NCCN Policy Summit: Cancer Across Geography.

Geographic location of a patient directly impacts access to care, including preventive screenings and early detection. Although there is a higher prevalence of the most common cancers in urban areas, mortality rates are higher in rural communities. Notably, indigenous communities residing on tribal lands often experience heightened access issues and environmental exposure to known and probable human carcinogens. The burdens associated with a cancer diagnosis can be exacerbated by various barriers to accessing quality care; however, there are emerging best practices to overcome these barriers. Understanding the interplay between geography and a patient's access to cancer care services is crucial for addressing existing disparities and ensuring equitable health care provision across regions. By leveraging innovative policy and practice solutions, communities can begin to close care gaps and establish bidirectional trust between patients and providers across the care continuum, which is necessary to enact meaningful reforms. To advance the conversation on geographic disparities and strategies that mitigate associated barriers to care, NCCN hosted the Policy Summit "Cancer Across Geography" on June 15, 2023, at the National Press Club in Washington, DC. Through keynote addresses and multistakeholder panel discussions, this hybrid event explored care imbalances across geography, recent policy and technology advancements, and current challenges associated with cancer care. This created a forum for a diverse group of attendees to thoughtfully discuss policies and practices to advance high-quality, effective, efficient, equitable, and accessible cancer care for all. Speakers and attendees featured multidisciplinary clinicians, epidemiologists, community oncologists, researchers, payers, patient advocates, industry, providers, policymakers, and leaders representing underserved communities, among others.

The Notch pathway regulates the bone gain induced by PTH anabolic signaling.

Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt ) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone-targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.

Examining the Role of Hypothalamus-Derived Neuromedin-U (NMU) in Bone Remodeling of Rats.

Global loss of the neuropeptide Neuromedin-U (NMU) is associated with increased bone formation and high bone mass in male and female mice by twelve weeks of age, suggesting that NMU suppresses osteoblast differentiation and/or activity in vivo. NMU is highly expressed in numerous anatomical locations including the skeleton and the hypothalamus. This raises the possibility that NMU exerts indirect effects on bone remodeling from an extra-skeletal location such as the brain. Thus, in the present study we used microinjection to deliver viruses carrying short-hairpin RNA designed to knockdown Nmu expression in the hypothalamus of 8-week-old male rats and evaluated the effects on bone mass in the peripheral skeleton. Quantitative RT-PCR confirmed approximately 92% knockdown of Nmu in the hypothalamus. However, after six weeks, micro computed tomography on tibiae from Nmu-knockdown rats demonstrated no significant change in trabecular or cortical bone mass as compared to controls. These findings are corroborated by histomorphometric analyses which indicate no differences in osteoblast or osteoclast parameters between controls and Nmu-knockdown samples. Collectively, these data suggest that hypothalamus-derived NMU does not regulate bone remodeling in the postnatal skeleton. Future studies are necessary to delineate the direct versus indirect effects of NMU on bone remodeling.

Conditional Loss of Nmp4 in Mesenchymal Stem Progenitor Cells Enhances PTH-Induced Bone Formation.

Activation of bone anabolic pathways is a fruitful approach for treating severe osteoporosis, yet FDA-approved osteoanabolics, eg, parathyroid hormone (PTH), have limited efficacy. Improving their potency is a promising strategy for maximizing bone anabolic output. Nmp4 (Nuclear Matrix Protein 4) global knockout mice exhibit enhanced PTH-induced increases in trabecular bone but display no overt baseline skeletal phenotype. Nmp4 is expressed in all tissues; therefore, to determine which cell type is responsible for driving the beneficial effects of Nmp4 inhibition, we conditionally removed this gene from cells at distinct stages of osteogenic differentiation. Nmp4-floxed (Nmp4fl/fl ) mice were crossed with mice bearing one of three Cre drivers including (i) Prx1Cre+  to remove Nmp4 from mesenchymal stem/progenitor cells (MSPCs) in long bones; (ii) BglapCre+  targeting mature osteoblasts, and (iii) Dmp1Cre+  to disable Nmp4 in osteocytes. Virgin female Cre+  and Cre- mice (10 weeks of age) were sorted into cohorts by weight and genotype. Mice were administered daily injections of either human PTH 1-34 at 30 µg/kg or vehicle for 4 weeks or 7 weeks. Skeletal response was assessed using dual-energy X-ray absorptiometry, micro-computed tomography, bone histomorphometry, and serum analysis for remodeling markers. Nmp4fl/fl ;Prx1Cre+  mice virtually phenocopied the global Nmp4-/- skeleton in the femur, ie, a mild baseline phenotype but significantly enhanced PTH-induced increase in femur trabecular bone volume/total volume (BV/TV) compared with their Nmp4fl/fl ;Prx1Cre- controls. This was not observed in the spine, where Prrx1 is not expressed. Heightened response to PTH was coincident with enhanced bone formation. Conditional loss of Nmp4 from the mature osteoblasts (Nmp4fl/fl ;BglapCre+ ) failed to increase BV/TV or enhance PTH response. However, conditional disabling of Nmp4 in osteocytes (Nmp4fl/fl ;Dmp1Cre+ ) increased BV/TV without boosting response to hormone under our experimental regimen. We conclude that Nmp4-/- Prx1-expressing MSPCs drive the improved response to PTH therapy and that this gene has stage-specific effects on osteoanabolism. © 2022 American Society for Bone and Mineral Research (ASBMR).

NMUR1 in the NMU-Mediated Regulation of Bone Remodeling.

Neuromedin-U (NMU) is an evolutionarily conserved peptide that regulates varying physiologic effects including blood pressure, stress and allergic responses, metabolic and feeding behavior, pain perception, and neuroendocrine functions. Recently, several lines of investigation implicate NMU in regulating bone remodeling. For instance, global loss of NMU expression in male and female mice leads to high bone mass due to elevated bone formation rate with no alteration in bone resorption rate or observable defect in skeletal patterning. Additionally, NMU treatment regulates the activity of osteoblasts in vitro. The downstream pathway utilized by NMU to carry out these effects is unknown as NMU signals via two G-protein-coupled receptors (GPCRs), NMU receptor 1 (NMUR1), and NMU receptor 2 (NMUR2), and both are expressed in the postnatal skeleton. Here, we sought to address this open question and build a better understanding of the downstream pathway utilized by NMU. Our approach involved the knockdown of Nmur1 in MC3T3-E1 cells in vitro and a global knockout of Nmur1 in vivo. We detail specific cell signaling events (e.g., mTOR phosphorylation) that are deficient in the absence of NMUR1 expression yet trabecular bone volume in femora and tibiae of 12-week-old male Nmur1 knockout mice are unchanged, compared to controls. These results suggest that NMUR1 is required for NMU-dependent signaling in MC3T3-E1 cells, but it is not required for the NMU-mediated effects on bone remodeling in vivo. Future studies examining the role of NMUR2 are required to determine the downstream pathway utilized by NMU to regulate bone remodeling in vivo.

Are human service agencies ready for disasters? Findings from a mixed-methods needs assessment and planning project.

A mixed-methods design was used to assess the current capacity of human service agencies to provide services in a major disaster, identify challenges and successful strategies for providing those services, and formulate specific recommendations for government planners and the nonprofit sector to promote the integration of human service agencies into emergency preparedness and response. A web-based survey was completed by 188 unique human service agencies, 31 semistructured interviews were conducted with human service agency and government leaders from southeastern Pennsylvania and the mid-Atlantic region, and a collaborative planning meeting was held to review the findings and develop systems-based recommendations. Survey results indicated that human service agencies serve the most vulnerable communities during disasters and would welcome integration into preparedness and response plans, but they currently face challenges that include a lack of real-time communication and opportunities for collaborative planning with government partners. Interview findings were grouped according to 5 themes that emerged: capacity, coordination, communication, training, and leadership. This study identified recommendations to assist human service agencies, local health departments, and emergency management agencies as they work to ensure that needed human services are available during disasters, despite the resource challenges that most agencies face.