Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling.

Inositol phosphates are widely produced throughout animal and plant tissues. Diphosphoinositol pentakisphosphate (InsP7) contains an energetic pyrophosphate bond. Here we demonstrate that disruption of inositol hexakisphosphate kinase 1 (InsP6K1), one of the three mammalian inositol hexakisphosphate kinases (InsP6Ks) that convert inositol hexakisphosphate (InsP6) to InsP7, conferred enhanced phosphatidylinositol-(3,4,5)-trisphosphate (PtdIns(3,4,5)P3)-mediated membrane translocation of the pleckstrin homology domain of the kinase Akt and thus augmented downstream PtdIns(3,4,5)P3 signaling in mouse neutrophils. Consequently, these neutrophils had greater phagocytic and bactericidal ability and amplified NADPH oxidase-mediated production of superoxide. These phenotypes were replicated in human primary neutrophils with pharmacologically inhibited InsP6Ks. In contrast, an increase in intracellular InsP7 blocked chemoattractant-elicited translocation of the pleckstrin homology domain to the membrane and substantially suppressed PtdIns(3,4,5)P3-mediated cellular events in neutrophils. Our findings establish a role for InsP7 in signal transduction and provide a mechanism for modulating PtdIns(3,4,5)P3 signaling in neutrophils.

Hypofractionated radiotherapy does not increase acute toxicity in large-breasted women: results from a prospectively collected series.

BACKGROUND AND PURPOSE: To compare the acute toxicity of hypofractionated whole breast radiotherapy (HypoRT) to conventionally fractionated radiotherapy (ConvRT) in large-breasted women with early stage disease. MATERIALS AND METHODS: Women with breast volume>1500 cm, body mass index>30 kg/m, or separation>25 cm treated with HypoRT or ConvRT from 2005 through 2010 were identified from a prospective database and included in the analysis. Acute toxicity was scored for each treated breast. RESULTS: Ninety-two patients were treated to 96 breasts. The median body mass index was 33 kg/m and median breast volume was 1932 cm for the ConvRT group compared with 32.4 kg/m and 1825 cm for the HypoRT group. Maximum acute skin toxicity consisted of focal moist desquamation in 26% and 11% of the ConvRT and HypoRT patients, respectively (P=0.002). Breast volume was the only patient factor significantly associated with moist desquamation on multivariable analysis (P=0.01). Among those with a breast volume >2500 cm, focal moist desquamation occurred in 40.7% (11/27) compared with 11.1% (7/63) in patients with breast volume <2500 cm (P=0.002). CONCLUSIONS: Among obese and large-breasted women, there was no increase in acute skin toxicity with the use of HypoRT. HypoRT should be considered in obese and large-breasted women when advanced planning techniques are used.

Lentigo maligna: review of salient characteristics and management.

Lentigo maligna is a melanocytic neoplasm, often regarded as 'melanoma in situ,' which may progress to lentigo maligna melanoma. Lentigo maligna clinically presents as a pigmented, asymmetric macule that originates on the head and neck and spreads slowly. The preferred method for diagnosing lentigo maligna is excisional biopsy. Histology shows proliferation of atypical melanocytes at the epidermal-dermal junction in small nests or single cells. The differential diagnosis includes solar lentigo, seborrheic keratosis, lichen planus-like keratosis, pigmented actinic keratosis, and melanocytic nevus. Stains used in diagnosis include hematoxylin and eosin, HMB-45, MART-1/Melan-A, Mel-5, and S-100. Surgical excision is the preferred treatment for lentigo maligna. Second-line techniques include medical (topical imiquimod) and destructive therapy.