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Abstract Background Osseointegration depends on the implant surface, bone quality and the local and systemic host environment, which can differ in male and female patients. This study was undertaken in order to determine if male and female cells respond differently to titanium surfaces that have micron-scale roughness and if interactions of calciotropic hormones [1α,25(OH)2D3 and 17β-oestradiol (E2)] and microstructured surfaces on osteoblasts are sex dependent. Methods Osteoblasts from 6-week old Sprague-Dawley rats were cultured on tissue culture polystyrene (TCPS) or on titanium (Ti) disks with two different surface topographies, a smooth pretreated (PT) surface and a coarse grit-blasted/acid-etched (SLA) surface, and treated with 1α,25(OH)2D3, E2, or E2 conjugated to bovine serum albumin (E2-BSA). Results Male and female cells responded similarly to Ti microstructure with respect to cell number and levels of osteocalcin, transforming growth factor-β1, osteoprotegerin and prostaglandin E2 in their conditioned media, exhibiting a more differentiated phenotype on SLA than on PT or TCPS. E2 and E2-BSA increased differentiation and local factor production, an effect that was microstructure dependent and found only in female osteoblasts. 1α,25(OH)2D3 increased osteoblast differentiation and local factor production in female and male cells, but the effect was more robust in male cells. Conclusions Male and female rat osteoblasts respond similarly to surface microstructure but exhibit sexual dimorphism in substrate-dependent responses to systemic hormones. Oestrogen affected only female cells while 1α,25(OH)2D3 had a greater effect on male cells. These results suggest that successful osseointegration in males and females may depend on the implant surface design and correct levels of calciotropic hormones.

Immobilization‐induced skeletal unloading results in muscle atrophy and rapid bone loss, thereby increasing the risk of falling and the need for implant therapy in patients with extended bed rest or neuromuscular injuries. Skeletal unloading causes bone loss by altering bone growth and resorption, suggesting that implant performance might be affected. To test this, we focused on early events in implant osseointegration. We used the rat sciatic neurectomy‐induced disuse model under two different settings. In Study 1, 16 Sprague Dawley rats (SD) were separated into control, sham operated+cast immobilization, and sciatic neurectomy+casting groups; titanium implants with multiscale microtextured topography and hydrophilic chemistry (modSLA) were inserted in the distal femoral metaphysis. Neurectomy surgeries and casting were performed at the same surgical setting as implant placement; rats were euthanized 4 weeks post‐implantation. In Study 2, we established the unloaded condition before implantation. A total of 12 SD rats were divided into control and sciatic+femoral neurectomy groups. A total of 24 days after sciatic and femoral neurectomy surgery, rats received implants. Study 2 rats were euthanized at 4 weeks post‐implantation. MicroCT and histomorphometry showed that trabecular bone and osseointegration were reduced when disuse was established before implantation. Osteoblasts isolated from Study 1 sciatic neurectomy tibial bones exhibited impaired differentiation on modSLA culture disks, revealing a possible mechanism responsible for the decreased osseointegration observed in the Study 2 rats. This study addressed the importance of considering the mechanical unloading and muscle function history before implant insertion and suggests that implant performance was reduced due to poor cellular ability to regenerate. [ABSTRACT FROM AUTHOR]

Revenue management (RM) systems forecast demand and optimize prices to maximize a hotel's revenue. The RM function operates in coordination between a system and an analyst. Systems provide recommendations while analysts review the forecasts and prices to approve or make subjective adjustments. In many cases the recommendations are a "black box" with little insight regarding how recommendations are derived. This article proposes the k-Nearest Neighbor (k-NN) algorithm as a forecasting approach that can transition the "black box" to a "glass box." The benefits of the k-NN are discussed in detail and compared with neural networks. The analysis is conducted on 35 hotels in partnership with a leading RM service provider. The results indicate similar performance for both techniques, leading to an important discussion on model evaluation outside of accuracy. In particular, the article discusses some of the unique advantages k-NN provides for the RM discipline. [ABSTRACT FROM AUTHOR]

Craniosynostosis is the premature fusion of cranial sutures, which can result in progressive cranial deformations, increased intracranial pressure, and restricted brain growth. Most cases of craniosynostosis require surgical reconstruction of the cranial vault with the goal of increasing the intracranial volume and correcting the craniofacial deformities. However, patients often experience rapid post-operative bone regrowth, known as re-synostosis, which necessitates additional surgical intervention. Bone morphogenetic protein (BMP) inhibitors have tremendous potential to treat re-synostosis, but the realization of a clinically viable inhibitor-based therapeutic requires the development of a delivery vehicle that can localize the release to the site of administration. Here, we present an in situ rapidly crosslinking injectable hydrogel that has the properties necessary to encapsulate co-administered proteins and demonstrate that the delivery of rmGremlin1 via our hydrogel system delays bone regrowth in a weanling mouse model of re-synostosis. Our hydrogel is composed of two mutually reactive poly(ethylene glycol) macromolecules, which when mixed crosslink via a bio-orthogonal Cu free click reaction. Hydrogels containing Gremlin caused a dose dependent inhibition of bone regrowth. In addition to craniofacial applications, our injectable click hydrogel has the potential to provide customizable protein, small molecule, and cell delivery to any site accessible via needle or catheter.

Simple Summary: Vitamin D supplementation's effectiveness in reducing cancer is widely debated. The controversy may be explained by differences in 25(OH)D3 metabolism. Previous studies showed that breast cancer cells produce vitamin D3 metabolites locally, and their ability to regulate tumorigenesis is related to the presence of estrogen receptor alpha 66 (ERα66). The present study examined this process in another estrogen-dependent cancer, laryngeal cancer. This study evaluated the effects of the active vitamin D3 metabolite 24R,25(OH)2D3 on cell growth, whether these cells can produce their own secreted vitamin D3 metabolites, and whether this ability is related to the presence or absence of ERα66. To address these questions, ERα-positive (UM-SCC-12) and ERα-negative (UM-SCC-11A) laryngeal cancer cell lines were examined for the presence of ERα66; the enzymes responsible for metabolizing 25(OH)D3 (CYP24A1 and CYP27B1); the local production of 24,25(OH)2D3 and 1,25(OH)2D3; and the effect of 24R,25(OH)2D3 on cell growth and markers of metastasis. The results showed that laryngeal cancer cells express CYP24A1 and CYP27B1, produce 24,25(OH)2D3, and respond differently to 24R,25(OH)2D3, in correlation with ERα66 levels. These findings suggest that tumor cells locally produce vitamin D metabolites to regulate their growth, which must be considered when recommending vitamin D supplementation. Studies have evaluated vitamin D3's therapeutic potential in estrogen-responsive cancers, with conflicting findings. We have shown that the proliferation of breast cancer cells is regulated by 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) depending on estrogen receptor alpha 66 (ERα66) expression, suggesting that this could also be the case for estrogen-sensitive laryngeal cancer cells. Accordingly, we examined levels of ERα isoforms in ERα66-positive UM-SCC-12 and ERα66-negative UM-SCC-11A cells and their response to 24R,25(OH)2D3. 24R,25(OH)2D3 stimulated proliferation, increased the expression of metastatic markers, and inhibited apoptosis in UM-SCC-12 cells while having the opposite effect in UM-SCC-11A cells. To evaluate if vitamin metabolites could act via autocrine/paracrine mechanisms, we assessed the expression, protein levels, and activity of vitamin D3 hydroxylases CYP24A1 and CYP27B1. Both cell types expressed both mRNAs; but the levels of the enzymes and their activities were differentially regulated by estrogen. ERα66-negative UM-SCC-11A cells produced more 24,25(OH)2D3 than UM-SCC-12 cells, but comparable levels of 1,25(OH)2D3 when treated with 25(OH)D3 These results suggest that the regulation of vitamin D3 metabolism in laryngeal cancer cells is modulated by ERα66 expression, and support a role for 24R,25(OH)2D3 as an autocrine/paracrine regulator of laryngeal cancer. The local metabolism of 25(OH)D3 should be considered when determining the potential of vitamin D3 in laryngeal cancer. [ABSTRACT FROM AUTHOR]

Triple–negative breast cancer (TNBC) is thought to be an estradiol–independent, hormone therapy–resistant cancer because of lack of estrogen receptor alpha 66 (ERα66). We identified a membrane–bound splice variant, ERα36, in TNBC cells that responds to estrogen (E2) and may contribute to bone osteolysis. We demonstrated that the MDA-MB-231 TNBC cell line, which expresses ERα36 similarly to MCF7 cells, is responsive to E2, forming osteolytic tumors in vivo. MDA-MB-231 cells activate osteoclasts in a paracrine manner. Conditioned media (CM) from MDA-MB-231 cells treated with bovine serum albumin–bound E2 (E2-BSA) increased activation of human osteoclast precursor cells; this was blocked by addition of anti–ERα36 antibody to the MDA-MB-231 cultures. Osteoclast activation and bone resorption genes were elevated in RAW 264.7 murine macrophages following treatment with E2-BSA–stimulated MDA-MB-231 CM. E2 and E2-BSA increased phospholipase C (PLC) and protein kinase C (PKC) activity in MDA-MB-231 cells. To examine the role of ERα36 signaling in bone osteolysis in TNBC, we used our bone–cancer interface mouse model in female athymic homozygous Foxn1nu mice. Mice with MDA-MB-231 tumors and treated with tamoxifen (TAM), E2, or TAM/E2 exhibited increased osteolysis, cortical bone breakdown, pathologic fracture, and tumor volume; the combined E2/TAM group also had reduced bone volume. These results suggest that E2 increased osteolytic lesions in TNBC through a membrane–mediated PLC/PKC pathway involving ERα36, which was enhanced by TAM, demonstrating the role of ERα36 and its membrane–associated signaling pathway in bone tumors. This work suggests that ERα36 may be a potential therapeutic target in patients with TNBC. [ABSTRACT FROM AUTHOR]

Three‐dimensional macroporous titanium–aluminum–vanadium (TiAl6V4) implants produced by additive manufacturing (AM) can be grit blasted (GB) to yield microtextured exterior surfaces, with additional micro/nano‐scale surface features provided by subsequent acid etching (AE). However, the line‐of‐sight nature of GB causes the topography of exterior GB + AE‐modified surfaces to differ from internal GB‐inaccessible surfaces. Previous in vitro studies using dense TiAl6V4 substrates indicated that a nonline‐of‐sight, calciothermic‐reaction (CaR)‐based process provided homogeneous osteogenic nanotextures on GB + AE surfaces, suggesting it could be used to achieve a homogeneous nanotopography on external and internal surfaces of macroporous AM constructs. Macroporous TiAl6V4 (3D) constructs were produced by direct laser melting and modified by GB + AE, with the CaR process then applied to 50% of constructs (3DCaR). The CaR process yielded nanoporous/nanorough internal surfaces throughout the macroporous constructs. Skeletally mature, male Sprague–Dawley rats were implanted with these constructs using a cranial on‐lay model. Prior to implantation, a Cu++‐free click hydrogel was applied to half of the constructs (3D + H, 3DCaR + H) to act as a challenge to osseointegration. Osseointegration was compared between the four implant groups (3D, 3DCaR, 3D + H, 3DCaR + H) at 4w. 3D + H implants exhibited lower bone volume (BV) and percent bone ingrowth (%BI) than the 3D implants. In contrast, osseointegrated 3DCaR + H implants had similar BV and %BI as the 3DCaR implants. Implant pull‐off forces correlated with these results. In vitro analyses indicated that human bone marrow stromal cells (MSCs) exhibited enhanced production of osteoblast differentiation markers and factors associated with osteogenesis when grown on CaR‐modified 3D substrates relative to control (TCPS) substrates. This work confirms that the CaR process provides osteogenic nanotextures on internal surfaces of macroporous 3D implants, and suggests that CaR‐modified surfaces can promote osseointegration in cases where osteogenesis is impaired. [ABSTRACT FROM AUTHOR]

Judgmental adjustments of algorithmic predictions with the aim of improving demand forecast accuracy are a common revenue management practice. While empirical evidence on the impact of these user overrides is growing, little research attention has been given to the time horizon and the frequency in which these adjustments take place. Utilizing a multilevel regression model for repeated measures, 20,081,973 forecasts comprising seven different time horizons were analyzed. Data were collected from 1752 hotels of different hotel types belonging to 232 hotel chains in seven geographical regions. We find that the accuracy of algorithmic computer forecasts improves as time nears the date of stay and that the number of user overrides impacts this accuracy. The effect of the override frequency depends on the type of the forecasted demand and on the presence of special events. A higher number of user overrides is beneficial for group segment, but damaging for the transient segment. During special events periods, override frequency enhances accuracy. [ABSTRACT FROM AUTHOR]

Hotel cancellation policies have shifted considerably in recent years. This is mainly in response to growing rates of last-minute cancellations and no shows and the resulting negative impact on the hotel's performance. This study explores how two key policy elements, the penalty and the cancellation window, are likely to benefit the hotel. That is, how the severity of the policies is likely to positively impact the hotel's financial performance. We developed a mathematical model and used cancellation and performance information data from a random sample of over 500 U.S. hotels to examine the effectiveness of a range of cancellation policies. The empirical findings support the mathematical model's prediction that moderate cancellation policies are likely to generate better financial performance levels, compared to more lenient or more stringent policies. [ABSTRACT FROM AUTHOR]

Aim: To determine the effects of RVX‐208, a selective bromodomain and extra‐terminal domain (BET) inhibitor targeting bromodomain 2 (BD2), on periodontal inflammation and bone loss. Materials and Methods: Macrophage‐like cells (RAW264.7) and human gingival epithelial cells were challenged by Porphyromonas gingivalis (Pg) with or without RVX‐208. Inflammatory gene expression and cytokine production were measured by reverse transcription polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. RAW264.7 cells were induced to osteoclast differentiation. After RVX‐208 treatment, osteoclast differentiation was evaluated by histology, tartrate‐resistant‐acid‐phosphatase (TRAP) activity and the expression of osteoclast‐specific genes. The effect of RVX‐208 on osteoclast transcriptome was studied by RNA sequencing. Periodontitis was induced in rats by ligature and local RVX‐208 treatment was administered every other day. Alveolar bone loss was measured by micro‐computed tomography. Results: RVX‐208 inhibited inflammatory gene expression and cytokine production in Pg‐infected cells. Osteoclast differentiation was inhibited by RVX‐208, as evidenced by reduced osteoclast number, TRAP activity and osteoclast‐specific gene expression. RVX‐208 displayed a more selective and less profound suppressive impact on transcriptome compared with pan‐BET inhibitor, JQ1. RVX‐208 administration prevented the alveolar bone loss in vivo. Conclusions: RVX‐208 regulated both upstream (inflammatory cytokine production) and downstream (osteoclast differentiation) events that lead to periodontal tissue destruction, suggesting that it may be a promising 'epi‐drug' for the prevention of periodontitis. [ABSTRACT FROM AUTHOR]