genetic testing with broad panels that include both breast cancer susceptibility genes as well as genes more specific for extramammary sites. As a result, patients are often incidentally found to have germline mutations in genes that are not necessarily related to breast cancer risk. One such gene is MUTYH. To understand the role MUTYH may play in breast cancer, the clinicopathological features of patients with monoallelic MUTYH germline mutation and breast cancer were examined. METHODS: The clinicopathological characteristics of the breast cancers from patients with monoallelic MUTYH mutation were compared to breast cancer patients with other germline mutations in known breast cancer susceptibility genes, including ATM, BRCA1/2, CHEK2, and PALB2. The breast cancer patients who received genetic counseling but tested negative for the aforementioned gene mutations were used as a control group. RESULTS: Histologic characteristics of the breast cancers arising in monoallelic MUTYH mutation carriers had significantly larger tumor size, higher tumor grade, and more high-risk biomarker profiles (i.e., Her2-positive and triple-negative) than breast cancer patients with susceptibility genes, except for BRCA1. MUTYH mutation carriers also showed a trend of more frequent intratumoral divergency in terms of tumor grade and biomarker profiles. CONCLUSION: Although germline monoallelic MUTYH mutation is not thought to confer a meaningfully increased risk of breast cancer development, it may contribute to pathological aggressiveness and diversity of breast cancers when they sporadically arise in MUTYH carriers.

Evidences for agmatine alterations in Aß1-42induced memory impairment in mice.

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.

Management of systemic unfractionated heparin anticoagulation during therapeutic plasma exchange.

BACKGROUND: Therapeutic plasma exchange (TPE) may remove medications from the patient's plasma. Data is limited on the effect of TPE on unfractionated heparin (UFH). STUDY DESIGN AND METHODS: A retrospective review was performed of patients receiving TPE and continuous IV infusion UFH from 1/1/2008 to 6/30/2010. TPE with plasma or 5% albumin for replacement fluid and pre and post anti-Xa levels within approximately six hours were analyzed. RESULTS: Three patients had 15 TPE with plasma replacement. Anti-Xa levels decreased 47% (mean, -0.25 IU/mL) for two TPE when UFH was not changed, 78% (-0.35 IU/mL) for one TPE when the UFH rate was decreased 25%; and 61% (mean -0.72 IU/mL) for two single volume TPE and 87% (-0.65 IU/mL) for one 1.5 plasma volume TPE when UFH was stopped. During nine TPE, the UFH rate was increased by 65% resulting in a mean increase in the anti-Xa level (mean 0.06 IU/mL, 30%). One patient had five single plasma volume TPE with 5% albumin. Anti-Xa levels decreased when the UFH was not changed (-0.06 IU/mL, 38%) and increased when UFH was increased by 30% (0.19 IU/mL, 61%) and 69% (mean 0.04 IU/mL, 15% in three TPE). The PTT increased with all albumin procedures, with more marked increases observed when the UFH rate was increased, while the antithrombin level decreased (mean 65%). CONCLUSION: Heparin was removed from the patient's plasma during TPE. Adjustment of the dose during TPE may be necessary to maintain therapeutic drug levels. Methods for monitoring UFH therapy may not agree. J. Clin. Apheresis 31:507-515, 2016. © 2016 Wiley Periodicals, Inc.