26 results on '"Gabriel M. Pagnotti"'
Search Results
2. Low-Magnitude Mechanical Signals Combined with Zoledronic Acid Reduce Musculoskeletal Weakness and Adiposity in Estrogen-Deprived Mice
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Gabriel M. Pagnotti, Trupti Trivedi, Laura E. Wright, Sutha K. John, Sreemala Murthy, Ryan R. Pattyn, Monte S. Willis, Yun She, Sukanya Suresh, William R. Thompson, Clinton T. Rubin, Khalid S. Mohammad, and Theresa A. Guise
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Article - Abstract
Combination treatment of Low-Intensity Vibration (LIV) with zoledronic acid (ZA) was hypothesized to preserve bone mass and muscle strength while reducing adipose tissue accrual associated with complete estrogen (E2)-deprivation in young and skeletally mature mice. Complete E2-deprivation (surgical-ovariectomy (OVX) and daily injection of aromatase inhibitor (AI) letrozole) were performed on 8-week-old C57BL/6 female mice for 4 weeks following commencement of LIV administration or control (no LIV), for 28 weeks. Additionally, 16-week-old C57BL/6 female E2-deprived mice were administered ±LIV twice daily and supplemented with ±ZA (2.5 ng/kg/week). By week 28, lean tissue mass quantified by dual-energy X-ray absorptiometry was increased in younger OVX/AI+LIV(y) mice, with increased myofiber cross-sectional area of quadratus femorii. Grip strength was greater in OVX/AI+LIV(y) mice than OVX/AI(y) mice. Fat mass remained lower in OVX/AI+LIV(y) mice throughout the experiment compared with OVX/AI(y) mice. OVX/AI+LIV(y) mice exhibited increased glucose tolerance and reduced leptin and free fatty acids than OVX/AI(y) mice. Trabecular bone volume fraction and connectivity density increased in the vertebrae of OVX/AI+LIV(y) mice compared to OVX/AI(y) mice; however, this effect was attenuated in the older cohort of E2-deprived mice, specifically in OVX/AI+ZA mice, requiring combined LIV with ZA to increase trabecular bone volume and strength. Similar improvements in cortical bone thickness and cross-sectional area of the femoral mid-diaphysis were observed in OVX/AI+LIV+ZA mice, resulting in greater fracture resistance. Our findings demonstrate that the combination of mechanical signals in the form of LIV and anti-resorptive therapy via ZA improve vertebral trabecular bone and femoral cortical bone, increase lean mass, and reduce adiposity in mice undergoing complete E2-deprivation.One Sentence Summary:Low-magnitude mechanical signals with zoledronic acid suppressed bone and muscle loss and adiposity in mice undergoing complete estrogen deprivation.Translational RelevancePostmenopausal patients with estrogen receptor-positive breast cancer treated with aromatase inhibitors to reduce tumor progression experience deleterious effects to bone and muscle subsequently develop muscle weakness, bone fragility, and adipose tissue accrual. Bisphosphonates (i.e., zoledronic acid) prescribed to inhibit osteoclast-mediated bone resorption are effective in preventing bone loss but may not address the non-skeletal effects of muscle weakness and fat accumulation that contribute to patient morbidity. Mechanical signals, typically delivered to the musculoskeletal system during exercise/physical activity, are integral for maintaining bone and muscle health; however, patients undergoing treatments for breast cancer often experience decreased physical activity which further accelerates musculoskeletal degeneration. Low-magnitude mechanical signals, in the form of low-intensity vibrations, generate dynamic loading forces similar to those derived from skeletal muscle contractility. As an adjuvant to existing treatment strategies, low-intensity vibrations may preserve or rescue diminished bone and muscle degraded by breast cancer treatment.
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- 2023
3. Exercise to Mend Aged-tissue Crosstalk in Bone Targeting Osteoporosis & Osteoarthritis
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Clinton T. Rubin, Maya Styner, Eric L. Klett, Sarah E. Little-Letsinger, Gabriel M. Pagnotti, Cody McGrath, Janet Rubin, and Brian O. Diekman
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Senescence ,Osteoporosis ,Osteoblast ,Cell Biology ,Osteoarthritis ,Biology ,medicine.disease ,Bioinformatics ,Crosstalk (biology) ,medicine.anatomical_structure ,Osteoclast ,medicine ,Bone marrow ,Stem cell ,Developmental Biology - Abstract
Aging induces alterations in bone structure and strength through a multitude of processes, exacerbating common aging- related diseases like osteoporosis and osteoarthritis. Cellular hallmarks of aging are examined, as related to bone and the marrow microenvironment, and ways in which these might contribute to a variety of age-related perturbations in osteoblasts, osteocytes, marrow adipocytes, chondrocytes, osteoclasts, and their respective progenitors. Cellular senescence, stem cell exhaustion, mitochondrial dysfunction, epigenetic and intracellular communication changes are central pathways and recognized as associated and potentially causal in aging. We focus on these in musculoskeletal system and highlight knowledge gaps in the literature regarding cellular and tissue crosstalk in bone, cartilage, and the bone marrow niche. While senolytics have been utilized to target aging pathways, here we propose non-pharmacologic, exercise-based interventions as prospective "senolytics" against aging effects on the skeleton. Increased bone mass and delayed onset or progression of osteoporosis and osteoarthritis are some of the recognized benefits of regular exercise across the lifespan. Further investigation is needed to delineate how cellular indicators of aging manifest in bone and the marrow niche and how altered cellular and tissue crosstalk impact disease progression, as well as consideration of exercise as a therapeutic modality, as a means to enhance discovery of bone-targeted therapies.
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- 2022
4. Postural Stability in Obese Preoperative Bariatric Patients Using Static and Dynamic Evaluation
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Kai-Yu Tong, Clinton T. Rubin, Ariel Yang, Amna Haider, M. Ete Chan, Gabriel M. Pagnotti, Catherine Tuppo, Aurora D. Pryor, and Kathryn Cottell
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Adult ,Male ,0301 basic medicine ,obesity ,medicine.medical_specialty ,Health (social science) ,Adolescent ,fall risk ,Postural instability ,lcsh:TX341-641 ,030209 endocrinology & metabolism ,Body Mass Index ,Cohort Studies ,Young Adult ,03 medical and health sciences ,Bariatrics ,0302 clinical medicine ,Physical medicine and rehabilitation ,Center of pressure (terrestrial locomotion) ,Physiology (medical) ,medicine ,Humans ,Postural Balance ,lcsh:RC620-627 ,Physical Therapy Modalities ,Aged ,Balance (ability) ,Involuntary movement ,musculoskeletal health ,030109 nutrition & dietetics ,business.industry ,bariatric intervention ,Middle Aged ,Torso ,medicine.disease ,Obesity ,Obesity, Morbid ,lcsh:Nutritional diseases. Deficiency diseases ,medicine.anatomical_structure ,Preoperative Period ,postural instability ,Cohort ,Postural stability ,Female ,business ,lcsh:Nutrition. Foods and food supply ,Research Article - Abstract
Introduction: Globally, 300 million adults have clinical obesity. Heightened adiposity and inadequate musculature secondary to obesity alter bipedal stance and gait, diminish musculoskeletal tissue quality, and compromise neuromuscular feedback; these physiological changes alter stability and increase injury risk from falls. Studies in the field focus on obese patients across a broad range of body mass indices (BMI >30 kg/m2) but without isolating the most morbidly obese subset (BMI ≥40 kg/m2). We investigated the impact of obesity in perturbing postural stability in morbidly obese subjects elected for bariatric intervention, harboring a higher-spectrum BMI. Subjects and Methods: Traditional force plate measurements and stabilograms are gold standards employed when measuring center of pressure (COP) and postural sway. To quantify the extent of postural instability in subjects with obesity before bariatric surgery, we assessed 17 obese subjects with an average BMI of 40 kg/m2 in contrast to 13 nonobese subjects with an average BMI of 30 kg/m2. COP and postural sway were measured from static and dynamic tasks. Involuntary movements were measured when patients performed static stances, with eyes either opened or closed. Two additional voluntary movements were measured when subjects performed dynamic, upper torso tasks with eyes opened. Results: Mean body weight was 85% (p < 0.001) greater in obese than nonobese subjects. Following static balance assessments, we observed greater sway displacement in the anteroposterior (AP) direction in obese subjects with eyes open (87%, p < 0.002) and eyes closed (76%, p = 0.04) versus nonobese subjects. Obese subjects also exhibited a higher COP velocity in static tests when subjects’ eyes were open (47%, p = 0.04). Dynamic tests demonstrated no differences between groups in sway displacement in either direction; however, COP velocity in the mediolateral (ML) direction was reduced (31%, p < 0.02) in obese subjects while voluntarily swaying in the AP direction, but increased in the same cohort when swaying in the ML direction (40%, p < 0.04). Discussion and Conclusion: Importantly, these data highlight obesity’s contribution towards increased postural instability. Obese subjects exhibited greater COP displacement at higher AP velocities versus nonobese subjects, suggesting that clinically obese individuals show greater instability than nonobese subjects. Identifying factors contributory to instability could encourage patient-specific physical therapies and presurgical measures to mitigate instability and monitor postsurgical balance improvements.
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- 2020
5. Translational Strategies to Target Metastatic Bone Disease
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Gabriel M. Pagnotti, Trupti Trivedi, and Khalid S. Mohammad
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Humans ,Bone Neoplasms ,General Medicine ,Bone Remodeling - Abstract
Metastatic bone disease is a common and devastating complication to cancer, confounding treatments and recovery efforts and presenting a significant barrier to de-escalating the adverse outcomes associated with disease progression. Despite significant advances in the field, bone metastases remain presently incurable and contribute heavily to cancer-associated morbidity and mortality. Mechanisms associated with metastatic bone disease perpetuation and paralleled disruption of bone remodeling are highlighted to convey how they provide the foundation for therapeutic targets to stem disease escalation. The focus of this review aims to describe the preclinical modeling and diagnostic evaluation of metastatic bone disease as well as discuss the range of therapeutic modalities used clinically and how they may impact skeletal tissue.
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- 2022
6. Combating osteoporosis and obesity with exercise: leveraging cell mechanosensitivity
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Vihitaben S. Patel, Gabriel M. Pagnotti, Janet Rubin, Clinton T. Rubin, Maya Styner, Gunes Uzer, Laura E. Wright, Kirsten K. Ness, and Theresa A. Guise
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0301 basic medicine ,Aging ,Anabolism ,Endocrinology, Diabetes and Metabolism ,Osteoporosis ,Population ,030209 endocrinology & metabolism ,Bioinformatics ,Article ,Childhood obesity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Endocrinology ,Adipocyte ,Adipocytes ,medicine ,Animals ,Humans ,Obesity ,Bone Resorption ,Muscle, Skeletal ,education ,Exercise ,education.field_of_study ,Osteoblasts ,business.industry ,Stem Cells ,Body Weight ,Type 2 Diabetes Mellitus ,medicine.disease ,030104 developmental biology ,chemistry ,Stem cell ,business - Abstract
Osteoporosis, a condition of skeletal decline that undermines quality of life, is treated with pharmacological interventions that are associated with poor adherence and adverse effects. Complicating efforts to improve clinical outcomes, the incidence of obesity is increasing, predisposing the population to a range of musculoskeletal complications and metabolic disorders. Pharmacological management of obesity has yet to deliver notable reductions in weight and debilitating complications are rarely avoided. By contrast, exercise shows promise as a non-invasive and non-pharmacological method of regulating both osteoporosis and obesity. The principal components of exercise - mechanical signals - promote bone and muscle anabolism while limiting formation and expansion of fat mass. Mechanical regulation of bone and marrow fat might be achieved by regulating functions of differentiated cells in the skeletal tissue while biasing lineage selection of their common progenitors - mesenchymal stem cells. An inverse relationship between adipocyte versus osteoblast fate selection from stem cells is implicated in clinical conditions such as childhood obesity and increased marrow adiposity in type 2 diabetes mellitus, as well as contributing to skeletal frailty. Understanding how exercise-induced mechanical signals can be used to improve bone quality while decreasing fat mass and metabolic dysfunction should lead to new strategies to treat chronic diseases such as osteoporosis and obesity.
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- 2019
7. Exercise and Diet: Uncovering Prospective Mediators of Skeletal Fragility in Bone and Marrow Adipose Tissue
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Maya Styner, Sarah E. Little-Letsinger, Cody McGrath, and Gabriel M. Pagnotti
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0301 basic medicine ,medicine.medical_specialty ,Calorie ,Bioenergetics ,Endocrinology, Diabetes and Metabolism ,Calorie restriction ,Adipose tissue ,030209 endocrinology & metabolism ,Anorexia ,Bone and Bones ,Article ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Bone Density ,Bone Marrow ,Internal medicine ,Bone cell ,medicine ,Adipocytes ,Animals ,Humans ,Exercise ,business.industry ,medicine.disease ,Obesity ,Diet ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,medicine.symptom ,business ,Energy Metabolism - Abstract
PURPOSE OF REVIEW: To highlight recent basic, translational, and clinical work demonstrating exercise and diet regulation of marrow adipose tissue (MAT) and bone, and how this informs current understanding of the relationship between marrow adiposity and musculoskeletal health. RECENT FINDINGS: Marrow adipocytes accumulate in bone in the setting of hypercaloric intake (calorie excess; e.g. diet-induced obesity), but also with hypocaloric intake (calorie restriction; e.g. anorexia), despite the fact that these states affect bone differently. With hypercaloric intake, bone quantity is largely unaffected whereas with hypocaloric intake, bone quantity and quality are greatly diminished. Voluntary running exercise in rodents was found to lower MAT and promote bone in eucaloric and hypercaloric states, while degrading bone in hypocaloric states, suggesting differential modulation of MAT and bone, dependent upon whole body energy status. Energy status alters bone metabolism and bioenergetics via substrate availability or excess, which plays a key role in the response of bone and MAT to mechanical stimuli. SUMMARY: Marrow adipose tissue (MAT) is a fat depot with a potential role in – as well as responsivity to – whole body energy metabolism. Understanding the localized function of this depot in bone cell bioenergetics and substrate storage, principally in the exercised state, will aid to uncover putative therapeutic targets for skeletal fragility.
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- 2020
8. Mechanical suppression of breast cancer cell invasion and paracrine signaling to osteoclasts requires nucleo-cytoskeletal connectivity
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Gabriel M. Pagnotti, Xin Yi, Gunes Uzer, William R. Thompson, Uma Sankar, Khalid S. Mohammad, Theresa A. Guise, Joseph M. Wallace, Laura E. Wright, Katherine M Powell, and Clinton T. Rubin
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Gene knockdown ,Histology ,lcsh:QP1-981 ,biology ,Physiology ,Chemistry ,Endocrinology, Diabetes and Metabolism ,LINC complex ,Cancer ,medicine.disease ,Article ,lcsh:Physiology ,Bone quality and biomechanics ,Cell biology ,Paracrine signalling ,medicine.anatomical_structure ,lcsh:Biology (General) ,Osteoclast ,RANKL ,Cancer cell ,Bone cancer ,medicine ,biology.protein ,Secretion ,lcsh:QH301-705.5 - Abstract
Exercise benefits the musculoskeletal system and reduces the effects of cancer. The effects of exercise are multifactorial, where metabolic changes and tissue adaptation influence outcomes. Mechanical signals, a principal component of exercise, are anabolic to the musculoskeletal system and restrict cancer progression. We examined the mechanisms through which cancer cells sense and respond to low-magnitude mechanical signals introduced in the form of vibration. Low-magnitude, high-frequency vibration was applied to human breast cancer cells in the form of low-intensity vibration (LIV). LIV decreased matrix invasion and impaired secretion of osteolytic factors PTHLH, IL-11, and RANKL. Furthermore, paracrine signals from mechanically stimulated cancer cells, reduced osteoclast differentiation and resorptive capacity. Disconnecting the nucleus by knockdown of SUN1 and SUN2 impaired LIV-mediated suppression of invasion and osteolytic factor secretion. LIV increased cell stiffness; an effect dependent on the LINC complex. These data show that mechanical vibration reduces the metastatic potential of human breast cancer cells, where the nucleus serves as a mechanosensory apparatus to alter cell structure and intercellular signaling.
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- 2020
9. Role of Osteoblasts in Cancer-Induced Bone Disease
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Gabriel M. Pagnotti, Silvia Marino, Daniela N. Petrusca, Teresita Bellido, G. David Roodman, and Jesus Delgado-Calle
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- 2020
10. The Role of TGF-β in Bone Metastases
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Theresa A. Guise, Trupti Trivedi, Khalid S. Mohammad, and Gabriel M. Pagnotti
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TGF-β therapeutic targets ,Epithelial-Mesenchymal Transition ,Angiogenesis ,transforming growth factor-β (TGF-β) ,Cell ,Bone Neoplasms ,Review ,Microbiology ,Biochemistry ,Bone and Bones ,Bone resorption ,Prostate cancer ,immune cells ,Immune system ,bone metastases ,Transforming Growth Factor beta ,medicine ,Humans ,programmed cell death ligand (PD-L1) ,check-point inhibitors ,Molecular Biology ,business.industry ,Cancer ,medicine.disease ,QR1-502 ,medicine.anatomical_structure ,Cancer cell ,Cancer research ,business ,bone resorption ,Transforming growth factor - Abstract
Complications associated with advanced cancer are a major clinical challenge and, if associated with bone metastases, worsen the prognosis and compromise the survival of the patients. Breast and prostate cancer cells exhibit a high propensity to metastasize to bone. The bone microenvironment is unique, providing fertile soil for cancer cell propagation, while mineralized bone matrices store potent growth factors and cytokines. Biologically active transforming growth factor β (TGF-β), one of the most abundant growth factors, is released following tumor-induced osteoclastic bone resorption. TGF-β promotes tumor cell secretion of factors that accelerate bone loss and fuel tumor cells to colonize. Thus, TGF-β is critical for driving the feed-forward vicious cycle of tumor growth in bone. Further, TGF-β promotes epithelial-mesenchymal transition (EMT), increasing cell invasiveness, angiogenesis, and metastatic progression. Emerging evidence shows TGF-β suppresses immune responses, enabling opportunistic cancer cells to escape immune checkpoints and promote bone metastases. Blocking TGF-β signaling pathways could disrupt the vicious cycle, revert EMT, and enhance immune response. However, TGF-β’s dual role as both tumor suppressor and enhancer presents a significant challenge in developing therapeutics that target TGF-β signaling. This review presents TGF-β’s role in cancer progression and bone metastases, while highlighting current perspectives on the therapeutic potential of targeting TGF-β pathways.
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- 2021
11. The Novel Role of Checkpoint Inhibitor PD-1H/VISTA in Osteoclast Activation and Multiple Myeloma Bone Disease
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Suzanne Lentzsch, Huihui Ma, Shirong Li, Lewis M. Brown, Jun Yang, Jing Fu, Stephen J. Weiss, Markus Y. Mapara, and Gabriel M. Pagnotti
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Bone disease ,business.industry ,Immune checkpoint inhibitors ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Osteoclast ,Cancer research ,Medicine ,business ,Multiple myeloma - Abstract
Introduction Multiple myeloma (MM)-induced bone disease remains one of its most devastating complications, caused by increased bone resorption by overactivated osteoclasts coupled with impaired bone formation. MM cells produce osteoclast-activating factors that induce osteoclast activation and extensive bone resorption. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor that is highly secreted by MM cells (Fu J etc. JCI. 2016). We also identified that the checkpoint inhibitor, programmed death-1 homolog (PD-1H/VISTA), serves as the MMP-13 receptor in osteoclasts and mediates MMP-13-dependent osteoclastogenic function which is largely blocked in Pd-1h -/-osteoclasts (Fu J etc. ASH 2019, 2020). While the inhibitory role of PD-1H/VISTA in T-cells has recently been described (ElTanbouly MA etc. Science 2020), its cellular binding proteins remain unclear, and its role in osteoclast activation andMM bone disease have not been addressed. Methods and Results To identify its interacting proteins, PD-1H-His 6 recombinant protein was expressed in mouse bone marrow mononuclear cells, the associated proteins pulled down by Ni-NTA agarose beads from cell lysates and identified by mass spectrometry. Functional annotation charting of the 75 proteins enriched in PD-1H pull-down samples (with signal ratio of PD-1H-His 6 pull-down vs control >2) indicated that almost 30% of the interacting targets were either cytoskeletal or cytoskeleton-associated proteins. Given that the F-actin cytoskeleton undergoes dynamic reorganization during osteoclast differentiation and plays critical roles in bone resorption, we further addressed the role of PD-1H in F-actin cytoskeleton regulation. Initially, osteoclasts form F-actin-rich adhesive structures, termed podosomes. At later stages, podosomes collectively rearrange into clusters and rings and finally into sealing belts to mediate osteoclast spreading, migration and bone resorption (Teitelbaum SL. Ann N Y Acad Sci. 2011). By confocal immunofluorescence microscopy, we found that PD-1H co-localized with F-actin podosome clusters, rings and sealing belts during osteoclast differentiation (Figure 1A). The functional role of PD-1H in F-actin cytoskeleton reorganization was addressed using Pd-1h -/- osteoclast wherein Pd-1h knockout lead to the disruption of podosome clusters at early stages relative to WT controls, while at later stages, Pd-1h -/-osteoclasts exhibited significantly fewer F-actin rings and belts (Figure 1B). Further, binding of MMP-13 to PD-1H increased the number of osteoclasts forming F-actin rings and belts, as well as the size of F-actin belts, which was blocked in Pd-1h -/- osteoclasts. To determine the role of PD-1H in the development of myeloma-induced lytic bone lesions, 5TGM1 myeloma cells were bilaterally intratibially injected into Pd-1h wtRag2 -/- or Pd-1h -/-Rag2 -/- mice (n=10) to induce lytic bone lesions. Three weeks following intratibial 5TGM1 injection, tibiae were harvested for micro-computed tomography. Subsequent quantitative histomorphology analyses of the trabecular and cortical bones confirmed that the knockout of Pd-1h reduced MM-induced bone destruction with significantly less decrease in trabecular bone volume (Tb. [BV/TV]), trabecular bone number (Tb. N.), trabecular bone thickness (Tb. Th.), as well as less increase in trabecular bone spacing (Tb. Sp.) and bone specific surface (Tb. [BS/BV]) compared to Pd-1h wtRag2 -/- mice. Similar effects were observed in cortical bone with less decrease in cortical bone thickness (CT. Th.), cortical bone area fraction (CT. [BA/TA]), and cortical tissue mineral density (CT. TMD) in 5TGM1 bearing Pd-1h -/-Rag2 -/- mice vs Pd-1h wtRag2 -/- mice (Table 1). Conclusions Taken together, our study, for the first time, reveals the novel role of checkpoint inhibitor, PD-1H/VISTA, in osteoclasts and myeloma bone disease. PD-1H associates with cytoskeleton proteins and regulates the F-actin cytoskeleton reorganization which is critical for osteoclast bone resorption activity. Further, PD-1H mediates MMP-13-induced osteoclast fusion, F-actin belts formation, and osteoclast activation. Pd-1h -/-in recipient mice significantly impairs MM-induced bone loss, demonstrating that PD-1H/VISTA plays a critical role in MM bone disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2021
12. OAB-020: The role of checkpoint inhibitor PD-1H/VISTA in Multiple Myeloma bone disease
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Shirong Li, Jun Yang, Gabriel M. Pagnotti, Suzanne Lentzsch, Markus Y. Mapara, Jing Fu, Stephen J. Weiss, and Huihui Ma
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Cancer Research ,Bone disease ,business.industry ,medicine.medical_treatment ,Immunosuppression ,Hematology ,Osteoclast fusion ,medicine.disease ,Bone resorption ,Immune system ,medicine.anatomical_structure ,Oncology ,Osteoclast ,Cancer research ,medicine ,Receptor ,business ,Multiple myeloma - Abstract
Background Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues, and neurological deficits. MM cells secret pro-osteoclastogenic factors which lead to osteoclast (OCL) activation. Our previous work showed that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor highly secreted by MM cells and induces OCL fusion and bone resorption independently of its proteolytic activity (JCI 2016). We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed on OCLs and mediates MMP-13 induced OCL fusion and bone resorption activity (ASH 2019). Bone resorption activity is significantly impaired in Pd-1h-/- OCLs in vitro. However, the function of PD-1H in MM bone disease has not been defined. Methods The role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model. Pd-1h-/-Rag2-/- mice were generated by crossbreeding Pd-1h-/- with Rag2-/- mice. Firefly luciferase-expressing 5TGM1 cells were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=10). 3 weeks later, tibiae were harvested for quantitative micro-CT followed by histological analysis. Results Morphological analyses of trabecular and cortical bones confirmed that Pd-1h-/- recipient mice exhibited significantly less 5TGM1-induced bone loss (P Conclusions Taken together, our study, for the first time, reveals that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation, and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/- mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment.
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- 2021
13. Suppression of cancer-associated bone loss through dynamic mechanical loading
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Theresa A. Guise, William R. Thompson, Gabriel M. Pagnotti, and Clinton T. Rubin
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0301 basic medicine ,Histology ,Physiology ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Bioinformatics ,Mechanotransduction, Cellular ,Article ,Bone and Bones ,Skeletal tissue ,Bone remodeling ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,medicine ,Musculoskeletal tissue ,Humans ,Tumor growth ,Mechanotransduction ,business.industry ,Cancer ,medicine.disease ,Bone Diseases, Metabolic ,030104 developmental biology ,Cancer cell ,Osteoporosis ,Stress, Mechanical ,Secondary osteoporosis ,business - Abstract
Patients afflicted with or being treated for cancer constitute a distinct and alarming subpopulation who exhibit elevated fracture risk and heightened susceptibility to developing secondary osteoporosis. Cancer cells uncouple the regulatory processes central for the adequate regulation of musculoskeletal tissue. Systemically taxing treatments to target tumors or disrupt the molecular elements driving tumor growth place considerable strain on recovery efforts. Skeletal tissue is inherently sensitive to mechanical forces, therefore attention to exercise and mechanical loading as non-pharmacological means to preserve bone during treatment and in post-treatment rehabilitative efforts have been topics of recent focus. This review discusses the dysregulation that cancers and the ensuing metabolic dysfunction that confer adverse effects on musculoskeletal tissues. Additionally, we describe foundational mechanotransduction pathways and the mechanisms by which they influence both musculoskeletal and cancerous cells. Functional and biological implications of mechanical loading at the tissue and cellular levels will be discussed, highlighting the current understanding in the field. Herein, in vitro, translational, and clinical data are summarized to consider the positive impact of exercise and low magnitude mechanical loading on tumor-bearing skeletal tissue.
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- 2021
14. Checkpoint Inhibitor PD-1H/VISTA Mediates MMP-13 Induced Osteoclast Activation and Multiple Myeloma Bone Disease
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Jing Fu, Suzanne Lentzsch, Huihui Ma, Shirong Li, Markus Y. Mapara, Jun Yang, Stephen J. Weiss, and Gabriel M. Pagnotti
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Bone disease ,business.industry ,Immune checkpoint inhibitors ,Immunology ,Cell Biology ,Hematology ,Matrix metalloproteinase ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Osteoclast ,medicine ,Cancer research ,business ,Multiple myeloma - Abstract
Introduction Multiple myeloma (MM) bone disease remains one of the most devastating complications of this incurable cancer, causing bone fractures, pain, mobility issues and neurological deficits. MM cells produce osteoclast-activating factors that induce osteoclast activation, thereby leading to excessive bone resorption and lytic bone lesions1. Our previous work demonstrated that matrix metalloproteinase 13 (MMP-13) is a critical osteoclastogenic factor that is highly secreted by MM cells. MMP-13 induces osteoclast fusion and bone-resorption via a mechanism independent of its proteolytic activity2. We recently reported that MMP-13 binds to checkpoint inhibitor programmed death-1 homolog (PD-1H/VISTA), a surface receptor that is expressed in osteoclasts at high levels3. Binding of MMP-13 to PD-1H/VISTA induces osteoclast fusion and bone resorption activity whereas knockdown or knockout of PD-1H/VISTA largely block MMP-13 mediated effects on osteoclasts3. However, the function of PD-1H inMM bone disease in vitro or in vivo has not been previously defined. Methods and Results To confirm the role of PD-1H in MMP-13 induced bone disease in MM, we first conducted MM-osteoclast trans-well co-culture assay using murine MM cell line, 5TGM1 cells, and bone marrow mononuclear cells from Pd-1h-/- or wild type (WT) mice. 5TGM1 control cells or MMP-13 knockdown 5TGM1 cells were seeded in the upper wells of the transwell plates; while WT or Pd-1h-/- bone marrow mononuclear cells were seeded in the lower wells and cultured for osteoclast differentiation assessed by TRAP staining. Results show that 5TGM1 induced differentiation of WT osteoclasts with significantly increased osteoclast size and nuclei number/osteoclast. Consistent with our previous results2, MMP-13 knockdown blocked the 5TGM1 MM cells-induced activation of WT osteoclasts. In contrast, neither 5TGM1 MM cells nor MMP-13 knockdown cells had significant effects on Pd-1h-/- osteoclasts. Hence, knockout of Pd-1h abrogated MMP-13 mediated MM induction of osteoclasts, indicating that MMP-13/PD-1H interactions are critically involved in MM-induced osteoclast activation. The in vivo role of PD-1H in MM bone disease was investigated using the intratibial 5TGM1 Rag2-/- MM bone disease mice model2. For this purpose, Pd-1h-/-Rag2-/- mice were generated by crossbreeding C57BL/6 Pd-1h-/- with C57BL/6 Rag2-/- mice. 3x105 firefly luciferase expressing 5TGM1 cells (5TGM1-luc) were intratibially injected into age and sex-paired Rag2-/- or Pd-1h-/-Rag2-/- mice (N=5). Tumor progression was monitored by weekly bioluminescence imaging (BLI). 3 weeks after tumor inoculation, tibiae were harvested for quantitative micro-CT, followed by histological analysis. Histological staining showed that intratibial injection of 5TGM1-luc MM cells induced extensive lytic lesions and trabecular bone loss in Rag2-/- mice. In contrast, in Pd-1h-/-Rag2-/- mice,the bone structure was maintained with markedly less bone loss. Morphological analyses of trabecular bone across proximal tibiae further indicated that in Rag2-/- mice, 5TGM1 induced significant changes in bone microarchitecture, with decreased bone volume fraction (bone volume/tissue volume), connective density, trabecular bone numbers, and trabecular bone thickness, as well as increased trabecular bone spacing (Table 1). In contrast, in Pd-1h-/-Rag2-/- mice, 5TGM1 failed to induce significant loss of trabecular bone, confirming the critical role of PD-1H in MM induced bone disease in vivo. Conclusions Taken together, our study, for the first time, reveal that checkpoint inhibitor PD-1H/VISTA is the critical receptor for MMP-13 in osteoclasts, thereby mediating MMP-13-induced osteoclast fusion, activation and bone resorption. MM-induced trabecular bone loss was significantly lower in Pd-1h-/-mice, demonstrating that PD-1H/VISTA plays a critical role in MMP-13-induced MM bone disease. Given the checkpoint role of PD-1H/VISTA in cancer immunosuppression, we further posit that targeting the interaction of MMP-13 and PD-1H may represent a novel therapeutic strategy to treat MM bone disease and modulate the MM immune environment. References 1. Marino S, Petrusca DN, Roodman GD. Br J Pharmacol. 2019;10.1111/bph.14889. 2. Fu J, Li S, Feng R, et al. J Clin Invest. 2016;126(5):1759-1772. 3. Fu J, Li S, Yang C, et al. Blood. 2019; 134 (Supplement_1): 3072. Disclosures Lentzsch: Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Celularity: Consultancy, Other; Magenta: Current equity holder in private company; Karyopharm: Research Funding; Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months.
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- 2020
15. Incorporating Refractory Period in Mechanical Stimulation Mitigates Obesity-Induced Adipose Tissue Dysfunction in Adult Mice
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Gabriel M. Pagnotti, Vihitaben S. Patel, Janet Rubin, Clinton T. Rubin, Danielle M. Frechette, and M. Ete Chan
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0301 basic medicine ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Medicine (miscellaneous) ,Adipose tissue ,030209 endocrinology & metabolism ,Inflammation ,Stimulation ,Carbohydrate metabolism ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Insulin resistance ,Internal medicine ,Medicine ,2. Zero hunger ,Nutrition and Dietetics ,business.industry ,Mesenchymal stem cell ,food and beverages ,medicine.disease ,030104 developmental biology ,Tumor necrosis factor alpha ,medicine.symptom ,Adipocyte hypertrophy ,business - Abstract
Objective The aim of this study was to determine whether inclusion of a refractory period between bouts of low-magnitude mechanical stimulation (LMMS) can curb obesity-induced adipose tissue dysfunction and sequelae in adult mice. Methods A diet-induced obesity model that included a diet with 45% of kilocalories from fat was employed with intention to treat. C57BL/6J mice were weight matched into four groups: low-fat diet (LFD, n = 8), high-fat diet (HFD, n = 8), HFD with one bout of 30-minute LMMS (HFDv, n = 9), and HFD with two bouts of 15-minute LMMS with a 5-hour separation (refractory period, RHFDv, n = 9). Two weeks of diet was followed by 6 weeks of diet plus LMMS. Results HFD and HFDv mice continued gaining body weight and visceral adiposity throughout the experiment, which was mitigated in RHFDv mice. Compared with LFD mice, HFD and HFDv mice had increased rates of adipocyte hypertrophy, increased immune cell infiltration (B cells, T cells, and macrophages) into adipose tissue, increased adipose tissue inflammation (tumor necrosis factor alpha gene expression), and a decreased proportion of mesenchymal stem cells in adipose tissue, all of which were rescued in RHFDv mice. Glucose intolerance and insulin resistance were elevated in HFD and HFDv mice, but not in RHFDv mice, as compared with LFD mice. Conclusions Incorporating a 5-hour refractory period between bouts of LMMS attenuates obesity-induced adipose tissue dysfunction and improves glucose metabolism.
- Published
- 2017
16. Exercise Decreases Marrow Adipose Tissue Through ß-Oxidation in Obese Running Mice
- Author
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Gunes Uzer, Buer Sen, Xiaopeng Zong, Gabriel M. Pagnotti, Martin Styner, Clinton T. Rubin, Zhihui Xie, Maya Styner, Xin Wu, Cody McGrath, and Janet Rubin
- Subjects
0301 basic medicine ,endocrine system ,medicine.medical_specialty ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,medicine.disease ,Obesity ,03 medical and health sciences ,chemistry.chemical_compound ,Basal (phylogenetics) ,030104 developmental biology ,Endocrinology ,chemistry ,Adipocyte ,Internal medicine ,Perilipin ,medicine ,Lipolysis ,Orthopedics and Sports Medicine ,business ,S oxidation ,Beta oxidation - Abstract
The relationship between marrow adipose tissue (MAT) and bone health is poorly understood. We used running exercise to ask whether obesity-associated MAT can be attenuated via exercise and whether this correlates with gains in bone quantity and quality. C57BL/6 mice were divided into diet-induced obesity (DIO, n = 14) versus low-fat diet (LFD, n = 14). After 3 months, 16-week-old mice were allocated to an exercise intervention (LFD-E, DIO-E) or a control group (LFD, DIO) for 6 weeks (4 groups, n = 7/group). Marrow adipocyte area was 44% higher with obesity (p
- Published
- 2017
17. Autologous augmentation of hiatal hernia repair with filtered platelet concentrate improves tissue remodeling in a swine model
- Author
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Gabriel M. Pagnotti, Angelique Corthals, Maria S. Altieri, Dana A. Telem, Kenneth R. Shroyer, Aurora D. Pryor, and Mark A. Talamini
- Subjects
Blood Platelets ,medicine.medical_specialty ,Swine ,Inflammation ,Platelet Transfusion ,03 medical and health sciences ,0302 clinical medicine ,Vascularity ,Internal medicine ,Ultimate tensile strength ,medicine ,Animals ,Platelet ,Herniorrhaphy ,Hiatal hernia repair ,Wound Healing ,business.industry ,Hepatology ,Platelet Activation ,Surgery ,Disease Models, Animal ,Hernia, Hiatal ,030220 oncology & carcinogenesis ,Female ,030211 gastroenterology & hepatology ,Analysis of variance ,Leukocyte Reduction Procedures ,medicine.symptom ,business ,Abdominal surgery - Abstract
Autologus augmentation of wound remodeling with platelet concentrate is a burgeoning field with promising results. We hypothesized that the addition of filtered platelet concentrate (fPC) to an acellular biologic graft would improve crural healing and tissue integrity in hiatal hernia repair. Sixteen healthy Yorkshire female pigs were divided into three groups: hiatus repair (HR) (n = 7), HR with biologic graft (HRM; n = 8, and HR with biologic graft and fPC (fPC; n = 9). Surgeries were performed by a single surgeon. Animals were euthanized at 8 weeks, and the distal esophagus with hiatus was harvested en-block. Tissue was graded by a histopathologist on collagen deposition, vascularization, and inflammation at the graft–hiatal interface. Tensile strength testing was performed using the Teststar IIs (MTS), coupled with a strain extensometer (Epsilon). Samples of equal dimensions were preloaded to 1 N and deformed at a constant rate of 0.2 mm/s. Statistical analysis was performed via Kruskal–Wallis one-way analysis of variance. Aspirate analysis revealed a mean platelet count of 3 million platelets/1 mL of aspirate. Animals in the fPC group had significantly increased mean chronic inflammation (3.1 ± 1.1 vs. 1.8 ± 1.6, 1.2 ± 1.2, p = 0.04) compared to HR alone and HR + biologic graft. Vascular deposition did not differ between groups (p = 0.8). A trend toward increased collagen deposition was demonstrated for the fPC group (1.4 ± 1.1 vs. 2.0 ± 0.6 in HR group and 3.0 ± 1.2 in HRM group, p = 0.06). There was a statistically significant increase in tensile strength, yield force, and Young’s modulus in the fPC group compared with HR and HR + biologic mesh (p
- Published
- 2016
18. Impact of a Long-Term High Fat Diet on Bone Microarchitecture and Muscle Structure in Adult Male and Female Normal Mice
- Author
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Sutha John, Gabriel M. Pagnotti, Yun She, Weston He, Trupti Trivedi, Jack Truitt, Khalid S. Mohammad, Sreemala Murthy, and Theresa A. Guise
- Subjects
Bone mineral ,medicine.medical_specialty ,Medullary cavity ,business.industry ,Muscle weakness ,Ocean Engineering ,Histology ,medicine.disease ,Endocrinology ,medicine.anatomical_structure ,Insulin resistance ,Osteoclast ,Internal medicine ,Cohort ,medicine ,Myocyte ,medicine.symptom ,business - Abstract
Background and Hypothesis: Hyperglycemia is a major source of disease and morbidity among the adult population. Prior studies correlate long-term high fat diet (HFD) mediated hyperglycemia with bone fragility and muscle weakness. Furthermore, the mechanism driving hyperglycemia between sexes are unknown. Our group previously showed that HFDs induced insulin resistance in male mice and glucose intolerance in female mice. This establishes the need to study the impact of long-term HFDs on the bones and muscles using an older cohort of both male and female mice. For that, we hypothesized a long-term HFD mediated hyperglycemia will change bone and muscle structures and impair their functions in adult male and female mice. Experimental Design or Project Methods: 22-week C57Bl6 mice were fed either a HFD or low fat diet (LFD) for 25 weeks. After euthanasia, bones and muscles were harvested and evaluated using MicroCT, histology, and mechanical testing. Statistical analysis was performed using GraphPad Prism with p
- Published
- 2019
19. Impact of excess TGFβ on bone and muscle in condition of diet-induced obesity in mice with Camurati-Engelmann Disease
- Author
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Theresa A. Guise, Khalid M. Mohammad, Trupti Trivedi, Asma S. Bahrami, and Gabriel M. Pagnotti
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,Medicine ,Ocean Engineering ,Camurati–Engelmann disease ,business ,medicine.disease ,Obesity - Abstract
Background and Hypothesis: Camurati-Engelmann Disease (CED) is characterized by extreme bone turnover and excess TGF-β release. We previously showed that bone-derived TGF-β causes glucose intolerance, increases skeletal muscle weakness, and exacerbates diet-induced obesity in CED mice. However, it is unknown whether glucose intolerance and obesity alter bone and muscle phenotypes. Thus, we hypothesized that impaired glucose metabolism and diet-induced obesity exacerbate bone and muscle loss in a mouse model of CED. Experimental Design: 45-week WT and CED mice were fed either high-fat diet (HFD) or low-fat diet (LFD) for 15 weeks. Ex vivo bone micro-CT and histomorphometry were used to evaluate bone and muscle. Statistical analysis was performed using GraphPad Prism with p
- Published
- 2018
20. Quantifying the effects of mechanical signals on musculoskeletal quality in a model of complete estrogen deprivation
- Author
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Theresa A. Guise, Gabriel M. Pagnotti, Khalid S. Mohammad, and Reid Wilson
- Subjects
business.industry ,media_common.quotation_subject ,Medicine ,Ocean Engineering ,Quality (business) ,business ,Estrogen deprivation ,Bioinformatics ,hormones, hormone substitutes, and hormone antagonists ,media_common - Abstract
Background and Hypothesis: Post-menopausal, estrogen-receptor positive breast cancer patients are treated with aromatase inhibitors (AIs) to limit tumor progression; however, this causes adverse musculoskeletal effects. Zoledronic acid (ZA) is prescribed to inhibit bone resorption. Mechanical signals, delivered via low intensity vibration (LIV), stimulate bone formation. We hypothesize that combining LIV with ZA will mitigate bone loss in a murine model of complete estrogen-deprivation more effectively than either treatment alone. Project Methods: 21-week-old C57BL/6 mice (n=20/group) were ovariectomized, receiving daily letrozole injections (OVX/AI) with LIV (OVX/AI+LIV), ZA (OVX/AI+ZA), LIV and ZA (OVX/AI+LIV/ZA) or underwent sham surgery with daily PBS (vehicle) injections (SH-OVX) for 22 weeks. Longitudinal dual energy X-ray absorptiometry (DEXA) and micro-computed tomography scans were analyzed for changes in body composition and bone microarchitecture, respectively. Results: OVX/AI reduced whole body (p< 0.0001) and lumbar spine (p
- Published
- 2018
21. B7-H4 is Inversely Correlated With T-Cell Infiltration in Clear Cell but Not Serous or Endometrioid Ovarian Cancer
- Author
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Ali Akalin, Mallory B. Korman, Gabriel M. Pagnotti, Richard M. Atkinson, Jamie L. Romeiser, and Kenneth R. Shroyer
- Subjects
0301 basic medicine ,Oncology ,CD4-Positive T-Lymphocytes ,medicine.medical_specialty ,Histology ,T cell ,Biology ,CD8-Positive T-Lymphocytes ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,Carcinoma ,medicine ,Humans ,Ovarian Neoplasms ,Tumor-infiltrating lymphocytes ,Cystadenofibroma ,V-Set Domain-Containing T-Cell Activation Inhibitor 1 ,medicine.disease ,Neoplasm Proteins ,Medical Laboratory Technology ,Serous fluid ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Female ,Ovarian cancer ,Carcinoma, Endometrioid ,Clear cell ,CD8 - Abstract
B7-H4, a tumor-associated cell surface protein, is expressed in endometrioid (EM), serous (SE), and clear cell (CC) ovarian carcinomas. Prior in vitro studies from other groups indicated that elevated B7-H4 expression by tumor cells blocks T-cell activation; therefore, it had been postulated to play a role in shielding cancer cells from immune surveillance and averting apoptotic programs. To test the validity of these hypotheses, the present study was designed to compare the immunohistochemical staining intensity of B7-H4 in tumor cells of ovarian cancers with the number of tumor-infiltrating T cells and macrophages and with the levels of caspase-3 staining in apoptotic debris. Serial tissue sections from EM, SE, and CC carcinomas were analyzed across representative cross-sections of tumor resection specimens, demonstrating different levels of B7-H4 expression, highest in CC cancers. B7-H4 staining in CC tissue sections was significantly correlated with the number of CD3, CD4, and CD8 tumor-infiltrating T cells and with the number of CD14 tumor-infiltrating macrophages, but was not significantly related to caspase-3 staining. These results support the concept that high levels of B7-H4 expression are inversely correlated with tumor T-cell infiltration and with CD14-labeled macrophages but not caspase-3 expression in CC carcinomas. We did not, however, find clear evidence of a relationship between the lower levels of B7-H4 seen in EM and SE carcinomas and T cell or macrophage infiltration. Thus, high levels of B7-H4, as seen in CC carcinomas, is associated with decreased tumor infiltration by T cells and macrophages but the lower levels of expression, as observed in EM and SE carcinomas, appear less likely to play an effective role in protection from immune surveillance. Furthermore, we found no evidence of a correlation between B7-H4 expression and apoptosis. These findings highlight the importance of further investigation of B7-H4 as an immunomodulatory protein, to support the development of novel therapeutic interventions for improved efficacy of treatments for CC carcinoma.
- Published
- 2017
22. Incorporating Refractory Period in Mechanical Stimulation Mitigates Obesity-Induced Adipose Tissue Dysfunction in Adult Mice
- Author
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Vihitaben S, Patel, M Ete, Chan, Gabriel M, Pagnotti, Danielle M, Frechette, Janet, Rubin, and Clinton T, Rubin
- Subjects
Male ,Mice, Inbred C57BL ,Mice ,chronic inflammation ,immunosuppression ,Adipose Tissue ,adipocyte hypertrophy ,low intensity vibration ,Animals ,Obesity ,Article - Abstract
The aim of this study was to determine whether inclusion of a refractory period between bouts of low-magnitude mechanical stimulation (LMMS) can curb obesity-induced adipose tissue dysfunction and sequelae in adult mice.A diet-induced obesity model that included a diet with 45% of kilocalories from fat was employed with intention to treat. C57BL/6J mice were weight matched into four groups: low-fat diet (LFD, n = 8), high-fat diet (HFD, n = 8), HFD with one bout of 30-minute LMMS (HFDv, n = 9), and HFD with two bouts of 15-minute LMMS with a 5-hour separation (refractory period, RHFDv, n = 9). Two weeks of diet was followed by 6 weeks of diet plus LMMS.HFD and HFDv mice continued gaining body weight and visceral adiposity throughout the experiment, which was mitigated in RHFDv mice. Compared with LFD mice, HFD and HFDv mice had increased rates of adipocyte hypertrophy, increased immune cell infiltration (B cells, T cells, and macrophages) into adipose tissue, increased adipose tissue inflammation (tumor necrosis factor alpha gene expression), and a decreased proportion of mesenchymal stem cells in adipose tissue, all of which were rescued in RHFDv mice. Glucose intolerance and insulin resistance were elevated in HFD and HFDv mice, but not in RHFDv mice, as compared with LFD mice.Incorporating a 5-hour refractory period between bouts of LMMS attenuates obesity-induced adipose tissue dysfunction and improves glucose metabolism.
- Published
- 2017
23. Exercise Decreases Marrow Adipose Tissue Through ß-Oxidation in Obese Running Mice
- Author
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Maya, Styner, Gabriel M, Pagnotti, Cody, McGrath, Xin, Wu, Buer, Sen, Gunes, Uzer, Zhihui, Xie, Xiaopeng, Zong, Martin A, Styner, Clinton T, Rubin, and Janet, Rubin
- Subjects
endocrine system ,Mice ,Adipose Tissue ,Lipolysis ,Physical Conditioning, Animal ,Adipocytes ,Animals ,Bone Marrow Cells ,Female ,Obesity ,X-Ray Microtomography ,Dietary Fats ,Article - Abstract
The relationship between marrow adipose tissue (MAT) and bone health is poorly understood. We used running exercise to ask whether obesity-associated MAT can be attenuated via exercise and whether this correlates with gains in bone quantity and quality. C57BL/6 mice were divided into diet-induced obesity (DIO, n = 14) versus low-fat diet (LFD, n = 14). After 3 months, 16-week-old mice were allocated to an exercise intervention (LFD-E, DIO-E) or a control group (LFD, DIO) for 6 weeks (4 groups, n = 7/group). Marrow adipocyte area was 44% higher with obesity (p 0.0001) and after exercise 33% lower in LFD (p 0.0001) and 39% lower in DIO (p 0.0001). In LFD, exercise did not affect adipocyte number; however, in DIO, the adipocyte number was 56% lower (p 0.0001). MAT was 44% higher in DIO measured by osmium-μCT, whereas exercise associated with reduced MAT (-23% in LFD, -48% in DIO, p 0.05). MAT was additionally quantified by 9.4TMRI, and correlated with osmium-µCT (r = 0.645; p 0.01). Consistent with higher lipid beta oxidation, perilipin 3 (PLIN3) rose with exercise in tibial mRNA (+92% in LFD, +60% in DIO, p 0.05). Tibial µCT-derived trabecular bone volume (BV/TV) was not influenced by DIO but responded to exercise with an increase of 19% (p 0.001). DIO was associated with higher cortical periosteal and endosteal volumes of 15% (p = 0.012) and 35% (p 0.01), respectively, but Ct.Ar/Tt.Ar was lower by 2.4% (p 0.05). There was a trend for higher stiffness (N/m) in DIO, and exercise augmented this further. In conclusion, obesity associated with increases in marrow lipid-measured by osmium-μCT and MRI-and partially due to an increase in adipocyte size, suggesting increased lipid uptake into preexisting adipocytes. Exercise associated with smaller adipocytes and less bone lipid, likely invoking increased ß-oxidation and basal lipolysis as evidenced by higher levels of PLIN3. © 2017 American Society for Bone and Mineral Research.
- Published
- 2016
24. Low magnitude mechanical signals mitigate osteopenia without compromising longevity in an aged murine model of spontaneous granulosa cell ovarian cancer
- Author
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Benjamin J. Adler, Kenneth R. Shroyer, Danielle E. Green, Janet Rubin, Wesley G. Beamer, Clinton T. Rubin, M. Ete Chan, Danielle M. Frechette, and Gabriel M. Pagnotti
- Subjects
Pathology ,medicine.medical_specialty ,Histology ,Anabolism ,Bone density ,Physiology ,Endocrinology, Diabetes and Metabolism ,Longevity ,Biology ,Vibration ,Article ,Mice ,Bone Marrow ,Internal medicine ,Image Processing, Computer-Assisted ,medicine ,Animals ,Survival analysis ,Granulosa Cell Tumor ,Ovarian Neoplasms ,Tibia ,Mesenchymal stem cell ,virus diseases ,Cancer ,Mesenchymal Stem Cells ,Organ Size ,X-Ray Microtomography ,Flow Cytometry ,medicine.disease ,Survival Analysis ,Hindlimb ,Osteopenia ,Bone Diseases, Metabolic ,Disease Models, Animal ,Endocrinology ,Tumor progression ,Female ,Ovarian cancer - Abstract
Cancer progression is often paralleled by a decline in bone mass, raising risk of fracture. Concerns persist regarding anabolic interventions for skeletal protection, as these may inadvertently exacerbate neoplastic tissue expansion. Given bone's inherent mechanosensitivity, low intensity vibration (LIV), a mechanical signal that encourages osteoblastogenesis, could possibly slow cancer-associated bone loss, but this goal must be achieved without fostering disease progression. Seventy 12w female F1-SWRxSWXJ-9 mice, a strain prone to developing granulosa cell tumors, were randomized into baseline control (BC: n=10), age-matched control (AC: n=30), and LIV (n=30), which received mechanical signals (90Hz @ 0.3g) for 15m/day, 5 day/w over the course of 1 year. Survival curves for AC (10 died) and LIV (8 died) followed similar trends (p=0.62), indicating longevity was unperturbed by LIV. At 1 year, bone volume of proximal tibiae in LIV mice was 25% greater than AC (p
- Published
- 2012
25. Focal enhancement of the skeleton to exercise correlates to mesenchymal stem cell responsivity rather than peak external forces
- Author
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Stefan Judex, Gabriel M. Pagnotti, Lynn E. Copes, Brigitte Demes, Ian J. Wallace, Jasper Rubin-Sigler, Matthew Naeher, and Clinton T. Rubin
- Subjects
education.field_of_study ,Physiology ,Mesenchymal stem cell ,Population ,Hindlimb ,Anatomy ,Aquatic Science ,Biology ,medicine.anatomical_structure ,Insect Science ,medicine ,Animal Science and Zoology ,Cortical bone ,Femur ,Tibia ,Progenitor cell ,Forelimb ,education ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics - Abstract
Force magnitudes have been suggested to drive bone's structural response to exercise. As importantly, the degree to which any given bone can adapt to functional challenges may be enabled, or constrained, by regional variation in the capacity of marrow progenitors to differentiate into bone-forming cells. Here, we investigate the relationship between bone adaptation and mesenchymal stem cell (MSC) responsivity in growing mice subject to exercise. First, using a force plate, we show that peak external forces generated by forelimbs during quadrupedal locomotion are significantly higher than hindlimb forces. Second, by treating mice with treadmill running and then measuring bone structure with μCT, we show that skeletal effects of exercise are site-specific but not defined by load magnitudes. Specifically, in the forelimb, where external forces generated by running were highest, exercise failed to augment diaphyseal structure in either the humerus or radius, nor did it affect humeral trabecular structure. In contrast, in the ulna, femur, and tibia, exercise led to significant enhancements of diaphyseal bone areas and moments of area. Trabecular structure was also enhanced by running in the femur and tibia. Finally, using flow cytometry, we show that marrow-derived MSCs in the femur are more responsive to exercise-induced loads than humeral cells, such that running significantly lowered MSC populations only in the femur. Together, these data suggest that the ability of the progenitor population to differentiate toward osteoblastogenesis may be a better correlate to bone structural adaptation than peak external forces caused by exercise.
- Published
- 2015
26. The association between sleeve gastrectomy and histopathologic changes consistent with esophagitis in a rodent model
- Author
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Dana A. Telem, M. Ete Chan, Gabriel M. Pagnotti, Aurora D. Pryor, Kenneth R. Shroyer, Mark A. Talamini, and Maria S. Altieri
- Subjects
medicine.medical_specialty ,Sleeve gastrectomy ,medicine.medical_treatment ,Gastroenterology ,Severity of Illness Index ,Esophagus ,Gastrectomy ,Internal medicine ,medicine ,Animals ,Esophagitis ,Intestinal Mucosa ,Rats, Wistar ,business.industry ,Confounding ,Reflux ,Rodent model ,medicine.disease ,Prognosis ,Surgery ,Obesity, Morbid ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,GERD ,Analysis of variance ,business ,Follow-Up Studies - Abstract
Background As the association between sleeve gastrectomy (SG) and gastroesophageal reflux disease remains unclear, the aim of this study was to evaluate whether performance of SG impacts the development and severity of esophagitis in a rodent model. Setting: University Hospital. Methods Wistar rats (Charles River Institute, Wilmington, MA) were fed a high fat diet (HFD) for 4 months and then were divided into 3 cohorts of nearly equal mean weight: HFD only (n = 25), sham operation+HFD (n = 29), and SG+HFD (n = 19). Animals were euthanized at 12 weeks. The esophagus was harvested en-bloc and processed for histologic assessment by a board certified pathologist, blinded to the animal treatment group. Reflux was graded by severity and defined as the presence of inflammation in the esophageal squamous mucosa. Results Rats who underwent SG had significantly increased reflux severity, compared with sham and HFD alone (21.1% versus 0% versus 4.5%, P = .02), respectively. No difference was demonstrated in negative, mild, or moderate esophagitis between the control, sham, and sleeve groups. Using nonparametric ANOVA, the mean severity score for severe esophagitis was significantly increased in the SG group versus sham or HFD group (1.5 versus .81 versus 1.36, P = .0202) respectively. Following multinomial logistic regression to assess for confounding variables to the severity scores, final weight, and change in weight, had no effect on severity of esophagitis between the 3 groups (P> .373). Conclusions SG is independently associated with histopathologic changes consistent with severe esophagitis in an animal model, likely secondary to gastroesophageal reflux.
- Published
- 2014
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