Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function.

Vertebrate Hedgehog (HH) signaling is controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity. However, the molecular mechanisms used by these inhibitors remain poorly understood. In this paper, we investigated the mechanisms underlying HHIP1 antagonism of HH signaling. Strikingly, we found evidence that HHIP1 non-cell-autonomously inhibits HH-dependent neural progenitor patterning and proliferation. Furthermore, this non-cell-autonomous antagonism of HH signaling results from the secretion of HHIP1 that is modulated by cell type-specific interactions with heparan sulfate (HS). These interactions are mediated by an HS-binding motif in the cysteine-rich domain of HHIP1 that is required for its localization to the neuroepithelial basement membrane (BM) to effectively antagonize HH pathway function. Our data also suggest that endogenous, secreted HHIP1 localization to HS-containing BMs regulates HH ligand distribution. Overall, the secreted activity of HHIP1 represents a novel mechanism to regulate HH ligand localization and function during embryogenesis.

Influence of cognitive decline on sexuality in individuals with dementia and their caregivers.

Sexuality is an important element of human life that is strongly influenced by the social environment. People assess themselves and relate their roles to one another in terms of sexuality. More attention must be directed at the sexual needs of individuals with dementia and their caregivers. A myth believed by society is that individuals with dementia are asexual and that sexual desires and needs for connection will wane over time; whereas in reality many couples living with dementia remain sexually active as the disease progresses. The sexual needs of individuals with dementia are similar to those of younger people but might vary in occurrence and expression. An increase or decline in sexual desire is dependent on the level of cognitive impairment. Sexuality in individuals with dementia may be expressed as inappropriate or hypersexual behavior due to disinhibition and forgetting social cues. Although hypersexuality is often less common than other challenging behaviors that can occur in dementia, it affects both the health of the individual with dementia and the health of his or her caregiver.

Refractory cervical esophagogastric anastomotic strictures: management and outcomes.

OBJECTIVE: For recalcitrant cervical esophagogastric anastomotic strictures after transhiatal esophagectomy, a protocol of self-dilatation was developed at the University of Michigan Medical Center, as previously described. This study was undertaken to determine the outcomes of this treatment. METHODS: Self-dilatation was required in 158 (7.6%) of 2075 patients with cervical esophagogastric anastomotic strictures after transhiatal esophagectomy. An esophageal-specific survey evaluated the frequency and duration of dilatation, swallowing function, and satisfaction with treatment. The relationship among anastomotic leak, subsequent stricture, and the need for self-dilatation was assessed. A validated survey tool, the Short Form 36-item, version 2, was used to assess quality of life. RESULTS: At the time of this study, 78 of 158 patients were alive; 34 (43%) participated in the esophageal-specific survey. Median duration of self-dilatation was 10 years. The majority were satisfied with their ability to eat. No adverse events were reported. All patients said they would use self-dilatation therapy again under similar circumstances. Of these patients, 20 (59%) responded to the Short Form 36-item, version 2. Compared with the general population, 55% and 70% of participants scored at or above the norm for physical health and mental health status, respectively. Patients who required self-dilatation were twice as likely to have a history of cervical esophagogastric anastomotic leak as those who did not require this therapy (P=.0002). CONCLUSIONS: Refractory cervical esophagogastric anastomotic strictures are best managed initially with frequent outpatient dilatations, then transitioning to self-dilatation. Home use of Maloney dilators is a safe, well-tolerated, convenient, and cost-effective way to maintain comfortable swallowing. The effectiveness of self-dilatation therapy is reflected in this cohort's good quality of life and level of functioning.

Metastatic potential of cancer stem cells in head and neck squamous cell carcinoma.

OBJECTIVE: to design in vitro and in vivo models of metastasis to study the behavior of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC). DESIGN: cells were sorted for CD44 expression using flow cytometry. Sorted cells were used in an in vitro invasion assay. For in vivo studies, CSCs and non-CSCs were injected into the tail veins of mice, and lungs were either harvested or imaged to evaluate for lesions. RESULTS: in vitro, CD44(high) cells were more motile but not more invasive than CD44(low) cells. In vivo, 8 of 17 mice injected with CD44(high) cells and 0 of 17 mice injected with CD44(low) cells developed lung lesions. Two of the lesions arose from CSCs from a primary tumor and 6 from CSCs from HNSCC cell lines. CONCLUSIONS: in vitro, CSCs do not have an increased ability to invade through basement membrane, but they migrate more efficiently through a porous barrier. In contrast, CSCs efficiently formed lung lesions in vivo, whereas non-CSCs did not give rise to any distant disease. This phenomenon could be due to the enhanced migratory capacity of CSCs, which may be more important than basement membrane degradation in vivo.

Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence.

PURPOSE: The goal of this study was to examine the effect of tobacco use on disease recurrence (local/regional recurrence, distant metastasis, or second primary) among patients with human papillomavirus (HPV)-positive squamous cell carcinoma of the oropharynx (SCCOP) following a complete response to chemoradiation therapy. EXPERIMENTAL DESIGN: Between 1999 and 2007, 124 patients with advanced SCCOP (86% with stage IV) and adequate tumor tissue for HPV analysis who were enrolled in one of two consecutive University of Michigan treatment protocols were prospectively included in this study. Patients were categorized as never-, former, or current tobacco users. The primary end points were risk of disease recurrence and time to recurrence; secondary end points were disease-specific survival and overall survival. RESULTS: One hundred and two patients (82.3%) had HPV-positive tumors. Over two thirds (68%) of patients with HPV-positive tumors were tobacco users. Among HPV-positive patients, current tobacco users were at significantly higher risk of disease recurrence than never-tobacco users (hazard ratio, 5.2; confidence interval, 1.1-24.4; P = 0.038). Thirty-five percent of HPV-positive ever tobacco users recurred compared with only 6% of HPV-positive never users and 50% of HPV-negative patients. All HPV-negative patients were tobacco users and had significantly shorter times to recurrence (P = 0.002), and had reduced disease-specific survival (P = 0.004) and overall survival (P < 0.001) compared with HPV-positive patients. Compared with HPV-positive never-tobacco users, those with a tobacco history showed a trend for reduced disease-specific survival (P = 0.064) but not overall survival (P = 0.221). CONCLUSIONS: Current tobacco users with advanced, HPV-positive SCCOP are at higher risk of disease recurrence compared with never-tobacco users.