Integrin signalling regulates YAP and TAZ to control skin homeostasis.

The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

Mutant p53 drives invasion by promoting integrin recycling.

p53 is a tumor suppressor protein whose function is frequently lost in cancers through missense mutations within the Tp53 gene. This results in the expression of point-mutated p53 proteins that have both lost wild-type tumor suppressor activity and show gain of functions that contribute to transformation and metastasis. Here, we show that mutant p53 expression can promote invasion, loss of directionality of migration, and metastatic behavior. These activities of p53 reflect enhanced integrin and epidermal growth factor receptor (EGFR) trafficking, which depends on Rab-coupling protein (RCP) and results in constitutive activation of EGFR/integrin signaling. We provide evidence that mutant p53 promotes cell invasion via the inhibition of TAp63, and simultaneous loss of p53 and TAp63 recapitulates the phenotype of mutant p53 in cells. These findings open the possibility that blocking alpha5/beta1-integrin and/or the EGF receptor will have therapeutic benefit in mutant p53-expressing cancers.

Squamous cell carcinoma developing in two Chinese patients with chronic discoid lupus erythematosus: the need for continued surveillance.

Squamous cell carcinoma (SCC) is a rare late sequel of chronic discoid lupus erythematosus (CDLE). We report two cases of SCC developing in Chinese patients with CDLE. The first patient had prior biopsies from the same site that showed viral warts and the second patient had multiple histologically confirmed viral warts around the vicinity of the previously excised SCC. In this paper, we emphasize the need to be suspicious of warty lesions on skin afflicted by CDLE, and repeat biopsies should be performed if there is failure to respond to conventional therapy.

Economic evaluation of the familial cancer programme in Western Australia: predictive genetic testing for familial adenomatous polyposis and hereditary non-polyposis colorectal carcinoma.

AIM: To evaluate costs and outcomes of genetic testing for familial colorectal cancer through services provided by Genetic Services of Western Australia (GSWA). METHODS: Costs and outcomes of predictive DNA-based testing for inherited colorectal cancers (CRC) were assessed, specifically for familial adenomatous polyposis (FAP) and hereditary non-polyposis CRC (HNPCC) using a decision-analysis model. Costs were assigned according to standards of care in Western Australia (WA). Cancer risks and the efficacy of surveillance on long-term outcomes were derived from the published literature. RESULTS: The cost-effectiveness of genetic testing was compared in first-degree relatives of known mutation carriers who have a 50% risk of carrying the mutated gene (intervention group) to individuals with the same risk but who do not undergo a genetic test (control subjects). Compared with control subjects undergoing the same high-level surveillance and surgery, the FAP and HNPCC intervention groups provided total savings of 13,390 US dollars and 14,783-15,460 per person (males-females), respectively. HPNCC mutation carriers also gained 1 CRC-free year. Compared to control subjects having only population surveillance, individuals in the FAP intervention group delayed the onset of CRC by 40 years for a net cost of 9,042 US dollars. Individuals in the HNPCC intervention group delayed the onset of CRC by 8 years at a net cost of 12,141 US dollars for males and 12,596 US dollars for females. CONCLUSIONS: Genetic testing for familial CRC in WA allows targeted surveillance for mutation carriers, which ensures the efficient use of resources and reduces cancer-related morbidity, if clinical recommendations for intervention are adopted.

Characteristics of Hori naevus: a prospective analysis.

BACKGROUND: Acquired, bilateral naevus of Ota-like macules or Hori naevus (HN) is a common dyschromia seen in Orientals. Other than the original report which documented the clinical spectrum in a group of 22 patients, there have not been many epidemiological reports of this condition. OBJECTIVES: To evaluate the epidemiology and clinical characteristics of HN in Asian patients. METHODS: A prospective analysis of 161 patients with HN seen from June 2003 to June 2004 was performed. RESULTS: All 161 patients in the study were women. Patients were Chinese (n = 155), Eurasian (n = 4), Malay (n = 1) and Indian (n = 1). The median age at onset was 30 years. The malar region was the most frequently affected area. Discrete brown macules were the most common early presentation. Confluent slate-grey macules occurred later. Aggravating factors included sun exposure and pregnancy. Sixty-seven patients reported a positive family history. CONCLUSIONS: We report our data on the largest series of HN in the literature so far. Predisposing factors in our study are Chinese race, female sex and positive family history. HN became progressively more confluent and grey over time, suggesting migration from the epidermis to the deeper dermis. More studies are needed to confirm the pathogenesis.

Autosomal dominant familial chronic mucocutaneous candidiasis associated with acne rosacea.

INTRODUCTION: Autosomal dominant chronic mucocutaneous candidiasis (CMC) without endocrinopathy (OMIM 114580) is a well-described entity. The associations recorded with this disorder to date are intercellular adhesion molecule-1 (ICAM-1) deficiency and hyper-immunoglobulin E syndrome. CLINICAL PICTURE: We report a new association in a family (mother and nonidentical twin sons) where acne rosacea is a prominent feature together with CMC. In addition, antibodies to thyroid microsomal and antiparietal cell were also isolated. The autoantibodies might be associated with a current "latent" endocrinopathy in particular autoimmune thyroiditis. TREATMENT: The patient was treated with intermittent pulses of itraconazole for the candidiasis and doxycycline initially before being substituted with isotretinoin 6 months later for the rosacea. OUTCOME: The patient's candidiasis responded well and has been in remission for 3 months while his rosacea continues to improve.

Sporadic duodenal adenoma is associated with colorectal neoplasia.

OBJECTIVE: The objective of this study was to assess the association between colorectal neoplasia and sporadic duodenal adenoma. METHODS: A retrospective case control study was conducted using the databases of two major teaching hospitals in Western Australia. The frequency of colorectal neoplasia in patients with sporadic duodenal adenomas was compared with that in a control group of patients presenting for endoscopies. The frequency of colorectal cancer in duodenal adenoma patients was also compared with the population incidence. RESULTS: Of 56 sporadic duodenal adenoma patients, 34 (61%) had been colonoscoped. When comparing the findings between patients with sporadic duodenal adenoma and an endoscoped control group, all colorectal neoplasias were significantly more common in the duodenal adenoma group (56% v 33%; odds ratio (OR) 2.4 (95% confidence intervals (CI) 1.1-5.4)). Although finding either advanced colorectal adenoma or cancer was also more common in duodenal adenoma patients (38% v 19%; OR 2.3 (95% CI 1.0-5.2)), as was finding colorectal cancer alone (21% v 8%; OR 3.0 (95% CI 1.0-9.1)), the results were not statistically significant. However, the incidence of colorectal cancer was much greater in duodenal adenoma patients than in the population (p<0.001). CONCLUSIONS: Sporadic duodenal adenoma has a clinically important association with colorectal neoplasia. Thus patients with duodenal adenomas should undergo colonoscopy to detect colorectal neoplasia.

Resolution of vulvitis circumscripta plasmacellularis with topical imiquimod: two case reports.

Vulvitis circumscripta plasmacellularis (VCP) is a rare but well-described entity. It is notorious for its recalcitrant nature to various modalities of treatment. Intralesional interferon-alpha showed some promise, with complete resolution, but is coupled with the side-effect of myelosuppression. Topical imiquimod is a novel immune response modifier with the ability to induce the production of interferon-alpha. In this paper, we report two cases of VCP whose lesions were resistant to antibiotics, topical and oral corticosteroids, but resolved after a treatment trial with imiquimod.

Paired-homeodomain transcription factor PAX4 acts as a transcriptional repressor in early pancreatic development.

The paired-homeodomain transcription factor PAX4 is expressed in the developing pancreas and along with PAX6 is required for normal development of the endocrine cells. In the absence of PAX4, the numbers of insulin-producing beta cells and somatostatin-producing delta cells are drastically reduced, while the numbers of glucagon-producing alpha cells are increased. To gain insight into PAX4 function, we cloned a full-length Pax4 cDNA from a beta-cell cDNA library and identified a bipartite consensus DNA binding sequence consisting of a homeodomain binding site separated from a paired domain binding site by 15 nucleotides. The paired half of this consensus sequence has similarities to the PAX6 paired domain consensus binding site, and the two proteins bind to common sequences in several islet genes, although with different relative affinities. When expressed in an alpha-cell line, PAX4 represses transcription through the glucagon or insulin promoters or through an isolated PAX4 binding site. This repression is not simply due to competition with the PAX6 transcriptional activator for the same binding site, since PAX4 fused to the unrelated yeast GAL4 DNA binding domain also represses transcription through the GAL4 binding site in the alpha-cell line and to a lesser degree in beta-cell lines and NIH 3T3 cells. Repressor activity maps to more than one domain within the molecule, although the homeodomain and carboxyl terminus give the strongest repression. PAX4 transcriptional regulation apparently plays a role only early in islet development, since Pax4 mRNA as determined by reverse transcriptase PCR peaks at embryonic day 13.5 in the fetal mouse pancreas and is undetectable in adult islets. In summary, PAX4 can function as a transcriptional repressor and is expressed early in pancreatic development, which may allow it to suppress alpha-cell differentiation and permit beta-cell differentiation.

Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma.

Cancers share many similarities in growth patterns, cellular morphology, and oncofetal antigen expression with embryonic tissue. To better understand the mechanisms underlying malignant transformation and its relationship to developmental processes, we studied the expression of Cdx-2, an intestinal epithelium-specific homeodomain protein, in colorectal adenoma and carcinoma. By immunohistochemistry with a polyclonal Cdx-2 antibody we have shown that Cdx-2 expression is markedly reduced in the later stages of human colorectal carcinogenesis, namely, high grade dysplasia and invasive carcinoma. The same findings occur in 1,2-dimethylhydrazine-induced rat colorectal tumors, confirming the parallels between the rat model and the human disease. As homeodomain proteins play major roles in directing the regionalization of body parts and in organogenesis and cellular phenotypic specification, a reduction of Cdx-2 expression in the late stages of colorectal carcinogenesis may reflect a concomitant deviation of the neoplastic tissue from the normal intestinal epithelial phenotype.

Haemorrhage due to erosion of a metal biliary stent through the duodenal wall.

Self-expanding, metal biliary stents have recently been used in malignant obstructive jaundice as their large diameter reduces the likelihood of occlusion by biliary sludge and bacterial biofilm. However, there is a significant rate of late obstruction by tumour overgrowth and infiltration through the wire mesh. Our case of stent erosion through the duodenal wall, resulting in massive haemorrhage, is a hitherto unreported serious complication of the Wallstent (Schneider). Its occurrence may be suggested by continuous upper abdominal pain, gastrointestinal bleeding or late expansion of the stent.

Exposure to grain dust and changes in lung function.

Respiratory symptoms and lung function were assessed in 41 seasonal grain handlers and related to duration of employment and level of exposure to grain dust. Ten public works department employees, not exposed to grain dust, were examined during the same period. Respiratory symptoms, forced expired volume in one second (FEV1), and bronchial responsiveness (dose of methacholine provoking a 20% fall in FEV1-PD20) were assessed before starting work and at weekly intervals during a period of employment lasting up to four weeks. Two atopic grainhandlers with pronounced bronchial hyperresponsiveness (PD20 less than 1 mumol) and a history of asthma withdrew from the study within two weeks because they developed severe asthma. Respiratory symptoms were more frequent and more often attributed to work in the grainhandlers than in the non-exposed subjects. In the grainhandlers the FEV1 decreased by a mean (95% confidence intervals) of 321 ml (198-444) (p less than 0.05) and the mean (95% confidence interval) PD20 decreased from 20.6 mumol (10.3-41.2) to 6.0 mumol (2.8-12.5) (p less than 0.05) after one week of work. Over the next three weeks the mean FEV1 returned towards the prestudy values. The mean PD20, however, remained significantly lower than the initial value. The mean FEV1 and PD20 did not change significantly in the non-exposed subjects. The frequency of symptoms and decreases in FEV1 were greater in grainhandlers when working in jobs where total exposure to dust was greater than 20 mg/m3 than when working in jobs where it was less than 10 mg/m3. The results indicate that occupational exposure to grain dust results in respiratory symptoms and changes in lung function, including increased airway responsiveness, within the first week of exposure to grain dust at work. These changes appear to be determined by the degree of dust exposure and suggest a direct effect of grain dust on the lung in these subjects.