Correlation-Based Predictions of Gas Solute Diffusivity in Ionic Liquid Solvents Based on Solvent-Accessible Surface Area.

In our prior study [Olowookere, F. V.; Turner, C. H. J. Phys. Chem. B 2023, 127(42), 9144-9154], we introduced a new scaling relationship to predict gas solute diffusion at challenging conditions, focusing on CO2 and SO2 diffusion in multivalent ionic liquid (IL) solvents. This work extends our initial exploratory study into a much broader array of systems, encompassing additional solutes (N2, CH4, C2H6, C3H8, C3H8O, and H2O) and a variety of different ionic liquid species ([Bzmim3]3+, [Bzmim4]4+, [BMIM]+, [EMIM]+, [HMIM]+, [NapO2]2-, [BzO3]3-, [BF4]-, [Tf2N]-, and [PF6]-). Our study demonstrates a remarkably robust logarithmic correlation between solute diffusion and solvent accessible surface area (SA) across 20 different additional systems. We perform comprehensive analyses of the underlying molecular phenomena responsible for this correlation, including solute lifetime distributions, void space dynamics, and Voronoi tessellation, in order to elucidate a stronger mechanistic understanding of this behavior. Our findings highlight a direct link between the solvent accessible SA and the size of the void domains. Overall, our scaling approach provides an efficient and reliable approach for predicting diffusion from analyses of short simulations at higher temperatures.

Understanding Gas Solubility of Pure Component and Binary Mixtures within Multivalent Ionic Liquids from Molecular Simulations.

Understanding the molecular-level solubility of CO2 and its mixtures is essential to the progress of gas-treating technologies. Herein, we use grand canonical Monte Carlo simulations to study the single-component gas absorption of SO2, N2, CH4, and H2 and binary mixtures of CO2/SO2, CO2/N2, CO2/CH4, and CO2/H2 of varying mole fractions within multivalent ionic liquids (ILs). Our results highlight the importance of the free volume effect and the anion effect when interpreting the absorption behavior of these mixtures, similar to the behavior of CO2 found in our previous study (Phys. Chem. Chem. Phys. 2020, 22, 20618-20633). The deviation of gas solubility between the pure component absorption versus the binary absorption, as well as the solubility selectivity, highlights the importance of the relative affinity of gas species within a mixture to the different anions. The absorption selectivity within a specific IL system can be predicted based on the relative gas affinity to the anion.

An updated report on the incidence and epidemiological trends of keratinocyte cancers in the United Kingdom 2013-2018.

Introduction: The most common cancers in the UK are keratinocyte cancers (KCs): the combined term for basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (cSCCs). Registration of KC is challenging due to high numbers and multiplicity of tumours per person. Methods: We provide an updated report on the descriptive epidemiology of trends in KC incidence for the resident populations of UK countries (England, Northern Ireland, Scotland and Wales) using population-based cancer registry and pathology report data, 2013-18. Results: Substantial increases in cSCC incidence in England, Scotland and Northern Ireland can be detected for the period of 2013-18, and the incidence of cSCC also increased in Wales from 2016 to 2018. In contrast, however, the pattern of annual change in the incidence of BCC across the nations differs. In England, the incidence of BCC declined slightly from 2016 to 2018, however, the overall trend across 2013-18 is not statistically significant. In Scotland, the incidence of BCC shows some variability, declining in 2017 before increasing in 2018, and the overall trend across 2013-18 was also not statistically significant. In Northern Ireland, the incidence of BCC increased significantly over the study period, and in Wales, the incidence of BCC increased from 2016 to 2018. One in five people will develop non-melanoma skin cancers (NMSC) in their lifetime in England. This estimate is much higher than the lifetime risk of melanoma (1 in 36 males and 1 in 47 females born after 1960 in the UK), which further highlights the burden of the disease and importance of early prevention strategies. Conclusions: We highlight how common these tumours are by publishing the first ever lifetime incidence of NMSC. Additionally, the first time reporting of the age standardised incidence of KC in Wales further confirms the scale of the disease burden posed by these cancers in the UK. With approximately one in five people developing NMSC in their lifetime, optimisation of skin cancer prevention, management and research are essential.

Molecular Simulation of Ionic Polyimides and Composites with Ionic Liquids as Gas-Separation Membranes.

Polyimides are at the forefront of advanced membrane materials for CO2 capture and gas-purification processes. Recently, ionic polyimides (i-PIs) have been reported as a new class of condensation polymers that combine structural components of both ionic liquids (ILs) and polyimides through covalent linkages. In this study, we report CO2 and CH4 adsorption and structural analyses of an i-PI and an i-PI + IL composite containing [C4mim][Tf2N]. The combination of molecular dynamics (MD) and grand canonical Monte Carlo (GCMC) simulations is used to compute the gas solubility and the adsorption performance with respect to the density, fractional free volume (FFV), and surface area of the materials. Our results highlight the polymer relaxation process and its correlation to the gas solubility. In particular, the surface area can provide meaningful guidance with respect to the gas solubility, and it tends to be a more sensitive indicator of the adsorption behavior versus only considering the system density and FFV. For instance, as the polymer continues to relax, the density, FFV, and pore-size distribution remain constant while the surface area can continue to increase, enabling more adsorption. Structural analyses are also conducted to identify the nature of the gas adsorption once the ionic liquid is added to the polymer. The presence of the IL significantly displaces the CO2 molecules from the ligand nitrogen sites in the neat i-PI to the imidazolium rings in the i-PI + IL composite. However, the CH4 molecules move from the imidazolium ring sites in the neat i-PI to the ligand nitrogen atoms in the i-PI + IL composite. These molecular details can provide critical information for the experimental design of highly selective i-PI materials as well as provide additional guidance for the interpretation of the simulated adsorption systems.

Laparoscopic ventral rectopexy for rectal prolapse and rectal intussusception using a biological mesh.

AIM: Laparoscopic ventral rectopexy (LVR) is a nerve-sparing technique for the treatment of rectal prolapse. Concerns about the use of synthetic meshes in the pelvis and the associated risk of erosion have led to the recent use of biological meshes in some colorectal units. This retrospective study aims to assess the outcomes of patients undergoing LVR using a noncross-linked nondermal biological mesh. METHOD: The medical notes of all patients who underwent LVR between 1 December 2011 and 31 May 2014 were reviewed. The rate of obstructed defaecation before surgery was retrospectively determined from medical records using the Rome III criteria. The rates of obstructed defaecation and faecal incontinence following surgery were determined using a self-reported questionnaire. RESULTS: A total of 51 patients had LVR between 1 December 2011 and 31 May 2014. Their mean age was 57.3 ± 2.5 years and the mean follow-up was 23 ± 1 months. There were seven (13.7%) postoperative complications. In total, 45 (88%) patients completed the functional outcome questionnaires. Before surgery, 33 (73.3%) patients complained of symptoms of obstructed defaecation. At the end of follow-up, 22 (48.8%, P = 0.001) patients continued to have some symptoms of obstructed defaecation. Before surgery, 12 (26.7%) patients complained of faecal incontinence. At the end of follow-up, only three (6.7%, P = 0.004) patients reported faecal incontinence. At the end of follow-up, recurrence of symptoms had occurred in six (13.3%) patients. CONCLUSION: LVR using a biological mesh is safe and results in significant reduction in symptoms associated with external rectal prolapse and rectal intussusception.

Hic-5 remodeling of the stromal matrix promotes breast tumor progression.

The remodeling of the stromal extracellular matrix (ECM) has a crucial, but incompletely understood role during tumor progression and metastasis. Hic-5, a focal adhesion scaffold protein, has previously been implicated in tumor cell invasion, proliferation and metastasis. To investigate the role of Hic-5 in breast tumor progression in vivo, Hic-5-/- mice were generated and crossed with the Mouse Mammary Tumor Virus-Polyoma Middle T-Antigen mouse. Tumors from the Hic-5-/-;PyMT mice exhibited increased latency and reduced growth, with fewer lung metastases, as compared with Hic-5+/-;PyMT mice. Immunohistochemical analysis showed that Hic-5 is primarily expressed in the cancer-associated fibroblasts (CAFs). Further analysis revealed that the Hic-5-/-;PyMT tumor stroma contains fewer CAFs and exhibits reduced ECM deposition. The remodeling of the stromal matrix by CAFs has been shown to increase tumor rigidity to indirectly regulate FAK Y397 phosphorylation in tumor cells to promote their growth and invasion. Accordingly, the Hic-5-/-;PyMT tumor cells exhibited a reduction in FAK Y397 phosphorylation. Isolated Hic-5-/-;PyMT CAFs were defective in stress fiber organization and exhibited reduced contractility. These cells also failed to efficiently deposit and organize the ECM in two and three dimensions. This, in turn, impacted three-dimensional MDA-MB-231 tumor cell migration behavior. Thus, using a new knockout mouse model, we have identified Hic-5 expression in CAFs as a key requirement for deposition and remodeling of the stromal ECM to promote non-cell autonomous breast tumor progression.

Enteral feeding reduces metabolic activity of the intestinal microbiome in Crohn's disease: an observational study.

BACKGROUND/OBJECTIVES: Enteral feeding will induce remission in as many as 80-90% of compliant patients with active Crohn's disease (CD), but its method of action remains uncertain. This study was designed to examine its effects on the colonic microbiome. METHODS/SUBJECTS: Healthy volunteers and patients with CD followed a regimen confined to enteral feeds alone for 1 or 2 weeks, respectively. Chemicals excreted on breath or in faeces were characterised at the start and at the end of the feeding period by gas chromatography/mass spectrometry. RESULTS: One week of feeding in healthy volunteers caused significant changes in stool colour and deterioration in breath odour, together with increased excretion of phenol and indoles on the breath. Feeding for 2 weeks in patients with CD produced significant improvements in symptoms and a decrease in the concentration of C-reactive protein. The faecal concentrations of microbial products, including short-chain fatty acids (SCFAs), and potentially toxic substances, including 1-propanol, 1-butanol and the methyl and ethyl esters of SCFAs, showed significant falls. CONCLUSIONS: A significant change occurs in the production of microbial metabolites after enteral feeding in both healthy volunteers and patients with CD. Many of those detected in CD are toxic and may feasibly lead to the immunological attack on the gut microbiota, which is characteristic of inflammatory bowel disease. The reduction in the production of such metabolites after enteral feeding may be the reason for its effectiveness in CD.

Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy.

BACKGROUND: Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. OBJECTIVES: The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. METHODS: Using human skin samples and an animal model of bleomycin-induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. RESULTS: Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post-treatment with bleomycin. However, Flii-deficient (Flii(+/-) ) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross-sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin-treated Flii-overexpressing mice (Flii(Tg/Tg) ) showed increased scar dermal thickness, larger cross-sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. CONCLUSIONS: This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring.

Electrostatic potential within the free volume space of imidazole-based solvents: insights into gas absorption selectivity.

In this work, a variety of molecular simulation tools are used to help characterize the selective absorption of CO2 and CH4 in imidazole-based solvents. We focus our efforts on a series of 1-n-alkyl-2-methyl-imidazoles and ether-functionalized imidazoles, over a temperature range from 293 to 353 K, and we perform detailed analysis of the free volume. We find that the electrostatic potential within the solvent free volume cavities provides a useful indication of the selective absorption of CO2 and CH4. The electrostatic potential calculation is significantly faster than the direct calculation of the chemical potential, and tests with the 1-n-alkyl-2-methyl-imidazoles and the ether-functionalized imidazoles indicate that this may be a useful screening tool for other solvents.

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

A phase I trial of oral ridaforolimus (AP23573; MK-8669) in combination with bevacizumab for patients with advanced cancers.

AIMS: This phase I dose-escalation study was designed to evaluate the combination of the mammalian target of rapamycin inhibitor ridaforolimus with the vascular endothelial growth factor inhibitor bevacizumab. MATERIALS AND METHODS: Seventeen adult patients with refractory advanced solid tumours received oral ridaforolimus (30 or 40 mg) once daily for 5 days per week (QDx5/wk) combined with intravenous bevacizumab (10 mg/kg every 2 weeks [Q2wk] or 15 mg/kg every 3 weeks [Q3wk]). Patients were evaluated for dose-limiting toxicities, safety and anti-tumour activity. RESULTS: A 40 mg dose of ridaforolimus with either bevacizumab dosing schedule was the recommended phase II dose. No dose-limiting toxicities were reported; the most common drug-related adverse events were mucosal inflammation and anorexia. Seven patients, with clinical features that included primary tumour of the abdominal origin (colorectal, pancreatic or gynaecological cancers) and previous abdominal radiotherapy, reported serious adverse events related to bowel perforations. There were no objective responses, but 65% of patients had a best response of stable disease. CONCLUSION: Oral ridaforolimus (40 mg QDx5/wk) is feasible to combine with standard doses of bevacizumab, although careful patient selection would be needed to mitigate the risk of bowel perforation-related adverse events. Combination therapy produced prolonged stable disease in several heavily pretreated patients.

Quantitative approaches to cancer stem cells and epithelial-mesenchymal transition.

The last decade has witnessed significant advances in the application of mathematical and computational models to biological systems, especially to cancer biology. Here, we present stochastic and deterministic models describing tumour growth based on the cancer stem cell hypothesis, and discuss the application of these models to the epithelial-mesenchymal transition. In particular, we discuss how such quantitative approaches can be used to validate different possible scenarios that can lead to an increase in stem cell activity following induction of epithelial-mesenchymal transition, observed in recent experimental studies on human breast cancer and related cell lines. The utility of comparing mammosphere data to computational mammosphere simulations in elucidating the growth characteristics of mammary (cancer) stem cells is discussed as well.

Synthesis and growth mechanism of iron oxide nanowhiskers.

Iron oxide nanowhiskers with dimensions of approximately 2 × 20 nm were successfully synthesized by selectively heating an iron oleate complex. Such nanostructures resulted from the difference in the ligand coordination microenvironments of the Fe(III) oleate complex, according to our electronic structure calculations and thermogravimetric analysis. A ligand-directed growth mechanism was subsequently proposed to rationalize the growth process. The formation of the nanowhiskers provides a unique example of shape-controlled nanostructures, offering additional insights into nanoparticle synthesis.

Platelet apoptosis and activation in platelet concentrates stored for up to 12 days in plasma or additive solution.

BACKGROUND: Several studies suggest that apoptosis of platelets occurs during storage of platelet concentrates (PC). We sought to determine whether storage of PC in additive solution alters levels of apoptosis during storage beyond the current shelf life (5-7 days). STUDY DESIGN AND METHODS: Pooled buffy coat PC (n = 7) were prepared in either 100% plasma or 70% Composol and stored at 22 °C for 12 days. A third arm of the study stored PC in 100% plasma at 37 °C, which is thought to induce apoptosis. PC were tested for mitochrondrial membrane potential, annexin V binding, microparticles, caspase-3/7 activity and decoy cell death receptor 2, as well as standard platelet quality tests. RESULTS: Composol units remained ≥pH 6·88, with 36% lower lactate and higher pH vs plasma by day 12 (P < 0·001). Platelet function was better maintained, and activation and apoptotic markers tended to be lower in Composol units towards the end of storage. However, levels of all apoptosis markers assessed were not significantly different in units stored in Composol. Storage at 37 °C saw stronger correlation of apoptotic markers with standard quality tests compared to 22 °C, but loss of correlation of caspase-3/7 activity with other apoptosis markers. CONCLUSION: We conclude that storage of platelets in 70% Composol vs 100% plasma does not increase the rate of platelet apoptosis. Our data agree with other studies suggesting that platelet apoptosis is sequential to high levels of activation, but share a significant degree of overlap.

Investigating the link between epithelial-mesenchymal transition and the cancer stem cell phenotype: A mathematical approach.

Under the cancer stem cell (CSC) hypothesis, sustained metastatic growth requires the dissemination of a CSC from the primary tumour followed by its re-establishment in a secondary site. The epithelial-mesenchymal transition (EMT), a differentiation process crucial to normal development, has been implicated in conferring metastatic ability on carcinomas. Balancing these two concepts has led researchers to investigate a possible link between EMT and the CSC phenotype-indeed, recent evidence indicates that, following induction of EMT in human breast cancer and related cell lines, stem cell activity increased, as judged by the presence of cells displaying the CD44(high)/CD24(low) phenotype and an increase in the ability of cells to form mammospheres. We mathematically investigate the nature of this increase in stem cell activity. A stochastic model is used when small number of cells are under consideration, namely in simulating the mammosphere assay, while a related continuous model is used to probe the dynamics of larger cell populations. Two scenarios of EMT-mediated CSC enrichment are considered. In the first, differentiated cells re-acquire a CSC phenotype-this model implicates fully mature cells as key subjects of de-differentiation and entails a delay period of several days before de-differentiation occurs. In the second, pre-existing CSCs experience accelerated division and increased proportion of self-renewing divisions; a lack of perfect CSC biomarkers and cell sorting techniques requires that this model be considered, further emphasizing the need for better characterization of the mammary (cancer) stem cell hierarchy. Additionally, we suggest the utility of comparing mammosphere data to computational mammosphere simulations in elucidating the growth characteristics of mammary (cancer) stem cells.

Multiple genetic mechanisms lead to loss of functional TbAT1 expression in drug-resistant trypanosomes.

The P2 aminopurine transporter, encoded by TbAT1 in African trypanosomes in the Trypanosoma brucei group, carries melaminophenyl arsenical and diamidine drugs into these parasites. Loss of this transporter contributes to drug resistance. We identified the genomic location of TbAT1 to be in the subtelomeric region of chromosome 5 and determined the status of the TbAT1 gene in two trypanosome lines selected for resistance to the melaminophenyl arsenical, melarsamine hydrochloride (Cymelarsan), and in a Trypanosoma equiperdum clone selected for resistance to the diamidine, diminazene aceturate. In the Trypanosoma brucei gambiense STIB 386 melarsamine hydrochloride-resistant line, TbAT1 is deleted, while in the Trypanosoma brucei brucei STIB 247 melarsamine hydrochloride-resistant and T. equiperdum diminazene-resistant lines, TbAT1 is present, but expression at the RNA level is no longer detectable. Further characterization of TbAT1 in T. equiperdum revealed that a loss of heterozygosity at the TbAT1 locus accompanied loss of expression and that P2-mediated uptake of [(3)H]diminazene is lost in drug-resistant T. equiperdum. Adenine-inhibitable adenosine uptake is still detectable in a DeltaTbat1 T. b. brucei mutant, although at a greatly reduced capacity compared to that of the wild type, indicating that an additional adenine-inhibitable adenosine permease, distinct from P2, is present in these cells.

Rapamycin impairs trabecular bone acquisition from high-dose but not low-dose intermittent parathyroid hormone treatment.

The osteo-anabolic effects of intermittent parathyroid hormone (PTH) treatment require insulin-like growth factor (IGF) signaling through the IGF-I receptor. A major downstream target of the IGF-I receptor (via Akt) is the mammalian target of rapamycin (mTOR), a kinase involved in protein synthesis. We investigated whether the bone-building effects of intermittent PTH require functional mTOR signaling. Mice were treated with daily PTH 1-34 (0, 10, 30, or 90 microg/kg) for 6 weeks in the presence or absence of rapamycin, a selective inhibitor of mTOR. We found that all PTH doses were effective in enhancing bone mass, whether rapamycin was present or not. Rapamycin had little to no effect on the anabolic response at low (10 microg) PTH doses, small effects in a minority of anabolic measures at moderate doses (30 microg), but the anabolic effects of high-dose PTH (90 microg) were consistently and significantly suppressed by rapamycin ( approximately 4-36% reduction). Serum levels of Trap5b, a marker of resorption, were significantly enhanced by rapamycin, but these effects were observed whether PTH was absent or present. Our data suggest that intermittent PTH, particularly at lower doses, is effective in building bone mass in the presence of rapamycin. However, the full anabolic effects of higher doses of PTH are significantly suppressed by rapamycin, suggesting that PTH might normally activate additional pathways (including mTOR) for its enhanced high-dose anabolic effects. Clinical doses of intermittent PTH could be an effective treatment for maintaining or increasing bone mass among patients taking rapamycin analogs for unrelated health issues.

Skeletal health: primate model of postmenopausal osteoporosis.

Currently, the nonhuman primate is the most widely used large animal model to evaluate the safety and efficacy of new drug entities to treat or prevent estrogen-deficiency-induced bone loss and osteoporosis. Surgical ovariectomy (OVX) induces a state of high bone turnover and rapid bone loss establishing a new steady-state bone mass within 8-9 months. Many systems in the monkey are similar to humans, including skeletal and reproductive physiology and the immune system, making this a plausible model suitable to evaluate the effects of new bone drugs. The long-term sequelae following OVX and withdrawal of monthly exposure to cyclic reproductive hormones in older female monkeys (cynomolgus and rhesus) mimics estrogen depletion and postmenopausal bone loss occurring in women. Characterization of the primate model revealed an apparent limitation to the extent of bone loss. Animals lose bone mass after OVX, but the extent of the bone loss cannot be described as osteoporotic. The small differences between OVX and sham-operated controls in many important bone measurements is overcome by including 15-20 animals per group to provide adequate statistical power. The long-term, at least 16 month, bone safety studies performed to satisfy regulatory guidelines provide an opportunity to study treatment effects for an extended period not covered in shorter-term safety studies. In vivo end-points such as densitometry and biochemical markers translate easily to clinical use, while biomechanical end-points that cannot be measured clinically can be used to predict fracture prevention. To date, the monkey OVX model has been used to support submissions for many new drugs including anabolics, bisphosphonates and selective estrogen receptor modulators. Despite its limitations, the OVX monkey model remains the best characterized of the large animal models of osteopenia and has become integral to osteoporosis drug development.