Phase I trial of a monoclonal antibody specific for alphavbeta3 integrin (MEDI-522) in patients with advanced malignancies, including an assessment of effect on tumor perfusion.

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.     

Accuracy and reliability of forensic handwriting comparisons

Forensic handwriting examination involves the comparison of writing samples by forensic document examiners (FDEs) to determine whether or not they were written by the same person. Here we report the results of a large-scale study conducted to assess the accuracy and reliability of handwriting comparison conclusions. Eighty-six practicing FDEs each conducted up to 100 handwriting comparisons, resulting in 7,196 conclusions on 180 distinct comparison sets, using a five-level conclusion scale. Erroneous “written by” conclusions (false positives) were reached in 3.1% of the nonmated comparisons, while 1.1% of the mated comparisons yielded erroneous “not written by” conclusions (false negatives). False positive rates were markedly higher for nonmated samples written by twins (8.7%) compared to nontwins (2.5%). Notable associations between training and performance were observed: FDEs with less than 2 y of formal training generally had higher error rates, but they also had higher true positive and true negative rates because they tended to provide more definitive conclusions; FDEs with at least 2 y of formal training were less likely to make definitive conclusions, but those definitive conclusions they made were more likely to be correct (higher positive predictive and negative predictive values). We did not observe any association between writing style (cursive vs. printing) and rates of errors or incorrect conclusions. This report also provides details on the repeatability and reproducibility of conclusions, and reports how conclusions are affected by the quantity of writing and the similarity of content.

Forensic science is under scrutiny, particularly for pattern-based disciplines in which source conclusions are reported. The National Research Council report Strengthening Forensic Science in the United States: A Path Forward (1) stated that “The scientific basis for handwriting comparisons needs to be strengthened” and noted that “there has been only limited research to quantify the reliability and replicability of the practices used by trained document examiners.” The President’s Council of Advisors on Science and Technology (PCAST) report Forensic Science in Criminal Courts: Ensuring Scientific Validity of Feature-Comparison Methods (2) expressed concerns regarding the validity and reliability of conclusions made by forensic examiners, and called for empirical testing: “The only way to establish the scientific validity and degree of reliability of a subjective forensic feature-comparison method—that is, one involving significant human judgment—is to test it empirically by seeing how often examiners actually get the right answer. Such an empirical test of a subjective forensic feature-comparison method is referred to as a ‘black-box test.’” The National Commission on Forensic Science also called for such testing (3). Although the accuracy and reliability of conclusions made by forensic document examiners (FDEs) have been the focus of multiple studies over the years (4–10), the designs of those studies are notably different from this study (and from PCAST’s recommendations), and therefore the resulting rates are not directly comparable (in particular, when comparing open-set to closed-set studies, comparing studies based on one-to-one vs. one-to-many examinations, and comparing studies that use notably different conclusion scales; see SI Appendix, Appendix B for a summary).This study was conducted to provide data that can be used to assess the scientific validity of handwriting comparisons, for use by policy makers, laboratory managers, the legal community, and FDEs. This study follows the approach used in the previous FBI Laboratory–Noblis latent print black box study (11) and later recommended by the PCAST report. The design utilizes open-set, one-to-one document comparisons to evaluate the conclusions reached by practicing FDEs when comparing writing samples selected to be broadly comparable to casework. The primary purposes of the study are to measure the accuracy of conclusions by FDEs when comparing handwriting samples and to assess reliability by measuring the reproducibility (interexaminer variability) and repeatability (intraexaminer variability) of those conclusions. Secondary purposes include reporting any associations between the accuracy of the decisions in this study, factors related to the participants (such as training or experience), and factors related to the samples (such as quantity of writing, comparability of content, limitations, or style of writing).     

Biochemical Modulation of Aracytidine (Ara-C) Effects by GTI-2040, a Ribonucleotide Reductase Inhibitor, in K562 Human Leukemia Cells

GTI-2040 is a potent antisense to the M2 subunit of the ribonucleotide reductase (RNR), an enzyme involved in the de novo synthesis of nucleoside triphosphates. We hypothesized that combination of GTI-2040 with the cytarabine (Ara-C) could result in an enhanced cytotoxic effect with perturbed intracellular deoxynucleotide/nucleotide (dNTP/NTP) pools including Ara-C triphosphate (Ara-CTP). This study aims to provide a direct experimental support of this hypothesis by monitoring the biochemical modulation effects, intracellular levels of Ara-CTP, dNTPs/NTPs following the combination treatment of Ara-C, and GTI-2040 in K562 human leukemia cells. GTI-2040 was introduced into cells via electroporation. A hybridization-ligation ELISA was used to quantify intracellular GTI-2040 concentrations. Real-time PCR and Western blot methods were used to measure the RNR M2 mRNA and protein levels, respectively. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay was used to measure the cytotoxicity following various drug treatments. A non-radioactive HPLC-UV method was used for measuring the intracellular Ara-CTP, while a LC-MS/MS method was used to quantify intracellular dNTP/NTP pools. GTI-2040 was found to downregulate M2 mRNA and protein levels in a dose-dependent manner and showed significant decrease in dNTP but not NTP pool. When combining GTI-2040 with Ara-C, a synergistic cytotoxicity was observed with no further change in dNTP/NTP pools. Importantly, pretreatment of K562 cells with GTI-2040 was found to increase Ara-CTP level for the first time, and this effect may be due to inhibition of RNR by GTI-2040. This finding provides a laboratory justification for the current phase I/II evaluation of GTI-2040 in combination with Ara-C in patients with acute myeloid leukemia.     

The past,present, and future of sleep measurement in mild cognitive impairment and early dementia—towards a core outcome set: a scoping review

Study ObjectivesSleep abnormalities emerge early in dementia and may accelerate cognitive decline. Their accurate characterization may facilitate earlier clinical identification of dementia and allow for assessment of sleep intervention efficacy. This scoping review determines how sleep is currently measured and reported in Mild Cognitive Impairment (MCI) and early dementia, as a basis for future core outcome alignment.MethodsThis review follows the PRISMA Guidelines for Scoping Reviews. CINAHL, Embase, Medline, Psychinfo, and British Nursing Index databases were searched from inception—March 12, 2021. Included studies had participants diagnosed with MCI and early dementia and reported on sleep as a key objective/ outcome measure.ResultsNineteen thousand five hundred and ninety-six titles were returned following duplicate removal with 188 studies [N] included in final analysis. Sleep data was reported on 17 139 unique, diagnostically diverse participants (n). “Unspecified MCI” was the most common diagnosis amongst patients with MCI (n = 5003, 60.6%). Despite technological advances, sleep was measured most commonly by validated questionnaires (n = 12 586, N = 131). Fewer participants underwent polysomnography (PSG) (n = 3492, N = 88) and actigraphy (n = 3359, N = 38) with little adoption of non-PSG electroencephalograms (EEG) (n = 74, N = 3). Sleep outcome parameters were reported heterogeneously. 62/165 (37.6%) were described only once in the literature (33/60 (60%) in interventional studies). There was underrepresentation of circadian (n = 725, N = 25) and micro-architectural (n = 360, N = 12) sleep parameters.ConclusionsAlongside under-researched areas, there is a need for more detailed diagnostic characterization. Due to outcome heterogeneity, we advocate for international consensus on core sleep outcome parameters to support causal inference and comparison of therapeutic sleep interventions.     

Checklists for Assessing Skills of Children With Type 1 Diabetes on Insulin Injection Technique

Background:School-aged children often participate in type 1 diabetes (T1D) self-care tasks. Despite widespread discussion about the importance of developing self-care skills in childhood, few explain how the health care team should assess the skills of children with T1D when performing insulin injections.Objective:We sought to assess content validity evidence in two checklists regarding injection technique performed by children.Methods:Two checklists were designed based on a systematic review of the insulin injection technique. Experts in pediatric diabetes, health literacy, and diabetes education assessed the checklists regarding their clarity, objectivity, and relevance. Content validity was assessed using the content validity ratio (CVR).Results:Eleven providers (72% nurses or physicians, professional experience 19.4 ± 10.1 years, 45% of specialists in endocrinology, and 18% in pediatrics) participated in the assessment. Experts considered items containing the word homogeneity inappropriate. Items related to the needle insertion angle and the skin fold did not reach the CVR critical value. The final version of the checklist for syringe injection comprised 22 items with CVR = 0.91, and the checklist for pen injection comprised 18 items with CVR = 0.87.Conclusions:The checklists presented clear, objective, and relevant content that assesses the skills of children with T1D for insulin injection. The checklists formally present the order of the technique and all the steps for insulin injection and allow a quantitative assessment of the operational skills of children. The developed instruments offer providers the possibility of continuous assessment of the progress of the pediatric clientele until they reach independence in diabetes self-care.