1α, 25-Dihydroxyvitamin D3 and the vitamin D receptor regulates ΔNp63α levels and keratinocyte proliferation.

1α, 25-dihydroxyvitamin D3 (VD3), a secosteriod that has been explored as an anti-cancer agent, was also shown to promote cell survival. Its receptor, the Vitamin D Receptor (VDR), is a direct target of the proto-oncogene ΔNp63α, which is overexpressed in non-melanoma skin cancers. The interconnection between VDR/VD3 signaling and ΔNp63α, led us to examine whether VDR/VD3 signaling promotes keratinocyte proliferation by regulating ΔNp63α levels. Our data demonstrate that VDR regulates ΔNp63α expression at both the transcript and protein level. Interestingly, although low doses of VD3 led to an increase in ΔNp63α protein levels and keratinocyte proliferation, high doses of VD3 failed to increase ΔNp63α protein levels and resulted in reduced proliferation. Increased expression of ΔNp63α by low dose VD3 was shown to be dependent on VDR and critical for the proliferative effects of VD3. VD3-mediated increases in ΔNp63α protein levels occur via activation of both p38 MAPK and Akt kinases. Finally, analysis of samples from patients with squamous cell carcinoma (SCC), basal cell carcinoma and precursors to invasive SCC demonstrated a significant correlation between p63 and VDR levels when compared with healthy normal skin control samples. Delineation of the mechanisms by which VD3 exerts its effect on ΔNp63α and cell proliferation is critical for determining the future of VD3 in cancer therapies.

ΔNp63α regulates keratinocyte proliferation by controlling PTEN expression and localization.

ΔNp63α, implicated as an oncogene, is upregulated by activated Akt, part of a well-known cell survival pathway. Inhibition of Akt activation by phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and the presence of putative p63-binding sites in the pten promoter led us to investigate whether ΔNp63α regulates PTEN expression. Knockdown of ΔNp63α led to increases in PTEN levels and loss of activated Akt, while overexpression of ΔNp63α decreased PTEN levels and elevated active Akt. The repression of PTEN by ΔNp63α occurs independently of p53 status, as loss of ΔNp63α increases PTEN expression in cell lines with and without functional p53. In addition, decreased levels of ΔNp63α resulted in an increase in nuclear PTEN. Conversely, in vivo nuclear PTEN was absent in the proliferative basal layer of the epidermis where ΔNp63α expression is highest. Additionally, we show that in keratinocytes a balance between ΔNp63α and PTEN regulates Akt activation and maintains normal proliferation rates. This balance is disrupted in non-melanoma skin cancers through increased ΔNp63α levels, and could enhance proliferation and subsequent neoplastic development. Our studies show that ΔNp63α negatively regulates PTEN, thereby providing a feedback loop between PTEN, Akt and ΔNp63α, which has an integral role in skin cancer development.

p73 is essential for vitamin D-mediated osteoblastic differentiation.

The secosteroid hormone vitamin D3 (VD3) exerts its biological actions through its cognate receptor, the vitamin D receptor (VDR). Vitamin D3 and VDR have a key function in bone formation and keratinocyte differentiation, exert antiproliferative actions in human cancer, and is widely used as a chemotherapeutic agent for cancer. In addition, VD3 promotes differentiation of human osteosarcoma cells by up-regulating genes involved in cell cycle arrest and osteoblastic differentiation. Although considerable work has been carried out in understanding the molecular mechanisms underlying the VD3-mediated differentiation of human osteosarcoma cells, the upstream regulation of VD3 signaling pathway is still unclear. In this study, we show that p73 acts as an upstream regulator of VD3-mediated osteoblastic differentiation. Transcription factor p73, a p53 homolog, has been shown to have a function in development and recently been termed as a tumor suppressor. Silencing p73 results in a significant reduction of VD3-mediated osteoblastic differentiation; although DNA damage induced p73 leads to an increase in VD3-mediated differentiation of osteosarcoma cells. Together, our data implicate a novel function for p73 in vitamin D-mediated differentiation of human osteosarcoma cells.

Prevalence and risk factors for latent tuberculosis infection among health care workers in Georgia.

BACKGROUND: Tuberculosis (TB) is a major public health problem in Georgia, but few TB infection control measures have been implemented in health care facilities. OBJECTIVE: To assess the prevalence and risk factors for latent TB infection (LTBI) among Georgian health care workers (HCWs) using two diagnostic tests, the tuberculin skin test (TST) and the QuantiFERON-TB Gold In Tube test (QFT-3G), an interferon-gamma release assay. METHODS: A cross-sectional study was conducted between June and August 2006 among HCWs at the Georgian National TB Program. RESULTS: Of 265 HCWs enrolled, 177 (67%) had a positive TST and 159 (60%) had a positive QFT-3G; 203 (77%) had a positive result for at least one of the tests and 50% tested positive for both tests. There was moderately good agreement between the tests (74%, kappa = 0.43, 95%CI 0.33-0.55). In multivariate analysis, employment for >5 years was associated with increased risk of a positive TST (OR 5.09, 95%CI 2.77-9.33) and QFT-3G (OR 2.26, 95%CI 1.27-4.01); age >30 years was associated with an increased risk of a positive QFT-3G (OR 2.91, 95%CI 1.32-6.43). DISCUSSION: A high prevalence of LTBI was found among Georgian HCWs and longer duration of employment was associated with increased risk. These data highlight the need for effective TB infection control measures and provide important baseline information as TB infection control measures are implemented.

Risk factors for mortality among adult patients with newly diagnosed tuberculosis in Samara, Russia.

SETTING: Five out-patient tuberculosis (TB) clinics and one in-patient TB hospital in Samara, Russia. OBJECTIVE: To identify predictors of all-cause mortality among patients with newly diagnosed TB. DESIGN: A retrospective case-control study of adult TB cases registered over a 5-year period from 1999 to 2003 using multivariate logistic regression modeling. Cases were defined as patients with TB who died within 12 months of diagnosis. Controls were patients with TB who survived at least 12 months. RESULTS: The case fatality rate was 3.6%. A total of 92 cases and 368 controls were identified. Mean age was 43 years; 71% were male; 4% were human immunodeficiency virus (HIV) seropositive. The median survival time for cases was 39.5 days. In multivariate analysis, independent predictors of mortality included bilateral lung involvement (OR 3.65), cavitary lesions on chest radiograph (CXR) (OR 2.45), symptoms >4 weeks at the time of diagnosis (OR 2.62), anemia (OR 5.24), and injection drug use (IDU) (OR 4.45), controlling for age. CONCLUSION: Advanced TB disease at the time of diagnosis (as demonstrated by having bilateral lung involvement, cavitary disease, symptoms >1 month, and anemia) and IDU were associated with increased TB mortality in Samara. Interventions targeted at improving earlier TB case diagnosis and treatment may help to reduce mortality among patients with tuberculosis in this region.

Laryngeal histoplasmosis.

Histoplasma capsulatum is an endemic fungus found in moist, fertile soil; in North America, it is most prevalent in the river valleys of the central United States. Most primary infections in the immunocompetent host are asymptomatic or are thought to be a flu-like illness. Disseminated histoplasmosis most commonly occurs in immunosuppressed patients. Histoplasmosis infection involving the larynx is an extremely rare manifestation. Here, we describe the case of an immunocompetent man with symptomatic, acute pulmonary histoplasmosis with laryngeal involvement who presented with a chief complaint of hoarseness. We also review the literature of immunocompetent patients with laryngeal histoplasmosis.

Respiratory failure caused by tuberculous pneumonia requiring extracorporeal membrane oxygenation.

While a common pathogen, Mycobacterium tuberculosis (TB) pneumonitis is only rarely reported as a cause for respiratory failure in developed countries. We report an adolescent with TB pneumonitis and respiratory failure requiring extracorporeal membrane oxygenation (ECMO) with eventual survival. With the incidence of TB rising globally, TB should be suspected and treated as early as possible. ECMO should be considered as a treatment option if conventional ventilatory support is inadequate. ECMO survival with TB pneumonia and anti-TB antimicrobial therapy is possible.