Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen.

Evasion of apoptosis is critical for the development and growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family, associated with tumor aggressiveness, poor survival, and drug resistance. Development of Mcl-1 inhibitors implies blocking of protein-protein interactions, generally requiring a lengthy optimization process of large, complex molecules. Herein, we describe the use of DNA-encoded chemical library synthesis and screening to directly generate complex, yet conformationally privileged macrocyclic hits that serve as Mcl-1 inhibitors. By applying a conceptual combination of conformational analysis and structure-based design in combination with a robust synthetic platform allowing rapid analoging, we optimized in vitro potency of a lead series into the low nanomolar regime. Additionally, we demonstrate fine-tuning of the physicochemical properties of the macrocyclic compounds, resulting in the identification of lead candidates 57/59 with a balanced profile, which are suitable for future development toward therapeutic use.

Teaching Old Polymers New Tricks: Improved Synthesis and Anomalous Crystallinity for a Lost Semi-Fluorinated Polyaryl Ether via Interfacial Polymerization of Hexafluoroacetone Hydrate and Diphenyl Ether.

A practical and direct electrophilic polymerization of hexafluoroacetone hydrate with diphenyl ether toward the preparation of semi-fluorinated polyaryl ethers (PAE) is reported. Electrophilic aromatic substitution (EAS) polymerization under interfacial conditions with phase transfer catalyst (Aliquat 336) proceeds in trifluoromethanesulfonic anhydride by generation of trifluoromethanesulfonic acid and the protonated hexafluoroacetone (HFA) in situ affording 1,1,1,3,3,3-hexafluoroisopropylidene (6F) PAE with high regioselectivity (4,4'-DPE) and high molecular weight (≈60 kDa). Although first reported in a 1966 US Patent by DuPont using harsh conditions, improved synthetic methods or modern characterization has not been disclosed until now. Despite the presence of the 6F group, known to impart disordered morphology, this simple semi-fluorinated PAE exhibits anomalous crystallinity with polymorphic melting points (Tm ) ranging from 230-309 °C, high solubility in common organic solvents, a glass transition (Tg ) of 163 °C, and thermo-oxidative stability above 500 °C. Tough optically clear films prepared from solution give transmittance higher than 90% throughout the visible region. Synthesis, mechanistic aspects, and characterization including surface and dielectric properties are discussed.

Ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ): tunable halogenation and quinone formation using NaX/Oxone.

Ring-fused benzimidazolequinones are well-known anti-tumour agents, but dimeric ring-fused adducts are new. The alicyclic [1,2-a] ring-fused dimethoxybenzimidazole-benzimidazolequinone (DMBBQ) intermediate allows late-stage functionalization of bis-p-benzimidazolequinones. DMBBQs are chlorinated and brominated at the p-dimethoxybenzene site using nontoxic sodium halide and Oxone in HFIP/water. X-ray crystallography is used to rationalize site preference in terms of the discontinuity in conjugation in the DMBBQ system. Quinone formation occurs by increasing in situ halogen generation and water. Conversely, radical trifluoromethylation occurs at the quinone of the DMBBQ.

The Critical Role of Passive Permeability in Designing Successful Drugs.

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.

Single Anastomosis Duodenal Switch: 1-Year Outcomes.

INTRODUCTION: Single-anastomosis duodenal switch has been suggested to be an effective bariatric procedure that offers excellent weight loss and by lengthening the common channel the potential to reduce micronutrient deficiencies. PURPOSE: To evaluate the weight loss, comorbidity resolution and the 1-year nutritional outcomes of the single-anastomosis duodenal switch (SADS) procedure. SETTING: Multiple US Hospitals. METHODS: From October 2014 to January 2017, 120 patients were enrolled at six sites across the USA and underwent the SADS procedure. Weight loss, comorbidities, quality of life, and adverse events were followed post-procedure for 12 months. RESULTS: At 1, 6, and 12 months, 98.3%, 85.5%, and 77.1% of the patients were available for assessment, respectively. At 12 months, patients showed significantly reduced body mass index when compared to baseline (46.8 ± 5.8 vs 29.8 ± 4.4, P < 0.001 respectively). Sixty-five patients had type 2 diabetes at baseline; however, 11 patients lost to follow-up. Of the available data (54 patients), 96.3% of the patients had a resolution of type 2 diabetes by 12 months with a mean A1C reduction from 7.8 ± 1.6 to 5.3 ± 0.7. Additionally, there were reductions in hyperlipidemia, sleep apnea, and hypertension at 12 months. Patient gastroesophageal reflux disease satisfaction and quality of life (SF-36) scores were significantly higher at 12 months post-procedure (P < 0.001 in all cases) while 12-month protein levels remained at normal values. There were abnormalities of parathyroid hormone and vitamin D at 1 year with all other nutritional markers being not significantly different at 1 year from baseline. There were 10, IIIb, or greater complications according to the Clavien-Dindo scoring system during the study period, not all of which were related to the surgery. CONCLUSIONS: SADS is a highly efficacious weight loss procedure with significant comorbidity reduction at 1 year. At 1 year, complications and vitamin and mineral deficits appear to be consistent with other malabsorption operations. Long-term follow-up is needed, especially around complications and vitamin deficiencies.

The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance.

The Lysosomal sequestration of weak-base anticancer drugs is one putative mechanism for resistance to chemotherapy but it has never been directly proven. We addressed the question of whether the lysosomal sequestration of tyrosine kinase inhibitors (TKIs) itself contributes to the drug resistance in vitro. Our analysis indicates that lysosomal sequestration of an anticancer drug can significantly reduce the concentration at target sites, only when it simultaneously decreases its extracellular concentration due to equilibrium, since uncharged forms of weak-base drugs freely diffuse across cellular membranes. Even though the studied TKIs, including imatinib, nilotinib, and dasatinib, were extensively accumulated in the lysosomes of cancer cells, their sequestration was insufficient to substantially reduce the extracellular drug concentration. Lysosomal accumulation of TKIs also failed to affect the Bcr-Abl signaling. Cell pre-treatment with sunitinib significantly enhanced the lysosomal accumulation of the TKIs used; however, without apparent lysosomal biogenesis. Importantly, even increased lysosomal sequestration of TKIs neither decreased their extracellular concentrations nor affected the sensitivity of Bcr-Abl to TKIs. In conclusion, our results clearly show that the lysosomal sequestration of TKIs failed to change their concentrations at target sites, and thus, can hardly contribute to drug resistance in vitro.

Intracellular and Intraorgan Concentrations of Small Molecule Drugs: Theory, Uncertainties in Infectious Diseases and Oncology, and Promise.

The distribution of a drug within the body should be considered as involving movement of unbound drug between the various aqueous spaces of the body. At true steady state, even for a compound of restricted lipoidal permeability, unbound concentrations in all aqueous compartments (blood, extracellular, and intracellular) are considered identical, unless a compartment has a clearance/transport process. In contrast, total drug concentrations may differ greatly, reflecting binding or partitioning into constituents of each compartment. For most highly lipid permeable drugs, this uniform unbound concentration is expected to apply. However, many compounds have restricted lipoidal permeability and are subjected to transport/clearance processes causing a gradient between intracellular and extracellular unbound concentrations even at steady state. Additional concerns arise where the drug target resides in a site of limited vascularity. Many misleading assumptions about drug concentrations and access to drug targets are based on total drug. Correction, if made, is usually by measuring tissue binding, but this is limited by the lack of homogenicity of the organ or compartment. Rather than looking for technology to measure the unbound concentration it may be better to focus on designing high lipoidal permeable molecules with a high chance of achieving a uniform unbound drug concentration. It is hoped this paper will stimulate greater understanding of the path from circulation to cell interior, and thereby in part avoid or minimize the need to provide the experimentally very determining, and sometimes still questionable, answer to this problem.

Return to the Primary Acute Care Service Among Patients With Multiple Myeloma on an Acute Inpatient Rehabilitation Unit.

BACKGROUND: Pancytopenia, immunosuppression, and other factors may place patients with multiple myeloma at risk for medical complications. These patients often require inpatient rehabilitation. No previous studies have looked at risk factors for return to the primary acute care service of this patient population. OBJECTIVE: To determine the percentage of and factors associated with return to the primary acute care service of multiple myeloma rehabilitation inpatients. DESIGN: Retrospective review. SETTING: Acute inpatient rehabilitation unit within a National Cancer Institute Comprehensive Cancer Center. PARTICIPANTS: All patients with multiple myeloma admitted to the inpatient rehabilitation unit between March 1, 2004, and February 28, 2015. MAIN OUTCOME MEASURES: Return to the primary acute care service was analyzed with demographic information, multiple myeloma characteristics, medications, laboratory values, and hospital admission characteristics. RESULTS: One hundred forty-three inpatient rehabilitation admissions were found during the study period. After we removed multiple admissions of the same patients and planned transfers to the primary acute care service, 122 admissions were analyzed. Thirty-two (26%) patients transferred back to the primary acute care service for unplanned reasons. Multivariate analysis revealed male gender and thrombocytopenia as significantly associated with return to the primary acute care service. The median survival of patients who transferred back to the inpatient primary acute care service was 180 days versus 550 days for those who did not (P < .001). CONCLUSION: Because of their medical fragility, clinicians caring for rehabilitation inpatients with multiple myeloma should maintain close contact with the primary oncology service. Factors associated with an increased risk of transfer back to the primary acute care service include male gender and thrombocytopenia. LEVEL OF EVIDENCE: IV.

Managing incidental pancreatic cystic neoplasms with integrated molecular pathology is a cost-effective strategy.

BACKGROUND AND STUDY AIMS: Current guidelines recommend using endoscopic ultrasound (EUS), carcinoembryonic antigen (CEA) testing and cytology to manage incidental pancreatic cystic neoplasms (PCN); however, studies suggest a strategy including integrated molecular pathology (IMP) of cyst fluid may further aid in predicting risk of malignancy. Here, we evaluate several strategies for diagnosing and managing asymptomatic PCN using healthcare economic modeling. PATIENTS AND METHODS: A third-party-payer perspective Markov decision model examined four management strategies in a hypothetical cohort of 1000 asymptomatic patients incidentally found to have a 3 cm solitary pancreatic cystic lesion. Strategy I used cross-sectional imaging, recommended surgery only if symptoms or risk factors emerged. Strategy II considered patients for resection without initial EUS. Strategy III (EUS + CEA + Cytology) referred only those with mucinous cysts (CEA > 192 ng/mL) for resection. Strategy IV implemented IMP; a commercially available panel provided a "Benign," "Mucinous," or "Aggressive" classification based on the level of mutational change in cyst fluid. "Benign" and "Mucinous" patients were followed with surveillance; "Aggressive" patients were referred for resection. Quality-adjusted life-years (QALY), relative risk with 95 %CI, Number Needed to Treat (NNT), and incremental cost-effectiveness ratios were calculated. RESULTS: Strategy IV provided the greatest increase in QALY at nearly identical cost to the cheapest approach, Strategy I. Relative risk of malignancy compared to the current standard of care and nearest competing strategy, Strategy III, was 0.18 (95 %CI 0.06 - 0.53) with an NNT of 56 (95 %CI 34 - 120). CONCLUSIONS: Use of IMP was the most cost-effective strategy, supporting its routine clinical use.

Symptom Burden and Functional Gains in a Cancer Rehabilitation Unit.

BACKGROUND/AIMS: To determine if there is a relationship between patient symptoms and functional improvement on inpatient rehabilitation. METHODS: Retrospective review of medical records at an American tertiary referral-based cancer center of all patients admitted to an inpatient rehabilitation unit between 3/1/2013-5/20/2013. Main outcome measures included the Edmonton Symptom and Assessment Scale (ESAS) and Functional Independence Measure (FIM). FINDINGS: The medical records for 71 unique cancer rehabilitation inpatients were analyzed. Statistical analysis of total admission ESAS on total FIM change found no significant relationships. The symptom burden of the patients was mild. Patients demonstrated statistically significant improvements in function and symptoms during inpatient rehabilitation. The mean change in total FIM and total ESAS were an increase of 19.20 and decrease of 7.41 respectively. Statistically significant changes occurred in fatigue, sleep, pain, and anxiety. CONCLUSION: Both symptom and functional scores improved significantly during inpatient rehabilitation. However, no significant relationships were found between symptoms at admission and improvement in FIM.

Assessment of mutational load in biopsy tissue provides additional information about genomic instability to histological classifications of Barrett's esophagus.

PURPOSE: Progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is associated with accumulated genomic instability. Current risk stratification of BE for EAC relies on histological classification and grade of dysplasia. However, histology alone cannot assess the risk of patients with inconsistent or non-dysplastic BE histology. We, therefore, examined the presence and extent of genomic instability in advanced and less advanced BE histology using mutational load (ML). METHODS: ML summarized the presence and clonality of loss of heterozygosity (LOH) mutations and the emergence of new alleles, manifested as microsatellite instability (MSI) mutations, in ten genomic loci around tumor suppressor genes associated with EAC. The ML of 877 microdissected targets from BE biopsies was correlated to their histology. Histological targets were categorized into three levels: no ML, low ML, and high ML. RESULTS: Increasing ML correlated with increasingly severe histology. By contrast, proportions of targets that lacked mutations decreased with increasingly severe histology. A portion of targets with non-dysplastic and low-grade histology shared a similar ML as those with higher risk and EAC disease. The addition of MSI characterization to ML helped to differentiate the ML between advanced and less advanced histology. CONCLUSIONS: Given that EAC is associated with accumulated genomic instability, high ML in less severe histology may identify BE disease at greater risk of progression to EAC. ML may help to better manage BE in early histological stages and when histology alone provides insufficient information.

Frequency and reasons for return to the primary acute care service among patients with lymphoma undergoing inpatient rehabilitation.

OBJECTIVE: To assess the frequency and risk factors for return to the primary acute care service among patients with lymphoma undergoing inpatient rehabilitation. DESIGN: Retrospective study. SETTING: Tertiary referral-based cancer center. PATIENTS: All patients with a history of lymphoma admitted to an inpatient rehabilitation between October 1, 2003, and January 30, 2013. MAIN OUTCOME MEASURES: Items analyzed from patient records included return to the primary acute care service with demographic information, lymphoma characteristics, medications, hospital admission characteristics, and laboratory values. RESULTS: A total of 143 unique patient admissions were analyzed, and 54 of these 143 lymphoma inpatient rehabilitation admissions (38%) returned to the primary acute care service. However, 16 of 54 (30%) returned because they needed additional chemotherapy. Excluding patients who returned to the primary acute care service for chemotherapy, statistically significant or approaching statistically significant factors (P < .10) associated with return to the primary acute care service included a creatinine level ≥ 1.3 mg/dL (P = .0002), male gender (P = .001), history of hematopoietic stem cell transplantation (P = .0355), and presence of an intravenous antifungal agent (P = .0717). Of the patients transferred back to the primary acute care service, 13 of 38 (34%) were discharged directly home, 10 of 38 (26%) died in the hospital, 7 of 38 (18%) were transferred to a subacute rehabilitation facility, and 4 of 38 (11%) were transferred to inpatient rehabilitation. CONCLUSIONS: When excluding patients who returned for chemotherapy, patients with lymphoma who were male, had undergone hematopoietic stem cell transplantation, and had a creatinine level ≥ 1.3 mg/dL demonstrated increased risk for return to the primary acute care service.

Frequency and reasons for return to acute care in patients with leukemia undergoing inpatient rehabilitation: a preliminary report.

OBJECTIVE: The aim of this study was to assess the frequency and reasons for return to the primary acute care service among patients with leukemia undergoing inpatient rehabilitation. DESIGN: This is a retrospective study of all patients with leukemia, myelodysplastic syndrome, aplastic anemia, or myelofibrosis admitted to inpatient rehabilitation at a tertiary referral-based cancer center between January 1, 2005, and April 10, 2012. Items analyzed from patient records included return to the primary acute care service with demographic information, leukemia characteristics, medications, hospital admission characteristics, and laboratory values. RESULTS: Two hundred twenty-five patients were admitted a total of 255 times. Ninety-three (37%) of the 255 leukemia inpatient rehabilitation admissions returned to the primary acute care service. Eighteen (19%) and 42 (45%) of the 93 patients died in the hospital and were discharged home, respectively. Statistically significant factors (P < 0.05) associated with return to the primary acute care service include peripheral blast percentage and the presence of an antifungal agent on the day of the inpatient rehabilitation transfer. Using additional two factors (platelet count and the presence of an antiviral agent, both P < 0.11), the Return to Primary-Leukemia Index was formulated. CONCLUSIONS: Patients with leukemia with the presence of circulating peripheral blasts and/or an antifungal agent may be at increased risk for return to the primary acute care service. The Return to Primary-Leukemia Index should be tested in prospective studies to determine its usefulness.

Return to primary service among bone marrow transplant rehabilitation inpatients: an index for predicting outcomes.

OBJECTIVE: To assess rehabilitation inpatient risk of return to primary (RTP) service in patients with bone marrow transplant (BMT). DESIGN: Retrospective review. SETTING: Inpatient rehabilitation unit within a tertiary referral-based cancer center. PARTICIPANTS: All patients with BMT (131) who were admitted a total of 147 times to inpatient rehabilitation between January 1, 2002, and April 30, 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: We analyzed RTP service and demographic information, cancer characteristics, medications, hospital admission characteristics, and laboratory values. RESULTS: A total of 61 (41%) of 147 of BMT admissions were transferred from the inpatient rehabilitation unit back to the primary service. Of those transferred back, 23 (38%) of 61 died after being transferred back to the primary service. Significant or near-significant relationships were found for a platelet count of <43,000 per microliter (P<.01); a creatinine level of >0.9 milligrams/deciliter (P<.01); the presence of an antiviral agent (P=.0501); the presence of an antibacterial agent (P=.0519); the presence of an antifungal agent (P<.05); and leukemia, lymphoma, or multiple myeloma diagnosis (P<.05). Using 5 of these factors, the RTP-BMT index was formulated to determine the likelihood of return to the primary team. CONCLUSIONS: Patients with BMT have a high rate of transfer from the inpatient rehabilitation unit back to the primary service. The RTP-BMT index score can be a useful tool to help clinicians predict the likelihood of return to the primary acute care service.

Effect of exercise dosages on adiposity indices in overweight girls / Efecto de programas de ejercicio en los índices de adiposidad en niñas con sobrepeso

Objective. The primary purpose of this study was to determine the impact of two exercise dosages on reducing adiposity in minority girls. Materials and methods. Sixty-two overweight Hispanic and African-American girls participated in one of two intense summer interventions in Houston, TX: Intervention A (exposure to about 40 hours physical activities) or Intervention B (exposure to 60 hours of physical activities). Adiposity indices (percent body fat, waist circumference, body mass index) were taken pre- and post-intervention. Results. Intervention B had a significantly greater decrease in adiposity indicators (p= 0.006) when compared to Intervention A. Waist circumference displayed the most significant decrease (p = 0.001). Both interventions significantly increased daily minutes of moderate-to-vigorous physical activity (p= 0.020). Conclusions. Intense physical activity interventions may effectively reduce abdominal fat in minority girls.

Objetivo. Determinar el impacto de dos programas de ejercicio en la reducción de los índices de adiposidad en niñas de grupos minoritarios. Material y métodos. Sesenta y dos niñas latinas y africano-americanas participaron en una de dos intervenciones intensivas durante el verano: la intervención A (exposición a aproximadamente 40 horas de actividad física) o la intervención B (exposición a 60 horas de actividad física) en Houston, TX. Los indicadores de adiposidad (índice de masa corporal, porcentaje de grasa corporal y grasa abdominal) se midieron antes y después de cada intervención. Resultados. La intervención B tuvo una disminución más significativa en el nivel de adiposidad (p=0.006) comparado con la intervención A. La circunferencia abdominal fue la que más disminuyó (p=0.001). Ambas intervenciones aumentaron significativamente la actividad física moderada a intensa (p=0.020). Conclusiones. Las intervenciones cortas e intensas pueden ser efectivas en la reducción de la grasa abdominal en niñas de grupos minoritarios.

Correlation of the presence and extent of loss of heterozygosity mutations with histological classifications of Barrett's esophagus.

BACKGROUND: Recent advances in the management of Barrett's Esophagus (BE) have placed greater emphasis on accurate diagnosis of BE as well as better prediction of risk for progression to esophageal adenocarcinoma (EAC). Histological evaluation of BE is particularly challenging with significant inter-observer variability. We explored the presence and extent of genomic instability in BE biopsy specimens as a means to add supplementary information to the histological classification and clinical decision-making related to early disease. METHODS: We reviewed histology slides from 271 patients known to have BE. Using histological features as a guide, we microdissected target cell populations with various histological classifications of BE (intestinal metaplasia, "indefinite for dysplasia", low grade dysplasia, or high grade dysplasia). DNA was extracted from microdissected targets and analyzed for loss of heterozygosity (LOH) using a panel of 16 LOH mutational markers associated with tumor suppressor genes at chromosomal loci 1p, 3p, 5q, 9p, 10q, 17p, 17q, 18q, 21q, 22q. The presence or absence of mutations and the clonality of each mutation were determined for each marker. RESULTS: The presence and clonal expansion of LOH mutations was formulated into mutational load (ML) for each microdissected target analyzed. ML correlated with the histological classification of microdissected targets, with increasingly severe histology having higher ML. Three levels of mutation load (no ML, low ML, and high ML) were defined based on the population of microdissected targets histologically classified as intestinal metaplasia. All microdissected targets with dysplasia had mutations, with a high ML consistently present in high grade dysplasia targets. Microdissected targets histologically classified as intestinal metaplasia or "indefinite for dysplasia" spanned a range of no, low, and high ML. CONCLUSIONS: The results of this study reinforce the association of genomic instability with disease progression in BE. The presence and extent (clonality) of genomic instability, as assessed by mutational load, may assist histology in defining early stages of BE that are potentially at greater risk for disease progression. Assessment of mutational load using our panel of LOH mutational markers may be a useful adjunct to microscopic inspection of biopsy specimens, and thereby, improve patient management.

An exploration of transactional states and cessation-related social variables within adolescent smokers.

BACKGROUND: Given the high rate of adolescent smoking, cessation remains a vital public health priority. This study explored archival data using a structured phenomenological framework known as Reversal Theory (RT). In order to better understand aspects of adolescent tobacco use we compared the transactional, psychological states described by RT to the factor structure of adolescents' self-reported social environment influencing tobacco use. METHODS: In a two step analysis of questions about self-reported tobacco use cognitions, attitudes, and behaviors from youth enrolled during the 2003-2004 period in a Texas, state-wide, mandated tobacco cessation program (N=1807), four factors and 11 items were identified as significantly related to the influence of social context and adolescents' tobacco use. These first step results guided the items to be selected for further analysis. In step two the variables were subjected to a factor analysis using principal components extraction and varimax rotation. The resulting factor structure was compared and interpreted within the context of descriptions of RT transactional states. RESULTS: The analysis indicated that four factors were closely aligned to descriptions of the Reversal Theory transactional states and could be reinterpreted from within the framework of RT. The first factor included feelings of self-efficacy for quitting (autic mastery). The second and third transactional factors diverged between one factor to quit, and an opposing transactional factor to continue to smoke. Both of these transactional states are variants of the autocentric state where one wants to experience feelings of gain with the help of others. The fourth factor could be interpreted as 'confidence' or 'optimism'. CONCLUSIONS: This intra-individual conflict revealed by the opposition of factors two and three clarifies a paradoxical issue where an adolescent wants to quit smoking with social support in one setting yet in another social environment chooses to smoke to gain or retain peer acceptance. These data illustrate that adolescent' self-identified quit skills and social support structures are important to the quitting process. This exploratory investigation has important implications for addressing RT state reversals in youth cessation programming activities.

Grafting of chain-end-functionalized perfluorocyclobutyl (PFCB) aryl ether ionomers onto mesoporous carbon supports.

Water-soluble perfluorocyclobutyl (PFCB) aryl ether ionomers bearing sulfonic acid groups in the main chain and phosphonic acid end groups were prepared and used to modify the surfaces of mesoporous carbon materials containing dispersed zirconia nanoparticles. Ionomer surface grafting occurred via phosphonate bonding onto the zirconia particle surfaces.

Mutational profiling of sporadic versus toxin-associated brain cancer formation: initial findings using loss of heterozygosity profiling.

The role of environmental and occupational toxin exposure as a cause of or contributing factor for cancer development and progression is incompletely understood. A unique signature of specific mutational change to discriminate toxin-exposed from sporadic cancer is generally sought but not often encountered. We report an approach to better understand cancer causality based on the measurement of the cumulative DNA damage (via loss of heterozygosity) over a defined genomic region (chromosome 3) that is applicable to archival, fixative-treated tissue and cytology specimens of cancer. Our method was applied to (1) a cohort of 10 brain tumor subjects (9 gliomas, 1 hemangioblastoma) with potential exposure to chlorinated solvents and (2) a control cohort of sporadic brain cancer controls (7 gliomas, 1 hemangioblastoma). We show that brain tumors arising in potentially toxin-exposed subjects bear a significantly higher level of passenger LOH mutations compared to sporadic cancer controls. The methodology utilized tissue microdissection, PCR amplification and capillary electrophoresis (fragment analysis for LOH determination, DNA sequencing for specific point mutations), and examined a panel of 15 microsatellite markers distributed along both arms of chromosome 3 that aimed at capturing passenger mutational change accrued during stages of clonal expansion of neoplastic cells. This proof-of-principle study using mutational profiling for passenger LOH mutational damage provides support for the utility of this approach and further studies in order to differentiate between genotoxin-associated versus sporadic (unexposed) cancer development.

P-glycoprotein related drug interactions: clinical importance and a consideration of disease states.

IMPORTANCE OF THE FIELD: P-glycoprotein (P-gp) is the most characterized drug transporter in terms of its clinical relevance for pharmacokinetic disposition and interaction with other medicines. Clinically significant P-gp related drug interactions appear restricted to digoxin. P-gp may act as a major barrier to current and effective drug treatment in a number of diseases including cancer, AIDS, Alzheimer's and epilepsy due to its expression in tumors, lymphocytes, cell membranes of brain capillaries and the choroid plexus. AREAS COVERED IN THIS REVIEW: This review summarizes the current understanding of P-gp structure/function, clinical importance of P-gp related drug interactions and the modulatory role this transporter may contribute towards drug efficacy in disease states such as cancer, AIDS, Alzheimer's and epilepsy. WHAT THE READER WILL GAIN: The reader will gain an understanding that the clinical relevance of P-gp in drug interactions is limited. In certain disease states, P-gp in barrier tissues can modulate changes in regional distribution. TAKE HOME MESSAGE: P-gp inhibition in isolation will not result in clinically important alterations in systemic exposure; however, P-gp transport may be of significance in barrier tissues (tumors, lymphocytes, brain) resulting in attenuated efficacy.