Implementation of SAMHSA-funded Offender Re-Entry Programs Addressing Substance Use and Co-occurring Disorders among Justice Involved Latino Adults

Objectives: Racial and ethnic minorities have high rates of incarceration and persons entering the criminal justice system have disproportionate rates of mental health and substance use disorders Justice involved individuals do not receive adequate treatment resulting in greater risk of recidivism and relapse. This study examines the facilitators and barriers to implementing a SAMHSA-funded Offender Re-Entry Program (ORP) to better understand the factors that influence successful implementation of integrated bilingual/bicultural treatment, recovery, and re-entry services for recently incarcerated adult Latino individuals with substance use and co-occurring behavioral health disorders. Methods: Structured interviews were conducted with leadership, direct staff, and non-direct staff involved in the development and implementation of the Rumbo a Casa ORP at Casa Esperanza, Inc. Using the Consolidated Framework for Implementation Research (CFIR), we investigated the domains and constructs that were critical to successful implementation. Interviews were analyzed using NVivo 11 software. Results: Qualitative analyses show that across all domains, inner setting, particularly the implementation climate of an organization, is reported most often as influencing (positively or negatively) the implementation of the program. Findings show that the current process structure and the characteristics of individuals are greatly impacting program implementation as reported by direct staff. These findings demonstrate that the process of implementation which includes planning, engaging, executing, reflecting and evaluating constructs is essential for the successful implementation an offender-reentry program. Dedicated leadership is necessary to enhance implementation of fundamental program activities using a Plan-Do-Study-Act (PDSA) quality improvement cycle. Conclusion: An established implementation research framework can identify key issues critical to the implementation and evaluation processes. This study provides a deepened understanding of components critical to the successful implementation of an ORP and adds to the limited implementation research knowledge on evidence-based care approaches for justice involved Latino adults

Inherent Interfacial Mechanical Gradients in 3D Hydrogels Influence Tumor Cell Behaviors

Cells sense and respond to the rigidity of their microenvironment by altering their morphology and migration behavior. To examine this response, hydrogels with a range of moduli or mechanical gradients have been developed. Here, we show that edge effects inherent in hydrogels supported on rigid substrates also influence cell behavior. A Matrigel hydrogel was supported on a rigid glass substrate, an interface which computational techniques revealed to yield relative stiffening close to the rigid substrate support. To explore the influence of these gradients in 3D, hydrogels of varying Matrigel content were synthesized and the morphology, spreading, actin organization, and migration of glioblastoma multiforme (GBM) tumor cells were examined at the lowest (<50 µm) and highest (>500 µm) gel positions. GBMs adopted bipolar morphologies, displayed actin stress fiber formation, and evidenced fast, mesenchymal migration close to the substrate, whereas away from the interface, they adopted more rounded or ellipsoid morphologies, displayed poor actin architecture, and evidenced slow migration with some amoeboid characteristics. Mechanical gradients produced via edge effects could be observed with other hydrogels and substrates and permit observation of responses to multiple mechanical environments in a single hydrogel. Thus, hydrogel-support edge effects could be used to explore mechanosensitivity in a single 3D hydrogel system and should be considered in 3D hydrogel cell culture systems

Glioblastoma Behaviors in Three-Dimensional Collagen-Hyaluronan Composite Hydrogels

Glioblastoma multiforme (GBM) tumors, which arise from glia in the central nervous system (CNS), are one of the most deadly forms of human cancer with a median survival time of ∼1 year. Their high infiltrative capacity makes them extremely difficult to treat, and even with aggressive multimodal clinical therapies, outcomes are dismal. To improve understanding of cell migration in these tumors, three-dimensional (3D) multicomponent composite hydrogels consisting of collagen and hyaluronic acid, or hyaluronan (HA), were developed. Collagen is a component of blood vessels known to be associated with GBM migration; whereas, HA is one of the major components of the native brain extracellular matrix (ECM). We characterized hydrogel microstructural features and utilized these materials to investigate patient tumor-derived, single cell morphology, spreading, and migration in 3D culture. GBM morphology was influenced by collagen type with cells adopting a rounded morphology in collagen-IV versus a spindle-shaped morphology in collagen-I/III. GBM spreading and migration were inversely dependent on HA concentration; with higher concentrations promoting little or no migration. Further, noncancerous astrocytes primarily displayed rounded morphologies at lower concentrations of HA; in contrast to the spindle-shaped (spread) morphologies of GBMs. These results suggest that GBM behaviors are sensitive to ECM mimetic materials in 3D and that these composite hydrogels could be used to develop 3D brain mimetic models for studying migration processes

Epidemiological Investigation of Type 2 Diabetes and Alzheimer’s Disease in a Pakistani Population

The epidemic of type 2 diabetes mellitus (T2DM) and the possibility of it contributing to the risk of Alzheimer&rsquo;s disease (AD) have become important health concerns worldwide and in Pakistan, where the co-occurrence of T2DM and AD is becoming more frequent. To gain insights on this phenomenon, a cross-sectional study was initiated. We recruited and interviewed 820 research participants from four cities in Pakistan: 250 controls, 450 T2DM, 100 AD, and 20 with both diseases. Significant differences between groups were observed for age (p &lt; 0.0001), urban vs. rural locality (p = 0.0472) and residing near industrial areas. The average HbA1c (%) level was 10.68 &plusmn; 2.34 in the T2DM group, and females had a lower level than males (p = 0.003). In the AD group, significant relationships existed between education and family history. Overall, the results suggest that T2DM and AD were associated with both socio-demographic and environmental factors in Pakistani participants. Detailed molecular investigations are underway in our laboratory to decipher the differential genetic pathways of the two diseases to address their increasing prevalence in this developing nation

Mechanics of the gel-glass interface modeled using FEM.

<p>(A) Stress contour plots of Matrigel with varying height. Axisymmetric elements used. Von Mises stress is an equivalent stress that includes both normal stress (tension/compression) and shear stress contributions. It is calculated from the stress components acting at each location and gives a convenient way of comparing the overall magnitude of stress in different regions. (B) Stress felt at the Matrigel-glass interface as a function of gel height.</p

OSU-2 actin organization in 3D hydrogels at a higher observation (>∼500 µm) and lower observation (<∼50 µm) plane.

<p>Scale bar = 100 µm.</p

Quantification of migration speeds (average) of OSU-2 cells at the lowest (<∼50 µm) and highest observation planes (>∼500 µm) investigated.

<p>* indicates statistical significance.</p

Reaction force vs. 5 µm displacement of the indenter.

<p>Insert illustrates a decrease in stiffness with increasing Matrigel height due to a 5 µm indenter displacement. The stiffness insert is the slope extracted from the displacement vs. reaction force plot using the reaction force experienced by Matrigel when the indenter reaches a displacement of 5 µm.</p

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 &micro;M). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability

Valosin-containing protein (VCP) mutations in sporadic amyotrophic lateral sclerosis

We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease