Sclerostin-Neutralizing Antibody Treatment Rescues Negative Effects of Rosiglitazone on Mouse Bone Parameters

Obesity, a growing pandemic, is a risk factor for many cancers and causes increased bone marrow adipose tissue (BMAT). in vitro studies and obese animal models suggest that BMAT contributes to cancer progression, but there is a lack of preclinical models to directly test BMAT's role in cancer. Overactivation of peroxisome-proliferator-activated receptor-γ (PPARγ) can skew bone formation and resorption rates, resulting in increased BMAT and trabecular bone loss. Thiazolidinediones (eg, rosiglitazone) are anti-diabetic therapies that promote adipogenesis through PPARγ activation. We investigated if rosiglitazone increases BMAT in an immunocompromised model, commonly used in cancer research, and if these effects could be reversed by co-administering a bone anabolic agent (sclerostin-neutralizing antibody [Scl-Ab]), which has been shown to inhibit adipogenesis, using DXA, μCT, OsO4 μCT, and dynamic histomorphometry. Four weeks of rosiglitazone in female SCID Beige mice (cohort 1) significantly decreased trabecular bone volume (BV/TV) by about one-half, through increased osteoclast and suppressed osteoblast activity, and significantly increased BMAT. In cohort 2, mice were administered rosiglitazone ± Scl-Ab for 4 weeks, and then rosiglitazone was discontinued and Scl-Ab or vehicle were continued for 6 weeks. Scl-Ab significantly increased bone parameters (eg, BV/TV, N.Ob/B.Pm, and MS/BS) in both groups. Scl-Ab also overcame many negative effects of rosiglitazone (eg, effects on trabecular bone parameters, increased mineralization lag time [MLT], and decreased bone formation rate [BFR]). Interestingly, Scl-Ab significantly decreased rosiglitazone-induced BMAT in the femur, mostly due to a reduction in adipocyte size, but had a much weaker effect on tibial BMAT. These data suggest targeting sclerostin can prevent rosiglitazone-induced bone loss and reduce BM adiposity, in some, but not all BMAT locations. Collectively, our data demonstrate that rosiglitazone increases BMAT in SCID Beige mice, but concomitant changes in bone may confound its use to specifically determine BMAT's role in tumor models. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Are all forms of feature binding disturbed in schizophrenia? Evidence from a central vs. peripheral distinction in working memory

In this study we investigated central and peripheral feature binding in a group of 24 high pre-morbid IQ patients with schizophrenia and 24 healthy controls. In particular, participants were asked to remember specific single (e.g., word, colour) or multiple features (e.g., coloured words) of experimental items with central (coloured word) vs. peripheral (a coloured frame) attributes in a working memory binding task. Performance of the patients was significantly inferior to that of controls, especially when required to remember the peripheral combination of multiple features. Results suggest that patients with schizophrenia may have difficulties in unitizing peripheral features in working memory.     

On the Similarity Between the tRNAs of Organelles and Prokaryotes

Fluorescence studies with organelle transfer RNAs separated from their cytoplasmic counterparts revealed that phenylalanine tRNA from Euglena chloroplasts or Neurospora mitochondria does not contain a fluorescent "base Y." In contrast, cytoplasmic phenylalanine tRNA from Euglena and cytoplasmic tRNA from Neurospora were found to contain fluorescent bases. The fluorescence-emission spectra of Neurospora cytoplasmic tRNAs and those of the related ascomycete Saccharomyces cerevisiue were observed to be quite different. The results support the generalization that eukaryotic tRNAs contain a fluorescent base, but indicate that their respective organelle tRNAs do not. They also indicate a striking parallelism between organelle and prokaryotic tRNAs.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Colorectal cancer extracellular acidosis decreases immune cell killing and is partially ameliorated by pH-modulating agents that modify tumor cell cytokine profiles

Tumor cells upregulate myriad proteins that are important for pH regulation, resulting in the acidification of the extracellular tumor microenvironment (TME). Abnormal pH is known to dampen immune function, resulting in a worsened anti-tumor immune response. Understanding how extrinsic alterations in pH modulate the interactions between immune cells and tumors cells will help elucidate opportunities for new therapeutic approaches. We observed that pH impacts the function of immune cells, both natural killer (NK) and T cells, which is relevant in the context of a highly acidic TME. Decreased NK and T cell activity was correlated with decreasing pH in a co-culture immune cell-mediated tumor cell-killing assay. The addition of pH-modulating drugs cariporide, lansoprazole, and acetazolamide to the co-culture assay was able to partially mitigate this dampened immune cell function. Treatment of colorectal cancer (CRC) cells with NHE1 inhibitor cariporide increased CRC cell-secreted cytokines involved in immune cell recruitment and activation and decreased cytokines involved in epithelial-mesenchymal transition (EMT). Cariporide treatment also decreased CRC cell shed TRAIL-R2, TRAIL-R3, and PD-L1 which is relevant in the context of immunotherapy. These experiments can help inform future investigations into how the pH of the tumor microenvironment may be extrinsically modulated to improve anti-tumor immune response in solid tumors such as colorectal cancer.     

Engineering controls for furniture strippers to meet the OSHA methylene chloride PEL

This case study demonstrates how methylene chloride exposures during furniture stripping can be reduced to below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 25 ppm (as an 8-hour time-weighted average). Five surveys were conducted at one facility; the first four resulted in employee exposure geometric means from 39 to 332 ppm. For the fifth survey local exhaust ventilation was used at the stripping tank and the rinsing area, which together exhausted 138 m3/min (4860 ft3/min). Additional controls included providing adequate make-up air, adding paraffin wax to the stripping solution, raising the level of the stripping solution in the tank, and discussing good work practices with the employee. The employees' methylene chloride exposures during the fifth survey resulted in a geometric mean of 5.6 ppm with a 95% upper confidence limit of 8.3 ppm, which was found to be significantly lower than the OSHA PEL and the OSHA action level of 12.5 ppm. The cost of the ventilation system was $8900.     

The impact of maintenance and design for ventilation systems

Ventilation systems need to be designed to include access for cleaning and preventive maintenance. Without such access, the exhaust volume will deteriorate. Because of access difficulties and the many demands on their time, plant managers are sometimes errant in performing proper preventive maintenance. Three surveys measuring workers' exposures to methylene chloride were conducted at the same furniture stripping facility. A new ventilation system was installed for the first survey, resulting in an exhaust volume of 2900 cfm and worker exposure to methylene chloride of 59 ppm (geometric mean). Immediately after the first survey, the gasoline-powered fan was replaced by a smaller capacity electrically powered fan. Deterioration in the ventilation system was seen after seven years. Problems included clogged slots, paint chips and sawdust deposits in plenums, and a loose and frayed fan belt. The second survey indicated a reduction in exhaust volume to 1060 cfm and increased worker exposure to 330 ppm. With the smaller capacity fan still in place, the system was otherwise upgraded to allow for easier access and maintenance was performed. The third survey showed that the ventilation system performance was better (exhaust volume improved to 2080 cfm) and the worker exposures were reduced to 73 ppm. This study shows the benefits of designing for preventive maintenance and the necessity of keeping the ventilation systems clean.     

Research and dissemination needs for ergonomics in agriculture

In 1998, the National Institute for Occupational Safety and Health convened a conference of researchers interested in the ergonomics of agricultural workers. Participants included 20 representatives from universities, state governments, private agricultural and insurance companies, migrant worker organizations, agricultural industry organizations, and the Agricultural Extension Service. The attendees divided into three groups and brainstormed about research ideas and dissemination methods related to ergonomics for farm workers. The groups separately reported that interventions, cost-benefit analyses, and cultural belief systems were the main topics that needed to be researched to reduce physical risk factors for musculoskeletal disorders. The participants also presented ideas for disseminating information to farm owners and workers.