Automated Reinforcement Management System (ARMS): focused phase I provider feedback.

BACKGROUND: Alcohol use increases risk for morbidity and mortality and is associated with over 3 million annual deaths worldwide. Contingency Management (CM) is one of the most effective interventions for substance use disorders, and has recently been coupled with technologies to promote novel treatments for alcohol use disorders (AUD). Leveraging these technological advances, we are developing the Automated Reinforcement Management System (ARMS), an integrated CM system designed to enable CM treatment as a component of a digital therapeutic or adjunct therapy remotely to anyone with a smartphone. OBJECTIVE: To collect detailed provider feedback on ARMS and determine the need for modifications to make the system most feasible, acceptable, and useful to providers. METHODS: Seven providers completed one-hour structured interviews/focus groups wherein we described the ARMS system and its application to clinical care. Providers viewed screen shots of the ARMS provider facing and patient facing systems. Providers gave feedback on their current AUD treatment practices, preferences for the functionality and appearance of the system, preferences for receipt of information on their patients, why they and their patients would or would not use the system, suggestions for improvement, and the proposed intervention overall. To analyze the qualitative data gathered, we used a qualitative descriptive approach with content analysis methods. RESULTS: The overarching theme of Individualized Treatment emerged throughout the interviews. This sentiment supports use of ARMS, as it is intended to supplement provider communication and intervention as an adjunctive and customizable tool with the ability to reach rural patients, not a stand-alone option. Themes of Accountability and Objective Assessment arose during discussions of why people would use the system. Themes within provider obstacles included, Information Overload and Clinical Relevance, and in patient obstacles, Sustained Engagement and Security Concerns. Two themes emerged regarding suggestions for improvement: Increasing Accessibility and Bi-directional Communication. DISCUSSION: Themes from provider input are being used to modify ARMS to make it more user friendly, time saving, and relevant to treatment of AUD. If successful, ARMS will provide effective, individualized-digital therapeutic for those needing adjunctive treatment or those living in rural remote areas needing better connected care.

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research.

Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders the maintenance and differentiation of stem cells. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative and is cheaper than Y-27632. It increased hPSC growth following thawing and passaging, like Y-27632, and did not affect pluripotency, differentiation ability, and chromosome integrity. Furthermore, fasudil promoted retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells (NCCs) during differentiation. It was also useful for single-cell passaging of hPSCs and during aggregation. These findings suggest that fasudil can replace Y-27632 for use in stem research.

Ginger and its bioactive component 6-shogaol mitigate lung inflammation in a murine asthma model.

Asthma, a common disorder associated with airway inflammation and hyperresponsiveness, remains a significant clinical burden in need of novel therapeutic strategies. Patients are increasingly seeking complementary and alternative medicine approaches to control their symptoms, including the use of natural products. Ginger, a natural product that we previously demonstrated acutely relaxes airway smooth muscle (ASM), has long been reported to possess anti-inflammatory properties, although a precise mechanistic understanding is lacking. In these studies, we demonstrate that chronic administration of whole ginger extract or 6-shogaol, a bioactive component of ginger, mitigates in vivo house dust mite antigen-mediated lung inflammation in mice. We further show that this decrease in inflammation is associated with reduced in vivo airway responsiveness. Utilizing in vitro studies, we demonstrate that 6-shogaol augments cAMP concentrations in CD4 cells, consistent with phosphodiesterase inhibition, and limits the induction of nuclear factor-κB signaling and the production of proinflammatory cytokines in activated CD4 cells. Sustained elevations in cAMP concentration are well known to inhibit effector T cell function. Interestingly, regulatory T cells (Tregs) utilize cAMP as a mediator of their immunosuppressive effects, and we demonstrate here that 6-shogaol augments the Treg polarization of naïve CD4 cells in vitro. Taken together with previous reports, these studies suggest that ginger and 6-shogaol have the potential to combat asthma via two mechanisms: acute ASM relaxation and chronic inhibition of inflammation.

Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche.

The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.

Starved epithelial cells uptake extracellular matrix for survival.

Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize ß4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell ß4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition.

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP.

Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors. Cancer Res; 76(24); 7168-80. ©2016 AACR.

ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling.

Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2.

The epithelial-mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer.

Legislating separation and solidarity in plural societies: the Chinese in Indonesia and Malaysia.

The Chinese minority plays a dominant role in the economies of Indonesia and Malaysia, a fact that evokes indigenous resentment. However, Indonesia and Malaysia dealt differently with the issue. Malaysia legislated the Malays into the economy and protected Chinese citizenship, making them an integral part of a multicultural state. By contrast, New Order Indonesia adopted policies of economic manipulation, forced assimilation, and unequal citizenship. Only when the New Order regime fell did Chinese integration begin. The policy trajectories of Indonesia and Malaysia offer important lessons for plural states.

Retention and retention of effect of topical formulations in dry eye subjects.

PURPOSE: It was the purpose of this investigation to examine both retention time (RT) and retention of effect of two ophthalmic formulations in the same dry eye subjects. METHODS: This was a randomized, subject-masked cross-over study. Dry eye subjects, characterized by sub-type, were recruited. For direct RT measurement, fluorescein isothiocyanate (FITC)-dextran, 70 kDa molecular weight, was admixed at 0.1% wt/vol concentration into buffered saline (active control) and a viscous marketed artificial tear formulations (test formulation). RT in minutes was estimated directly as the return to baseline intrinsic fluorescence with an objective scanning fluorometer. Retention of effect was measured with a xeroscope as non-invasive breakup time (NIBUT) and by use of a numerical rating scale for comfort. RESULTS: Eleven subjects, with most being classified as having non-inflammatory meibomian gland dysfunction, completed the study. The RTs averaged 17.7 (+/-10.0) and 26.8 (+/-16.5) minutes for the saline and test formulations, respectively. The averages for NIBUT were 8.73 (+/-6.1) and 19.5 (+/-4.9) minutes, for saline and the test formulations, respectively. Return to baseline for the numerical rating scale comfort averages were 9.91 (+/-4.1) and 20.21 (+/-6.4) minutes for the saline and test formulations, respectively. When residence time was subtracted from the retention of effect measures, no statistical significance was found for the polymeric solution (vs. comfort, p = 0.153; vs. NIBUT, p = 0.109). However, statistical differences were found for direct retention compared against comfort (p = 0.01) and NIBUT (p = 0.004) for buffered saline. CONCLUSIONS: It seems that these two retention of effect measures are much shorter than RT measured directly. Future work should aim to confirm these findings in additional dry eye sub-types and in those with more severe disease manifestations.

Iritis presumed as secondary to disseminated coccidioidomycosis.

BACKGROUND: Coccidioidomycosis is a systemic disease caused by a fungus found in soil and transmitted through inhalation. It is prevalent in western and southwestern United States, Mexico, and South and Central America. Results of skin testing, serologic testing, and tissue cultures confirm the diagnosis. Coccidioidomycosis can manifest in various ways: the infected individual may present asymptomatically, with an acute respiratory infection, or, in more severe or chronic cases, with a multiorgan presentation. Ocular involvement may include anterior segment, posterior segment, or extraorbital involvement. CASE REPORT: A case concerning a patient with iritis presumed as secondary to disseminated coccidioidomycosis is discussed. The patient initially presented to our clinic with signs and symptoms of acute, unilateral iritis and a recent history of iritis in the contralateral eye. The active inflammation was treated topically with Pred Forte and cyclopentolate and resolved without sequelae. Because the presentation was bilateral with an asymmetric timecourse, laboratory tests were ordered to rule out systemic association. Because all tests yielded negative results, the known history of disseminated coccidioidomycosis was presumed to be the etiology of this iritis. CONCLUSION: Although eye findings are rare, disseminated coccidioidomycosis is an important differential to consider when a patient presents with uveitis. For this reason, awareness and recognition of ocular signs and symptoms of this disease is significant in proper patient care and management.

Breast conserving surgery and accelerated partial breast irradiation using the MammoSite system: initial clinical experience.

HYPOTHESIS: Balloon catheter-based accelerated partial breast irradiation (APBI) may result in desirable short-term outcomes in patients undergoing breast conserving surgery. DESIGN: Prospective consecutive case series. SETTING: Tertiary multidisciplinary referral center. PATIENTS: Forty selected patients with invasive breast carcinoma undergoing breast conserving surgery and MammoSite device placement. INTERVENTIONS: Breast conserving surgery, sentinel and/or axillary node dissection, placement of the new balloon catheter applicator (MammoSite device), and APBI. MAIN OUTCOME MEASURES: Infection, early and late seroma, device explantation, time to initiating APBI, acute toxic effects on the skin, and cosmesis using the Harvard Scale. RESULTS: Thirty-nine patients underwent MammoSite device placement at the time of lumpectomy; 1 patient underwent percutaneous device placement after lumpectomy. Nineteen patients (49%) had drainage catheters placed in the breast cavity at the time of lumpectomy. Wound infection developed in 3 patients (8%). Five devices (12%) were explanted because of unfavorable final pathological findings or infection. The mean time to the start of APBI in patients who did not undergo simultaneous drain placement was 7.2 days (range, 5-12 days), compared with 5.1 days (range, 3-8 days) in patients who did (P = .008). With a mean follow-up of 13.3 months (range, 2-28 months), patients completing APBI had limited toxic effects on the skin, with excellent or good cosmetic results in 39 patients (97%). CONCLUSIONS: Use of the MammoSite system in APBI has favorable short-term outcomes. Infection and radiation treatment delay are common and may warrant use of perioperative antibiotics and drain placement, respectively. A small number of patients who have device placement at the time of lumpectomy will require explantation because of unfavorable final pathological findings. Short-term outcomes of MammoSite brachytherapy support further studies comparing APBI with standard whole breast irradiation in patients undergoing breast conserving surgery.

Treatment of T3 and T4 anal carcinoma with combined chemoradiation and interstitial 192Ir implantation: a 10-year experience.

PURPOSE: To report our experience in treating T3 and T4 anal carcinoma with combined external beam (EBRT) and chemotherapy, followed by interstitial (192)Ir implant boost. METHODS AND MATERIALS: From 1990 to 2000, 31 patients with T3 and T4 anal carcinoma were treated with: 30 Gy EBRT (2 Gy fractions, 5 days/week) + 5-fluorouracil + mitomycin-C. Median implant dose was 31.3 Gy at 0.5 cm, delivered at a mean rate of 0.52 Gy/h. RESULTS: Six patients had local persistence and 4 eventually developed local-regional recurrence. Eight underwent abdomino-perineal resection (APR). With the addition of APR in selected cases, the ultimate local-regional control after initial treatment was 84%. Distant metastases occurred in 10. Of the initial cohort, 55% is still alive and NED. Eight had radiation proctitis and 7 developed postimplant ulceration. Only 1 required surgical intervention. CONCLUSIONS: Treatment of T3 and T4 anal cancer with combined chemotherapy and EBRT, followed by interstitial implant results in an ultimate local-regional control of 84%, after the inclusion of selected APR. It is well tolerated, with acceptable toxicity.