SERPINE1: Role in Cholangiocarcinoma Progression and a Therapeutic Target in the Desmoplastic Microenvironment.

A heterogenous population of inflammatory elements, other immune and nonimmune cells and cancer-associated fibroblasts (CAFs) are evident in solid malignancies where they coexist with the growing tumor mass. In highly desmoplastic malignancies, CAFs are the prominent mesenchymal cell type in the tumor microenvironment (TME), where their presence and abundance signal a poor prognosis. CAFs play a major role in the progression of various cancers by remodeling the supporting stroma into a dense, fibrotic matrix while secreting factors that promote the maintenance of cancer stem-like characteristics, tumor cell survival, aggressive growth and metastasis and reduced sensitivity to chemotherapeutics.

The dark art of syphilis serology - an analysis of testing algorithms at a UK reference laboratory.

Due to the complex nature of treponemal serology interpretation, testing algorithms vary across the UK. There is currently no gold standard method for interpretation of discordant serology results. To analyse serological response in early infection and to determine the best approach for discordant total antibody EIA and TPPA samples.

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney.

Tubulointerstitial fibrosis is a common and diagnostic hallmark of a spectrum of chronic renal disorders. While the etiology varies as to the causative nature of the underlying pathology, persistent TGF-β1 signaling drives the relentless progression of renal fibrotic disease. TGF-β1 orchestrates the multifaceted program of kidney fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery or re-differentiation, capillary collapse and subsequent interstitial fibrosis eventually leading to chronic and ultimately end-stage disease.

The TGF-β1/p53/PAI-1 Signaling Axis in Vascular Senescence: Role of Caveolin-1.

Stress-induced premature cellular senescence is a significant factor in the onset of age-dependent disease in the cardiovascular system. Plasminogen activator inhibitor-1 (PAI-1), a major TGF-β1/p53 target gene and negative regulator of the plasmin-based pericellular proteolytic cascade, is elevated in arterial plaques, vessel fibrosis, arteriosclerosis, and thrombosis, correlating with increased tissue TGF-β1 levels. Additionally, PAI-1 is necessary and sufficient for the induction of p53-dependent replicative senescence.

TGF-β1-p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications.

Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide.

Syphilitic jaundice: a rare manifestation of the secondary stage presenting a missed opportunity to prevent ocular syphilis.

The classical presentation of secondary syphilis comprises skin rashes, mucosal ulceration and lymphadenopathy. However, this disseminated stage can also present with symptoms and signs of ocular, neurological, pulmonary, renal, musculoskeletal and digestive tract disease. We report the case of a gay man who presented with icteric hepatitis.

TGF-β1/p53 signaling in renal fibrogenesis.

Fibrotic disorders of the renal, pulmonary, cardiac, and hepatic systems are associated with significant morbidity and mortality. Effective therapies to prevent or curtail the advancement to organ failure, however, remain a major clinical challenge. Chronic kidney disease, in particular, constitutes an increasing medical burden affecting >15% of the US population.

Screening for asymptomatic neurosyphilis in HIV patients after treatment of early syphilis: an observational study.

Objective: To determine the prevalence of asymptomatic neurosyphilis (ANS) in HIV-positive individuals after treatment of early syphilis with single-dose benzathine penicillin G (BPG) or oral antibiotic alternatives.

Methods: Patients at high risk of neurosyphilis (defined by serum rapid plasma reagin (RPR) titre ≥1:32 and/or peripheral blood CD4 lymphocyte count ≤350/μL) underwent lumbar puncture (LP) at a median time of 8.2 months post treatment.

Primary herpes simplex virus infection mimicking cervical cancer.

We report the case of an 18-year-old woman presenting with ulceration of the cervix caused by primary type 2 herpes simplex infection in the absence of skin lesions. The differential diagnosis included cervical cancer and we referred the patient for urgent colposcopy. However, laboratory tests proved the viral aetiology of the cervical ulceration and the cervix had healed completely 3 weeks later.

A small molecule PAI-1 functional inhibitor attenuates neointimal hyperplasia and vascular smooth muscle cell survival by promoting PAI-1 cleavage.

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of urokinase-and tissue-type plasminogen activators (uPA and tPA), is an injury-response gene implicated in the development of tissue fibrosis and cardiovascular disease. PAI-1 mRNA and protein levels were elevated in the balloon catheter-injured carotid and in the vascular smooth muscle cell (VSMC)-enriched neointima of ligated arteries. PAI-1/uPA complex formation and PAI-1 antiproteolytic activity can be inhibited, via proteolytic cleavage, by the small molecule antagonist tiplaxtinin which effectively increased the VSMC apoptotic index in vitro and attenuated carotid artery neointimal formation in vivo.

Yaws.

Yaws is a non-venereal endemic treponemal infection caused by Treponema pallidum sub-species pertenue, a spirochaete bacterium closely related to Treponema pallidum ssp. pallidum, the agent of venereal syphilis. Yaws is a chronic, relapsing disease predominantly affecting children living in certain tropical regions.

The basic helix-loop-helix/leucine zipper transcription factor USF2 integrates serum-induced PAI-1 expression and keratinocyte growth.

Plasminogen activator inhibitor type-1 (PAI-1), a major regulator of the plasmin-dependent pericellular proteolytic cascade, is prominently expressed during the tissue response to injury although the factors that impact PAI-1 induction and their role in the repair process are unclear. Kinetic modeling using established biomarkers of cell cycle transit (c-MYC; cyclin D1; cyclin A) in synchronized human (HaCaT) keratinocytes, and previous cytometric assessments, indicated that PAI-1 transcription occurred early after serum-stimulation of quiescent (G0) cells and prior to G1 entry. It was established previously that differential residence of USF family members (USF1→USF2 switch) at the PE2 region E box (CACGTG) characterized the G0  → G1 transition period and the transcriptional status of the PAI-1 gene.

SERPINE1: A Molecular Switch in the Proliferation-Migration Dichotomy in Wound-"Activated" Keratinocytes.

A highly interactive serine protease/plasmin/matrix metalloproteinase axis regulates stromal remodeling in the wound microenvironment. Current findings highlight the importance of stringent controls on protease expression and their topographic activities in cell proliferation, migration, and tissue homeostasis. Targeting elements in this cascading network may lead to novel therapeutic approaches for fibrotic diseases and chronic wounds.

Rash and hepatitis within days of starting a new antiretroviral regimen: nevirapine hypersensitivity, secondary syphilis or both?

We report a case in which an HIV-positive man developed general malaise, skin rash and biochemical hepatitis within days of starting a nevirapine-based antiretroviral treatment regimen. At the same time, his syphilis serology proved positive. We discuss the diagnostic dilemma: was this a nevirapine hypersensitivity reaction, secondary syphilis or both?

Complex Regulation of the Pericellular Proteolytic Microenvironment during Tumor Progression and Wound Repair: Functional Interactions between the Serine Protease and Matrix Metalloproteinase Cascades.

Spatial and temporal regulation of the pericellular proteolytic environment by local growth factors, such as EGF and TGF-β, initiates a wide repertoire of cellular responses coupled to a plasmin/matrix metalloproteinase (MMP) dependent stromal-remodeling axis. Cell motility and invasion, tumor metastasis, wound healing, and organ fibrosis, for example, represent diverse events controlled by expression of a subset of genes that encode various classes of tissue remodeling proteins. These include members of the serine protease and MMP families that functionally constitute a complex system of interacting protease cascades and titrated by their respective inhibitors.

PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells.

Malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was previously found to be dependent on transcriptional activation of the PAI-1 (SERPINE1) gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators). NaB-initiated PAI-1 expression preceded induced cell spreading and entry into G(1) arrest.

PAI-1: An Integrator of Cell Signaling and Migration.

Cellular migration, over simple surfaces or through complex stromal barriers, requires coordination between detachment/re-adhesion cycles, involving structural components of the extracellular matrix and their surface-binding elements (integrins), and the precise regulation of the pericellular proteolytic microenvironment. It is now apparent that several proteases and protease inhibitors, most notably urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1), also interact with several cell surface receptors transducing intracellular signals that significantly affect both motile and proliferative programs. These events appear distinct from the original function of uPA/PAI-1 as modulators of the plasmin-based proteolytic cascade.

Redox-induced Src kinase and caveolin-1 signaling in TGF-β1-initiated SMAD2/3 activation and PAI-1 expression.

Background: Plasminogen activator inhibitor-1 (PAI-1), a major regulator of the plasmin-based pericellular proteolytic cascade, is significantly increased in human arterial plaques contributing to vessel fibrosis, arteriosclerosis and thrombosis, particularly in the context of elevated tissue TGF-β1. Identification of molecular events underlying to PAI-1 induction in response to TGF-β1 may yield novel targets for the therapy of cardiovascular disease.

Principal Findings: Reactive oxygen species are generated within 5 minutes after addition of TGF-β1 to quiescent vascular smooth muscle cells (VSMCs) resulting in pp60(c-src) activation and PAI-1 expression.

TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis.

Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone. Diabetes, hypertension, ischemia, acute injury, and urological obstruction contribute to renal fibrosis, a common pathological hallmark of chronic kidney disease. Regardless of etiology, elevated TGF-β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin, glucose, and oxidative stress.

Management of cases testing positive for gonococcal infection in a community-based chlamydia screening programme.

Background: The National Chlamydia Screening Programme in Greater Manchester (NCSP-GM) commissioned an evaluation of the management of gonorrhoea cases identified using the Gen-Probe APTIMA Combo 2 assay (AC2).

Methods: NCSP-GM provided data on gonorrhoea cases from a 6-month period (September 2007-February 2008). Data were collected from patient referral pathways to genitourinary medicine (GUM) clinics, including confirmatory testing, antibiotic resistance patterns and contact tracing.

PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes.

Cooperative interactions between growth factor signaling pathways are important elements in carcinoma progression. A model system combining transforming growth factor-beta1 (TGF-beta1) and EGF was developed to investigate mechanisms underlying induced epithelial-to-mesenchymal transition (EMT) in ras-transformed human (HaCaT II-4) keratinocytes. Dual stimulation with TGF-beta1+EGF resulted in keratinocyte "plasticity" and pronounced colony dispersal.

TGF-beta1-Induced Expression of the Poor Prognosis SERPINE1/PAI-1 Gene Requires EGFR Signaling: A New Target for Anti-EGFR Therapy.

Increased transforming growth factor-beta (TGF-beta) expression and epidermal growth factor receptor (EGFR) amplification accompany the emergence of highly aggressive human carcinomas. Cooperative signaling between these two growth factor/receptor systems promotes cell migration and synthesis of stromal remodeling factors (i.e.