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Successful treatment of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), remains a significant challenge for neurologists due to the undesirable curative outcomes. Apart from surgeries, most drugs are only used to relieve the patients’ symptoms without a permanent cure of the disease. The development of novel biomaterials targeting NDDs is greatly hindered by the limited understanding of underlying molecular mechanisms. Considering the difficulties in NDD drug development and clinical trials, a comprehensive and up-to-date review of disease pathogenesis and related novel therapies are needed. In the current article, the basic concepts and pathogenic characteristics of NDDs are firstly illustrated. Following the detailed description of molecular mechanisms underlying three common NDDs, recent advances of drug development based on targeting different pathogenic mechanisms are clarified. Hopefully, this review will be beneficial to address the gap between materials and targeted mechanisms while simultaneously provide suggestions for the future design of precise NDD medicine.

Ischemic stroke is still a serious threat to human life and health, but there are few therapeutic options available to treat stroke because of limited blood-brain penetration. The development of nanotechnology may overcome some of the problems related to traditional drug development. In this review, we focus on the potential applications of nanotechnology in stroke. First, we will discuss the main molecular pathological mechanisms of ischemic stroke to develop a targeted strategy. Second, considering the important role of the blood-brain barrier in stroke treatment, we also delve mechanisms by which the blood-brain barrier protects the brain, and the reasons why the therapeutics must pass through the blood-brain barrier to achieve efficacy. Lastly, we provide a comprehensive review related to the application of nanomaterials to treat stroke, including liposomes, polymers, metal nanoparticles, carbon nanotubes, graphene, black phosphorus, hydrogels and dendrimers. To conclude, we will summarize the challenges and future prospects of nanomedicine-based stroke treatments., Graphical abstract Image 1, Highlights • Discussed the main molecular pathological mechanisms of ischemic stroke. • Reviewed several treatments for stroke. • Discussed the blood-brain barrier in detail.Summarized the applications of various nanomaterials in stroke. • Summarized the challenges and future prospects of nanomedicine-based stroke treatment.

Photodynamic therapy (PDT) is a non-invasive or minimally-invasive treatment which applies photosensitizers (PSs) to create reactive oxygen species (ROS) exposed to light trigger to destroy cancer cells. PDT can activate host anti-tumor immune responses but not powerful enough to kill metastatic tumors. Because of its carrier advantage, imaging, and therapeutic function together with enhanced permeability and retention (EPR) effect, nano-materials have already been used in photo-immunotherapy. Herein, photodynamic immunotherapy (PDIT) based on nanotechnology seems to be a hopeful new form of cancer therapy. In this article, we firstly summarize the recent development in photodynamic immunotherapy based on nanotechnology.

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.

Objective: We sought to determine the long-term bioavailability of single doses of intramuscular (IM) vita-min D2 (D2) in healthy adults. Methods: Forty healthy volunteers with hypovitaminosis D received a single dose of 200,000, 400,000, or 600,000 IU intramuscular D2 or no treatment. Levels of 25-hydroxyvitamin D2 (25lOH]D2) and 25-hydroxyvitamin D3 (25lOH]D3) in serum were measured by liquid chromatography-tandem mass spectrometry. Vitamin D binding protein (DBP) and intact parathyroid hormone (iPTH), bone turnover markers (BTMs), and serum and urinary calcium were also measured. Results: After a single dose of D2 injection, the level of 25(OH)D2 increased slowly and reached a plateau at 8 weeks. The plateau remained stable for 12 weeks. The mean increase in 25(OH)D2 was 6.8, 9.6, or 15.6 ng/mL after injection of 200,000 IU, 400,000 IU, or 600,000 IU D2. Although endogenous 25(OH)D3 levels were reduced by IM D2, the total 25(OH)D levels increased by 5.0, 7.0, or 10.3 ng/mL in average after injection of 200,000 IU, 400,000 IU, or 600,000 IU D2. The iPTH levels were also decreased by IM D2. However, levels of serum calcium, BTMs, and DBP and urinary calcium were not altered by IM D2. Conclusion: A single dose of 200,000 IU, 400,000 IU, or 600,000 IU IM D2 raises total 25-hydroxyvitamin D levels by 5.0, 7.0, or 10.3 ng/mL on average for at least 12 weeks and reduces iPTH and endogenous 25(OH)D3 levels without affecting levels of serum calcium, BTMs, DBP, and urinary calcium.

Despite the large number of osteoporosis patients in China, the diagnosis and treatment rates remain low. The Fracture Risk Assessment Tool (FRAX) can be used to effectively evaluate fracture risk. In this study, we explored the Chinese-specific thresholds of FRAX without the T-score. In all, 264 postmenopausal women aged > 50 years were randomly recruited from community-medical centers. All subjects completed self-reported questionnaires, BMD measurements, and spinal radiographs. The 10-year hip and major osteoporotic fracture risks were calculated by FRAX. A new threshold for both 10-year hip and major osteoporotic fracture risk was explored with receiver operating characteristic (ROC) curve analysis. Overall, 92 subjects were diagnosed with osteoporosis. Among them, 14 participants with T-score > − 2.5 were diagnosed with osteoporosis based on clinical fractures. ROC analysis showed the cut-off value of the 10-year hip osteoporotic fracture for detecting osteoporosis was 0.95%, while that of 10-year major osteoporotic fracture was 4.95%. The sensitivity and specificity of the 10-year hip osteoporotic fracture probability for detecting osteoporosis were 0.86 and 0.59, respectively, while the guideline-recommended threshold had a sensitivity of 0.49 and specificity of 0.83. The sensitivity and specificity of the 10-year major osteoporotic fractures with the new threshold were 0.76 and 0.69, respectively, while the recommended threshold had a sensitivity of 0 and specificity of 1. Current guideline-recommended FRAX thresholds without BMD showed low sensitivity. Therefore, 10-year osteoporotic hip fracture probability ≥ 0.95% and 10-year osteoporotic major fracture probability ≥ 4.95% are recommended as the new thresholds.

Photodynamic therapy (PDT) is a promising non-invasive therapy approach for various diseases including malignant tumor. The process of PDT involves three interrelated aspects, namely photosensitizer (PS), light source, and oxygen, among which PS is the decisive factor that determines its anticancer efficiency. There exist some defects in currently applied PDT, such as inadequate production of reactive oxygen species (ROS), poor penetration of exciting light, insufficient oxygen supply, and nonselective distribution of PS. With unique physicochemical and optical properties, two-dimensional nanomaterials (2DNMs) have aroused great interest in biomedical fields. 2DNMs-based PDT is promising to significantly improve antitumor efficacy compared to conventional PDT. In this review, we will firstly introduce the underlying mechanism of PDT and how 2DNMs are absorbed and distribute inside tumor cells. After that, we will not only illustrate how 2DNMs-based PDT can enhance tumor-killing efficacy and minimize side-effects through conquering the above-mentioned defects of conventional PDT and the preparation process of 2DNMs, but also elaborate recent advances about 2DNMs-based PDT. Lastly, we will summarize the challenges and future prospects of 2DNMs-based PDT.

In recent years, nanomaterials and nanotechnology have emerged as vital factors in the medical field with a unique contribution to cancer medicine. Given the increasing number of cancer patients, it is necessarily required to develop innovative strategies and therapeutic modalities to tackle hypoxia, which forms a hallmark and great barrier in treating solid tumors. The present review details the challenges in nanotechnology-based hypoxia, targeting the strategies and solutions for better therapeutic performances. The interaction between hypoxia and tumor is firstly introduced. Then, we review the recently developed engineered nanomaterials towards multimodal hypoxia tumor therapies, including chemotherapy, radiotherapy, and sonodynamic treatment. In the next part, we summarize the nanotechnology-based strategies for overcoming hypoxia problems. Finally, current challenges and future directions are proposed for successfully overcoming the hypoxia tumor problems.

Optoelectronic science and 2D nanomaterial technologies are currently at the forefront of multidisciplinary research and have numerous applications in electronics and photonics. The unique energy and optically induced interfacial electron transfer in these nanomaterials, enabled by their relative band alignment characteristics, can provide important therapeutic modalities for healthcare. Given that nano-heterostructures can facilitate photoinduced electron-hole separation and enhance generation of reactive oxygen species (ROS), 2D nano-heterostructure-based photosensitizers can provide a major advancement in photodynamic therapy (PDT), to overcome the current limitations in hypoxic tumor microenvironments. Herein, a bismuthene/bismuth oxide (Bi/BiOx)-based lateral nano-heterostructure synthesized using a regioselective oxidation process is introduced, which, upon irradiation at 660 nm, effectively generates 1 O2 under normoxia but produces cytotoxic •OH and H2 under hypoxia, which synergistically enhances PDT. Furthermore, this Bi/BiOx nano-heterostructure is biocompatible and biodegradable, and, with the surface molecular engineering used here, it improves tumor tissue penetration and increases cellular uptake during in vitro and in vivo experiments, yielding excellent oxygen-independent tumor ablation with 660 nm irradiation, when compared with traditional PDT agents.

Background Fragility fracture is associated with bone mineral density (BMD), and most databases used in related researches are instrument-matched. Little is known about the relationship between BMD and fragility fracture risk of native Chinese, especially using local databases as reference databases. Objective To investigate relationship between BMD and risk of fragility fracture in native China. Methods 3,324 cases, including 2,423 women (67.7 ± 8.9 years) and 901 men (68.4 ± 11.6 years) having radiological fragility fractures and 3,324 age- and gender-matched controls participated in the study. We measured BMD at posteroanterior spine and hip using dual-energy X-ray absorptiometry (DXA), calculated BMD measurement parameters based on our own BMD reference database. Results BMDs and mean T-scores were lower in case group (with clinical fragility) than in control group (without clinical fragility). In patients with fragility fractures, prevalence of lumbar osteoporosis, low bone mass, and normal BMD were 78.9 %, 19.3 %, and 1.8 %, respectively, in women, and 49.5, 44.8 %, and 5.7 %, respectively, in men. In hip, these prevalence rates were 67.2 %, 28.4 %, and 4.4 % in females, and 43.2 %, 45.9 %, and 10.9 % in males, respectively, showing differences between females and males. Multivariate Cox regression analysis showed that after adjusting age, height, weight, and body mass index, fracture hazard ratio (HR) increased by 2.7–2.8 times (95 % CI 2.5–3.1) and 3.6–4.1 times (95 %CI 3.0–5.1) for women and men respectively with decreasing BMD parameters. In both sexes, risk of fragility fracture increased approximately 1.6–1.7 times (95 % CI 1.5–1.8) for every 1 T-score reduction in BMD. Conclusions Risk of clinical fragility fracture increases with decreasing BMD measurement parameters and anthropometric indicators in native China, and fracture HR varies from gender and site.

Photothermal therapy (PTT) based on two-dimensional (2D) nanomaterials has shown significant potential in cancer treatment. However, developing 2D nanomaterial-based theranostic agents with good biocompatibility and high therapeutic efficiency remains a key challenge. Bulk titanium (Ti) has been widely used as biomedical materials for their reputable biocompatibility, whereas nanosized Ti with a biological function remains unexplored. In this work, the 2D Ti nanosheets (NSs) are successfully exfoliated from nonlayer bulk Ti and utilized as an efficient theranostic nanoplatform for dual-modal computed tomography/photoacoustic (CT/PA) imaging-navigated PTT. Besides the excellent biocompatibility obtained by TiNSs as expected, they are found to show strong absorption ability with an extinction coefficient of 20.8 L g-1 cm-1 and high photothermal conversion ability with an efficiency of 61.5% owing to localized surface plasmon resonances, which exceeds most of other well-known photothermal agents, making it quite promising for PTT against cancer. Furthermore, the metallic property and light-heat-acoustic transformation endow 2D Ti with the strong CT/PA imaging signal and efficient cancer therapy, simultaneously. This work highlights the enormous potential of nanosized Ti in both the diagnosis and treatment of cancer. As a paradigm, this study also paves a new avenue for the elemental transition-metal-based cancer theranostics.

Objective To bridge the efficacy and compare the safety of the 24-week teriparatide treatment in a Chinese osteoporosis study ({"type":"clinical-trial","attrs":{"text":"NCT00414973","term_id":"NCT00414973"}}NCT00414973) to a large international trial (FPT, {"type":"clinical-trial","attrs":{"text":"NCT00670501","term_id":"NCT00670501"}}NCT00670501) to determine whether long-term results from the international study were applicable to Chinese patients.

Basal-like breast cancer exhibits a triple-negative phenotype and has a poor prognosis, even with traditional chemical and anti-human epidermal growth factor receptor (HER) treatments. However, the high mutation rate of this obstinate cancer type renders it suitable for immunotherapy. Photothermal therapy (PTT) is a high-efficiency method for inducing tumor neoantigen release in situ, which has great potential for use in cancer immunotherapy. Here, we prepared a biomimetic black phosphorus quantum dot (BPQDs) formulation to induce breast cancer cell apoptosis in situ by near-infrared (NIR) laser irradiation to mobilize the immune system to eliminate the residual and metastatic cancer cells. Erythrocyte membranes (RMs) were used to coat the BPQDs, forming a BPQD-RM nanovesicle (BPQD-RMNV) biomimetic formulation that exhibited a long circulation time and tumor accumulation in vivo. The basal-like 4T1 breast tumor underwent apoptosis and necrosis with the irradiation and recruited dendritic cells (DCs) to capture the tumor antigens in vivo. Furthermore, programmed cell death protein 1 (PD-1) antibody (aPD-1) was employed to prevent the CD8+ T cells from exhaustion. Notably, BPQD-RMNV-mediated PTT combined with aPD-1 treatment significantly delayed residual and metastatic tumor growth in vivo. Hence, BPQD-RMNV-mediated PTT combined with immune checkpoint blockade antibody increased the infiltration and activity of CD8+ T cells in the tumor, which directly restrained basal-like breast tumor growth in vivo.

Black phosphorus quantum dots(BPQDs) have shown a good application prospect in the field of tumor therapy due to their photoelectric effect and good biodegradability. Due to the active endocytosis and fast metabolic efficiency of tumor cells, BPQDs are easy to be absorbed by tumor cells. However, this does not guarantee that BPQDs will be completely targeted to tumor cells, and normal cells will also absorb BPQDs. Because the cell membrane is negatively charged, BPQDs are also negatively charged and are not easily absorbed by cells under the action of electrostatic repulsion. Surface pegylation is the most common modification method of black phosphorus at present. However, surface pegylation can reduce the uptake of BPQDs by tumor cells. Positive PEG is also easy to be recognized and swallowed by the reticuloendothelial system. The inherent instability and poor tumor targeting of BPQDs under physiological conditions limit further research and clinical application. For this purpose, we selected cationic polymer polyethylenimine (PEI) to modify BPQDs and then added RGD peptides targeting tumor cells. An outer layer of negatively charged PEG+DMMA makes the nanosystem more stable . In the acidic environment of the tumor, the PEG layer has a charge reversal, and the positively charged PEI and the RGD polypeptide BPQDs targeted by the tumor cells are released into the tumor cells. It provides a new method for efficiently and accurately transporting BPQDs, a novel photosensitive nanomaterial, into tumor cells for photodynamic therapy.

Summary Introduction Vitamin D supplementation has been widely recommended to prevent falls. However, considerable controversy exists regarding the association of such supplementation and fall risk. Previous meta-analyses yielded inconsistent results because of differences in the baseline of 25-hydroxyvitamin D [25(OH)D] and dose of vitamin D and use of vitamin D or in combination with calcium in different studies. Furthermore, some studies published recently were not included in the previous meta-analyses. Therefore, an updated and comprehensive meta-analysis is warranted. Methods We systematically searched several literature databases including PubMed and the Embase from inception to September 2020. The protocol for this meta-analysis was registered with PROSPERO (CRD42021226380). Randomized clinical trials (RCTs) reporting the effect of vitamin D supplementation alone or with calcium on fall incidence were selected from studies. Qualitative and quantitative information was extracted; the random-effects model was conducted to pool the data for fall; statistical heterogeneity was assessed using the I2 test and potential for publication bias was assessed qualitatively by a visual estimate of the funnel plot and quantitatively by calculation of the Begg's test and the Egger's test. Results Of the citations retrieved, 31 eligible studies involving 57 867 participants met inclusion criteria, reporting 17 623 falls. A total of 21 RCTs of vitamin D alone and 10 RCTs of vitamin D plus calcium were included in the meta-analysis. The meta-analysis of 21 RCTs (51 984 participants) of vitamin D supplementation alone (daily or intermittent doses of 400–60 000 IU) did not show a reduced risk of falls (The risk ratio [RR] 1.00, 95% confidence intervals [CI] 0.95 to 1.05) compared to placebo or no treatment. Subgroup analyses showed that the baseline of serum 25(OH)D concentration less than 50 nmol/L resulted in a reduction of fall risk (RR 0.77, 95% CI 0.61 to 0.98). In contrast, the meta-analysis of 10 RCTs (5883 participants) of combined supplementation of vitamin D (daily doses of 700–1000 IU) and calcium (daily doses of 1000–1200 mg) showed a 12% reduction in the risk of fall (RR 0.88, 95% CI 0.80 to 0.97). Conclusions The combination of vitamin D and calcium have beneficial effects on prevention falls in old adults. Although vitamin D supplementation alone has no effect on fall risk in old adults with 25(OH)D levels higher than 50 nmol/L, vitamin D supplementation alone does have a benefit on prevention of falls in old adults with 25(OH)D levels lower than 50 nmol/L.

The aim was to compare the National Osteoporosis Foundation (NOF) and the UK National Osteoporosis Guideline Group (NOGG) guidelines for the detection of vertebral fractures in postmenopausal Chinese women. The NOF guidelines had higher accuracy than the UK guidelines for spinal radiography examination. To compare the National Osteoporosis Foundation (NOF) and the UK National Osteoporosis Guideline Group (NOGG) guidelines for the detection of vertebral fractures in postmenopausal Chinese women. A cross-sectional study on 255 community-dwelling postmenopausal women was conducted in Hunan province in 2017. Demographic and clinical characteristics and risk factors were recorded through questionnaires. Height and weight were measured using standard methods, and bone mineral density (BMD) was measured with dual-energy X-ray absorptiometry. Vertebral fractures were diagnosed by radiography using semi-quantitative morphometry. The prevalence of vertebral fractures was 9.4%. Women with vertebral fractures were significantly older and shorter, had higher years-since menopause and height loss values and lower BMD and T-scores at the femoral neck and total hip, and were more likely to have a history of previous fractures. The sensitivity and specificity of the NOF guidelines were 91.7% and 39.8%, respectively, while the NOGG guidelines had lower sensitivity (87.5%) and specificity (32.5%). However, a higher percentage had indications for radiography in the 50-64 years age group according to the NOGG guidelines, while a higher percentage had indications for radiography in the ≥ 65 year group according to the NOF guidelines. The NOF guidelines were better than the NOGG guidelines for spinal radiography examination in the Chinese postmenopausal women.

p120-catenin (p120) serves as a stabilizer of the calcium-dependent cadherin-catenin complex and loss of p120 expression has been observed in several types of human cancers. The p120-dependent E-cadherin-β-catenin complex has been shown to mediate calcium-induced keratinocyte differentiation via inducing activation of plasma membrane phospholipase C-γ1 (PLC-γ1). On the other hand, PLC-γ1 has been shown to interact with phosphatidylinositol 3-kinase enhancerin the nucleus and plays a critical role in epidermal growth factor-induced proliferation of oral squamous cell carcinoma (OSCC) cells. To determine whether p120 suppresses OSCC proliferation and tumor growth via inhibiting PLC-γ1, we examined effects of p120 knockdown or p120 and PLC-γ1 double knockdown on proliferation of cultured OSCC cells and tumor growth in xenograft OSCC in mice. The results showed that knockdown of p120 reduced levels of PLC-γ1 in the plasma membrane and increased levels of PLC-γ1 and its signaling in the nucleus in OSCC cells and OSCC cell proliferation as well as xenograft OSCC tumor growth. However, double knockdown of p120 and PLC-γ1 or knockdown of PLC-γ1 alone did not have any effect. Immunohistochemical analysis of OSCC tissue from patients showed a lower expression level of p120 and a higher expression level of PLC-γ1 compared withthat of adjacent noncancerous tissue. These data indicate that p120 suppresses OSCC cell proliferation and tumor growth by inhibiting signaling mediated by nuclear PLC-γ1.

The present study demonstrated that the lower-extremity muscle performance in Chinese community-dwelling postmenopausal women with lower bone mineral density (BMD) was positively associated with hip BMD and negatively associated with estimated fracture risk. Postmenopausal women are at high risk for osteoporotic fractures. It has been shown that decreased lower-extremity muscle performance is associated with osteoporotic fractures. However, the relationship between muscle performance and bone mineral density in postmenopausal women is inconsistent in the literature. The present study was to investigate the relationship between lower-extremity muscle performance and BMD or estimated fracture risk in community-dwelling postmenopausal women. Two hundred forty-seven postmenopausal women aged 50–85 years were recruited in the study. The short physical performance battery (SPPB) tool including the chair stand test (CST), gait speed test (GST), and balance test (BT) was used to determine lower-extremity functioning and the CST, GST, BT, and SPPB total scores were recorded. The BMD of lumbar spine (LSBMD), femoral neck (FNBMD), and total hip (THBMD) were measured by dual-energy X-ray absorptiometry (DXA), and the vertebral fracture was confirmed by lateral spine X-rays radiographs. In addition, patients’ 10-year estimated major osteoporotic fracture risk (MOFR) and hip fracture risk (HFR) were assessed by the Fracture Risk Assessment Tool (FRAX). Linear regression analysis was used to analyze the association between muscle performance and BMD. The CST, GST, and SPPB total scores were positively associated with LSBMD, THBMD, and FNBMD before adjustment for age, height, and weight. The SPPB total score was positively associated with FNBMD and THBMD, but not with LSBMD after adjustment for age, height, and weight. The BT score was positively associated with FNBMD and THBMD, but not with LSBMD before and after adjustment for age, height, and weight. Moreover, the CST, GST, BT, and SPPB scores were negatively associated with the FRAX score. The lower-extremity muscle performance in community-dwelling postmenopausal women is positively associated with FNBMD and THBMD and negatively associated with the FRAX score.

The diagnosis and management of osteoporosis and osteoporotic fractures are challenging in rural and underdeveloped areas of China because medical resources are inaccessible; thus, a simple and accurate method is essential for the detection of vertebral fractures. We aimed to examine the relationship between historical height loss (HHL) and vertebral fractures in postmenopausal Chinese women.A cross-sectional study of 255 postmenopausal women aged 50 years or older was conducted in September 2017. Demographic data, including self-reported tallest historical height and current height were analyzed. Vertebral fractures were assessed using X-ray radiography and HHL thresholds were examined using specificity and sensitivity testing.The average age of the 255 participants was 66.3 ± 9.0 years and their mean HHL was 3.5 ± 2.8 cm. The 24 women who were found to have vertebral fractures were older, had more years since menopause (YSM), and a larger HHL compared to those without vertebral fractures. Logistic regression analysis showed that age was a better predictor of vertebral fractures than HHL was, and the cutoff age for detecting vertebral fractures was 71 years, with an area under the receiver operating characteristic curve of 0.750.Although the women in this study with vertebral fractures had a greater height loss than those without fractures, it was apparent that age, rather than HHL, is the best way to determine who is most likely to develop vertebral fractures.

Here, we describe a combination strategy of black phosphorus (BP)-based photothermal therapy together with anti-CD47 antibody (aCD47)-based immunotherapy to synergistically enhance cancer treatment. Tumour resistance to immune checkpoint blockades in most cancers due to immune escape from host surveillance, along with the initiation of metastasis through immunosuppressive cells in the tumour microenvironment, remains a significant challenge for cancer immunotherapy. aCD47, an agent for CD47/SIRPα axis blockade, induces modest phagocytic activity and a low response rate for monotherapy, resulting in failures in clinical trials. We showed that BP-mediated ablation of tumours through photothermal effects could serve as an effective strategy for specific immunological stimulation, improving the inherently poor immunogenicity of tumours, which is particularly useful for enhancing cancer immunotherapy. BP in combination with aCD47 blockade activates both innate and adaptive immunities and promotes local and systemic anticancer immune responses, thus offering a synergistically enhanced effect in suppression of tumour progression and in inducing abscopal effects for inhibition of metastatic cancers. Our combination strategy provides a promising platform in which photothermal agents could help to enhance the therapeutic efficacy of immunotherapy., Immunotherapy: enhancing the therapeutic effectiveness of photothermal cancer treatments By combining photothermal therapy and immunotherapy, scientists have improved cancer treatments. In cancer immunotherapy, the body’s immune system is artificially boosted to fight cancer. Some cancers, however, can protect themselves from immunotherapies by stimulating immune checkpoint targets, which regulate the immune system and prevent it from attacking non-cancerous cells. Checkpoint blockade immunotherapy helps the immune system to recognise and attack cancer cells. However, it is ineffective in treating patients suffering from most solid tumour cancers like melanomas. Now, a team of scientists, led by Paras Prasad from the State University of New York, have used a combination of black phosphorus-based photothermal therapy and antibody immunotherapy to enhance the therapeutic efficiency of the treatment. By exerting a synergistically enhanced antitumor effect, the technique has proved effective in suppressing the proliferation and growth of cancer cells.

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy.

This review focuses on the biologic importance of the vitamin D binding protein (DBP) with emphasis on its regulation of total and free vitamin D metabolite levels in various clinical conditions. Nearly all DBP is produced in the liver, where its regulation is influenced by estrogen, glucocorticoids and inflammatory cytokines but not by vitamin D itself. DBP is the most polymorphic protein known, and different DBP alleles can have substantial impact on its biologic functions. The three most common alleles-Gc1f, Gc1s, Gc2-differ in their affinity with the vitamin D metabolites and have been variably associated with a number of clinical conditions. Although DBP has a number of biologic functions independent of vitamin D, its major biologic function is that of regulating circulating free and total levels of vitamin D metabolites. 25 hydroxyvitamin D (25(OH)D) is the best studied form of vitamin D as it provides the best measure of vitamin D status. In a normal non-pregnant individual, approximately 0.03% of 25(OH)D is free; 85% is bound to DBP, 15% is bound to albumin. The free hormone hypothesis postulates that only free 25(OH)D can enter cells. This hypothesis is supported by the observation that mice lacking DBP, and therefore with essentially undetectable 25(OH)D levels, do not show signs of vitamin D deficiency unless put on a vitamin D deficient diet. Similar observations have recently been described in a family with a DBP mutation. This hypothesis also applies to other protein bound lipophilic hormones including glucocorticoids, sex steroids, and thyroid hormone. However, tissues expressing the megalin/cubilin complex, such as the kidney, have the capability of taking up 25(OH)D still bound to DBP, but most tissues rely on the free level. Attempts to calculate the free level using affinity constants generated in a normal individual along with measurement of DBP and total 25(OH)D have not accurately reflected directly measured free levels in a number of clinical conditions. In this review, we examine the impact of different clinical conditions as well as different DBP alleles on the relationship between total and free 25(OH)D, using only data in which the free 25(OH)D level was directly measured. The major conclusion is that a number of clinical conditions alter this relationship, raising the question whether measuring just total 25(OH)D might be misleading regarding the assessment of vitamin D status, and such assessment might be improved by measuring free 25(OH)D instead of or in addition to total 25(OH)D.

Parathyroid glands contain the vitamin D receptor (VDR) and 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1), which catalyze the production and degradation of 1,25-dihydroxyvitamin D [1,25(OH)2D], respectively. Previous studies have shown that the serum level of intact parathyroid hormone (iPTH) increases with age. We hypothesized that the expression of CYP27B1 or VDR in parathyroid glands decreases with age, which might account for the increased serum levels of iPTH due to decreased suppression of parathyroid hormone (PTH) secretion by 1,25(OH)2D in older people. To test this hypothesis, we examined relative expression levels of VDR, CYP27B1, CYP24A1, and PTH in specimens from parathyroid glands unintentionally removed during thyroidectomy for 70 patients varying in age from 10 to 70 years. The results showed that there was an inverse correlation between age and VDR, CYP27B1, and CYP24A1 expression (p<0.05). A significant positive correlation between PTH expression levels and age was also observed (p<0.05). These data indicate that older age is associated with decreased levels of VDR, CYP27B1, and CYP24A1 and increased levels of PTH in human parathyroid glands.

Ovarian cysts are one of the most common gynecologic affections for females. The most effective therapy is surgery, but not for all conditions. An 18-year-old woman was referred to our hospital because of menstruation disorder and abdominal distension. Ultrasound and computer tomography of the abdomen revealed a giant ovarian cyst. Magnetic resonance imaging revealed profound pituitary enlargement. Laboratory studies showed severe hypothyroidism, mild anemia, hyperlipidemia, hyperprolactinemia and an elevated level of cancer antigen-125. Regression of the giant ovarian cyst and pituitary enlargement was observed after a 5-month levothyroxine replacement therapy. Thus, for patients with ovarian cysts, hypothyroidism should be taken into account. Making correct diagnosis would avoid unnecessary surgery.

Various categories of biomaterials have been utilized for drug delivery, genetic modification, photodynamic and photothermal therapies due to their distinct physicochemical properties, including photothermal convertibility, stimuli-responsiveness, and inherent capability to generate photodynamical radicals. However, successful treatments of cancer are largely hindered by the limited accessibility of nanomaterials into hypoxic or metastatic tumor tissues. Among the various tumor-targeting strategies, bacterial fabrication exhibits particular advantages such as specific hypoxia tropism, high motility, and rapid self-replication. Biomineralization, i.e. bacterial modification, involves the fabrication of bacteria by nanomaterials for precise cancer imaging as well as targeted drug delivery, overcoming the physiological barriers and improving the therapeutic efficiency. Fabrication of bacteria strains can be conducted by various methods, including direct adsorption, electrostatic interaction, covalent ligation, and surface precipitation. In this review, a brief introduction to commonly-utilized biomaterials and bacteria species is provided. A systemic overview of recent advances of bacteria fabrication strategies and techniques are then discussed, followed by future prospective of bacteria-facilitated cancer therapy and diagnostics.

Due to their prominent physicochemical properties, 2D materials are broadly applied in biomedicine. Currently, 2D materials have achieved great success in treating many diseases such as cancer and tissue engineering as well as bone therapy. Based on their different characteristics, 2D materials could function in various ways in different bone diseases. Herein, the application of 2D materials in bone tissue engineering, joint lubrication, infection of orthopedic implants, bone tumors, and osteoarthritis are firstly reviewed comprehensively together. Meanwhile, different mechanisms by which 2D materials function in each disease reviewed below are also reviewed in detail, which in turn reveals the versatile functions and application of 2D materials. At last, the outlook on how to further broaden applications of 2D materials in bone therapies based on their excellent properties is also discussed.

Importance The aging of the population is associated with an increasing burden of fractures worldwide. However, the epidemiological features of fractures in mainland China are not well known. Objective To assess the prevalence of and factors associated with osteoporosis, clinical fractures, and vertebral fractures in an adult population 40 years or older in mainland China. Design, setting. and participants This cross-sectional study, the China Osteoporosis Prevalence Study, was conducted from December 2017 to August 2018. A random sample of individuals aged 20 years or older who represented urban and rural areas of China were enrolled, with a 99% participation rate. Main outcomes and measures Weighted prevalence of osteoporosis, clinical fracture, and vertebral fracture by age, sex, and urban vs rural residence as determined by x-ray absorptiometry, questionnaire, and radiography. Results A total of 20 416 participants were included in this study; 20 164 (98.8%; 11 443 women [56.7%]; mean [SD] age, 53 [13] years) had a qualified x-ray absorptiometry image and completed the questionnaire, and 8423 of 8800 (95.7%) had a qualified spine radiograph. The prevalence of osteoporosis among those aged 40 years or older was 5.0% (95% CI, 4.2%-5.8%) among men and 20.6% (95% CI, 19.3%-22.0%) among women. The prevalence of vertebral fracture was 10.5% (95% CI, 9.0%-12.0%) among men and 9.7% (95% CI, 8.2%-11.1%) among women. The prevalence of clinical fracture in the past 5 years was 4.1% (95% CI, 3.3%-4.9%) among men and 4.2% (95% CI, 3.6%-4.7%) among women. Among men and women, 0.3% (95% CI, 0.0%-0.7%) and 1.4% (95% CI, 0.8%-2.0%), respectively, with osteoporosis diagnosed on the basis of bone mineral density or with fracture were receiving antiosteoporosis treatment to prevent fracture. Conclusions and relevance In this cross-sectional study of an adult population in mainland China, the prevalence of osteoporosis and vertebral fracture were high and the prevalence of vertebral fracture and clinical fracture was similarly high in men and women. These findings suggest that current guidelines for screening and treatment of fractures among patients in China should focus equally on men and women and should emphasize the prevention of vertebral fractures.

Purpose: We aimed to investigate the status of serum 25-hydroxyvitamin D [25(OH)D] among Chinese postmenopausal women in a multicenter cross-sectional study.Methods: Non-institutionalized postmenopausal women aged ≥55 years were recruited from urban and rural areas in 7 geographically different regions in China. Subject enrollment was executed during the summer and the winter. Vitamin D insufficiency and deficiency were defined as 25(OH)D < 30 and< 20 ng/ml, and was measured by liquid chromatography-tandem mass spectrometry. Women were referred to a dual-energy x-ray absorptiometry (DXA) if they had a medium-to-high fracture risk suggested by Osteoporosis Self-Assessment Tool for Asians (OSTA).Results: Among all subjects, 91.2% (1,535/1,684, 95%CI: 89.7, 92.5) had vitamin D insufficiency and 61.3% had vitamin D deficiency (1,033/1,684, 95%CI: 59.0, 63.7). The prevalence of vitamin D deficiency was significantly higher in urban dwellers (64.9 vs. 57.7% in rural, P = 0.002) and in winter-enrolled subjects (84.7 vs. 41.3% in summer, P < 0.0001). The prevalence of vitamin D inadequacy did not increase in trend by latitude and was numerically lower in women who had high fracture risk and osteoporosis. A non-curvilinear change of intact parathyroid hormone (iPTH) levels was observed at 25(OH)D >16.78 ng/mL.Conclusions: The prevalence of vitamin D inadequacy was remarkable among Chinese postmenopausal women and independent of fracture risk assessed by OSTA or osteoporosis suggested by DXA. Winter season, urban residence, however not latitude, were significantly associated with a higher likelihood of vitamin D deficiency. Optimal vitamin D status for iPTH and bone-related outcomes merits further investigation in this population.

Nanomaterials are playing an advancing critical role in the prevention, diagnosis, and treatment of today’s human problems. By engineering with multi-active probes including biocompatible molecules, drugs, and target ligands, nanomaterials are able to inhibit or enhance the immune responses and prevent the detection ability of the immune system, thus treating autoimmune diseases. The present discussion systematically reviews the recent progress to treat autoimmune inflammation using nanomaterials of 0D, 1D, 2D, and composite systems. In addition, emphasis has laid on the using of nanomaterials-based immunotherapeutic strategies and the related autoimmune pathogenesis. Briefly discussions on current challenges and speculates on future directions have been provided to complement our drawbacks of present treatments on the basis of fascinating nanomaterials and novel nanotechnologies.

Therapeutic targeting of the immune system, including chimeric antigen receptor-T cell therapy, immune checkpoint blockade therapy, neoantigen vaccines, and small molecule modulators emerges as one of the most effective therapeutic modalities for treating various cancers in human patients. However, clinical efficacies of these immunotherapeutics are generally modest and only a minority of cancer patients benefit from immunotherapy. Further, broad adverse effects, lack of reliable biomarkers, tumour relapses, drug resistance, and metastasis have become increasingly recognized concerns, which may restrain their clinical utility. Unlike most other anticancer strategies, nanomaterial-based therapeutics parade unique and distinct biological features to achieve precision targeting, local drug release, and enhancing therapeutic efficacy. As long-term and sustained release of immunotherapeutics are necessary for enhancing anticancer immunity, nanotechnology ensures accumulation of immunotherapuetics, controlled release, and precision delivery of immune drugs. Combination of these two therapeutic modalities would provide synergistic efficacy for effectively treating various cancers in human patients. To the best of our knowledge, the concept of combination therapy employing nanomaterials and immunotherapy has been overlooked. In this article, we discuss possible mechanisms underlying nano-immunotherapy and unique opportunities of nanotechnology in synergizing cancer treatment.

Previous studies have shown that dietary calcium suppresses oral carcinogenesis, but the mechanism is unclear. p120-catenin (p120) is a cytoplasmic protein closely associated with E-cadherin to form the E-cadherin-β-catenin complex and may function as a tumor suppressor in the oral epithelium. To determine whether p120 is involved in the mechanism by which dietary calcium suppresses oral carcinogenesis, The normal, low, or high calcium diet was fed control mice (designated as floxed p120 mice) or mice in which p120 was specifically deleted in the oral squamous epithelium during the adult stage (designated as p120cKO mice). All mice were exposed to a low dose of oral cancer carcinogen 4-nitroquinoline 1-oxide and rates of oral squamous cell carcinoma (OSCC) and proliferation and differentiation in the cancerous and non-cancerous oral epithelium of these mice were examined. The results showed that the low calcium diet increased rates of OSCC and proliferation of the non-cancerous oral epithelium and decreased differentiation of the non-cancerous oral epithelium, but had no effect on cancerous oral epithelium. In contrast, the high calcium diet had opposite effects. However, the effect of the dietary calcium on the rates of OSCC, proliferation, and differentiation of the non-cancerous epithelium were not seen in p120cKO mice. Based on these results, we conclude that p120 is required for dietary calcium suppression of oral carcinogenesis and oral epithelial proliferation and dietary calcium induction of oral epithelial differentiation. J. Cell. Physiol. 232: 1360-1367, 2017. © 2016 Wiley Periodicals, Inc.

Although immunoassays in measuring 25-hydroxyvitamin D [25(OH)D] have been improved recently, relatively large differences are still seen between results of 25(OH)D measured by immunoassays and by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In the present studies, we compared two immunoassays with LC-MS/MS for measuring 25(OH)D concentrations. Concentrations of 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] in serum samples from 59 healthy subjects were measured by two immunoassays including Siemens ADVIA Centaur Vitamin D Total (Centaur) and Roche Elecsys Vitamin D Total (Elecsys) and LC-MS/MS. To determine the cross reactivity of Elecsys and Centaur toward 25(OH)D2, a dosage of 200,000 IU vitamin D2 was given after first sampling. Serum samples were obtained 30 days later and concentrations of 25(OH)D2 and 25(OH)D3 were measured again. The results showed poor agreement between the immunoassays and LC-MS/MS in 25(OH)D2 and 25(OH)D3 measurements. The percentage of 25(OH)D2 cross-reactivity was 45.3% for Centaur and 41.2% for Elecsys and there was no significant difference between Centaur and Elecsys. In conclusion, Centaur and Elecsys perform unsatisfactorily in measuring 25(OH)D levels, especially for 25(OH)D2 cross-reactivity. Therefore, clinicians need to be aware of the underestimation of vitamin D status when using these immunoassays for measuring individuals supplemented with vitamin D2.

Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia‐induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT‐photosensitizer and on‐demand designed anticancer prodrug SN38‐Nif, which is released and activated by photothermia and tumor‐overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia‐induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer., A biophotonic nanoplatform based on the zirconium carbide (ZrC) nanosheet as a deep photothermal therapy‐photosensitizer and on‐demand designed anticancer prodrug SN38‐Nif is developed. Both physically controlled and bioresponsive mode are employed to smartly release drugs. The ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation, and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.

Photodynamic therapy (PDT), as a non-invasive therapeutic modality that is alternative to radiotherapy and chemotherapy, is extensively investigated for cancer treatments. Although conventional organic photosensitizers (PSs) are still widely used and have achieved great progresses in PDT, the disadvantages such as hydrophobicity, poor stability within PDT environment and low cell/tissue specificity largely limit their clinical applications. Consequently, nano-agents with promising physicochemical and optical properties have emerged as an attractive alternative to overcome these drawbacks of traditional PSs. Herein, the up-to-date advances in the fabrication and fascinating applications of various nanomaterials in PDT have been summarized, including various types of nanoparticles, carbon-based nanomaterials, and two-dimensional nanomaterials, etc. In addition, the current challenges for the clinical use of PDT, and the corresponding strategies to address these issues, as well as future perspectives on further improvement of PDT have also been discussed.

The epidermal growth factor receptor (EGFR) is a key driver in the process of squamous cell carcinoma (SCC) cell mitogenesis. Phospholipase C-gamma1 (PLC-gamma1) is a downstream target of EGFR signaling, but the role and necessity of PLC-gamma1 in EGFR-induced cell mitogenesis remain unclear. In the present study, we report an elevated expression of PLC-gamma1 in human SCC biopsies relative to adjacent normal epidermis, and in human SCC cell lines compared to normal human keratinocytes. EGFR-induced SCC cell mitogenesis was blocked by small interfering RNA knockdown of PLC-gamma1. However, inhibition of the catalytic activity of phospholipase C had no effect on EGFR-induced SCC cell mitogenesis. In response to the EGFR ligand epidermal growth factor (EGF), PLC-gamma1 was translocated not only to the plasma membrane but also to the nucleus. These data suggest that PLC-gamma1 is required for EGFR-induced SCC cell mitogenesis and the mitogenic function of PLC-gamma1 is independent of its lipase activity.

Oyster has gained much attention recently for its anticancer activity but it is unclear whether calcium, the major antitumor ingredient in oyster shell, is responsible for the anticarcinogenic role of the oyster. To address this issue, C57BL/6 mice were fed with the carcinogen 4-nitroquinoline-1-oxide (4NQO, 50 µg/mL) and normal diet or a diet containing oyster powder, oyster calcium, or calcium depleted oyster powder. The tongue tissue specimens isolated from these mice were histologically evaluated for hyperplasia, dysplasia, and papillary lesions, and then analyzed for proliferation and differentiation markers by immunohistochemistry. The results showed that mice on the diet containing oyster calcium significantly reduced rates of tumors in the tongue and proliferation and enhanced differentiation in the oral epithelium compared with the diet containing calcium depleted oyster powder. These results suggest that calcium in oyster plays a critical role in suppressing formation of oral squamous cell carcinoma and proliferation and promoting differentiation of the oral epithelium.

Both calcium and 1,25(OH)(2)D promote the differentiation of keratinocytes in vitro. The autocrine or paracrine production of 1,25(OH)(2)D by keratinocytes combined with the critical role of the epidermal calcium gradient in regulating keratinocyte differentiation in vivo suggest the physiologic importance of this interaction. The interactions occur at a number of levels. Calcium and 1,25(OH)(2)D synergistically induce involucrin, a protein critical for cornified envelope formation. The involucrin promoter contains an AP-1 site essential for calcium and 1,25(OH)(2)D induction and an adjacent VDRE essential for 1,25(OH)(2)D but not calcium induction. Calcium regulates coactivator complexes that bind to the Vitamin D receptor (VDR). Nuclear extracts from cells grown in low calcium contain an abundance of DRIP(205), whereas calcium induced differentiation leads to reduced DRIP(205) and increased SRC 3 which replaces DRIP in its binding to the VDR. In vivo models support the importance of 1,25(OH)(2)D-calcium interactions in epidermal differentiation. The epidermis of 1alphaOHase null mice fails to form a normal calcium gradient, has reduced expression of proteins critical for barrier function, and shows little recovery of the permeability barrier when disrupted. Thus in vivo and in vitro, calcium and 1,25(OH)(2)D interact at multiple levels to regulate epidermal differentiation.

Keratinocytes express high levels of 25OHD 1alpha-hydroxylase (1OHase). The product of this enzyme, 1,25(OH)(2)D, promotes the differentiation of keratinocytes in vitro. To test whether 1OHase activity is essential for keratinocyte differentiation in vivo we examined the differentiation process in mice null for the expression of the 1alphaOHase gene (1alphaOHase(-/-)) by light and electron microscopy, by immunocytochemistry for markers of differentiation, by ion capture cytochemistry for calcium localization, and by function using transepidermal water loss (TEWL) to assess barrier integrity. Levels of involucrin, filaggrin, and loricrin-markers of differentiation in the keratinocyte and critical for the formation of the cornified envelope-were reduced in the epidermis of 1alphaOHase(-/-) mice. Calcium in the outer epidermis was reduced with loss of the calcium gradient from stratum basale to stratum granulosum. TEWL was normal in the resting state, but following disruption of the barrier, 1alphaOHase(-/-) mice had a markedly prolonged recovery of barrier function associated with a reduction in lamellar body secretion and a failure to reform the calcium gradient. Thus 1,25(OH)(2)D is essential for normal epidermal differentiation, most likely by inducing the proteins and mediating the calcium signaling in the epidermis required for the generation and maintenance of the barrier.

Keratinocytes express high levels of 25OHD 1alpha-hydroxylase (1OHase). The product of this enzyme, 1,25-dihydroxyvitamin D (1,25(OH)(2)D), promotes the differentiation of keratinocytes in vitro suggesting an important role for this enzyme in epidermal differentiation. To test whether 1OHase activity is essential for keratinocyte differentiation in vivo we examined the differentiation process in mice null for the expression of the 1alphaOHase gene (1alphaOHase(-/-)). Heterozygotes for the null allele were bred, and the progeny genotyped by PCR. The epidermis of the 1alphaOHase(-/-) animals and their wild-type littermates (1alphaOHase(+/+)) were examined by histology at the light and electron microscopic level, by immunocytochemistry for markers of differentiation, and by function examining the permeability barrier using transepidermal water loss (TEWL). No gross epidermal phenotype was observed; however, immunocytochemical assessment of the epidermis revealed a reduction in involucrin, filaggrin, and loricrin-markers of differentiation in the keratinocyte and critical for the formation of the cornified envelope. These observations were confirmed at the electron microscopic level, which showed a reduction in the F (containing filaggrin) and L (containing loricrin) granules and a reduced calcium gradient. The functional significance of these observations was tested using TEWL to evaluate the permeability barrier function of the epidermis. Although TEWL was normal in the basal state, following disruption of the barrier using tape stripping, the 1alphaOHase(-/-) animals displayed a markedly delayed recovery of normal barrier function. This delay was associated with a reduction in lamellar body secretion and a failure to reform the epidermal calcium gradient. Thus, the 25OHD 1OHase is essential for normal epidermal differentiation, most likely by producing the vitamin D metabolite, 1,25(OH)(2)D, responsible for inducing the proteins regulating calcium levels in the epidermis that are critical for the generation and maintenance of the barrier.

Involucrin is a major protein of the cornified envelope of keratinocytes that provides much of the structural integrity of skin. Its expression is stimulated by a number of agents including calcium and 1,25-dihydroxy-vitamin D3 that promote the differentiation process in keratinocytes. Within the distal regulatory region of the involucrin promoter lies an AP-1 site and an element homologous to other vitamin D response elements. In previous studies mutation of the AP-1 site was found to reduce basal activity and block calcium stimulation of the involucrin promoter, whereas the vitamin D response element was not critical for calcium regulation. In this study both elements proved to be important for 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. Mutation of the AP-1 site reduced basal activity and blocked 1,25-dihydroxyvitamin D3 stimulation of the involucrin promoter. In contrast, mutation of the vitamin D response element did not reduce basal expression of the involucrin promoter or prevent calcium stimulation of involucrin gene expression, but blocked 1,25-dihydroxyvitamin D3 stimulation. The vitamin D response element from the involucrin gene bound the vitamin D receptor and the retinoid X receptor, but not the retinoic acid receptor, in a specific manner. We conclude that the AP-1 site and the vitamin D response element in the involucrin promoter play important roles in mediating the action of 1,25-dihydroxyvitamin D3 on involucrin expression, but the vitamin D response element provides specificity for the 1,25-dihydroxyvitamin D3 response lacking at the AP-1 site.

Vitamin D deficiency is reportedly linked to a variety of autoimmune diseases. However, the relationship between thyroid autoimmunity in Graves disease (GD) and vitamin D deficiency is unclear. The goal of this study was to determine whether increased thyroid hormone autoantibody titer is associated with vitamin D deficiency in GD patients.A total of 70 patients with GD and 70 matched control subjects were recruited to our study. The levels of 25-hydroxyvitamin D (25[OH]D), calcium, parathyroid hormone (PTH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyrotropin-receptor antibody (TRAb), thyroid-peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) in serum collected from these patients and controls were examined.The level of 25(OH)D in serum from TRAb-positive GD patients was significantly lower than that in serum of healthy controls or TRAb-negative patients. However, compared with control subjects, the level of PTH in serum was increased in TRAb-positive GD patients. The rate of vitamin D deficiency (defined as serum 25[OH]D50 nmol/L) in TRAb-positive GD patients was significantly higher than in healthy controls or TRAb-negative GD patients. The level of 25(OH)D in serum was inversely correlated with TRAb titer in serum of TRAb-positive GD patients. However, our results did not show a correlation between 25(OH)D level and the levels of TPOAb, TGAb, FT3, FT4, or TSH.Low vitamin D status is associated with increased TRAb titer in GD, suggesting a possible link between vitamin D status and increased thyroid autoimmunity in GD patients.

OBJECTIVES Recent studies suggest that serum lipid profiles are related to bone mineral density (BMD). But data about this relationship on Chinese population are scarce. We investigated the relationships between serum lipid and BMD in postmenopausal Chinese women. METHODS A cross-sectional study was conducted in 790 Chinese postmenopausal women. BMDs were measured by dual X-ray absorptiometry. Serum lipid profiles were obtained after a 12-h fasting. RESULTS Women with serum high-density lipoprotein cholesterol (HDL-C) levels of at least 1·55 mmol/l had a greater prevalence of osteoporosis compared with women with lower HDL-C (≤1·54 mmol/l). After controlling for age, menopausal duration, body mass index, serum creatinine levels, outdoor activity, smoking and alcohol intake, high HDL-C levels were associated with osteoporosis (OR = 1·64, 95%CI 1·16-2·33, P < 0·01). BMD at femoral neck and total hip was significantly lower in the higher HDL-C class than the lower class (0·722 ± 0·118 vs 0·744 ± 0·120 g/cm(2) , P < 0·01; 0·800 ± 0·126 vs 0·824 ± 0·125 g/cm(2) , P < 0·01, respectively). No association was found between total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) with BMD. CONCLUSIONS In Chinese postmenopausal women, elevated levels of serum HDL-C had a greater probability of being osteoporosis than the lower HDL-C levels. Our analysis showed higher HDL-C level that is favourable for cardiovascular diseases should be regarded as a risk factor for osteoporosis.

Over the past few decades, there has been a growing interest in understanding the multifunctional characteristics and clinical importance of vitamin D binding protein (DBP). Multiple studies have shed light on DBP, giving rise to hopes of identifying novel mechanisms as well as utilizing DBP as a potential therapeutic agent. The current issue is comprised of 6 manuscripts, two of which are review articles. The areas covered in this special issue mostly highlight the potential role of DBP in several conditions including periodontitis and frailty, implying that measurement of DBP may provide useful information in addition to total 25-hydroxy vitamin D concentration. In this issue, the review by P. Yousefzadeh et al. titled “Vitamin D binding protein impact on 25-hydroxyvitamin D levels under different physiologic and pathologic conditions” calls for the implementation of DBP testing during the interpretation of 25-hydroxyvitamin D [25(OH)D] results under different clinical situations. I. Bhan reviews the recent findings regarding the association between the differences in vitamin D binding protein levels and bone density in his paper titled “Vitamin D binding protein and bone health.” The author has compiled studies concerned with DBP, including DBP polymorphisms in relation to bone health and its association with vitamin D bioavailability. These findings may impact not only strategies for designing novel therapeutic agents that influence DBP or its binding, but also our understanding of the mechanism of vitamin D in the context of bone health. Evidence is emerging that the DBP polymorphisms are associated with race and ethnicity, resulting in differences in DBP levels and binding affinity that affect the transport and metabolism of vitamin D and its metabolites. Using serum samples from various populations with varying DBP levels, J. Freeman et al., in their paper titled “Influence of vitamin D binding protein on accuracy of 25-hydroxyvitamin D measurement using the ADVIA Centaur vitamin D total assay,” assessed the agreement between the ADVIA Centaur vitamin D total assay for 25(OH)D testing and the liquid chromatography mass spectrometry (LS-MS/MS) method and concluded that the ADVIA Centaur vitamin D total assay demonstrated good performance compared to the LS-MS/MS method across the normal range of DBP concentrations. This is one example of methods development in the field to ensure accurate and simpler protocols for measuring circulating 25(OH)D in future study. X. Zhang et al., in their paper titled “Vitamin D-binding protein levels in plasma and gingival crevicular fluid (GCF) of patients with generalized aggressive periodontitis,” examined the association of DBP with generalized aggressive periodontitis (GAgP). The authors found that GAgP patients had higher plasma DBP concentrations but lower GCF DBP concentrations than healthy controls, suggesting that decreased GCF-DBP level and increased plasma DBP level are associated with periodontitis. This study adds to the growing evidence of the potential role of DBP in the pathogenesis of periodontitis. Existing evidence shows an association of high circulating 25(OH)D levels with low TSH levels in younger individuals, but there is insufficient information on whether it is the same in the elderly and middle-aged. Q. Zhang et al., in their paper titled “Association of high vitamin D status with low circulating thyroid-stimulating hormone independent of thyroid hormone levels in middle-aged and elderly males,” report that such an association does exist in middle-aged and elderly males, independent of thyroid hormone levels. The authors also demonstrated the link between vitamin D insufficiency and serum thyroid antibody levels. Y. Wang et al., in their paper entitled “Vitamin D binding protein affects the correlation of 25(OH)D and frailty in the older men,” assessed the frailty status in elderly men of Changsha city, China, and concluded that serum DBP levels should be measured when evaluating the 25(OH)D- frailty relationship. We hope that these articles convey new insights to readers and researchers into the current renewed interest in vitamin D and DBP research. Zhongjian Xie Arthur C. Santora Sue A. Shapses Xiangbing Wang

Keratinocytes produce vitamin D3 and convert it to the most active form, 1,25-dihydroxyvitamin D3, which regulates keratinocyte proliferation and differentiation. Phospholipase C-gamma1 is the most abundant member of the phospholipase C family in keratinocytes and is induced by 1,25-dihydroxyvitamin D3. Therefore, phospholipase C-gamma1 might be important in the signaling pathway mediating 1,25-dihydroxyvitamin-D3-induced keratinocyte differentiation. To test this hypothesis, phospholipase C-gamma1 expression in human keratinocytes was reduced by transfecting the cells with an antisense phospholipase C-gamma1 construct and then evaluating the response of the keratinocyte differentiation markers involucrin and transglutaminase to 1,25-dihydroxyvitamin D3. The results showed that involucrin and transglutaminase protein and mRNA levels were markedly reduced in keratinocytes transfected by the antisense phospholipase C-gamma1 construct. Cotransfection of keratinocytes with the involucrin or transglutaminase promoter construct and the antisense phospholipase C-gamma1 construct showed decreased involucrin or transglutaminase promoter activity in response to 1,25-dihydroxyvitamin D3. To further investigate the mechanism by which phospholipase C-gamma1 regulates keratinocyte differentiation, the calcium and inositol triphosphate levels in keratinocytes transfected by the antisense phospholipase C-gamma1 construct were measured following 1,25-dihydroxyvitamin D3 administration. The increase in keratinocyte intracellular free calcium and inositol triphosphate levels following 1,25-dihydroxyvitamin D3 administration were markedly reduced by the transfection of the antisense phospholipase C-gamma1 construct. These studies indicate that phospholipase C-gamma1 plays a critical role in the signal transduction pathway mediating 1,25-dihydroxyvitamin-D3-induced keratinocyte differentiation at least in part by mediating the increase in inositol triphosphate production and intracellular calcium mobilization following 1,25-dihydroxyvitamin D3 administration.