Challenges and recommendations to improve institutional review boards' review of community-engaged research proposals: A scoping review.

Academic and community investigators conducting community-engaged research (CEnR) are often met with challenges when seeking Institutional Review Board (IRB) approval. This scoping review aims to identify challenges and recommendations for CEnR investigators and community partners working with IRBs. Peer-reviewed articles that reported on CEnR, specified study-related challenges, and lessons learned for working with IRBs and conducted in the United States were included for review. Fifteen studies met the criteria and were extracted for this review. Four challenges identified (1) Community partners not being recognized as research partners (2) Cultural competence, language of consent forms, and literacy level of partners; (3) IRBs apply formulaic approaches to CEnR; & (4) Extensive delays in IRB preparation and approval potentially stifle the relationships with community partners. Recommendations included (1) Training IRBs to understand CEnR principles to streamline and increase the flexibility of the IRB review process; (2) Identifying influential community stakeholders who can provide support for the study; and (3) Disseminating human subjects research training that is accessible to all community investigator to satisfy IRB concerns. Findings from our study suggest that IRBs can benefit from more training in CEnR requirements and methodologies.

A Novel off-the-Shelf Trastuzumab-Armed NK Cell Therapy (ACE1702) Using Antibody-Cell-Conjugation Technology.

Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and showed enhanced T cell-recruiting capability and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.

Effectiveness of a Disability Preventive Intervention for Minority and Immigrant Elders: The Positive Minds-Strong Bodies Randomized Clinical Trial.

OBJECTIVE: To test the acceptability and effectiveness of a disability prevention intervention, Positive Minds-Strong Bodies (PMSB), offered by paraprofessionals to mostly immigrant elders in four languages. DESIGN: Randomized trial of 307 participants, equally randomized into intervention or enhanced usual care. SETTING: Community-based organizations in Massachusetts, New York, Florida, and Puerto Rico serving minority elders. Data collected at baseline, 2, 6, and 12 months, between May 2015 and March 2019. PARTICIPANTS: English-, Spanish-, Mandarin-, or Cantonese-speaking adults, age 60+, not seeking disability prevention services, but eligible per elevated mood symptoms and minor to moderate physical dysfunction. INTERVENTIONS: Ten individual sessions of cognitive behavioral therapy (PM) concurrently offered with 36 group sessions of strengthening exercise training (SB) over 6 months compared to enhanced usual care. MEASUREMENTS: Acceptability defined as satisfaction and attendance to >50% of sessions. Effectiveness determined by changes in mood symptoms (HSCL-25 and GAD-7), functional performance (SPPB), self-reported disability (LLFDI), and disability days (WHODAS 2.0). RESULTS: Around 77.6% of intervention participants attended over half of PM Sessions; 53.4% attended over half of SB sessions. Intent-to-treat analyses at 6 months showed significant intervention effects: improved functioning per SPPB and LLFDI, and lowered mood symptoms per HSCL-25. Intent-to-treat analyses at 12 months showed that effects remained significant for LLFDI and HSCL-25, and disability days (per WHODAS 2.0) significantly decreased 6-month after the intervention. CONCLUSIONS: PMSB offered by paraprofessionals in community-based organizations demonstrates good acceptability and seems to improve functioning, with a compliance-benefit effect showing compliance as an important determinant of the intervention response.

Dabrafenib Plus Trametinib for BRAF V600E-Mutant Non-small Cell Lung Cancer: A Patient Case Report.

Dabrafenib plus trametinib is US Food and Drug Administration approved combination therapy for use in patients with BRAF V600E-mutant non-small cell lung cancer, but information on use outside of clinical trials is limited. We report the case of a 70-year-old Asian woman (never smoker) who was diagnosed with lung adenocarcinoma in May 2014. Testing at diagnosis was negative for programmed death ligand 1 or EGFR, ALK, and ROS1 alterations. She was started on carboplatin-pemetrexed-bevacizumab and maintenance bevacizumab but progressed in September 2015. Subsequently, she progressed on second-line nivolumab and third-line docetaxel. In March 2016, pleural fluid obtained at diagnosis tested positive for the BRAF V600E mutation and she received dabrafenib plus trametinib. She experienced rapid tumor shrinkage and symptom improvement and became able to participate in regular daily activities with no notable adverse events. In December 2016, she died from a hemorrhagic stroke considered unrelated to treatment. In this heavily pretreated patient with non-small cell lung cancer, dabrafenib plus trametinib elicited an excellent response.

Development and Assessment of a Helicobacter pylori Medication Adherence and Stomach Cancer Prevention Curriculum for a Chinese American Immigrant Population.

Chinese American immigrants are at increased risk for Helicobacter pylori infection and stomach cancer. Despite their increased risk, very few prevention strategies exist which target this vulnerable population. The purpose of this article is to present the stakeholder engaged development, review, assessment, refinement, and finalization of a H. pylori treatment adherence and stomach cancer prevention curriculum specifically designed to engage vulnerable, limited English proficient Chinese Americans in New York City.

Suspect screening of maternal serum to identify new environmental chemical biomonitoring targets using liquid chromatography-quadrupole time-of-flight mass spectrometry.

The use and advantages of high-resolution mass spectrometry (MS) as a discovery tool for environmental chemical monitoring has been demonstrated for environmental samples but not for biological samples. We developed a method using liquid chromatography-quadrupole time-of-flight MS (LC-QTOF/MS) for discovery of previously unmeasured environmental chemicals in human serum. Using non-targeted data acquisition (full scan MS analysis) we were able to screen for environmental organic acids (EOAs) in 20 serum samples from second trimester pregnant women. We define EOAs as environmental organic compounds with at least one dissociable proton which are utilized in commerce. EOAs include environmental phenols, phthalate metabolites, perfluorinated compounds, phenolic metabolites of polybrominated diphenyl ethers and polychlorinated biphenyls, and acidic pesticides and/or predicted acidic pesticide metabolites. Our validated method used solid phase extraction, reversed-phase chromatography in a C18 column with gradient elution, electrospray ionization in negative polarity and automated tandem MS (MS/MS) data acquisition to maximize true positive rates. We identified "suspect EOAs" using Agilent MassHunter Qualitative Analysis software, to match chemical formulas generated from each sample run with molecular formulas in our unique database of 693 EOAs assembled from multiple environmental literature sources. We found potential matches for 282 (41%) of the EOAs in our database. Sixty-five of these suspect EOAs were detected in at least 75% of the samples; only 19 of these compounds are currently biomonitored in National Health and Nutrition Examination Survey. We confirmed two of three suspect EOAs by LC-QTOF/MS using a targeted method developed through LC-MS/MS, reporting the first confirmation of benzophenone-1 and bisphenol S in pregnant women's sera. Our suspect screening workflow provides an approach to comprehensively scan environmental chemical exposures in humans. This can provide a better source of exposure information to help improve exposure and risk evaluation of industrial chemicals.

Direct measurement of Bisphenol A (BPA), BPA glucuronide and BPA sulfate in a diverse and low-income population of pregnant women reveals high exposure, with potential implications for previous exposure estimates: a cross-sectional study.

BACKGROUND: Bisphenol A (BPA) is a ubiquitous, endocrine-disrupting environmental contaminant that increases risk of some adverse developmental effects. Thus, it is important to characterize BPA levels, metabolic fate and sources of exposure in pregnant women. METHODS: We used an improved liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytic method to directly and simultaneously measure unconjugated BPA (uBPA), BPA glucuronide and BPA sulfate in the urine of a population of ethnically and racially diverse, and predominately low-income pregnant women (n = 112) in their second trimester. We also administered a questionnaire on dietary and non-dietary sources of exposure to BPA. RESULTS: We found universal and high exposure to uBPA and its metabolites: median concentrations were 0.25, 4.67, and 0.31 µg/g creatinine for uBPA, BPA glucuronide, and BPA sulfate, respectively. The median Total BPA (uBPA + BPA in glucuronide and sulfate forms) level was more than twice that measured in U.S. pregnant women in NHANES 2005-2006, while 30 % of the women had Total BPA levels above the 95th percentile. On average, Total BPA consisted of 71 % BPA in glucuronide form, 15 % BPA in sulfate form and 14 % uBPA, however the proportion of BPA in sulfate form increased and the proportion of uBPA decreased with Total BPA levels. Occupational and non-occupational contact with paper receipts was positively associated with BPA in conjugated (glucuronidated + sulfated) form after adjustment for demographic characteristics. Recent consumption of foods and beverages likely to be contaminated with BPA was infrequent among participants and we did not observe any positive associations with BPA analyte levels. CONCLUSION: The high levels of BPA analytes found in our study population may be attributable to the low-income status of the majority of participants and/or our direct analytic method, which yields a more complete evaluation of BPA exposure. We observed near-universal exposure to BPA among pregnant women, as well as substantial variability in BPA metabolic clearance, raising additional concerns for effects on fetal development. Our results are consistent with studies showing thermal paper receipts to be an important source of exposure, point to the difficulty pregnant women have avoiding BPA exposure on an individual level, and therefore underscore the need for changes in BPA regulation and commerce.

Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population.

Bisphenol-A (BPA) is an endocrine disrupting chemical used in numerous consumer products, resulting in universal exposure in the United States. Prenatal exposure to BPA is associated with numerous reproductive and developmental effects in animals. However, little is known about human fetal exposure or metabolism of BPA during midgestation. In the present study, we present a new liquid chromatography-tandem mass spectrometry method to directly measure concentrations of BPA and two predominant metabolic conjugates-BPA glucuronide and BPA sulfate-in umbilical cord serum collected from elective second trimester pregnancy terminations. We detected at least one form of BPA in all umbilical cord serum samples: BPA (GM 0.16, range

Phase I study of nelfinavir in liposarcoma.

PURPOSE: HIV protease inhibitors are associated with HIV protease inhibitor-related lipodystrophy syndrome. We hypothesized that liposarcomas would be similarly susceptible to the apoptotic effects of an HIV protease inhibitor, nelfinavir. METHODS: We conducted a phase I trial of nelfinavir for liposarcomas. There was no limit to prior chemotherapy. The starting dose was 1,250 mg twice daily (Level 1). Doses were escalated in cohorts of three to a maximally evaluated dose of 4,250 mg (Level 5). One cycle was 28 days. Steady-state pharmacokinetics (PKs) for nelfinavir and its primary active metabolite, M8, were determined at Levels 4 (3,000 mg) and 5. RESULTS: Twenty subjects (13 males) were enrolled. Median (range) age was 64 years (37-81). One subject at Level 1 experienced reversible, grade 3 pancreatitis after 1 week and was replaced. No other dose-limiting toxicities were observed. Median (range) number of cycles was 3 (0.6-13.5). Overall best responses observed were 1 partial response, 1 minor response, 4 stable disease, and 13 progressive disease. Mean peak plasma levels and AUCs for nelfinavir were higher at Level 4 (7.3 mg/L; 60.9 mg/L × h) than 5 (6.3 mg/L; 37.7 mg/L × h). The mean ratio of M8:nelfinavir AUCs for both levels was ~1:3. CONCLUSIONS: PKs demonstrate auto-induction of nelfinavir clearance at the doses studied, although the mechanism remains unclear. Peak plasma concentrations were within range where anticancer activity was demonstrated in vitro. M8 metabolite is present at ~1/3 the level of nelfinavir and may also contribute to the anticancer activity observed.

Recursion relations for the impedance of periodic layers.

Previous numerical work is extended by deriving simple analytic expressions for the impedance of periodic layers over a wide frequency range within the reflection stop band (not just the center Bragg frequency) for an arbitrary number of periods in the structure, for arbitrary layer thicknesses (not just quarter-wave layers), for sizable absorption, and for arbitrary sizes of the refractive index differences. When the number of periods in the structure is infinite, exact expressions for impedance, which are valid for all frequencies in the reflection stop band, are derived. For a finite number of periods in the structure, it is shown that the asymptotic approach of the impedance toward its value for an infinite structure has a decaying exponential dependence. It is shown that the characteristic number of periods in this decaying exponential dependence is determined by the condition number of the transverse field matrix. Simple analytic expressions for the phase shift throughout the reflection stop band are derived, as well as simple analytic expressions to show that a small fractional error in the VCSEL cavity mode frequency can still result from a large fractional error in the cavity thickness if the layers in the Bragg mirror have a small refractive index difference. These simple analytic expressions are useful for design.

Form and structure factors for impedance and reflection from periodic layers.

In an exact treatment of the Maxwell equations, we derive form and structure factors for reflection from periodic layers, and we show that these factors are significantly different from their analogs in kinematic x-ray diffraction. Quite generally, we show that reflection and impedance can be written precisely as the sum of an additive form factor and the product of a structure factor and a second form factor. This additive form factor does not have an analog in kinematic x-ray diffraction. It is demonstrated that the form factors are found by analytic continuation to an arbitrary wavelength of expressions for the impedance both at long wavelengths and at quarter wavelengths. A correction to the Bragg law relating fringe spacing to the total structure thickness is derived. We go beyond previous numerical work by deriving simple analytic exact expressions for reflection and impedance of periodic layers for all frequencies within the reflection passband, and for an arbitrary number of periods in the structure, an arbitrary index profile within each period, arbitrary layer thicknesses (not just quarter-wave layers), and for arbitrary sizes of the refractive index differences.

Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors.

Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.

Gallium arsenide deep-level optical emitter for fibre optics.

Fibre-optic components fabricated on the same substrate as integrated circuits are important for future high-speed communications. One industry response has been the costly push to develop indium phosphide (InP) electronics. However, for fabrication simplicity, reliability and cost, gallium arsenide (GaAs) remains the established technology for integrated optoelectronics. Unfortunately, the GaAs bandgap wavelength (0.85 microm) is far too short for fibre optics at 1.3-1.5 microm. This has led to work on materials that have a large lattice mismatch on GaAs. Here we demonstrate the first light-emitting diode (LED) that emits at 1.5 microm fibre-optic wavelengths in GaAs using optical transitions from arsenic antisite (As(Ga)) deep levels. This is an enabling technology for fibre-optic components that are lattice-matched to GaAs integrated circuits. We present experimental results showing significant internal optical power (24 mW) and speed (in terahertz) from GaAs optical emitters using deep-level transitions. Finally, we present theory showing the ultimate limit to the efficiency-bandwidth product of semiconductor deep-level optical emitters.