Design of a Novel Intervention Model to Address Cardiovascular Health Disparities in the Rural Underserved Community of Phillips County Arkansas.

Devastating health-related disparities driven by an entanglement of factors disproportionately impact the underserved, low-wealth, and minority community of Phillips county (PC) in the Arkansas Delta Region (ADR). Cardiovascular disease continues to increase with widespread consequences on the local economy, health care systems, and population. Health care and community-based systems have been unsuccessful in reducing out-of-hospital cardiac death, particularly in the ADR, for many reasons. Herein, we share the strategy behind, planning, and goals of The Arkansas Lincoln Project, a novel neighborhood-based strategy bridging the gap between residents, social resources, and health care services in PC.

Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.

Visceral fat reduction and increase of intracellular fluid in weight loss participants on antihypertension medication.

OBJECTIVES: Complex physiological interactions between hypertension and obesity contribute to and perpetuate a heightened morbidity and mortality. With the prevalence of both hypertension and obesity reaching epidemic proportions, we asked whether antihypertensive medications affect the ability of participants to achieve the same level of body composition improvements as other participants in a comprehensive weight loss program focused on reduction of visceral adipose tissue. METHODS: Data was analyzed from 2200 subjects completing a commercially available, expert supervised weight loss program including ~6 weeks of a proprietary, nutritionally complete, very low-calorie diet (VLCD) followed by a ~3-week structured transition back to a normal dietary intake. Overall, 33% of the subjects reported taking at least one prescription antihypertensive medication. RESULTS: Our data show participants in both groups (± antihypertensive drugs) achieved clinically relevant and statistically significant improvements in standard measures of weight loss and endpoints directly related to inflammation and hypertension. CONCLUSION: A nonpharmacologic, nonsurgical VLCD-based weight loss and metabolic health program is capable of producing clinically meaningful improvements in body composition and physiological endpoints, including those linked to hypertension, cardiovascular disease and inflammation, and is as equally effective for adults taking prescription antihypertensives as it is for those participants who are not.

Resolution of Metabolic syndrome with reduction of visceral adipose tissue in a 47 year old patient with Type 2 Diabetes Mellitus.

BACKGROUND AND AIMS: Metabolic syndrome (MetS), defined as a cluster of metabolic abnormalities including visceral adiposity, insulin resistance, hypertension, and dyslipidemia, now affects more than a third of adults in the United States highlighting the need for effective complementary approaches to current treatments. METHODS: We present a case report of a 47-year-old man with a history of MetS and poorly controlled Type 2 Diabetes Mellitus (T2D) who completed a 20Lighter program (20L) including a very low calorie diet (VLCD). At the time of enrollment his BMI was 32.7, HbA1c was 9.6%, and prescription medication history included lisinopril, lovastatin, and metformin, glimepiride, and combination sitagliptin/metformin. RESULTS: Fifteen weeks after beginning 20L (6 weeks after program completion) marked reduction of weight, visceral adipose tissue and normalization of HbA1C was seen, and all medications were withdrawn. CONCLUSIONS: While longer follow-up is required, this case report shows that a comprehensive program including a relatively short period of nutritionally complete VLCD, followed by gradual return to moderate dietary lifestyle is capable of producing clinically significant improvements in health and quality of life in individuals with MetS and poorly controlled T2D.

Protein kinase G type II is required for night-to-day progression of the mammalian circadian clock.

Circadian clocks comprise a cyclic series of dynamic cellular states, characterized by the changing availability of substrates that alter clock time when activated. To determine whether circadian clocks, like the cell cycle, exhibit regulation by key phosphorylation events, we examined endogenous kinase regulation of timekeeping in the mammalian suprachiasmatic nucleus (SCN). Short-term inhibition of PKG-II but not PKG-Ibeta using antisense oligodeoxynucleotides delayed rhythms of electrical activity and Bmal1 mRNA. Phase resetting was rapid and dynamic; inhibition of PKG-II forced repetition of the last 3.5 hr of the cycle. Chronic inhibition of PKG-II disrupted electrical activity rhythms and tonically increased Bmal1 mRNA. PKG-II-like immunoreactivity was detected after coimmunoprecipitation with CLOCK, and CLOCK was phosphorylated in the presence of active PKG-II. PKG-II activation may define a critical control point for temporal progression into the daytime domain by acting on the positive arm of the transcriptional/translational feedback loop.

Specific uptake of 99mTc-NC100692, an αvß3-targeted imaging probe, in subcutaneous and orthotopic tumors.

INTRODUCTION: The αvß3 integrin, which is expressed by angiogenic epithelium and some tumor cells, is an attractive target for the development of both imaging agents and therapeutics. While optimal implementation of αvß3-targeted therapeutics will require a priori identification of the presence of the target, the clinical evaluation of these compounds has typically not included parallel studies with αvß3-targeted diagnostics. This is at least partly due to the relatively limited availability of PET radiopharmaceuticals in comparison to those labeled with (99m)Tc. In an effort to begin to address this limitation, we evaluated the tumor uptake of (99m)Tc-NC100692, a cyclic RGD peptide that binds to αvß3 with ~1-nM affinity, in an αvß3-positive tumor model as well as its in vivo specificity. METHODS: MicroSPECT imaging was used to assess the ability of cilengitide, a therapeutic with high affinity for αvß3, to block and displace (99m)Tc-NC100692 in an orthotopic U87 glioma tumor. The specificity of (99m)Tc-NC100692 was quantitatively evaluated in mice bearing subcutaneous U87MG tumors, by comparison of the biodistribution of (99m)Tc-NC100692 with that of the non-specific structural analogue (99m)Tc-AH-111744 and by blocking uptake of (99m)Tc-NC100692 with excess unlabeled NC100692. RESULTS: MicroSPECT imaging studies demonstrated that uptake of (99m)Tc-NC100692 in the intracranial tumor model was both blocked and displaced by the αvß3-targeted therapeutic cilengitide. Biodistribution studies provided quantitative confirmation of these imaging results. Tumor uptake of (99m)Tc-NC100692 at 1h post-injection was 2.8 ± 0.7% ID/g compared to 0.38 ± 0.1% ID/g for (99m)Tc-AH-111744 (p < 0.001). Blocking (99m)Tc-NC100692 uptake by pre-injecting the mice with excess unlabeled NC100692 reduced tumor uptake by approximately five-fold, to 0.68 ± 0.3% ID/g (p = 0.01). CONCLUSION: These results confirm that (99m)Tc-NC100692 does, in fact, target the αvß3 integrin and may, therefore, be useful in identifying patients prior to anti-αvß3 therapy as well as monitoring the response of these patients to therapy.

Requirement of mammalian Timeless for circadian rhythmicity.

Despite a central circadian role in Drosophila for the transcriptional regulator Timeless (dTim), the relevance of mammalian Timeless (mTim) remains equivocal. Conditional knockdown of mTim protein expression in the rat suprachiasmatic nucleus (SCN) disrupted SCN neuronal activity rhythms, and altered levels of known core clock elements. Full-length mTim protein (mTIM-fl) exhibited a 24-hour oscillation, where as a truncated isoform (mTIM-s) was constitutively expressed. mTIM-fl associated with the mammalian clock Period proteins (mPERs) in oscillating SCN cells. These data suggest that mTim is required for rhythmicity and is a functional homolog of dTim on the negative-feedback arm of the mammalian molecular clockwork.