Loan portfolio management and Liquidity Risk: The impact of limited liability and haircut

In this article, we consider the problem of a bank's loan portfolio in the context of liquidity risk, while allowing for the limited liability protection enjoyed by the bank. Accordingly, we construct a novel loan portfolio model with limited liability, while maintaining a threshold level of haircut in the portfolio. For the constructed three-time step loan portfolio, at the initial time, the bank raises capital via debt and equity, investing the same in several classes of loans, while at the final time, the bank either meets its liabilities or becomes insolvent. At the intermediate time step, a fraction of the deposits are withdrawn, resulting in liquidation of some of the bank's assets. The liquidated portfolio is designed with the goal of minimizing the liquidation cost. Our theoretical results show that model with the haircut constraint leads to lesser liquidity risk, as compared to the scenario of no haircut constraint being imposed. Finally, we present numerical results to illustrate the theoretical results which were obtained

Genotypic and phenotypic analysis of familial male breast cancer shows under representation of the HER2 and basal subtypes in BRCA-associated carcinomas

BACKGROUND: Male breast cancer (MBC) is an uncommon and relatively uncharacterised disease accounting for <1% of all breast cancers. A significant proportion occurs in families with a history of breast cancer and in particular those carrying BRCA2 mutations. Here we describe clinicopathological features and genomic BRCA1 and BRCA2 mutation status in a large cohort of familial MBCs. METHODS: Cases (n=60) included 3 BRCA1 and 25 BRCA2 mutation carries, and 32 non-BRCA1/2 (BRCAX) carriers with strong family histories of breast cancer. The cohort was examined with respect to mutation status, clinicopathological parameters including TNM staging, grade, histological subtype and intrinsic phenotype. RESULTS: Compared to the general population, MBC incidence was higher in all subgroups. In contrast to female breast cancer (FBC) there was greater representation of BRCA2 tumours (41.7% vs 8.3%, p=0.0008) and underrepresentation of BRCA1 tumours (5.0% vs 14.4%, p=0.0001). There was no correlation between mutation status and age of onset, disease specific survival (DSS) or other clincopathological factors. Comparison with sporadic MBC studies showed similar clinicopathological features. Prognostic variables affecting DSS included primary tumour size (p=0.003, HR:4.26 95%CI 1.63-11.11), age (p=0.002, HR:4.09 95%CI 1.65-10.12), lymphovascular (p=0.019, HR:3.25 95%CI 1.21-8.74) and perineural invasion (p=0.027, HR:2.82 95%CI 1.13-7.06). Unlike familial FBC, the histological subtypes seen in familial MBC were more similar to those seen in sporadic MBC with 46 (76.7%) pure invasive ductal carcinoma of no special type (IDC-NST), 2 (3.3%) invasive lobular carcinomas and 4 (6.7%) invasive papillary carcinoma. A further 8 (13.3%) IDC-NST had foci of micropapillary differentiation, with a strong trend for co-occurrence in BRCA2 carriers (p=0.058). Most tumours were of the luminal phenotype (89.7%), with infrequent HER2 (8.6%) and basal (1.7%) phenotype tumours seen. CONCLUSION: MBC in BRCA1/2 carriers and BRCAX families is different to females. Unlike FBC, a clear BRCA1 phenotype is not seen but a possible BRCA2 phenotype of micropapillary histological subtype is suggested. Comparison with sporadic MBCs shows this to be a high-risk population making further recruitment and investigation of this cohort of value in further understanding these uncommon tumours

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.This research was supported by grants from the National Breast Cancer Foundation and the CASS Foundation (ALC). We acknowledge the support of Victorian Government’s Operational Infrastructure Support Program and the National Health and Medical Research Council (NHMRC) of Australia Grants. ALC is supported by an NHMRC Career Development Fellowship (ID 1062247). We also acknowledge funding from the Sydney Breast Cancer Foundation (S.A.O’T), the RT Hall Foundation (S.A.O’T), Tag Family Foundation (S.A.O’T), and the O’Sullivan family (S.A.O’T)

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Genotypic phenotypic correlation in male breast cancer

© 2018 Dr. Siddhartha DebMale breast cancers (MBCs) are rare cancers, comprising less than 1% of all breast cancers and less than 1% of all cancers in men. As a result, these cancers have not been well characterized with almost all management extrapolated from the treatment of female breast cancers. More recent studies, however, have demonstrated differences from female breast cancers. This thesis has examined genotypic and phenotypic correlation in a group of 61 familial MBCs (kConFab) and 225 mixed familial and sporadic MBCs (Lund University, Sweden) with robust clinical and pathological data. The hypothesis is that: 1) male and female breast cancer (FBC) is different, 2) familial male and familial FBC is different and 3) familial and sporadic MBCs are different with possible differences within familial MBC subgroups. The penetrance of familial MBCs is different to that of familial FBC, showing an increased proportion of BRCA2 male carriers and underrepresentation of BRCA1 male tumours. Histopathology showed a paucity of lobular and medullary male breast cancers, with less frequent HER2 and Basal phenotypes. An association between BRCA2 mutation carrier status and invasive micropapillary subtype was seen. A BRCA1 associated medullary phenotype was not demonstrated and accordingly TP53 somatic mutations and associated hypoxic drive was not seen in these tumours, highly suggestive of a redundant role for BRCA1 in MBC. The somatic mutation profile in familial MBCs was similar to that seen in luminal A FBCs, with the rare E547K PIK3CA seen several times in MBCs suggesting a possible gender correlation. Methylation of the ERβ/eNOS complex associated tumour suppressor gene, GSTP1, was frequently seen in MBCs, more so in familial than sporadic MBCs. The clinical significance of this may be useful in screening for MBCs in these high-risk populations and may also be a risk modifier as high levels of GSTP1 methylation have also been seen in BRCA2-associated prostate cancers. Similar to familial FBCs, there was observed clustering of tumors by methylation patterns into different BRCA subgroups, albeit with small numbers. Compared to sporadic MBCs, familial MBCs overall showed an earlier median and mean age of onset, with more frequent multifocality or bilateral disease, Familial MBCs also showed a higher proportion of high grade tumours and invasive papillary carcinomas. Familial MBCs also showed a higher amount of gene losses and higher levels of candidate gene methylation. The study demonstrated several differences between male and female breast cancers and sporadic and familial MBCs

Microcystic adnexal carcinoma of the skin: The role of adjuvant radiotherapy

Introduction

DNA sequence dependent and independent conformational changes in multipartite operator recognition by λ-repressor

Binding of regulatory proteins to multipartite DNA binding sites often occurs with protein-protein interaction, resulting in cooperative binding. The operators of bacteriophage λ have several pairs of repressor binding sites (O<SUB>R</SUB>1-O<SUB>R</SUB>2, O<SUB>R</SUB>2-O<SUB>R</SUB>3, O<SUB>L</SUB>1-O<SUB>L</SUB>2, and O<SUB>L</SUB>2-O<SUB>L</SUB>3) separated by a variable number of base pairs, and thus, bacteriophage λ is a model system for studying multipartite operator recognition by DNA-binding proteins. Near-UV circular dichroism spectra show that the DNA is distorted in O<SUB>R</SUB>1-O<SUB>R</SUB>2 and O<SUB>L</SUB>2-O<SUB>L</SUB>3 but much less so in O<SUB>R</SUB>2-O<SUB>R</SUB>3. Upon titration of λ-repressor with single-operator sites O<SUB>R</SUB>1, O<SUB>R</SUB>2, and O<SUB>R</SUB>3, it was observed that the tryptophan fluorescence quenches to different degrees, suggesting different conformations of the protein in the three DNA-protein complexes. Acrylamide quenching of tryptophan fluorescence of λ-repressor bound to these single operators also shows different Stern-Volmer constants, supporting the above conclusions. Titration of λ-repressor with oligonucleotides containing pairs of operator sites also causes different degrees of fluorescence quenching. In particular, fluorescence quenching induced by O<SUB>R</SUB>1-O<SUB>R</SUB>2 binding is less than the quenching induced by either of the single operators alone, suggesting additional conformational changes upon establishment of protein-protein contact. Stern-Volmer constants obtained from acrylamide quenching of tryptophan fluorescence of λ-repressor bound cooperatively to pairs of operator sites are different from those of the single-operator-site-bound repressors. For example, O<SUB>R</SUB>2-O<SUB>R</SUB>3-bound repressor has significantly higher acrylamide quenchable components than either of the O<SUB>R</SUB>2- or O<SUB>R</SUB>3-bound proteins, again suggesting additional conformational changes upon establishment of protein-protein contact. We conclude that the strategy of recognition of multipartite operator by λ-repressor is complex and varied, involving conformational changes in both DNA and protein that are determined by the separation of the binding sites as well as the nucleic acid sequence