Dyadic and Longitudinal Influences of Sexual Communication on Relationship Satisfaction, Emotional Intimacy, and Daily Affect Among Same-Sex Male Couples.

The influences of sexual communication on relational outcomes have garnered attention in the current literature, but such dynamics have seldom been explored among same-sex couples using dyadic, longitudinal data. The current study investigates the actor (i.e. on the individual self) and partner (i.e. on the partner) effects of sexual communication (presence and quality) on relationship satisfaction, emotional intimacy, and daily affect among same-sex male couples using dyadic, longitudinal data. Interracial couple status and age discrepancies between partners are tested as moderating variables. One hundred and three diverse cis-gender male couples participated in a one-time pre-survey and a daily survey for 15 consecutive days. The results showed that the presence and quality of sexual communication had positive actor effects on relationship satisfaction, emotional intimacy, and daily affect. The presence of sexual communication also had a positive partner effect on emotional intimacy. Moreover, our results showed significant interactions between interracial couple status, age discrepancies, and sexual communication on several outcome variables. Theoretical contributions, practical implications, and study limitations were discussed.

A systematic review and meta-analysis of strategies to promote vaccination uptake.

Although immunization can dramatically curb the mortality and morbidity associated with vaccine-preventable diseases, vaccination uptake remains suboptimal in many areas of the world. Here, in this meta-analysis, we analysed the results from 88 eligible randomized controlled trials testing interventions to increase vaccination uptake with 1,628,768 participants from 17 countries with variable development levels (for example, Human Development Index ranging from 0.485 to 0.955). We estimated the efficacy of seven intervention strategies including increasing access to vaccination, sending vaccination reminders, providing incentives, supplying information, correcting misinformation, promoting both active and passive motivation and teaching behavioural skills. We showed that the odds of vaccination were 1.5 (95% confidence interval, 1.27 to 1.77) times higher for intervention than control conditions. Among the intervention strategies, using incentives and increasing access were most promising in improving vaccination uptake, with the access strategy being particularly effective in countries with lower incomes and less access to healthcare.

State policies increase vaccination by shaping social norms.

In a survey and four preregistered experiments, we examined if implementing a vaccine-promoting policy is likely to encourage vaccination by shaping the norms of a society. By combining state-level policy data with a longitudinal survey, we found that vaccine-supportive policies and laws are associated with more positive social norms. To establish a causal effect, we conducted four preregistered experiments to gauge the impact of policies, including the government recommendation for children to receive the COVID-19 vaccine and changes in funding for immunization programs. We find that vaccine-supportive policies strengthen the intention to receive an additional recommended COVID-19 booster shot and the intention to vaccinate children against COVID-19. We also find that these effects are mediated by the promotion of social norms supportive of vaccination. In this context, communicating about laws and policies in favor of vaccination may create a culture of vaccination and increase vaccination coverage.

A comparison of three methods to determine the subject matter in textual data.

This study compares three different methods commonly employed for the determination and interpretation of the subject matter of large corpuses of textual data. The methods reviewed are: (1) topic modeling, (2) community or group detection, and (3) cluster analysis of semantic networks. Two different datasets related to health topics were gathered from Twitter posts to compare the methods. The first dataset includes 16,138 original tweets concerning HIV pre-exposure prophylaxis (PrEP) from April 3, 2019 to April 3, 2020. The second dataset is comprised of 12,613 tweets about childhood vaccination from July 1, 2018 to October 15, 2018. Our findings suggest that the separate "topics" suggested by semantic networks (community detection) and/or cluster analysis (Ward's method) are more clearly identified than the topic modeling results. Topic modeling produced more subjects, but these tended to overlap. This study offers a better understanding of how results may vary based on method to determine subject matter chosen.

Bypassing misinformation without confrontation improves policy support as much as correcting it.

Curbing the negative impact of misinformation is typically assumed to require correcting misconceptions. Conceivably, however, bypassing the misinformation through alternate beliefs of opposite implications may reduce the attitudinal impact of the misinformation. Three experiments, one preregistered with a sample representative of the United States population, examined the impact of (a) directly correcting prior misinformation offered in support of restricting Genetically Modified (GM) foods (i.e., the correction strategy) and (b) discussing information in support of GM foods (i.e., the bypassing strategy), compared to a misinformation-only control condition. Findings consistently revealed that bolstering beliefs with opposite implications is just as effective at reducing opposition to GM foods as is correcting misinformation about GM foods. Thus, bypassing should be added to our arsenal of methods to curb the impact of misinformation.

Comparison of public discussions of gene editing on social media between the United States and China.

The world's first gene-edited babies event has stirred controversy on social media over the use of gene editing technology. Understanding public discussions about this controversy will provide important insights about opinions of science and facilitate informed policy decisions. This study compares public discussion topics about gene editing on Twitter and Weibo, as wel asthe evolution of these topics over four months. Latent Dirichlet allocation (LDA) was used to generate topics for 11,244 Weibo posts and 57,525 tweets from September 25, 2018, to January 25, 2019. Results showed a difference between the topics on Twitter versus Weibo: there were more nuanced discussions on Twitter, and the discussed topics between platforms focused on different areas. Temporal analysis showed that most discussions took place around gene-edited events. Based on our findings, suggestions were provided for policymakers and science communication practitioners to develop more effective communication strategies toward audiences in China and the U.S.

Socio-behavioral factors related to PrEP non-adherence among gay male PrEP users living in California and New York: A behavioral theory informed approach.

One effective preventative measure to reduce the number of new HIV infections is through the uptake of daily oral HIV pre-exposure prophylaxis (PrEP). Although previous clinical trials have proven the effectiveness of on-demand PrEP uptake, daily PrEP uptake is the most popular prevention method among PrEP users and is still recommended by most healthcare professionals and organizations. Informed by the integrative model of behavioral prediction, the current study examined the socio-behavioral factors associated with PrEP non-adherence. The present study conducted a cross-sectional survey of 210 gay male daily PrEP users living in California and New York. The results showed more than two-thirds of the sample indicated that they had skipped taking PrEP within the last 30 days, averaging around four to five missed doses. General attitudes toward desirable and undesirable outcomes, perceived behavioral control, and social-level barriers were associated with daily PrEP uptake non-adherence. The findings highlight providers' role in PrEP adherence and the importance of habit-forming, which can be enhanced by cost-effective strategies and technological innovations.

Understanding Human Papillomavirus Vaccine Promotions and Hesitancy in Northern California Through Examining Public Facebook Pages and Groups.

Human papillomavirus (HPV) vaccination coverage among adolescents is lower in rural regions and remains under the 80% coverage goal by Healthy People 2030. Through both sentiment analysis and topic modeling, this research examines how local health agencies and groups in nine Northern California counties promote HPV vaccines through Facebook and how target populations react to promotion posts in comments that elucidate their sentiments and hesitancy toward HPV vaccination. In January 2021, we identified 2,105 public Facebook pages and 1,065 groups related to health within the counties and collected a total of 212 posts and 505 comments related to the HPV vaccine. The posts were published between 2010 and 2021, with the majority (83%) published after 2017. There were large variations of Facebook activities across counties. We categorized four counties with HPV vaccination initiation rates below 40% as low-coverage counties and five counties with rates above 40% as high-coverage counties. In general, low-coverage counties had fewer Facebook activities in comparison to high coverage. Results showed that, on average, comments about the HPV vaccine exhibited more positive emotion, more negative emotion, and more anger than the posts. Overall, thematic topics that emerged from posts centered around awareness and screening of HPV and cervical cancer, STI testing services, information sources, and calls to action for health services. However, comment topics did not correspond to posts and were mostly related to vaccine hesitancy, discussing vaccine risks, safety concerns, and distrust in vaccine science, citing misinformation. When comparing high- versus low-coverage counties, posts expressed similar sentiments; however, comments within high-coverage counties expressed more anger than in low-coverage counties. Comments from both high- and low-coverage counties expressed concerns with vaccine safety, risks, and injury. It is important to note that commenters exchanged information sources and tried to address misinformation themselves. Our results suggest that the promotion of HPV vaccines from public Facebook pages and groups is limited in frequency and content diversity. This illustrates problems with generalized social media vaccination promotion without community tailoring and addressing specific hesitancy concerns. Public health agencies should listen to the thoughts of targeted audiences reflected through comments and design relevant messages to address these concerns for HPV vaccination promotion.

Effects of fact-checking social media vaccine misinformation on attitudes toward vaccines.

Social media vaccine misinformation can negatively influence vaccine attitudes. It is urgent to develop communication approaches to reduce the misinformation's impact. This study aimed to test the effects of fact-checking labels for misinformation on attitudes toward vaccines. An online survey experiment with 1198 participants recruited from a U.S. national sample was conducted in 2018. Participants were randomly assigned to six conditions: misinformation control, or fact-checking label conditions attributed to algorithms, news media, health institutions, research universities, or fact-checking organizations. We analyzed differences in vaccine attitudes between the fact-checking label and control conditions. Further, we compared perceived expertise and trustworthiness of the five categories of fact-checking sources. Fact-checking labels attached to misinformation posts made vaccine attitudes more positive compared to the misinformation control condition (P = .003, Cohen's d= 0.21). Conspiracy ideation moderated the effect of the labels on vaccine attitudes (P = .02). Universities and health institutions were rated significantly higher on source expertise than other sources. Mediation analyses showed labels attributed to universities and health institutions indirectly resulted in more positive attitudes than other sources through perceived expertise. Exposure to fact-checking labels on misinformation can generate more positive attitudes toward vaccines in comparison to exposure to misinformation. Incorporating labels from trusted universities and health institutions on social media platforms is a promising direction for addressing the vaccine misinformation problem. This points to the necessity for closer collaboration between public health and research institutions and social media companies to join efforts in addressing the current misinformation threat.

Opposition to Nonprescription Naloxone Access: Measurement and Psychosocial Predictors.

Background: Access of naloxone has been increased in recent years, yet opposition to unrestricted availability persists. Objectives: To validate a measure of opposition to the policy of nonprescription naloxone and foster a better understanding of the characteristics of individuals who oppose such a policy. Methods: Respondents from a crowdsource platform (N = 621) responded to an instrument developed to assess opposition to nonprescription naloxone. Construct validity was assessed by examining the relationship of the opposition scale with measures of social distance, belief in a just world, right wing authoritarianism, social dominance orientation (SDO), perceptions of the degree of threat to the nation presented by opioid users, past exposure to opioid misuse, and conservative political ideology. Results: A 9-item measure of opposition emerged (α=.96). Opposition to nonprescription naloxone was generally associated with construct validation variables as expected. In a regression analysis that adjusted for demographic characteristics, opposition was most strongly related to authoritarianism, the perception that opioid users present a threat to our nation, the belief that we live in a just world, social dominance orientation, greater perceived social distance between self and opioid users, and past experiences with users. Opposition scores differentiated those who supported versus opposed specific policies regarding naloxone access and were particularly high among Republicans. Most respondents did not oppose policies on nonprescription naloxone access. Conclusions/Importance: The instrument developed provides a reliable and valid tool that enables future investigations into understanding and overcoming the psychological, social, and political foundations of opposition to expanded naloxone access.

Combinatorial screening using orthotopic patient derived xenograft-expanded early phase cultures of osteosarcoma identify novel therapeutic drug combinations.

Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

Establishing a Preclinical Multidisciplinary Board for Brain Tumors.

Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with "standard-of-care" surgery and radiotherapy.Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654-66. ©2018 AACR.

Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice.

Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.

Measuring Absolute Blood Perfusion in Mice Using Dynamic Contrast-Enhanced Ultrasound.

We investigated the feasibility of estimating absolute tissue blood perfusion using dynamic contrast-enhanced ultrasound (CEUS) imaging in mice. We developed a novel method of microbubble administration and a model-free approach to estimate absolute kidney perfusion, and explored the kidney as a reference organ to estimate absolute perfusion of a neuroblastoma tumor. We performed CEUS on the kidneys of CD1 nude mice using the VisualSonics VEVO 2100 imaging system. We estimated individual kidney blood perfusion using the burst-replenishment (BR) technique. We repeated the kidney imaging on the mice after a week. We performed CEUS imaging of a neuroblastoma mouse xenograft tumor along with its right kidney using two sets of microbubble administration parameters to estimate absolute tumor blood perfusion. We performed statistical tests at a significance level of 0.05. Our estimated absolute kidney perfusion (425 ± 123 mL/min/100 g) was within the range of previously reported values. There was no statistical difference between the estimated absolute kidney blood perfusions from the 2 wk of imaging (paired t-test, p = 0.09). We estimated the absolute blood perfusion in the neuroblastoma tumor to be 16.49 and 16.9 mL/min/100 g for the two sets of microbubble administration parameters (Wilcoxon rank-sum test, p = 0.6). We have established the kidney as a reliable reference organ in which to estimate absolute perfusion of other tissues. Using a neuroblastoma tumor, we have determined the feasibility of estimating absolute blood perfusion in tissues using contrast-enhanced ultrasound imaging.

Extracellular Signal-Regulated Kinase Signaling in CD4-Expressing Cells Inhibits Osteochondromas.

Defects in cartilage homeostasis can give rise to various skeletal disorders including osteochondromas. Osteochondromas are benign bone tumors caused by excess accumulation of chondrocytes, the main cell type of cartilage. The extracellular signal-regulated kinase (ERK) pathway is a major signaling node that functions within chondrocytes to regulate their growth and differentiation. However, it is not known whether the ERK pathway in other cell types regulates cartilage homeostasis. We show here that mice with a germline deficiency of Erk1 and a conditional deletion of Erk2 in cells that express CD4, or expressed CD4 at one point in development, unexpectedly developed bone deformities. The bone lesions were due to neoplastic outgrowths of chondrocytes and disordered growth plates, similar to tumors observed in the human disease, osteochondromatosis. Chondrocyte accumulation was not due to deletion of Erk2 in the T cells. Rather, CD4cre was expressed in cell types other than T cells, including a small fraction of chondrocytes. Surprisingly, the removal of T cells accelerated osteochondroma formation and enhanced disease severity. These data show for the first time that T cells impact the growth of osteochondromas and describe a novel model to study cartilage homeostasis and osteochondroma formation.

Maternal bile acid transporter deficiency promotes neonatal demise.

Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition.

Dietary modulation of the microbiome affects autoinflammatory disease.

The incidences of chronic inflammatory disorders have increased considerably over the past three decades. Recent shifts in dietary consumption may have contributed importantly to this surge, but how dietary consumption modulates inflammatory disease is poorly defined. Pstpip2(cmo) mice, which express a homozygous Leu98Pro missense mutation in the Pombe Cdc15 homology family protein PSTPIP2 (proline-serine-threonine phosphatase interacting protein 2), spontaneously develop osteomyelitis that resembles chronic recurrent multifocal osteomyelitis in humans. Recent reports demonstrated a crucial role for interleukin-1ß (IL-1ß) in osteomyelitis, but deletion of the inflammasome components caspase-1 and NLRP3 failed to rescue Pstpip2(cmo) mice from inflammatory bone disease. Thus, the upstream mechanisms controlling IL-1ß production in Pstpip2(cmo) mice remain to be identified. In addition, the environmental factors driving IL-1ß-dependent inflammatory bone erosion are unknown. Here we show that the intestinal microbiota of diseased Pstpip2(cmo) mice was characterized by an outgrowth of Prevotella. Notably, Pstpip2(cmo) mice that were fed a diet rich in fat and cholesterol maintained a normal body weight, but were markedly protected against inflammatory bone disease and bone erosion. Diet-induced protection against osteomyelitis was accompanied by marked reductions in intestinal Prevotella levels and significantly reduced pro-IL-1ß expression in distant neutrophils. Furthermore, pro-IL-1ß expression was also decreased in Pstpip2(cmo) mice treated with antibiotics, and in wild-type mice that were kept under germ-free conditions. We further demonstrate that combined deletion of caspases 1 and 8 was required for protection against IL-1ß-dependent inflammatory bone disease, whereas the deletion of either caspase alone or of elastase or neutrophil proteinase 3 failed to prevent inflammatory disease. Collectively, this work reveals diet-associated changes in the intestinal microbiome as a crucial factor regulating inflammasome- and caspase-8-mediated maturation of IL-1ß and osteomyelitis in Pstpip2(cmo) mice.

Critical role for inflammasome-independent IL-1ß production in osteomyelitis.

The immune system plays an important role in the pathophysiology of many acute and chronic bone disorders, but the specific inflammatory networks that regulate individual bone disorders remain to be elucidated. Here, we characterized the osteoimmunological underpinnings of osteolytic bone disease in Pstpip2(cmo) mice. These mice carry a homozygous L98P missense mutation in the Pombe Cdc15 homology family phosphatase PSTPIP2 that is responsible for the development of a persistent autoinflammatory disease resembling chronic recurrent multifocal osteomyelitis in humans. We found that improper regulation of IL-1ß production resulted in secondary induction of inflammatory cytokines, inflammatory cell infiltration in the bone, and unremitting bone inflammation. Aberrant Il1ß expression precedes the development of osteolytic damage in young Pstpip2(cmo) mice, and genetic deletion of Il1r and Il1ß, but not Il1α, rescued osteolytic bone disease in mutant mice. Intriguingly, caspase-1 and nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 activation in the inflammasome complex were dispensable for Pstpip2(cmo)-mediated bone disease. Thus, our findings establish a critical role for inflammasome-independent production of IL-1ß in osteolytic bone disease and identify PSTPIP2 as a negative regulator of caspase-1-autonomous IL-1ß production.

Deletion of MCL-1 causes lethal cardiac failure and mitochondrial dysfunction.

MCL-1 is an essential BCL-2 family member that promotes the survival of multiple cellular lineages, but its role in cardiac muscle has remained unclear. Here, we report that cardiac-specific ablation of Mcl-1 results in a rapidly fatal, dilated cardiomyopathy manifested by a loss of cardiac contractility, abnormal mitochondria ultrastructure, and defective mitochondrial respiration. Strikingly, genetic ablation of both proapoptotic effectors (Bax and Bak) could largely rescue the lethality and impaired cardiac function induced by Mcl-1 deletion. However, while the overt consequences of Mcl-1 loss were obviated by combining with the loss of Bax and Bak, mitochondria from the Mcl-1-, Bax-, and Bak-deficient hearts still revealed mitochondrial ultrastructural abnormalities and displayed deficient mitochondrial respiration. Together, these data indicate that merely blocking cell death is insufficient to completely overcome the need for MCL-1 function in cardiomyocytes and suggest that in cardiac muscle, MCL-1 also facilitates normal mitochondrial function. These findings are important, as specific MCL-1-inhibiting therapeutics are being proposed to treat cancer cells and may result in unexpected cardiac toxicity.

Th-MYCN mice with caspase-8 deficiency develop advanced neuroblastoma with bone marrow metastasis.

Neuroblastoma, the most common extracranial pediatric solid tumor, is responsible for 15% of all childhood cancer deaths. Patients frequently present at diagnosis with metastatic disease, particularly to the bone marrow. Advances in therapy and understanding of the metastatic process have been limited due, in part, to the lack of animal models harboring bone marrow disease. The widely used transgenic model, the Th-MYCN mouse, exhibits limited metastasis to this site. Here, we establish the first genetic immunocompetent mouse model for metastatic neuroblastoma with enhanced secondary tumors in the bone marrow. This model recapitulates 2 frequent alterations in metastatic neuroblastoma, overexpression of MYCN and loss of caspase-8 expression. Mouse caspase-8 gene was deleted in neural crest lineage cells by crossing a Th-Cre transgenic mouse with a caspase-8 conditional knockout mouse. This mouse was then crossed with the neuroblastoma prone Th-MYCN mouse. Although overexpression of MYCN by itself rarely caused bone marrow metastasis, combining MYCN overexpression and caspase-8 deletion significantly enhanced bone marrow metastasis (37% incidence). Microarray expression studies of the primary tumors mRNAs and microRNAs revealed extracellular matrix structural changes, increased expression of genes involved in epithelial to mesenchymal transition, inflammation, and downregulation of miR-7a and miR-29b. These molecular changes have been shown to be associated with tumor progression and activation of the cytokine TGF-ß pathway in various tumor models. Cytokine TGF-ß can preferentially promote single cell motility and blood-borne metastasis and therefore activation of this pathway may explain the enhanced bone marrow metastasis observed in this animal model.