The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats

The effect of a new drug (CP 68,722, Pfizer) on parameters of insulin sensitivity in an established insulin-resistant animal model was examined. Rates of hepatic glucose production (HGP) and peripheral glucose uptake in obese Zucker (fa/fa) rats treated with a 10-day course of the medication using a two-step (2 and 10 mU/kg/min) euglycemic hyperinsulinemic clamp technique were measured. In addition, changes in substrate concentrations after drug treatment were examined. Basal HGP rates were similar in the lean versus the obese animals (37 +/- 3 v 39 +/- 3 mumol/kg/min); however, the obese animals had impaired insulin-induced suppression of HGP at both 2 mU/kg/min (36 +/- 3 v 23 +/- 4 mumol/kg/min) and 10 mU/kg/min (18 +/- 5 v 2 +/- 1 mumol/kg/min). Insulin stimulation of glucose disposal was also defective in the obese animals (37 +/- 2 v 88 +/- 7 mumol/kg/min at 2 mU/kg/min and 98 +/- 9 v 219 +/- 18 mumol/kg/min at 10 mU/kg/min). In addition, obese animals had elevated free fatty acid (FFA) and ketone levels, both of which were resistant to insulin-induced suppression. After drug treatment, few alterations in glucose or lipid metabolism were found in the lean animals. In the obese animals, insulin suppression of HGP was normalized during the higher insulin infusion rate (0 v 18 +/- 5 mumol/kg/min at 10 mU/kg/min), and peripheral glucose disposal was enhanced at both steps of the insulin clamp (54 +/- 4 v 37 +/- 2 mumol/kg/min at 2 mU/kg/min and 134 +/- 12 v 98 +/- 9 mumol/kg/min at 10 mU/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

A strategy to improve treatment‐related mortality and abandonment of therapy for childhood ALL in a developing country reveals the impact of treatment delays

Background

Treatment‐related mortality and abandonment of therapy are major barriers to successful treatment of childhood acute lymphoblastic leukemia (ALL) in the developing world.

Procedure

A collaboration was undertaken between Instituto Nacional de Cancerologia (Bogota, Colombia), which serves a poor patient population in an upper‐middle income country, and Dana‐Farber/Boston Children's Cancer and Blood Disorders Center (Boston, USA). Several interventions aimed at reducing toxic deaths and abandonment were implemented, including a reduced‐intensity treatment regimen and a psychosocial effort targeting abandonment. We performed a cohort study to assess impact.

Results

The Study Population comprised 99 children with ALL diagnosed between 2007 and 2010, and the Historic Cohort comprised 181 children treated prior to the study interventions (1995–2004). Significant improvements were achieved in the rate of deaths in complete remission (13% to 3%; P = 0.005), abandonment (32% to 9%; P < 0.001), and event‐free survival with abandonment considered an event (47% to 65% at 2 years; P = 0.016). However, relapse rate did not improve. Medically unnecessary treatment delays were common, and landmark analysis revealed that initiating the PIII phase of therapy ≥4 weeks delayed predicted markedly inferior disease‐free survival (P = 0.016). Conversely, patients who received therapy without excessive delays had outcomes approaching those achieved in high‐income countries.

Conclusions

Implementation of a twinning program was followed by reductions in abandonment and toxic deaths, but relapse rate did not improve. Inappropriate treatment delays were common and strongly predicted treatment failure. These findings highlight the importance of adherence to treatment schedule for effective therapy of ALL. Pediatr Blood Cancer 2015;62:1395–1402. © 2015 Wiley Periodicals, Inc.     

Monoclonal anti-light chain idiotype as a tumor-specific probe for human neoplastic B lymphocytes

Tumor cells from patients with B cell neoplasms often secrete small amounts of free monoclonal light chains that can be found in the urine. Such tumor-derived light chains of the lambda type from a patient with typical chronic lymphocytic leukemia have been used to raise mouse monoclonal antibodies (MoAbs). A hybridoma-secreting antibody that recognized the idiotypic lambda chain but not normal lambda chains by a preliminary screen but which also reacted with idiotypic IgM from the patient's tumor cells was selected. This MoAb in fact recognized 1 in 20 X 10(3) molecules of pooled normal lambda chains, thus establishing its specificity for a private idiotypic determinant. It failed to give a detectable reaction with normal IgM, normal serum, or a panel of IgM paraproteins. The antibody bound to the patient's neoplastic B cells but not to normal tonsillar cells. The site of binding of the antibody to idiotypic IgM is clearly separate from that of another MoAb specific for idiotypic determinants on heavy plus light chains, since the two showed additive binding curves. The determinant also appeared to be less available in dimeric lambda chains than in monomeric lambda chains or in idiotypic IgM. Antibodies to idiotypic determinants on light chains show some technical advantages and should be useful for monitoring and possibly treating B cell tumors, either alone or together with the more conventional anti-idiotypic antibodies that usually recognize the heavy and light chain combination.     

Coherency image analysis to quantify collagen architecture: implications in scar assessment

An important histological difference between normal, uninjured dermis and scar tissue such as that found in keloid scars is the pattern (morphological architecture) in which the collagen is deposited and arranged. In the uninjured dermis, collagen bundle architecture appears randomly organized (or in a basket weave formation), whereas in pathological conditions such as keloid scar tissue, collagen bundles are often found in whorls or in a hypotrophic scar collagen is more densely packed in a parallel configuration. In the case of skin, a scar disables the dermis, leaving it weaker, stiff and with a loss of optimal functionality. The absence of objective and quantifiable assessments of collagen orientation is a major bottleneck in monitoring progression of scar therapeutics. In this article, a novel quantitative approach for analyzing collagen orientation is reported. The methodology is demonstrated using collagen produced by cells in a model scar environment and examines collagen remodeling post-TGFβ stimulation in vitro. The method is shown to be reliable and effective in identifying significant coherency differences in the collagen deposited by human keloid scar cells. The technique is also compared for analysing collagen architecture in rat sections of normal, scarred skin and tendon tissue. Results demonstrate that the proposed computational method provides a fast and robust way of analyzing collagen orientation in a manner surpassing existing methods. This study establishes this methodology as a preliminary means of monitoring in vitro and in tissue treatment modalities which are expected to alter collagen morphology.

A novel technique for the fast and robust quantification of collagen architecture following scarring.     

Exploring relation types for literature-based discovery

Objective Literature-based discovery (LBD) aims to identify “hidden knowledge” in the medical literature by: (1) analyzing documents to identify pairs of explicitly related concepts (terms), then (2) hypothesizing novel relations between pairs of unrelated concepts that are implicitly related via a shared concept to which both are explicitly related. Many LBD approaches use simple techniques to identify semantically weak relations between concepts, for example, document co-occurrence. These generate huge numbers of hypotheses, difficult for humans to assess. More complex techniques rely on linguistic analysis, for example, shallow parsing, to identify semantically stronger relations. Such approaches generate fewer hypotheses, but may miss hidden knowledge. The authors investigate this trade-off in detail, comparing techniques for identifying related concepts to discover which are most suitable for LBD.Materials and methods A generic LBD system that can utilize a range of relation types was developed. Experiments were carried out comparing a number of techniques for identifying relations. Two approaches were used for evaluation: replication of existing discoveries and the “time slicing” approach.¹Results Previous LBD discoveries could be replicated using relations based either on document co-occurrence or linguistic analysis. Using relations based on linguistic analysis generated many fewer hypotheses, but a significantly greater proportion of them were candidates for hidden knowledge.Discussion and Conclusion The use of linguistic analysis-based relations improves accuracy of LBD without overly damaging coverage. LBD systems often generate huge numbers of hypotheses, which are infeasible to manually review. Improving their accuracy has the potential to make these systems significantly more usable.