The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor

Mobilized blood has supplanted bone marrow (BM) as the primary source of hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Pharmacologically enforced egress of hematopoietic stem cells from BM, or mobilization, has been achieved by directly or indirectly targeting the CXCL12/CXCR4 axis. Shortcomings of the standard mobilizing agent, granulocyte colony-stimulating factor (G-CSF), administered alone or in combination with the only approved CXCR4 antagonist, Plerixafor, continue to fuel the quest for new mobilizing agents. Using Protein Epitope Mimetics technology, a novel peptidic CXCR4 antagonist, POL5551, was developed. In vitro data presented herein indicate high affinity to and specificity for CXCR4. POL5551 exhibited rapid mobilization kinetics and unprecedented efficiency in C57BL/6 mice, exceeding that of Plerixafor and at higher doses also of G-CSF. POL5551-mobilized stem cells demonstrated adequate transplantation properties. In contrast to G-CSF, POL5551 did not induce major morphological changes in the BM of mice. Moreover, we provide evidence of direct POL5551 binding to hematopoietic stem and progenitor cells (HSPCs) in vivo, strengthening the hypothesis that CXCR4 antagonists mediate mobilization by direct targeting of HSPCs. In summary, POL5551 is a potent mobilizing agent for HSPCs in mice with promising therapeutic potential if these data can be orroborated in humans

Biologic predictors of clinical improvement in rituximab-treated refractory myositis Clinical rheumatology and osteoporosis

Background: To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab. Methods: In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n∈=∈177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n∈=∈28, TIF-γ n∈=∈19, Mi-2 n∈=∈25, SRP n∈=∈21, MJ n∈=∈18, non-MAA n∈=∈24, unidentified autoantibody n∈=∈9, and no autoantibodies n∈=∈33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons. Results: The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p∈30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p∈=∈0.075). Conclusion: Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after rituximab

Prime movers : mechanochemistry of mitotic kinesins

Mitotic spindles are self-organizing protein machines that harness teams of multiple force generators to drive chromosome segregation. Kinesins are key members of these force-generating teams. Different kinesins walk directionally along dynamic microtubules, anchor, crosslink, align and sort microtubules into polarized bundles, and influence microtubule dynamics by interacting with microtubule tips. The mechanochemical mechanisms of these kinesins are specialized to enable each type to make a specific contribution to spindle self-organization and chromosome segregation

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Lgl2 Executes Its Function as a Tumor Suppressor by Regulating ErbB Signaling in the Zebrafish Epidermis

Changes in tissue homeostasis, acquisition of invasive cell characteristics, and tumor formation can often be linked to the loss of epithelial cell polarity. In carcinogenesis, the grade of neoplasia correlates with impaired cell polarity. In Drosophila, lethal giant larvae (lgl), discs large (dlg), and scribble, which are components of the epithelial apico-basal cell polarity machinery, act as tumor suppressors, and orthologs of this evolutionary conserved pathway are lost in human carcinoma with high frequency. However, a mechanistic link between neoplasia and vertebrate orthologs of these tumor-suppressor genes remains to be fully explored at the organismal level. Here, we show that the pen/lgl2 mutant phenotype shares two key cellular and molecular features of mammalian malignancy: cell autonomous epidermal neoplasia and epithelial-to-mesenchymal-transition (EMT) of basal epidermal cells including the differential expression of several regulators of EMT. Further, we found that epidermal neoplasia and EMT in pen/lgl2 mutant epidermal cells is promoted by ErbB signalling, a pathway of high significance in human carcinomas. Intriguingly, EMT in the pen/lgl2 mutant is facilitated specifically by ErbB2 mediated E-cadherin mislocalization and not via canonical snail–dependent down-regulation of E-cadherin expression. Our data reveal that pen/lgl2 functions as a tumor suppressor gene in vertebrates, establishing zebrafish pen/lgl2 mutants as a valuable cancer model

Modelling mammalian energetics: the heterothermy problem

Global climate change is expected to have strong effects on the world’s flora and fauna. As a result, there has been a recent increase in the number of meta-analyses and mechanistic models that attempt to predict potential responses of mammals to changing climates. Many models that seek to explain the effects of environmental temperatures on mammalian energetics and survival assume a constant body temperature. However, despite generally being regarded as strict homeotherms, mammals demonstrate a large degree of daily variability in body temperature, as well as the ability to reduce metabolic costs either by entering torpor, or by increasing body temperatures at high ambient temperatures. Often, changes in body temperature variability are unpredictable, and happen in response to immediate changes in resource abundance or temperature. In this review we provide an overview of variability and unpredictability found in body temperatures of extant mammals, identify potential blind spots in the current literature, and discuss options for incorporating variability into predictive mechanistic models

Being Mum’s Confidant, a Boon or Bane? Examining Gender Differences in the Association of Maternal Disclosure with Adolescents’ Depressive Feelings

This article reports on a longitudinal study investigating gender differences in the association between maternal disclosure and adolescents’ depressive symptoms. Little research has examined the relationship of parental disclosure to adolescents’ depressive symptoms and research on sex differences is particularly lacking. In a sample of 428 families with a mean age of 13.36 (52% female) of the target adolescents, maternal and children’s disclosure and depressive symptoms were assessed twice with an interval of 4 years. Controlling for the quality of the parent–child relationship and levels of maternal depressive symptoms, the analyses revealed an interaction effect for child’s gender, moderating the effect of maternal disclosure on adolescents’ depressive symptoms. Higher levels of maternal disclosure were accompanied by lower levels of depressive symptoms in girls and higher levels of depressive symptoms in boys. Gender differences in socialization, communication, individuation and social networks might explain why daughters and sons are differently affected by maternal disclosure

Rapid Reversal of Chondroitin Sulfate Proteoglycan Associated Staining in Subcompartments of Mouse Neostriatum during the Emergence of Behaviour

BACKGROUND: The neostriatum, the mouse homologue of the primate caudate/putamen, is the input nucleus for the basal ganglia, receiving both cortical and dopaminergic input to each of its sub-compartments, the striosomes and matrix. The coordinated activation of corticostriatal pathways is considered vital for motor and cognitive abilities, yet the mechanisms which underlie the generation of these circuits are unknown. The early and specific targeting of striatal subcompartments by both corticostriatal and nigrostriatal terminals suggests activity-independent mechanisms, such as axon guidance cues, may play a role in this process. Candidates include the chondroitin sulfate proteoglycan (CSPG) family of glycoproteins which have roles not only in axon guidance, but also in the maturation and stability of neural circuits where they are expressed in lattice-like perineuronal nets (PNNs). METHODOLOGY/PRINCIPAL FINDINGS: The expression of CSPG-associated structures and PNNs with respect to neostriatal subcompartments has been examined qualitatively and quantitatively using double-labelling for Wisteria floribunda agglutinin (WFA), and the mu-opioid receptor (muOR), a marker for striosomes, at six postnatal ages in mice. We find that at the earliest ages (postnatal day (P)4 and P10), WFA-positive clusters overlap preferentially with the striosome compartment. By P14, these clusters disappear. In contrast, PNNs were first seen at P10 and continued to increase in density and spread throughout the caudate/putamen with maturation. Remarkably, the PNNs overlap almost exclusively with the neostriatal matrix. CONCLUSIONS/SIGNIFICANCE: This is the first description of a reversal in the distribution of CSPG associated structures, as well as the emergence and maintenance of PNNs in specific subcompartments of the neostriatum. These results suggest diverse roles for CSPGs in the formation of functional corticostriatal and nigrostriatal connectivity within the striosome and matrix compartments of the developing caudate/putamen

Spatial inequity in access to healthcare facilities at a county level in a developing country: a case study of Deqing County, Zhejiang, China

Background The inequities in healthcare services between regions, urban and rural, age groups and diverse income groups have been growing rapidly in China. Equal access to basic medical and healthcare services has been recognized as “a basic right of the people” by Chinese government. Spatial accessibility to healthcare facilities has received huge attention in Chinese case studies but been less studied particularly at a county level due to limited availability of high-resolution spatial data. This study is focused on measuring spatial accessibility to healthcare facilities in Deqing County. The spatial inequity between the urban (town) and rural is assessed and three scenarios are designed and built to examine which scenario is instrumental for better reducing the spatial inequity. Methods This study utilizes highway network data, Digital Elevation Model (DEM), location of hospitals and clinics, 2010 census data at the finest level – village committee, residential building footprint and building height. Areal weighting method is used to disaggregate population data from village committee level to residential building cell level. Least cost path analysis is applied to calculate the travel time from each building cell to its closest healthcare facility. Then an integral accessibility will be calculated through weighting the travel time to the closest facility between three levels. The spatial inequity in healthcare accessibility between the town and rural areas is examined based on the coverages of areas and populations. The same method is used to compare three scenarios aimed at reducing such spatial inequity – relocation of hospitals, updates of weighting values, and the combination of both. Results 50.03 % of residents can reach a county hospital within 15 min by driving, 95.77 % and 100 % within 30 and 60 min respectively. 55.14 % of residents can reach a town hospital within 5 min, 98.04 % and 100 % within 15 and 30 min respectively. 57.86 % of residential building areas can reach a village clinic within 5 min, 92.65 % and 99.22 % within 10 and 15 min. After weighting the travel time between the three-level facilities, 30.87 % of residents can reach a facility within 5 min, 80.46 %% and 99.88 % within 15 and 30 min respectively. Conclusions The healthcare accessibility pattern of Deqing County has exhibited spatial inequity between the town and rural areas, with the best accessibility in the capital of the county and poorest in the West of the county. There is a high negative correlation between population ageing and healthcare accessibility. Allocation of more advanced medical and healthcare equipment and highly skillful doctors and nurses to village clinics will be an efficient means of reducing the spatial inequity and further consolidating the national medical security system. GIS (Geographical Information Systems) methods have proven successful method of providing quantitative evidence for policy analysis although the data sets and methods could be further improved