Bortezomib Augments Natural Killer Cell Targeting of Stem-Like Tumor Cells.

Tumor cells harboring stem-like/cancer stem cell (CSC) properties have been identified and isolated from numerous hematological and solid malignancies. These stem-like tumor cells can persist following conventional cytoreductive therapies, such as chemotherapy and radiotherapy, thereby repopulating the tumor and seeding relapse and/or metastasis. We have previously shown that natural killer (NK) cells preferentially target stem-like tumor cells via non- major histocompatibility complex (MHC) restricted mechanisms. Here, we demonstrated that the proteasome inhibitor, bortezomib, augments NK cell targeting of stem cell-like tumor cells against multiple solid human tumor-derived cancer lines and primary tissue samples. Mechanistically, this was mediated by the upregulation of cell surface NK ligands MHC class I chain-related protein A and B (MICA and MICB) on aldehyde dehydrogenases (ALDH)-positive CSCs. The increased expression of MICA and MICB on CSC targets thereby enhanced NK cell mediated killing in vitro and ex vivo from both human primary tumor and patient-derived xenograft samples. In vivo, the combination of bortezomib and allogeneic NK cell adoptive transfer in immunodeficient mice led to increased elimination of CSCs as well as tumor growth delay of orthotopic glioblastoma tumors. Taken together, our data support the combination bortezomib and NK transfer as a strategy for both CSC targeting and potentially improved outcomes in clinical cancer patients

Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma.

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

Compressive and Bending Performance of Selectively Laser Melted AlSi10Mg Structures

Selective laser melting (SLM) is a widely used additive manufacturing technique that effectively manufactures complex geometries such as cellular structures. However, challenges such as anisotropy and mechanical property variation are commonly found due to process parameters. In a bid to utilize this method for the commercial production of cellular structures, it is important to understand the behavior of a material under different loading conditions. In this work, the behavior of additively manufactured AlSi10Mg under compression, bending, and tension loads was investigated. Vertical and horizontal build directions are compared for each type of loading. Specimens were manufactured using the reduced build volume (RBV) chamber of the Renishaw AM 250 SLM machine

Can we really say getting stronger makes your tendon feel better? No current evidence of a relationship between change in Achilles tendinopathy pain or disability and changes in Triceps Surae structure or function when completing rehabilitation: A systematic review

Objectives: Determine if improvements in pain and disability in patients with mid-portion Achilles tendinopathy relate to changes in muscle structure and function whilst completing exercise rehabilitation. Design: A systematic review exploring the relationship between changes in pain/disability and muscle structure/function over time, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods: Six online databases and the grey literature were searched from database inception to 16th December 2022 whereas clinical trial registries were searched from database inception to 11th February 2020. We included clinical studies where participants received exercise rehabilitation (± placebo interventions) for mid-portion Achilles tendinopathy if pain/disability and Triceps Surae structure/function were measured. We calculated Cohen\u27s d (95 % confidence intervals) for changes in muscle structure/function over time for individual studies. Data were not pooled due to heterogeneity. Study quality was assessed using a modified Newcastle–Ottawa Scale. Results: Seventeen studies were included for synthesis. No studies reported the relationship between muscle structure/function and pain/disability changes. Twelve studies reported muscle structure/function outcome measures at baseline and at least one follow-up time-point. Three studies reported improvements in force output after treatment; eight studies demonstrated no change in structure or function; one study did not provide a variation measure, precluding within group change over time calculation. All studies were low quality. Conclusions: No studies explored the relationship between changes in tendon pain and disability and changes in muscle structure and function. It is unclear whether current exercise-based rehabilitation protocols for mid-portion Achilles tendinopathy improve muscle structure or function. Systematic review registration: PROSPERO (registration number: CRD42020149970)

Anatomy and Three-Dimensional Reconstructions of the Brain of a Bottlenose Dolphin (Tursiops truncatus) From Magnetic Resonance Images

Cetacean (dolphin, whale, and porpoise) brains are among the least studied mammalian brains because of the formidability of collecting and histologically preparing such relatively rare and large specimens. Magnetic resonance imaging offers a means of observing the internal structure of the brain when traditional histological procedures are not practical. Furthermore, internal structures can be analyzed in their precise anatomic positions, which is difficult to accomplish after the spatial distortions often accompanying histological processing. In this study, images of the brain of an adult bottlenose dolphin, Tursiops truncatus, were scanned in the coronal plane at 148 antero-posterior levels. From these scans a computer-generated three-dimensional model was constructed using the programs Voxel-View and VoxelMath (Vital Images, Inc.). This model, wherein details of internal and external morphology are represented in three-dimensional space, was then resectioned in orthogonal planes to produce corresponding series of virtual sections in the horizontal and sagittal planes. Sections in all three planes display the sizes and positions of major neuroanatomical features such as the arrangement of cortical lobes and subcortical structures such as the inferior and superior colliculi, and demonstrate the utility of MRI for neuroanatomical investigations of dolphin brains

Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection

The molecular immunopathogenesis of West Nile virus (WNV) infection is poorly understood. Here, we characterize a mouse model for WNV using a subcutaneous route of infection and delineate leukocyte subsets and immunoregulatory factors present in the brains of infected mice. Central nervous system (CNS) expression of the chemokine receptor CCR5 and its ligand CCL5 was prominently up-regulated by WNV, and this was associated with CNS infiltration of CD4+ and CD8+ T cells, NK1.1+ cells and macrophages expressing the receptor. The significance of CCR5 in pathogenesis was established by mortality studies in which infection of CCR5−/− mice was rapidly and uniformly fatal. In the brain, WNV-infected CCR5−/− mice had increased viral burden but markedly reduced NK1.1+ cells, macrophages, and CD4+ and CD8+ T cells compared with WNV-infected CCR5+/+ mice. Adoptive transfer of splenocytes from WNV-infected CCR5+/+ mice into infected CCR5−/− mice increased leukocyte accumulation in the CNS compared with transfer of splenocytes from infected CCR5−/− mice into infected CCR5−/− mice, and increased survival to 60%, the same as in infected CCR5+/+ control mice. We conclude that CCR5 is a critical antiviral and survival determinant in WNV infection of mice that acts by regulating trafficking of leukocytes to the infected brain

Does lower-limb osteoarthritis alter motor cortex descending drive and voluntary activation? A systematic review and meta-analysis

Purpose: The aim of the study was to quantify motor cortex descending drive and voluntary activation (VA) in people with lower-limb OA compared to controls. Methods: A systematic review and meta-analysis according to the PRISMA guidelines was carried out. Seven databases were searched until 30 December 2022. Studies assessing VA or responses to transcranial magnetic stimulation (TMS; i.e. motor evoked potential, intracortical facilitation, motor threshold, short-interval intracortical inhibition, and silent period) were included. Study quality was assessed using Joanna Briggs Institute criteria and evidence certainty using GRADE. The meta-analysis was performed using RevMan inverse variance, mixed-effect models. Results: Eighteen studies were included, all deemed low-quality. Quadriceps VA was impaired with knee OA compared to healthy controls (standardised mean difference (SMD)=0.84, 95% CI=−1.12–0.56, low certainty). VA of the more symptomatic limb was impaired (SMD=0.42, 95% CI=−0.75–0.09, moderate certainty) compared to the other limb in people with hip/knee OA. As only two studies assessed responses to TMS, very low-certainty evidence demonstrated no significant difference between knee OA and healthy controls for motor evoked potential, intracortical facilitation, resting motor threshold or short-interval intracortical inhibition. Conclusions: Low-certainty evidence suggests people with knee OA have substantial impairments in VA of their quadriceps muscle when compared to healthy controls. With moderate certainty we conclude that people with hip and knee OA had larger impairments in VA of the quadriceps in their more painful limb compared to their non-affected/other limb

CCR5 deficiency increases risk of symptomatic West Nile virus infection

West Nile virus (WNV) is a reemerging pathogen that causes fatal encephalitis in several species, including mouse and human. Recently, we showed that the chemokine receptor CCR5 is critical for survival of mice infected with WNV, acting at the level of leukocyte trafficking to the brain. To test whether this receptor is also protective in man, we determined the frequency of CCR5Δ32, a defective CCR5 allele found predominantly in Caucasians, in two independent cohorts of patients, one from Arizona and the other from Colorado, who had laboratory-confirmed, symptomatic WNV infection. The distribution of CCR5Δ32 in a control population of healthy United States Caucasian random blood donors was in Hardy-Weinberg equilibrium and CCR5Δ32 homozygotes represented 1.0% of the total group (n = 1,318). In contrast, CCR5Δ32 homozygotes represented 4.2% of Caucasians in the Arizona cohort (odds ratios [OR] = 4.4 [95% confidence interval [CI], 1.6–11.8], P = 0.0013) and 8.3% of Caucasians in the Colorado cohort (OR = 9.1 [95% CI, 3.4–24.8], P < 0.0001). CCR5Δ32 homozygosity was significantly associated with fatal outcome in the Arizona cohort (OR = 13.2 [95% CI, 1.9–89.9], P = 0.03). We conclude that CCR5 mediates resistance to symptomatic WNV infection. Because CCR5 is also the major HIV coreceptor, these findings have important implications for the safety of CCR5-blocking agents under development for HIV/AIDS

Unweaving the population structure and genetic diversity of Canadian shrub willow

Perennial shrub willow are increasingly being promoted in short-rotation coppice systems as biomass feedstocks, for phytoremediation applications, and for the diverse ecosystem services that can accrue. This renewed interest has led to widespread willow cultivation, particularly of non-native varieties. However, Canadian willow species have not been widely adopted and their inherent diversity has not yet been thoroughly investigated. In this study, 324 genotypes of Salix famelica and Salix eriocephala collected from 33 sites of origin were analyzed using 26,016 single nucleotide polymorphisms to reveal patterns of population structure and genetic diversity. Analyses by Bayesian methods and principal component analysis detected five main clusters that appeared to be largely shaped by geoclimatic variables including mean annual precipitation and the number of frost-free days. The overall observed (HO) and expected (HE) heterozygosity were 0.126 and 0.179, respectively. An analysis of molecular variance revealed that the highest genetic variation occurred within genotypes (69%), while 8% of the variation existed among clusters and 23% between genotypes within clusters. These findings provide new insights into the extent of genetic variation that exists within native shrub willow species which could be leveraged in pan-Canadian willow breeding programs.Fil: Murphy, Emily K. University of British Columbia. Faculty of Forestry. Department of Wood Science; CanadáFil: Cappa, Eduardo Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Recursos Biológicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Soolanayakanahally, Raju Y. Agriculture and Agri-Food Canada. Indian Head Research Farm; Canadá. Agriculture and Agri-Food Canada. Saskatoon Research and Development Centre; Canadá.Fil: El-Kassaby, Yousry A. University of British Columbia. Faculty of Forestry. Department of Forest and Conservation Sciences; CanadáFil: Parkin, Isobel A.P. Agriculture and Agri-Food Canada. Saskatoon Research and Development Centre; Canadá.Fil: Schroeder, William R. Agriculture and Agri-Food Canada. Indian Head Research Farm; CanadáFil: Mansfield, Shawn D. University of British Columbia. Faculty of Forestry. Department of Wood Science; Canad