Background: Cancer patients are regarded as a highly vulnerable group in the current Coronavirus Disease 2019 (COVID-19) pandemic. To date, the clinical characteristics of COVID-19-infected cancer patients remain largely unknown. Patients and methods: In this retrospective cohort study, we included cancer patients with laboratory-confirmed COVID-19 from three designated hospitals in Wuhan, China. Clinical data were collected from medical records from 13 January 2020 to 26 February 2020. Univariate and multivariate analyses were carried out to assess the risk factors associated with severe events defined as a condition requiring admission to an intensive care unit, the use of mechanical ventilation, or death. Results: A total of 28 COVID-19-infected cancer patients were included; 17 (60.7%) patients were male. Median (interquartile range) age was 65.0 (56.0e70.0) years. Lung cancer was the most frequent cancer type (n ¼ 7; 25.0%). Eight (28.6%) patients were suspected to have hospital-associated transmission. The following clinical features were shown in our cohort: fever (n ¼ 23, 82.1%), dry cough (n ¼ 22, 81%), and dyspnoea (n ¼ 14, 50.0%), along with lymphopaenia (n ¼ 23, 82.1%), high level of high-sensitivity C-reactive protein (n ¼ 23, 82.1%), anaemia (n ¼ 21, 75.0%), and hypoproteinaemia (n ¼ 25, 89.3%). The common chest computed tomography (CT) findings were ground-glass opacity (n ¼ 21, 75.0%) and patchy consolidation (n ¼ 13, 46.3%). A total of 15 (53.6%) patients had severe events and the mortality rate was 28.6%. If the last antitumour treatment was within 14 days, it significantly increased the risk of developing severe events [hazard ratio (HR) ¼ 4.079, 95% confidence interval (CI) 1.086e15.322, P ¼ 0.037]. Furthermore, patchy consolidation on CT on admission was associated with a higher risk of developing severe events (HR ¼ 5.438, 95% CI 1.498e19.748, P ¼ 0.010). Conclusions: Cancer patients show deteriorating conditions and poor outcomes from the COVID-19 infection. It is recommended that cancer patients receiving antitumour treatments should have vigorous screening for COVID-19 infection and should avoid treatments causing immunosuppression or have their dosages decreased in case of COVID-19 coinfection.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1R206H) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1R206H mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1R206H causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

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Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. It is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in control of cell cycle, apoptosis, and cell-fate determination. Owing to its antitumor activity, cantharidin has been frequently used in clinical practice. In the present study, we investigated the therapeutic potential of cantharidin in pancreatic cancer. Cantharidin efficiently inhibited the growth of pancreatic cancer cells, but presented a much lighter toxicity effect against normal pancreatic duct cells. It caused G2 ⁄ M cell-cycle arrest that was accompanied by the down-regulation of cyclin-dependent kinase 1 (CDK1) and up-regulation of p21 expression. It induced apoptosis and elevated the expressions of pro-apoptotic factors tumor necrosis factor-a (TNF-a), TNF-related apoptosis inducing receptor 1 (TRAILR1), TRAILR2, Bad, Bak, and Bid, and decreased the expression of antiapoptotic Bcl-2. Activation of caspase-8 and caspase-9 suggested that both extrinsic and intrinsic pathways are involved in the induction of apoptosis. Interestingly, unlike previous studies on other cancer cells, we found that the inhibitory role of cantharidin is independent of oxidative stress in pancreatic cancer cells. Mitogen-activated protein kinases (MAPKs), including ERK, JNK, and p38, were activated after treatment with cantharidin. Inhibition of JNK, but not ERK or p38, alleviated the cytotoxity effect of cantharidin, suggesting cantharidin exerted its anticancer effect through the JNK-dependent way. Hence, in addition to being an attractive candidate compound with therapeutic potential, cantharidin also highlighted the possibility of using PP2A as a therapeutic target for pancreatic cancer treatment. (Cancer Sci 2010; 101: 1226-1233

Summary Objective The objective of the present study was to validate the ability of EPIC-μCT to nondestructively assess cartilage morphology in the rat model. Design An appropriate contrast agent (Hexabrix) concentration and incubation time for equilibration were determined for reproducible segmentation of femoral articular cartilage from contrast-enhanced μCT scans. Reproducibility was evaluated by triplicate scans of six femora, and the measured articular cartilage thickness was independently compared to thickness determined from needle probe testing and histology. The validated technique was then applied to quantify age-related differences in articular cartilage morphology between 4, 8, and 16-week old (n=5 each) male Wistar rats. Results A 40% Hexabrix/60% PBS solution with 30 minute incubation was optimal for segmenting cartilage from the underlying bone tissue and other soft tissues in the rat model. High reproducibility was indicated by the low coefficient of variation (1.7-2.5%) in cartilage volume, thickness and surface area. EPIC-μCT evaluation of thickness showed a strong linear relationship and good agreement with both needle probing (r2=0.95, slope=0.81, p<0.01, mean difference 11±22μm, n=43) and histology (r2=0.99, slope=0.97, p<0.01, mean difference 12±10μm, n=30). Cartilage volume and thickness significantly decreased with age while surface area significantly increased. Conclusion EPIC-μCT imaging has the ability to nondestructively evaluate three-dimensional articular cartilage morphology with high precision and accuracy in a small animal model.

Mechanical signals are recognized as anabolic to both bone and muscle, but the specific parameters that are critical to this stimulus remain unknown. Here we examined the potential of extremely low-magnitude, high-frequency mechanical stimuli to enhance the quality of the adolescent musculoskeletal system. Eight-week-old female BALB/cByJ mice were divided into three groups: baseline controls (BC, n = 8), age-matched controls (AC, n = 12), and whole body vibration (WBV, n = 12) at 45 Hz (0.3 g) for 15 min/day. Following 6 wk of WBV, bone mineralizing surfaces of trabeculae in the proximal metaphysis of the tibia were 75% greater (P < 0.05) than AC, while osteoclast activity was not significantly different. The tibial metaphysis of WBV mice had 14% greater trabecular bone volume (P < 0.05) than AC, while periosteal bone area, bone marrow area, cortical bone area, and the moments of inertia of this region were all significantly greater (up to 29%, P < 0.05). The soleus muscle also realized gains by WBV, with total cross-sectional area as well as type I and type II fiber area as much as 29% greater (P < 0.05) in mice that received the vibratory mechanical stimulus. The small magnitude and brief application of the noninvasive intervention emphasize that the mechanosensitive elements of the musculoskeletal system are not necessarily dependent on strenuous, long-term activity to initiate a structurally relevant response in the adolescent musculoskeletal system. If maintained into adulthood, the beneficial structural changes in trabecular bone, cortical bone, and muscle may serve to decrease the incidence of osteoporotic fractures and sarcopenia later in life.

The Wnt antagonist Sost has emerged as a key regulator of bone homeostasis through the modulation of Lrp4/5/6 Wnt coreceptors. In humans, lack of Sclerostin causes sclerosteosis and van Buchem (VB) disease, two generalized skeletal hyperostosis disorders that result from hyperactive Wnt signaling. Unlike sclerosteosis, VB patients lack SOST coding mutations but carry a homozygous 52 kb noncoding deletion that is essential for the transcriptional activation of SOST in bone. We recently identified a putative bone enhancer, ECR5, in the VB deletion region, and showed that the transcriptional activity of ECR5 is controlled by Mef2C transcription factor in vitro. Here we report that mice lacking ECR5 or Mef2C through Col1-Cre osteoblast/osteocyte-specific ablation result in high bone mass (HBM) due to elevated bone formation rates. We conclude that the absence of the Sost-specific long-range regulatory element ECR5 causes VB disease in rodents, and that Mef2C is the main transcription factor responsible for ECR5-dependent Sost transcriptional activation in the adult skeleton. osteocytes S everal rare genetic disorders that interfere with Wnt signaling have provided strong evidence that the "canonical" Wnt signaling pathway is critical in bone (1). The Wnt coreceptor LRP5 has been described as a modulator of bone mass where loss-offunction mutations cause osteoporosis-pseudoglioma syndrome (OPPG) (2), an autosomal recessive disorder characterized by low bone mass and skeletal fragility; conversely, gain-of-function Lrp5 alleles cause high bone mass (HBM) (3). Similar hyperactive osteoblast activity due to elevated Wnt signaling was observed when Sost, a secreted Wnt inhibitor, was mutated in knockout (KO) mice or in sclerosteosis patients who suffer from generalized hyperostosis (4-6). Lrp5 gene targeting or SOST overexpression in transgenic (TG) mice causes osteopenia (3, 7), whereas TG overexpression of G171V Lrp5 allelic variant causes HBM, similar to the Sost KO phenotypes (4,8,9). The recapitulation of the human phenotypes in mouse models supports the conclusion that canonical Wnt signaling plays a critical role in bone metabolism, and points to Sost and Lrp5 as key regulators of bone mass.The skeletal phenotype describing sclerosteosis patients is similar to what has been documented for van Buchem (VB) disease. Although both VB and sclerosteosis map to the same locus on human chromosome 17 that includes the SOST transcript, the Sclerostin transcription unit was not affected in VB. All VB patients examined to date carry a 52-kb noncoding deletion, 35 kb downstream of SOST that results in the absence of postnatal SOST transcript and protein (10, 11). Although both sclerosteosis and VB are caused by sclerostin deficiency, the VB phenotype is a result of dysregulated SOST transcription. To identify the potential transcriptional regulatory elements responsible for Sost transcription in bone, we have characterized the expression of a human SOST transgene or an engineered allele corresponding to VB in mice. Only the wi...

Summary Objective The objective of this study was to evaluate the feasibility of quantifying the Equilibrium Partitioning of an Ionic Contrast agent via μCT (EPIC-μCT) to nondestructively assess sulfated glycosaminoglycan (sGAG) content and distribution in rat articular cartilage ex vivo, and in doing so to establish a paradigm for extension of this technique to other small animal models. Design After determination of an appropriate incubation time for the anionic contrast agent, EPIC-μCT was used to examine age-related differences in cartilage sGAG content between 4-, 8-, and 16-week old (n=5 each) male Wistar rats and to evaluate sGAG depletion in the right femora of each age group after 60 minutes of digestion with chondroitinase ABC. The EPIC-μCT measurements were validated by histological safranin-O staining, and reproducibility was evaluated by triplicate scans of six femora. Results Cartilage attenuation gradually increased with cumulative digestion time and reached a plateau at approximately 60 minutes with a 16.0% temporal increase (p<0.01). Average femoral articular cartilage attenuation increased by 14.2% from 4 to 8 weeks of age (p<0.01) and further increased by 2.5% from 8 to 16 weeks (p<0.05). After 60 minutes of digestion, femoral articular cartilage attenuations increased by 15-17% in each age group (p<0.01). Correspondingly, sGAG optical density decreased with age and digestion, and showed a linear correlation (r=−0.88, slope=−1.26, p<0.01, n=30) with EPIC-μCT cartilage attenuation. High reproducibility was indicated by a low coefficient of variation (1.5%) in cartilage attenuation. Conclusions EPIC-μCT imaging provides high spatial resolution and sensitivity to assess sGAG content and three-dimensional distribution in rat femoral articular cartilage.