Efficacy and delivery strategies of the dual Rac/Cdc42 inhibitor MBQ-167 in HER2 overexpressing breast cancer.

Trastuzumab and trastuzumab-based treatments are the standard of care for breast cancer patients who overexpress the human epidermal growth factor receptor 2 (HER2). However, patients often develop resistance to trastuzumab via signaling from alternative growth factor receptors that converge to activate guanine nucleotide exchange factors (GEFs) that in turn activate the Rho GTPases Rac and Cdc42. Since Rac and Cdc42 have been implicated in high tumor grade and therapy resistance, inhibiting the activity of Rac and Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Therefore, our group developed MBQ-167, a dual Rac/Cdc42 inhibitor with IC50s of 103 nM and 78 nM for Rac and Cdc42, respectively, which is highly effective in reducing cell and tumor growth and metastasis in breast cancer cell and mouse models. Herein, we created a trastuzumab resistant variant of the SKBR3 HER2 positive breast cancer cell line and show that Rac activation is a central mechanism in trastuzumab resistance. Next, we tested the potential of targeting MBQ-167 to HER2 overexpressing trastuzumab-resistant cell lines in vitro, and show that MBQ-167, but not trastuzumab, reduces cell viability and induces apoptosis. When MBQ-167 was targeted to mammary fatpad tumors established from HER2 overexpressing cells via immunoliposomes functionalized with trastuzumab, MBQ-167 and MBQ-167-loaded liposomes show equal efficacy in reducing the viability of trastuzumab-resistant cells, inhibiting tumor growth in mouse xenografts, and reducing metastasis to lungs and liver. This study demonstrates the efficacy of MBQ-167 as an alternative therapeutic in HER2 overexpressing cancers, delivered either in free form or in liposomes.

Vasculitides in HIV Infection.

PURPOSE OF REVIEW: To review the spectrum of vasculitides in HIV-infected patients and to identify the clinical features that characterize vasculitis in sero-positive HIV. RECENT FINDINGS: Epidemiological studies conducted in the post-HAART era described the rarity of vasculitis in the setting of HIV-infected patients. A study identified histopathological features such as leukocytoclastic vasculitis of the vasa vasorum and adventitial inflammation in the large artery pathology of HIV-positive patients compared with HIV-negative patients with critical lower limb ischemia. A recent retrospective cohort study reported that HIV-positive patients with LVV developed more vascular complications, responded less to antiretroviral therapy, and had worse outcome than HIV-negative patients with LVV. Vasculitides continue to be a rare disease in patients with HIV. The spectrum of vasculitis ranges from life-threatening conditions to relatively mild skin conditions. Recognizing vasculitis in the setting of HIV-positive patients is important because sometimes it require immunosuppressive treatment.

Human immunodeficiency virus infection (HIV)-associated rheumatic manifestations in thepre- and post-HAART eras.

Rheumatic manifestations remain an important clinical manifestation associated to HIV. To date after 4 decades of the onset of the HIV/AIDS pandemic, almost 37 million individuals are living with the infection, including close to 2 million of newly infected individuals. The status, however, of a considerable proportion of HIV/AIDS patients has changed from a near fatal disorder secondary to opportunistic infections to a chronic disease in which renal cardiovascular, diabetes, malignancy, and autoimmune co-morbid disorders have become prevalent and relevant. In addition, the spectrum of rheumatic disorders also has changed since the introduction of HAART and its diagnosis and treatment represents a challenge. The purpose of this review is to define and discuss the HIV-related rheumatic manifestations in the pre- and post-HAART eras.

HIV infection and its effects on the development of autoimmune disorders.

More than 35 years have elapsed since the initial outbreak of the HIV/AIDS epidemic and the status of a considerable number of patients has changed from a fatal disorder to a chronic one where comorbidities including sarcoidosis and autoimmune diseases have become relevant and dominant. HIV targets the immune system leading to a state of immunodeficiency in a setting of immune activation in which CD4+ T cell depletion plays a critical role. The onset, natural history and course of HIV-associated autoimmune disease has dramatically changed according to the stage of HIV infection and since the introduction of combined anti-retroviral therapy. There are some issues that need further study regarding therapy, especially when immunosuppressive drugs and biologic agents are under consideration. Currently, biologic agents and others immunosuppressive agents are recommended when patients have CD4+ T cell counts above 200 cells/mm3 and the HIV viral activity is completely suppressed.

Predictors of Poor Outcome in ANCA-Associated Vasculitis (AAV).

It is important to recognize factors that might predict poor outcome and prognosis in patients with AAV. The predictors reported in the literature encompass genetic, histopathological, and clinical ones. Genetic studies (genetic predictors) have found genes that are associated with prediction of poor response to treatment, deterioration of renal function, and risk of mortality. Histopathological studies (histopathological predictors) have shown that sclerotic renal lesions are associated with increased risk of progression to end-stage renal disease and death. Lastly, scores (clinical predictors) obtained with tool as FFS, Maldini risk score, VDI, and emerging new biomarkers could potentially be helpful in assessment of prognosis in the future.

CAREX Nicaragua and Panama: Worker exposures to carcinogenic substances and pesticides.

This study provides data on numbers of workers exposed at work to selected carcinogens and pesticides in Nicaragua (35 substances) and Panama (31), based on a modification of the CAREX data system. Population censuses provided industry- and sex-specific workforce numbers. The activity- and sex-specific proportions of exposed workers were estimated by experts from governmental agencies, workers' organizations, and employers' representatives. Finally, the numbers of those occupied in each activity/sex category were multiplied by the proportions of those exposed in the same categories, yielding numbers of those exposed in these categories for each agent. The study revealed high proportions (> 9%) of occupationally exposed workers in both countries for solar radiation and diesel engine emissions; environmental tobacco smoke in Panama; and some pesticides in Nicaragua. A high proportion of exposed was found for men for lead (12%), silica dust (10%), and hexavalent chromium (10%) in Panama.