Primary mesenchymal stromal cells in co-culture with leukaemic HL-60 cells are sensitised to cytarabine-induced genotoxicity, while leukaemic cells are protected.

Tumour microenvironments are hallmarked in many cancer types. In haematological malignancies, bone marrow (BM) mesenchymal stromal cells (MSC) protect malignant cells from drug-induced cytotoxicity. However, less is known about malignant impact on supportive stroma. Notably, it is unknown whether these interactions alter long-term genotoxic damage in either direction. The nucleoside analogue cytarabine (ara-C), common in haematological therapies, remains the most effective agent for acute myeloid leukaemia, yet one-third of patients develop resistance. This study aimed to evaluate the bidirectional effect of MSC and malignant cell co-culture on ara-C genotoxicity modulation. Primary MSC, isolated from patient BM aspirates for haematological investigations, and malignant haematopoietic cells (leukaemic HL-60) were co-cultured using trans-well inserts, prior to treatment with physiological dose ara-C. Co-culture genotoxic effects were assessed by micronucleus and alkaline comet assays. Patient BM cells from chemotherapy-treated patients had reduced ex vivo survival (P = 0.0049) and increased genotoxicity (P = 0.3172) than untreated patients. It was shown for the first time that HL-60 were protected by MSC from ara-C-induced genotoxicity, with reduced MN incidence in co-culture as compared to mono-culture (P = 0.0068). Comet tail intensity also significantly increased in ara-C-treated MSC with HL-60 influence (P = 0.0308). MSC sensitisation to ara-C genotoxicity was also demonstrated following co-culture with HL60 (P = 0.0116), which showed significantly greater sensitisation when MSC-HL-60 co-cultures were exposed to ara-C (P = 0.0409). This study shows for the first time that malignant HSC and MSC bidirectionally modulate genotoxicity, providing grounding for future research identifying mechanisms of altered genotoxicity in leukaemic microenvironments. MSC retain long-term genotoxic and functional damage following chemotherapy exposure. Understanding the interactions perpetuating such damage may inform modifications to reduce therapy-related complications, such as secondary malignancies and BM failure.

SELF BLOOD GLUCOSE MONITORING UNDERESTIMATES HYPERGLYCEMIA AND HYPOGLYCEMIA AS COMPARED TO CONTINUOUS GLUCOSE MONITORING IN TYPE 1 AND TYPE 2 DIABETES.

OBJECTIVE: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM). METHODS: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2™ system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators. RESULTS: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approximately 25 mg/dL higher in both T1DM ( P = .0232) and T2DM ( P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM ( P = .0005) and 55 mg/dL lower in T2DM ( P<.0001). HgBA1c correlated with the highest and average glucose by SBGM and CGM. The lowest glucose values were seen most frequently during sleep and before breakfast; the highest were seen during the evening and postprandially. CONCLUSION: SBGM accurately estimates the average glucose but underestimates glucose excursions. CGM uncovers glucose patterns that common SBGM patterns cannot. ABBREVIATIONS: CDE = certified diabetes educator; CGM = continuous glucose monitoring; HgBA1c = glycosylated hemoglobin; MAD = mean absolute difference; SBGM = self blood glucose monitoring; T1DM = type 1 diabetes; T2DM = type 2 diabetes.

Nutritional interventions in primary mitochondrial disorders: Developing an evidence base.

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

The Health Status of Women with Children Living in Public and Assisted Housing: Linkage of the National Health Interview Survey to U.S. Department of Housing and Urban Development Administrative Data.

For more than a decade, the U.S. Department of Housing and Urban Development (HUD) and the National Center for Health Statistics (NCHS) have partnered to link NCHS national health survey data with HUD administrative records on persons participating in federal public and assisted housing programs. This study used 2015-18 National Health Interview Survey (NHIS)-HUD linked data to examine women 18-44 years old with children and renting their home who were receiving HUD assistance (n=852) and a comparison population of women of the same age with children, who were low-income renters but did not link to HUD records at the time of their NHIS interview (n=894). The population of HUD-assisted women differed from the comparison group on key sociodemographic characteristics and health indicators. HUD-assisted women were more likely to report their health as fair or poor and to being a current smoker. HUD-assisted women also were less likely to be uninsured and more likely to have a regular source of care. The findings in this article are exploratory but demonstrate how the NCHS-HUD-linked data can be a resource for researchers and policymakers in further examining housing status as an important social determinant of health.

Prevalence of multiple chronic conditions among Medicare beneficiaries, United States, 2010.

INTRODUCTION: The increase in chronic health conditions among Medicare beneficiaries has implications for the Medicare system. The objective of this study was to use the US Department of Health and Human Services Strategic Framework on multiple chronic conditions as a basis to examine the prevalence of multiple chronic conditions among Medicare beneficiaries. ANALYSIS: We analyzed Centers for Medicare and Medicaid Services administrative claims data for Medicare beneficiaries enrolled in the fee-for-service program in 2010. We included approximately 31 million Medicare beneficiaries and examined 15 chronic conditions. A beneficiary was considered to have a chronic condition if a Medicare claim indicated that the beneficiary received a service or treatment for the condition. We defined the prevalence of multiple chronic conditions as having 2 or more chronic conditions. RESULTS: Overall, 68.4% of Medicare beneficiaries had 2 or more chronic conditions and 36.4% had 4 or more chronic conditions. The prevalence of multiple chronic conditions increased with age and was more prevalent among women than men across all age groups. Non-Hispanic black and Hispanic women had the highest prevalence of 4 or more chronic conditions, whereas Asian or Pacific Islander men and women, in general, had the lowest. SUMMARY: The prevalence of multiple chronic conditions among the Medicare fee-for-service population varies across demographic groups. Multiple chronic conditions appear to be more prevalent among women, particularly non-Hispanic black and Hispanic women, and among beneficiaries eligible for both Medicare and Medicaid benefits. Our findings can help public health researchers target prevention and management strategies to improve care and reduce costs for people with multiple chronic conditions.

A Comparison of the Mortality Experience of U.S. Adults Estimated With the 2006-2018 National Health Interview Survey Linked Mortality Files and the Annual U.S. Life Tables.

Objective-Linking data is a powerful mechanism to provide policy-relevant information. The National Center for Health Statistics' Data Linkage Program produces linked mortality files (LMFs) for research by linking data from the National Center for Health Statistics' surveys, including the National Health Interview Survey (NHIS), to mortality data from the National Death Index. Assessing the accuracy of the linked data is an important step in ensuring its analytic use. This report compares the cumulative survival probabilities estimated with the 2006-2018 NHIS LMFs to those from the annual U.S. life tables.

A convergent functional architecture of the insula emerges across imaging modalities.

Empirical evidence increasingly supports the hypothesis that patterns of intrinsic functional connectivity (iFC) are sculpted by a history of evoked coactivation within distinct neuronal networks. This, together with evidence of strong correspondence among the networks defined by iFC and those delineated using a variety of other neuroimaging techniques, suggests a fundamental brain architecture detectable across multiple functional and structural imaging modalities. Here, we leverage this insight to examine the functional organization of the human insula. We parcellated the insula on the basis of three distinct neuroimaging modalities - task-evoked coactivation, intrinsic (i.e., task-independent) functional connectivity, and gray matter structural covariance. Clustering of these three different covariance-based measures revealed a convergent elemental organization of the insula that likely reflects a fundamental brain architecture governing both brain structure and function at multiple spatial scales. While not constrained to be hierarchical, our parcellation revealed a pseudo-hierarchical, multiscale organization that was consistent with previous clustering and meta-analytic studies of the insula. Finally, meta-analytic examination of the cognitive and behavioral domains associated with each of the insular clusters obtained elucidated the broad functional dissociations likely underlying the topography observed. To facilitate future investigations of insula function across healthy and pathological states, the insular parcels have been made freely available for download via http://fcon_1000.projects.nitrc.org, along with the analytic scripts used to perform the parcellations.

Feasibility of a secondary school-based mental health intervention: Reprezents' On The Level.

AIMS: There is a need for innovative school-based mental health interventions to promote good mental health, healthy coping strategies, and engagement with support services. Consequently, Reprezent, a youth development organization, with mental health professionals and young people co-developed an online mental health intervention show, On The Level (OTL). This study assessed the acceptability and feasibility of delivering OTL to young people (aged 11-18 years) in 36 secondary schools across London and Essex, UK. METHODS: OTL was delivered online as part of the school curriculum, in classrooms at timepoint 1 (T1, 50 min). Follow-up data was collected at timepoint 2 (T2) 4-6 weeks later, during a 20-min OTL review show. For interactive OTL elements and data collection participants logged into an online survey. Measures of acceptability and engagement, mental health and well-being outcomes and intervention evaluation were taken at T1 and T2. We also assessed the feasibility of implementing the OTL intervention in secondary schools. RESULTS: 10,315 participants received the intervention (T1) and 3369 attended the follow-up session (T2), this high attrition, and potential selection bias, was due to only 30% of schools being able to take part in T2. Rates of acceptability were high among young people and school staff. At T1, 88% found OTL engaging, and 84% felt more confident they had the tools to help them better manage stress and anxiety. At T2, 66% viewed mental health in a more positive way, and 71% had better understanding of how to maintain good mental health. Rates of engagement with mental health tools and services were good, and significant reduction in levels of stress were found 4-6 weeks after the OTL show (T2). The low mental health and well-being indices reported by the school children at baseline strongly support the need and use for a mental health intervention such as OTL in secondary schools. CONCLUSION: These findings indicated good feasibility and acceptability of OTL intervention and support the delivery of the OTL mental health intervention at UK-based secondary schools to educate young people about mental health and well-being and give them the necessary tools to support their mental health.

A methodological assessment of privacy preserving record linkage using survey and administrative data.

BACKGROUND: The National Center for Health Statistics (NCHS) links data from surveys to administrative data sources, but privacy concerns make accessing new data sources difficult. Privacy-preserving record linkage (PPRL) is an alternative to traditional linkage approaches that may overcome this barrier. However, prior to implementing PPRL techniques it is important to understand their effect on data quality. METHODS: Results from PPRL were compared to results from an established linkage method, which uses unencrypted (plain text) identifiers and both deterministic and probabilistic techniques. The established method was used as the gold standard. Links performed with PPRL were evaluated for precision and recall. An initial assessment and a refined approach were implemented. The impact of PPRL on secondary data analysis, including match and mortality rates, was assessed. RESULTS: The match rates for all approaches were similar, 5.1% for the gold standard, 5.4% for the initial PPRL and 5.0% for the refined PPRL approach. Precision ranged from 93.8% to 98.9% and recall ranged from 98.7% to 97.8%, depending on the selection of tokens from PPRL. The impact of PPRL on secondary data analysis was minimal. DISCUSSION: The findings suggest PPRL works well to link patient records to the National Death Index (NDI) since both sources have a high level of non-missing personally identifiable information, especially among adults 65 and older who may also have a higher likelihood of linking to the NDI. CONCLUSION: The results from this study are encouraging for first steps for a statistical agency in the implementation of PPRL approaches, however, future research is still needed.

Using Synthetic Data to Replace Linkage Derived Elements: A Case Study.

While record linkage can expand analyses performable from survey microdata, it also incurs greater risk of privacy-encroaching disclosure. One way to mitigate this risk is to replace some of the information added through linkage with synthetic data elements. This paper describes a case study using the National Hospital Care Survey (NHCS), which collects patient records under a pledge of protecting patient privacy from a sample of U.S. hospitals for statistical analysis purposes. The NHCS data were linked to the National Death Index (NDI) to enhance the survey with mortality information. The added information from NDI linkage enables survival analyses related to hospitalization, but as the death information includes dates of death and detailed causes of death, having it joined with the patient records increases the risk of patient re-identification (albeit only for deceased persons). For this reason, an approach was tested to develop synthetic data that uses models from survival analysis to replace vital status and actual dates-of-death with synthetic values and uses classification tree analysis to replace actual causes of death with synthesized causes of death. The degree to which analyses performed on the synthetic data replicate results from analysis on the actual data is measured by comparing survival analysis parameter estimates from both data files. Because synthetic data only have value to the degree that they can be used to produce statistical estimates that are like those based on the actual data, this evaluation is an essential first step in assessing the potential utility of synthetic mortality data.

Using supervised machine learning to identify efficient blocking schemes for record linkage.

Record linkage enables survey data to be integrated with other data sources, expanding the analytic potential of both sources. However, depending on the number of records being linked, the processing time can be prohibitive. This paper describes a case study using a supervised machine learning algorithm, known as the Sequential Coverage Algorithm (SCA). The SCA was used to develop the join strategy for two data sources, the National Center for Health Statistics' (NCHS) 2016 National Hospital Care Survey (NHCS) and the Center for Medicare & Medicaid Services (CMS) Enrollment Database (EDB), during record linkage. Due to the size of the CMS data, common record joining methods (i.e. blocking) were used to reduce the number of pairs that need to be evaluated to identify the vast majority of matches. NCHS conducted a case study examining how the SCA improved the efficiency of blocking. This paper describes how the SCA was used to design the blocking used in this linkage.

Assessing Linkage Eligibility Bias in the National Health Interview Survey.

Background Linking health survey data to administrative records expands the analytic utility of survey participant responses, but also creates the potential for new sources of bias when not all participants are eligible for linkage. Residual differences-bias-can occur between estimates made using the full survey sample and the subset eligible for linkage. Objective To assess linkage eligibility bias and provide examples of how bias may be reduced by changes in questionnaire design and adjustment of survey weights for linkage eligibility. Methods Linkage eligibility bias was estimated for various sociodemographic groups and health-related variables for the 2000-2013 National Health Interview Surveys. Conclusions Analysts using the linked data should consider the potential for linkage eligibility bias when planning their analyses and use approaches to reduce bias, such as survey weight adjustments, when appropriate.

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy.

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.

Comparative Analysis of the National Health Interview Survey Public-use and Restricted-use Linked Mortality Files.

Linking national survey data with administrative data sources enables researchers to conduct analyses that would not be possible with each data source alone. Recently, the Data Linkage Program at the National Center for Health Statistics (NCHS) released updated linked mortality files, including the National Health Interview Survey data linked to the National Death Index mortality files. Two versions of the files were released: restricted-use files available through NCHS and Federal Statistical Research Data Centers and public-use files. To reduce the reidentification risk, statistical disclosure limitation methods were applied to the public-use files before they were released. This included limiting the amount of mortality information available and perturbing cause of death and follow-up time for select records. To assess the comparability of the restricted-use and public-use files, relative hazard ratios for all-cause and cause-specific mortality using Cox proportional hazards models were estimated and compared. The comparative analysis found that the two data files yielded very similar descriptive and model results.

The public-use National Health Interview Survey linked mortality files: methods of reidentification risk avoidance and comparative analysis.

The National Center for Health Statistics (NCHS) conducts mortality follow-up for its major population-based surveys. In 2004, NCHS updated the mortality follow-up for the 1986-2000 National Health Interview Survey (NHIS) years, which because of confidentiality protections was made available only through the NCHS Research Data Center. In 2007, NCHS released a public-use version of the NHIS Linked Mortality Files that includes a limited amount of perturbed information for decedents. The modification of the public-use version included conducting a reidentification risk scenario to determine records at risk for reidentification and then imputing values for either date or cause of death for a select sample of records. To demonstrate the comparability between the public-use and restricted-use versions of the linked mortality files, the authors estimated relative hazards for all-cause and cause-specific mortality risk using a Cox proportional hazards model. The pooled 1986-2000 NHIS Linked Mortality Files contain 1,576,171 records and 120,765 deaths. The sample for the comparative analyses included 897,232 records and 114,264 deaths. The comparative analyses show that the two data files yield very similar results for both all-cause and cause-specific mortality. Analytical considerations when examining cause-specific analyses of numerically small demographic subgroups are addressed.

Mortality experience of the 1986-2000 National Health Interview Survey Linked Mortality Files participants.

The National Center for Health Statistics (NCHS) has produced the 1986-2000 National Health Interview Survey (NHIS) Linked Mortality Files by linking eligible adults in the 1986-2000 NHIS cohorts through probabilistic record linkage to the National Death Index to obtain mortality follow-up through December 31, 2002. The resulting files contain more than 120,000 deaths and an average of 9 years of survival time. To assess how well mortality was ascertained in the linked mortality files, NCHS has conducted a comparison of the mortality experience of the 1986-2000 NHIS cohorts with that of the U.S. population. This report presents the results of this comparative mortality assessment. Methods The survival of each annual NHIS cohort was compared with that of the U.S. population during the same period. Cumulative survival probabilities for each annual NHIS cohort were derived using the Kaplan-Meier product limit method, and corresponding cumulative survival probabilities were computed for the U.S. population using information from annual U.S. life tables. The survival probabilities were calculated at various lengths of follow-up for each age-race-sex group of each NHIS cohort and for the U.S. population. Results As expected, mortality tended to be underestimated in the NHIS cohorts because the sample includes only civilian, noninstitutionalized persons, but this underestimation generally was not statistically significant. Statistically significant differences increased with length of follow-up, occurred more often for white females than for the other race-sex groups, and occurred more often in the oldest age groups. In general, the survival experience of the age-race-sex groups of each NHIS cohort corresponds quite closely to that of the U.S. population, providing support that the ascertainment of mortality through the probabilistic record linkage accurately reflects the mortality experience of the NHIS cohorts.

Hippocampal activation during episodic and semantic memory retrieval: comparing category production and category cued recall.

Whether or not the hippocampus participates in semantic memory retrieval has been the focus of much debate in the literature. However, few neuroimaging studies have directly compared hippocampal activation during semantic and episodic retrieval tasks that are well matched in all respects other than the source of the retrieved information. In Experiment 1, we compared hippocampal fMRI activation during a classic semantic memory task, category production, and an episodic version of the same task, category cued recall. Left hippocampal activation was observed in both episodic and semantic conditions, although other regions of the brain clearly distinguished the two tasks. Interestingly, participants reported using retrieval strategies during the semantic retrieval task that relied on autobiographical and spatial information; for example, visualizing themselves in their kitchen while producing items for the category kitchen utensils. In Experiment 2, we considered whether the use of these spatial and autobiographical retrieval strategies could have accounted for the hippocampal activation observed in Experiment 1. Categories were presented that elicited one of three retrieval strategy types, autobiographical and spatial, autobiographical and nonspatial, and neither autobiographical nor spatial. Once again, similar hippocampal activation was observed for all three category types, regardless of the inclusion of spatial or autobiographical content. We conclude that the distinction between semantic and episodic memory is more complex than classic memory models suggest.

Relationship between medication adherence and treatment outcomes: the COMBINE study.

BACKGROUND: Within the alcoholism field, there is mounting evidence supporting an important relationship between medication adherence and drinking outcomes. Little is known however, about the complex relationships between medication and treatment variables and drinking outcomes. The present paper reports on the differential impact of medication adherence and treatment factors on drinking outcomes. Data derived from the COMBINE Study was used to investigate the interrelationships between medication adherence, combination treatments and drinking outcomes. METHODS: Twelve hundred and twenty-six patients were randomized to 1 of 8 different combination treatments involving 2 medications--naltrexone and acamprosate and placebo, and 2 behavioral treatments--medical management (MM) and combined behavioral intervention (CBI). Two primary drinking outcomes were percent days abstinent (PDA) and time to first heavy drinking day. Medication adherence was defined as a proportion that reflects the number of pills taken by the maximum number of pills expected to be taken over the course of the trial. A generalized linear mixed model was used to estimate the effects of adherence on PDA while proportional hazards model was used to examine similar co-variate effects on time to first heavy drinking day. RESULTS: Concerning time to first heavy drinking day, a significant three-way interaction was found between medication adherence, CBI and naltrexone (p = 0.0160). Within the MM only plus placebo group (no CBI), significant differences were found in "recovery" (i.e., no heavy drinking days) rates between adherers and nonadherers (40% vs. 10%, p < 0.0001). Such differences became nonsignificant (p = 0.12) when CBI was introduced into the relationship. CBI did not add any such advantage to naltrexone-treated patients. CONCLUSIONS: CBI might serve a protective function for nonadherers in the placebo group; the median relapse time was reduced when these nonadherers were exposed to the alcohol specialty intervention. CBI offered little additional benefit to nonadherers in the naltrexone group. Among nonadherers in the naltrexone group, relapse rates appear to be more a function of inadequate exposure to the active medication and less influenced by CBI.

Beyond sexual abuse: the impact of other maltreatment experiences on sexualized behaviors.

This study sought to broaden research findings linking maltreatment to sexualized behaviors by investigating whether maltreatment experiences other than sexual abuse predict such behaviors. The sample included 690 children without reported sexual abuse histories who are participants in the LONGSCAN Consortium, a prospective multisite investigation of childhood maltreatment. Child Protective Service reports before age 8 years and caregiver reports on the Child Sexual Behavior Inventory-II at age 8 years were used to examine the relationship between maltreatment timing and type, and sexualized behaviors. Logistic regression analyses suggested that early (< 4) and late (4-8) reports of physical abuse were associated with more sexualized behaviors (odds ratios = 1.9-2.6). The pattern differed by gender, with physical abuse predicting sexual intrusiveness and displaying private parts in boys, and boundary problems in girls. Findings suggest that maltreatment other than sexual abuse, and the developmental periods in which it occurs, may be linked to the development of sexualized behaviors.

SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity: part 2: efficacy evaluations.

Pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. In addition, SJG-136 is highly active in vivo in hollow fiber assays. In the current investigation, SJG-136 was evaluated for in vivo efficacy in 10 tumor models selected on the basis of sensitivity of cells grown in the hollow fiber and in vitro time course assays: LOX IMVI and UACC-62 (melanomas); OVCAR-3 and OVCAR-5 (ovarian carcinomas); MDA-MB-435 (breast carcinoma); SF-295 and C-6 (gliomas); LS-174T (colon carcinoma); HL-60 TB (promyelocytic leukemia); and NCI-H522 (lung carcinoma). SJG-136 was active against small (150 mg) and large (250-400 mg) xenografts with tumor mass reductions in all 10 models. In addition, significant growth delays occurred in nine models, cell kill in six models ranged between 1.9 and 7.2 logs, and there were 1 to 4/6 tumor-free responses in six models. SJG-136 is active following i.v. bolus injections, as well as by 5-day continuous infusions. Of all of the schedules tested, bolus administrations for 5 consecutive days (qd x 5) conferred the greatest efficacy. SJG-136 is active over a wide dosage range in athymic mouse xenografts: on a qd x 5 schedule, the maximum-tolerated dose was approximately 120 microg/kg/dose (total dose: 0.6 mg/kg = 1.8 mg/m2) and the minimum effective dose in the most sensitive model (SF-295) was approximately 16 microg/kg/dose (total dose: 0.08 mg/kg = 0.24 mg/m2). Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, which are planned to commence shortly.