Jennifer A. Przybylo

Non-classical export of epimorphin and its adhesion to αV-integrin in regulation of epithelial morphogenesis

Epimorphin (also known as syntaxin 2) acts as an epithelial morphogen when secreted by stromal cells of the mammary gland, lung, liver, colon, pancreas and other tissues, but the same molecule functions within the cell to mediate membrane fusion. How this molecule, which lacks a signal sequence and contains a transmembrane domain at the C-terminus, translocates across the plasma membrane and is secreted to become a morphogen, and how it initiates morphogenic events is not clear. Here, we show that epimorphin is secreted through a non-classical mechanism, similar to that previously described for secretion of the leaderless protein FGF1, and we identify the key molecular elements responsible for translocation and secretion from the cell. We also show that secreted epimorphin binds to αv-integrin-containing receptors on target epithelial cells, leading to activation of specific downstream signaling pathways and induction of epithelial morphogenesis. These findings provide key insight into how epimorphin functions as an epithelial morphogen.

Matrix metalloproteinase-induced fibrosis and malignancy in breast and lung.

Fibrosis is a pathological condition in which tissue structure is disrupted by production of excess extracellular matrix (ECM), and chronic tissue fibrosis is associated with tumor development. Myofibroblasts are the principal mediators of fibrosis, producing abundant ECM as well as inflammatory and angiogenic factors. Myofibroblasts are also abundant in tumor stroma, where they facilitate tumor growth and progression. Matrix metalloproteinases (MMPs), enzymes that degrade and remodel the ECM, are believed to play a critical role in the development of fibrotic tissue, though the mechanism by which this occurs is unclear. Expression of MMP-3 in mammary epithelial cells of transgenic mice stimulates development of fibrosis and subsequent tumor formation. We have recently determined that exposure of mammary epithelial cells to MMP-3 induces a specialized form of epithelial-mesenchymal transition in which the cells acquire myofibroblast-like characteristics and that this process is dependent upon the generation of cellular reactive oxygen species (ROS). New data from culture models in which MMPs are inducibly expressed in human lung cell lines, and transgenic mouse models in which MMPs are inducibly expressed in lung alveolar epithelial cells, suggest that similar processes likely exist in the lung.

Smarter hospital communication: Secure smartphone text messaging improves provider satisfaction and perception of efficacy, workflow

BACKGROUND Though current hospital paging systems are neither efficient (callbacks disrupt workflow), nor secure (pagers are not Health Insurance Portability and Accountability Act [HIPAA]-compliant), they are routinely used to communicate patient information. Smartphone-based text messaging is a potentially more convenient and efficient mobile alternative; however, commercial cellular networks are also not secure. OBJECTIVE To determine if augmenting one-way pagers with Medigram, a secure, HIPAA-compliant group messaging (HCGM) application for smartphones, could improve hospital team communication. DESIGN Eight-week prospective, cluster-randomized, controlled trial SETTING Stanford Hospital INTERVENTION Three inpatient medicine teams used the HCGM application in addition to paging, while two inpatient medicine teams used paging only for intra-team communication. MEASUREMENTS Baseline and post-study surveys were collected from 22 control and 41 HCGM team members. RESULTS When compared with paging, HCGM was rated significantly (P < 0.05) more effective in: (1) allowing users to communicate thoughts clearly (P = 0.010) and efficiently (P = 0.009) and (2) integrating into workflow during rounds (P = 0.018) and patient discharge (P = 0.012). Overall satisfaction with HCGM was significantly higher (P = 0.003). 85% of HCGM team respondents said they would recommend using an HCGM system on the wards. CONCLUSIONS Smartphone-based, HIPAA-compliant group messaging applications improve provider perception of in-hospital communication, while providing the information security that paging and commercial cellular networks do not. Journal of Hospital Medicine 2014;9:573–578.

Susceptibility Loci Associated with Specific and Shared Subtypes of Lymphoid Malignancies

The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (PLYM = 3.89×10−8, OR = 1.29) and rs948562 (PLYM = 5.85×10−7, OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, PNHL = 5.72×10−7) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (PFL = 2.69×10−12, OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.

Germline single nucleotide polymorphisms associated with response of urothelial carcinoma to platinum-based therapy: the role of the host.

BACKGROUND Variations in urothelial carcinoma (UC) response to platinum chemotherapy are common and frequently attributed to genetic and epigenetic variations of somatic DNA. We hypothesized that variations in germline DNA may contribute to UC chemosensitivity. PATIENTS AND METHODS DNA from 210 UC patients treated with platinum-based chemotherapy was genotyped for 80 single nucleotide polymorphisms (SNPs). Logistic regression was used to examine the association between SNPs and response, and a multivariable predictive model was created. Significant SNPs were combined to form a SNP score predicting response. Eleven UC cell lines were genotyped as validation. RESULTS Six SNPs were significantly associated with 101 complete or partial responses (48%). Four SNPs retained independence association and were incorporated into a response prediction model. Each additional risk allele was associated with a nearly 50% decrease in odds of response [odds ratio (OR) = 0.51, 95% confidence interval 0.39-0.65, P = 1.05 × 10(-7)). The bootstrap-adjusted area under the curves of this model was greater than clinical prognostic factors alone (0.78 versus 0.64). The SNP score showed a positive trend with chemosensitivity in cell lines (P = 0.115). CONCLUSIONS Genetic variants associated with response of UC to platinum-based therapy were identified in germline DNA. A model using these genetic variants may predict response to chemotherapy better than clinical factors alone.

Genetic Variation in DNA Repair Pathways and Risk of Non-Hodgkin's Lymphoma

Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkins lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13–1.43, p = 6.77×10−5), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34–0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.

Association of single-nucleotide polymorphisms in BCL2L1 and TACC3 with response to bacillus Calmette-Guérin intravesical therapy in non-muscle-invasive bladder cancer.

260 Background: Bacillus Calmette-Guérin intravesical therapy (BCG) has an important role in the management of high risk non-muscle-invasive bladder cancer (NMIBC). This study examines the association between germline single nucleotide polymorphisms (SNPs) and response to BCG therapy. METHODS Saliva or blood was collected from pts with NMIBC treated at a single center and diagnosed between 1984 and 2010. SNPs were selected based on reported associations with bladder cancer and BCG response, and genotyped using the Sequenom MassARRAY iPLEX system. No response to BCG was defined as the presence at 6 months of pathologically documented tumor in the bladder. Univariate logistic regression was used to test the association between the outcome of interest (no response to BCG at 6 months) and clinical variables (stage, grade and multifocality), or individual SNPs. RESULTS The cohort consisted of 158 pts with a median age of 65 years who received intravesical BCG for NMIBC (35.2% stage T1, 32.7% stage Ta and 31.4% stage Tis) with 93% having high-grade disease. At 6 months follow up, 22 (13.9%) patients showed no response to BCG. We successfully genotyped 80 of the 88 selected SNPs. Of these, 2 SNPs were associated with lack of response to BCG; rs798766 is an intronic SNP in TACC3 (OR for no response is 2.4 for each T allele relative to CC genotype, P=0.01), and rs1994251 an intronic SNP in BCL2L1 (OR for no response is 3.2 for each C allele relative to AA, p= 0.0008). Both SNPs remained significantly associated with lack of response after adjusting for predictive clinical variables. CONCLUSIONS Single nucleotide polymorphisms of BCL2L1 and TACC3 may be predictive of BCG refractory bladder cancer. Future validation studies on independent datasets are needed to determine the clinical utility of these findings.