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Purpose: We aim to detect serum DKK1 level of pediatric patients with OI and to analyze its relationship with the genotype and phenotype of OI patients., Methods: A cohort of pediatric OI patients and age-matched healthy children were enrolled. Serum levels of DKK1 and bone turnover biomarkers were measured by enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by Dual-energy X-ray absorptiometry. Pathogenic mutations of OI were detected by next-generation sequencing and confirmed by Sanger sequencing., Results: A total of 62 OI children with mean age of 9.50 (4.86, 12.00) years and 29 healthy children were included in this study. The serum DKK1 concentration in OI children was significantly higher than that in healthy children [5.20 (4.54, 6.32) and 4.08 (3.59, 4.92) ng/mL, P < 0.001]. The serum DKK1 concentration in OI children was negatively correlated with height (r = - 0.282), height Z score (r = - 0.292), ALP concentration (r = - 0.304), lumbar BMD (r = - 0.276), BMD Z score of the lumbar spine and femoral neck (r = - 0.32; r = - 0.27) (all P < 0.05). No significant difference in serum DKK1 concentration was found between OI patients with and without vertebral compression fractures. In patients with spinal deformity (22/62), serum DKK1 concentration was positively correlated with SDI (r = 0.480, P < 0.05). No significant correlation was observed between serum DKK1 concentration and the annual incidence of peripheral fractures, genotype and types of collagen changes in OI children., Conclusion: The serum DKK1 level was not only significantly elevated in OI children, but also closely correlated to their skeletal phenotype, suggesting that DKK1 may become a new biomarker and a potential therapeutic target of OI., (© 2024. The Author(s).)

Objective: Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components., Methods: Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA., Results: A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors., Conclusion: Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Purpose: Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL)., Methods: A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and β-carboxy-terminal crosslinked telopeptide of type 1 collagen (β-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously., Results: PPGL patients had a higher level of β-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent., Conclusions: PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Purpose: Lipocalin 2 (LCN2) is a newly recognized bone-derived factor that is important in regulation of energy metabolism. We investigated the correlation of serum LCN2 levels and glycolipid metabolism, and body composition in a large cohort of patients with osteogenesis imperfecta (OI)., Methods: A total of 204 children with OI and 66 age- and gender-matched healthy children were included. Circulating levels of LCN2 and osteocalcin were measured by enzyme-linked immunosorbent assay. Serum levels of fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), and low- and high-density lipoprotein cholesterol (LDL-C, HDL-C) were measured by automated chemical analyzers. The body composition was measured by dual-energy X-ray absorptiometry. Grip strength and timed-up-and-go (TUG) were tested to evaluate the muscle function., Results: Serum LCN2 levels were 37.65 ± 23.48 ng/ml in OI children, which was significantly lower than those in healthy control (69.18 ± 35.43 ng/ml, P < 0.001). Body mass index (BMI) and serum FBG level were significantly higher and HDL-C levels were lower in OI children than healthy control (all P < 0.01). Grip strength was significantly lower (P < 0.05), and the TUG was significantly longer in OI patients than healthy control (P < 0.05). Serum LCN2 level was negatively correlated to BMI, FBG, HOMA-IR, HOMA-β, total body, and trunk fat mass percentage, and positively correlated to total body and appendicular lean mass percentage (all P < 0.05)., Conclusions: Insulin resistance, hyperglycemia, obesity, and muscle dysfunction are common in OI patients. As a novel osteogenic cytokine, LCN2 deficiency may be relevant to disorders of glucose and lipid metabolism, and dysfunction of muscle in OI patients., (© 2023. The Author(s).)

Purpose: To evaluate the genotypic and phenotypic relationship in a large cohort of OI patients and to compare the differences between eastern and western OI cohorts., Methods: A total of 671 OI patients were included. Pathogenic mutations were identified, phenotypic information was collected, and relationships between genotypes and phenotypes were analyzed. Literature about western OI cohorts was searched, and differences were compared between eastern and western OI cohorts., Results: A total of 560 OI patients were identified as carrying OI pathogenic mutations, and the positive detection rate of disease-causing gene mutations was 83.5%. Mutations in 15 OI candidate genes were identified, with COL1A1 (n = 308, 55%) and COL1A2 (n = 164, 29%) being the most common mutations, and SERPINF1 and WNT1 being the most common biallelic variants. Of the 414 probands, 48.8, 16.9, 29.2 and 5.1% had OI types I, III, IV and V, respectively. Peripheral fracture was the most common phenotype (96.6%), and femurs (34.7%) were most commonly affected. Vertebral compression fracture was observed in 43.5% of OI patients. Biallelic or COL1A2 mutation led to more bone deformities and poorer mobility than COL1A1 mutation (all P < 0.05). Glycine substitution of COL1A1 or COL1A2 or biallelic variants led to more severe phenotypes than haploinsufficiency of collagen type I α chains, which induced the mildest phenotypes. Although the gene mutation spectrum varied among countries, the fracture incidence was similar between eastern and western OI cohorts., Conclusion: The findings are valuable for accurate diagnosis and treatment of OI, mechanism exploration and prognosis judgment. Genetic profiles of OI may vary among races, but the mechanism needs to be explored., (© 2023. The Author(s).)

Objective: Nonsurgical hypoparathyroidism (ns-HP) is a rare disease. There are few studies on Quality of Life (QoL) among patients with ns-HP. This study aimed to investigate the QoL among ns-HP patients with regular conventional treatment, and explore the influence factors affecting QoL among these Chinese ns-HP patients., Methods: This is a cross-sectional study comparing 101 patients identified as ns-HP and 101 healthy controls. The questionnaires of Short Form 36 Health Survey questionnaire version 2(SF-36v2) were used to evaluate QoL., Results: Scores of all eight subdomains of SF-36v2 and physical component scores (PCS), mental component scores (MCS) were significantly lower in the ns-HP group compared with the healthy controls. The indices of all subdomains of SF-36v2 between Q1 (the lowest quartile) and Q4 (the highest quartile) groups were compared, suggesting higher percentages of detectable parathyroid hormone (PTH) before treatment in Q4 group among all QoL indices except two subdomains (physical function and body pain)., Conclusion: Both mental and physical QoL were impaired in the ns-HP patients even with regular conventional treatment for hypocalcemia, which were more severe in cases with lower baseline PTH levels., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Early chronic kidney disease (CKD) and non-CKD individuals had similar morphometric vertebral fracture (mVF) incidence and longitudinal bone mineral density (BMD) change. CKD did not modify the association between BMD and incident mVF status. Patients with a higher baseline BMD had a higher longitudinal BMD loss in early CKD., Purpose: The aim of this 5-year longitudinal cohort study was to compare the risk of incident morphometric vertebral fracture (mVF) and longitudinal bone mineral density (BMD) change between individuals with early chronic kidney disease (CKD) and those without CKD., Methods: A total of 869 Chinese postmenopausal women were enrolled in the study. Serum creatinine levels were assessed using standard methods, and estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. Incident mVF was confirmed through lateral radiographs of the thoracolumbar spine. BMDs at the lumbar spine (LS) and femoral neck (FN) were measured using dual-energy X-ray absorptiometry. CKD was defined based on eGFR values: 60-89 mL/min/1.73m 2 for stage 2 (n = 511) and 30-59 mL/min/1.73m 2 for stage 3 (n = 92). The non-CKD group included individuals with an eGFR greater than or equal to 90 mL/min/1.73m 2 ., Results: The incidence of mVF was not statistically different between individuals with early CKD and those without CKD (4.1% in non-CKD, 6.3% in CKD stage 2, and 7.6% in CKD stage 3; p = 0.348). Neither eGFR nor CKD status was significantly associated with incident mVF in the multivariate logistic regression analysis. Baseline BMD T-scores were negatively associated with incident mVF (LS T-score, OR = 0.603, 95% CI = 0.468-0.777; FN T-score, OR = 0.511, 95% CI = 0.350-0.746). No evidence of interaction between BMD T-scores and CKD status were identified (p = 0.284-0.785) . The differences in longitudinal BMD changes between non-CKD and CKD groups were comparable (FN BMD: -6.31 ± 7.20% in non-CKD, -5.07 ± 8.20% in CKD stage 2, and -4.49 ± 8.40% in CKD stage 3, p = 0.556; LS BMD: -1.38 ± 8.18% in non-CKD, -0.32 ± 7.14% in CKD stage 2, and 1.5 ± 6.97% in CKD stage 3, p = 0.406). Individuals with a higher baseline FN BMD showed a greater longitudinal FN BMD loss (r = -0.185, p < 0.001) ., Conclusions: Our study revealed that early CKD was not associated with an increased risk of incident mVF or greater longitudinal BMD loss. Moreover, CKD did not modify the association between BMD and the risk of incident mVF, suggesting that the management and prevention of fractures in early CKD should be approached similarly to those without CKD. Measurement of BMD appears to be crucial for predicting incident mVF risk and longitudinal bone loss in early CKD., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Higher sclerostin levels in postmenopausal women are associated with improved bone microarchitecture, areal and volumetric bone mineral density, and bone strength. However, the serum sclerostin level had no independent associations with the prevalence of morphometric vertebral fractures in this population after multivariable adjustment., Purpose: We aim to investigate the associations between serum sclerostin levels and morphometric vertebral fractures (VFs) prevalence, bone mineral density (BMD), and bone microarchitecture in postmenopausal women., Methods: A total of 274 community-dwelling postmenopausal women were randomized enrolled. We collected general information and measured the serum sclerostin level. Morphometric VFs were assessed on the lateral thoracic and lumbar spine X-rays. Areal BMD and calculated trabecular bone score (TBS) were detected by dual-energy X-ray absorptiometry, and volumetric BMD and bone microarchitecture data were acquired from high-resolution peripheral quantitative computed tomography., Results: The prevalence of morphometric VFs was 18.6% in the cohort, and it was significantly higher in the lowest quartile of the sclerostin group than that in the highest quartile of the sclerostin group (27.9% vs. 11.8%, p<0.05). But the serum sclerostin had no independent association with the prevalence of morphometric VFs after adjusting by age, body mass index, BMD at the lumbar vertebrae 1-4, and fragility fracture history after 50 years old (odds ratio: 0.995, 95% confidence interval: 0.987-1.003, p=0.239). The serum sclerostin level positively correlated with the areal, volumetric BMDs, and TBS. It also had significant positive associations with Tb.BV/TV, Tb.N, Tb.Th, and Ct.Th, and negative associations with Tb.Sp and Tb.1/N.SD., Conclusion: Chinese postmenopausal women with higher serum sclerostin levels had a lower prevalence of morphometric VFs, higher BMDs, and better bone microarchitecture. Nevertheless, the serum sclerostin level had no independent association with the prevalence of morphometric VFs., (© 2023. International Osteoporosis Foundation and Bone Health and Osteoporosis Foundation.)

Purpose: Patients with tumor-induced osteomalacia (TIO) often suffer from irreversible height loss due to vertebral deformity. However, the prevalence of vertebral deformity in TIO patients varies among limited studies. In addition, the distribution and type of vertebral deformity, as well as its risk factors, remain unknown. This study aimed to identify the prevalence, distribution, type and risk factors for vertebral deformity in a large cohort of TIO patients., Methods: A total of 164 TIO patients were enrolled in this retrospective study. Deformity in vertebrae T4-L4 by lateral thoracolumbar spine radiographs was evaluated according to the semiquantitative method of Genant. Bone microstructure was evaluated by trabecular bone score (TBS) and high-resolution peripheral QCT (HR-pQCT)., Results: Ninety-nine (99/164, 60.4%) patients had 517 deformed vertebrae with a bimodal pattern of distribution (T7-9 and T11-L1), and biconcave deformity was the most common type (267/517, 51.6%). Compared with patients without vertebral deformity, those with vertebral deformity had a higher male/female ratio, longer disease duration, more height loss, lower serum phosphate, higher bone turnover markers, lower TBS, lower areal bone mineral density (aBMD), lower peripheral volumetric BMD (vBMD) and worse microstructure. Lower trabecular vBMD and worse trabecular microstructure in the peripheral bone and lower spine TBS were associated with an increased risk of vertebral deformity independently of aBMD. After adjusting for the number of deformed vertebrae, we found little difference in clinical indexes among the patients with different types of vertebral deformity. However, we found significant correlations of clinical indexes with the number of deformed vertebrae and the spinal deformity index., Conclusion: We reported a high prevalence of vertebral deformity in the largest cohort of TIO patients and described the vertebral deformity in detail for the first time. Risk factors for vertebral deformity included male sex, long disease duration, height loss, abnormal biochemical indexes and bone impairment. Clinical manifestation, biochemical indexes and bone impairment were correlated with the number of deformed vertebrae and degree of deformity, but not the type of deformity., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Introduction: Hemophilia is a rare X-linked recessive inherited bleeding disorder caused by mutations of the genes encoding coagulation factor VIII (FVIII) or IX (FIX). Patients with hemophilia (PWH) often have a high risk of osteoporosis and fractures that is usually ignored. Herein, we review the underlying mechanisms of osteoporosis and the increased risk of fractures and their treatment in patients with FVIII or FIX deficiency., Methods: The PubMed, Web of Science, Embase, and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on the mechanisms or treatment of osteoporosis in PWH., Results: The pathogenic mechanisms of osteoporosis in PWH are multifactorial and remain unclear. The available evidence shows that FVIII and FIX deficiency may directly affect bone metabolism by interfering with the RANK/RANKL/OPG pathway. Other potential mechanisms of osteoporosis in PWH include thrombin deficiency and the unloading and immobilization of bone, which will affect osteoblast and osteoclast activity by changing the cytokine profiles. The treatment of osteoporosis in PWH includes antiresorptive, anabolic, and dual-action drugs; weight-bearing exercise; fall prevention; and prophylactic coagulation factor replacement therapy. However, clinical studies of the efficacy of anti-osteoporotic agents in osteoporosis of PWH are urgently needed., Conclusion: This review summarizes recent progress in research on the pathogenesis of osteoporosis in PWH and provides insights into potential treatment for osteoporosis in PWH., (© 2022. The Author(s).)

Background: Abbreviated magnetic resonance imaging (Ab-MRI) has been evaluated for elevated breast cancer risk or dense breasts but has not been evaluated across all risk profiles., Methods: Patients selected underwent Ab-MRI from February 2020 to September 2021. Women were older than aged 30 years, up to date with screening mammography, and paid $299 cash., Results: A total of 93 patients were identified with a mean age of 52 years; 92.5% were Caucasian, 0% black, and 97.9% were from high socioeconomic status. Mean Gail score was 14.2, and 83.3% had a lifetime risk of breast cancer <20%. Reasons for Ab-MRI: dense breasts (36.6%); family history (24.7%); palpable mass (12.9%). Providers ordering: OBGYN (49.5%); breast surgeon (39.1%); primary care (6.6%). Thirteen biopsies (14%) detected one breast cancer. 31.1% had a change in follow-up screening: 58.6% 6-month MRI, 20.7% 6-month mammogram, and 10.3% 6-month ultrasound. Negative predictive value was 100% (95% confidence interval [CI]: 95-100%, p < 0.0001). Sensitivity was 100% (95% CI: 2.5-100%, p < 0.0001), and specificity was 87% (95% CI: 78.3-93.1%, p < 0.0001) compared with 77.6% and 98.8% for mammography. Only one cancer was detected: cost of $27,807 plus cost of 13 MRI or ultrasound (US)-guided biopsies and additional follow-up imaging. Historically 20% of abnormalities detected on full MRI are malignant; however, 7.7% of ab-MRI abnormalities were malignant CONCLUSIONS: One third of women were recommended a change in follow-up, which predominantly included a 6-month MRI. Ab-MRI may introduce average risk women to unnecessary follow-up and increased biopsies with a lower cancer detection rate. Ab-MRI should be evaluated closely before implementation., (© 2022. Society of Surgical Oncology.)

Purpose: Primary hyperparathyroidism (PHPT) is characterized by excessive secretion of parathyroid hormone (PTH). Vitamin D deficiency can stimulate parathyroid secretion. However, whether to correct vitamin D deficiency in patients with PHPT is controversial. We aimed to evaluate the safety and efficacy of vitamin D replacement in patients with PHPT., Methods: We searched PubMed, Cochrane Library, and Embase. The relevant data were extracted from the included documents. The methodological items for non-randomized studies score entries were used for evaluation of quality. Review Manager 5.3 and Stata 12.0 were used for statistical analysis., Results: A total of 11 articles were included with a total of 388 patients. The serum calcium mean difference (MD) was - 0.06 mg/dL [95% confidence interval (95% CI) - 0.16, 0.04]. Subgroup analysis showed that serum calcium levels did not change if the intervention time exceeded 1 month. The 24-h urinary calcium MD was 36.78 mg/day (95% CI - 37.15, 110.71), which indicated that there was no significant effect of vitamin D supplementation on 24-h urinary calcium levels. The MD of PTH was - 16.01 pg/mL (95% CI - 28.79, - 3.24). Subgroup analysis according to the intervention time showed that vitamin D intervention for more than 1 month significantly reduced PTH levels. The ALP MD was - 10.81 U/L (95% CI - 13.98, - 7.63), which indicated Vitamin D supplementation reduced its level. The MD of 25-hydroxyvitamin D was 22.09 μg/L (95% CI 15.01, 29.17), and no source of heterogeneity was found., Conclusion: Vitamin D supplementation in patients with PHPT and vitamin D deficiency significantly reduces PTH and ALP levels without causing hypercalcemia and hypercalciuria., (© 2021. Italian Society of Endocrinology (SIE).)

Breast cancer (BC) threatened the life health of a tremendous amount of the population, and the estimated number of death is still rising nowadays. We found that stress-induced phosphoprotein 1 (STIP1) is overexpressed in BC tissues compared to non-tumorous breast tissues. Our study is to validate the prognostic value of STIP1 and investigate its biological role in BC. We verified the upregulation of STIP1 in multiple databases, proved that STIP1 is upregulated in BC tissues and cell lines using real-time quantitative PCR (qRT-PCR). We used small interfering RNA to examine the function of STIP1 in BC cell lines (BT-549, MDA-MB-231, Hs-578 T) and explored the mechanism of function of STIP1 in BC cells using Western blotting and qRT-PCR. Analyses of multiple databases indicated that high STIP1 expression is a marker that effectively distinguishes BC patients from healthy control and predicts worse clinical outcomes in BC. The loss-of-function experiments showed that STIP1 silencing results in inhibition of cell proliferation and migration, inducing cell apoptosis, and S-phase arrest in vitro. Our study also showed that STIP1 downregulation inhibited the JAK2/STAT3 pathway and epithelial-mesenchymal transition process. Rescue experiments demonstrated that the oncogenic effect of STIP1 is partially dependent on mediating JAK2 expression. This study verified that STIP1 is an oncogenic gene that promotes BC progression and serves as a valuable diagnostic and outcome-related marker of BC.

Purpose: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS., Methods: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes., Results: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS., Conclusions: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

Purpose: Primary hypertrophic osteoarthropathy (PHO) is an inherited disease characterized by digital clubbing, periostosis and pachydermia with defects in the degradation of prostaglandin E2 (PGE2). Mutations in SLCO2A1 gene-encoding prostaglandin transporter (PGT) resulted in PHO, autosomal recessive 2 (PHOAR2). The spectrum of mutations and variable clinical complications of PHOAR2 has been delineated. In this study, we investigated a Chinese PHO family with a manifestation of Bartter-like hypokalemia., Methods: Clinical manifestations were collected and genetic analyses were performed in the PHO family., Results: The 33-year-old male proband had severe hypokalemia due to potassium loss from the kidney, while his brother had mild hypokalemia. After being treated with etoricoxib, the serum potassium level of the patient increased rapidly to the normal range which corresponded with the reduction in his serum PGE2 and PE2 metabolite (PGEM) levels. A novel SLCO2A1 compound heterozygous mutation of p.I284V and p.C459R was identified in two PHO patients in this family., Conclusions: The present findings supported that the Bartter-like hypokalemia is a new complication of PHOAR2 caused by the high level of PGE2. Etoricoxib was demonstrated to be effective for the renal hypokalemia in PHO patients.

The incidence of thyroid cancer detection is continually improving worldwide with the spread of diagnostic imaging and surveillance. Although we have made great progress, there are still unknown mechanisms of papillary thyroid cancer. We found that UNC5B-AS1 is a potential oncogene in thyroid cancer. Therefore, our study aimed to investigate the biological functions of the lncRNA UNC5B-AS1 in papillary thyroid cancer. As a result, RNA-seq data on primary papillary thyroid cancer (PTC) in the TCGA database were obtained. RT-qPCR was performed to evaluate the expression levels in thyroid tissue. We then analysed the expression level of UNC5B-AS1 and its association with clinicopathologic characteristics in the TCGA database. We downregulated UNC5B-AS1 using small interfering RNA and carried out assays of cell proliferation, colony formation, migration and invasion to explore the function of UNC5B-AS1 in PTC cell lines (TPC1 and BCPAP). These results suggested that the lncRNA UNC5B-AS1 was significantly upregulated in both the TCGA cohort and our tissue cohort. Upregulated UNC5B-AS1 correlated with lymph node metastasis (P < 0.001), tumor size (P = 0.002) and histological type (P = 0.013). We also achieved an area under the ROC curve (AUC) of 93.2% for our validated cohort, which was consistent with the AUC of 94.5% for the TCGA cohort, for differentiating between PTC tissues and normal tissues. Downregulating UNC5B-AS1 expression at the RNA level significantly inhibited cell proliferation, colony formation, migration, and invasion in PTC cell lines (TPC1 and BCPAP). This study demonstrated that the lncRNA UNC5B-AS1 plays an important role in tumourigenesis and metastasis of PTC and may be a potential therapeutic target for PTC.

Luminal B HER-2-negative (LBHN) subtype is one of the major subtypes of breast cancer according to different features, clinical behaviors, and treatment response. The LBHN subtype shows a poor prognosis and is insensitive to endocrine therapy. Our work aim is to investigate the prognostic factor in the LBHN subgroup and, meanwhile, try to obtain an optimal prognostic index (PI) contrapose LBHN subgroup which helps to guide chemotherapy. A total of 515 female LBNH patients who underwent diagnosis and surgery at our hospitals from August 2008 to August 2018 were enrolled. Clinical-pathological information was obtained and immunohistochemistry result was available. From these cases, a 30% Ki-67 LI was employed to divide LBHN into two groups with low and high levels; high Ki-67 LI was associated with GIII tumor grade (P < 0.001), positive axillary lymph nodes (ALN) status (P = 0.018) and negative PR status (P = 0.016), and also seemed to be related to T2-T3 tumor size (P = 0.058). High Ki-67 level (HR = 3.30; P < 0.011), positive ALN (HR = 7.29; P < 0.001) and PR negative (HR = 2.63; P = 0.034) significantly associated with poor 5-year DFS in multivariate Cox's proportional hazard regression model. A novel prognosis prediction model (KLP-PI), based on Ki-67 LI, ALN and PR status, showed a better discriminatory ability compared with traditional Nottingham prognostic index targeted to LBHN breast cancer. Our study highlights that high Ki-67 LI, positive ALN and negative PR status were associated with poor outcome in LBHN patients, and composed by these prognostic factors, KLP-PI improves the prognostic assessment using the Nottingham Prognostic Index when aiming at LBHN subtype.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disorder with poorly known etiology, pathophysiology, and therapy. We aimed to investigate the clinical characteristics of PLO and evaluate the effectiveness and safety of bisphosphonates on it. A total of 12 patients were diagnosed with PLO on the basis of medical history, bone mineral density (BMD), and/or fragility fractures during pregnancy and lactation. We investigated the clinical, biochemical, and radiological characteristics of patients. We assessed the effects of alendronate or zoledronic acid through observing the changes of bone turnover biomarkers and BMD during the treatment. Secondary osteoporosis was excluded by comprehensive differential diagnosis. The mean age of these patients was 31 ± 5 years old. All of these patients presented severe back pain. Multiple vertebral compression fractures (VCFs) were found in 10 patients, and the median (P25th, P75th) number of compressed vertebra was 3 (3, 5). Ten patients had vitamin D insufficiency or deficiency. Serum level of bone resorption marker (β-CTX with mean of 0.68 ± 0.41 ng/ml) was moderately higher than the normal range. BMD at lumbar spine, femoral neck, and total hip were low as 0.894 ± 0.153 g/cm 2 , 0.728 ± 0.090 g/cm 2 , and 0.728 ± 0.080 g/cm 2 , respectively. Either alendronate or zoledronic acid could effectively relieve bone pain, reduce β-CTX level, and increase BMD. PLO is a rare type of osteoporosis, which was characterized by increased bone resorption and decreased BMD, even VCFs. Bisphosphonate therapy was well tolerated and effective in management of PLO, but needed to be further verified in randomized controlled trial.

Gorham-Stout disease (GSD) is an exceedingly rare disease characterized by progressive osteolysis and angiomatosis. We investigate the features of this disease and evaluate the effects of bisphosphonates (BPs) on it. The clinical, radiological, and pathological characteristics of 12 patients diagnosed with GSD were summarized. Immunohistochemical staining with specific lymphatic endothelial markers (D2-40), vascular markers (CD 31, CD 34), and vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 3 (VEGFR-3) was performed in specimens of bone biopsy. Patients were treated with either BPs or conjunction therapy of radiation and BPs. The effects of BPs were evaluated by the change of radiological progression, bone mineral density (BMD) and bone turnover biomarkers. To further evaluate the prognosis, a literature review was done. Idiopathic massive osteolysis was found in all patients, including 11 polyostotic and one mono-ostotic osteolysis. Soft tissue lymphangioma was presented in four patents. Four patients were complicated with chylothorax. Endothelial cells lining the proliferative vessels were positive for CD31 and CD34 and D2-40. Mild expression of VEGF and VEGFR-3 was also revealed. Stabilization in osteolysis and improvement in BMD were observed after single therapy with BPs or combined with radiotherapy. High mortality rate was found in patients with chylothorax. Spontaneous, progressive osteolysis is the most typical sign of GSD. BPs and radiotherapy can contribute to the clinical stabilization in bone lesion of GSD. The complicated chylothorax possibly indicates poor prognosis.

The carbonic anhydrase II (CAII) deficiency syndrome is a rare autosomal recessive osteopetrosis with renal tubular acidosis (RTA) and cerebral calcifications (MIM259730). CAII deficiency syndrome is caused by mutations in the gene CAII, which encodes the enzyme carbonic anhydrase II. CAII mutations are rarely reported in the Asian population. Here, we described two unrelated CAII deficiency families of Chinese Han origin with clinical and genetic analysis. Altogether, 106 subjects, including 2 probands, 4 unaffected family members from two non-consanguineous Chinese families, and 100 healthy controls were recruited. All seven exons and the exon-intron boundaries of the CAII gene were amplified and directly sequenced. Reverse transcription PCR (RT-PCR) was used to study the effect of splice site mutation. All clinical and biochemical parameters of the probands were collected. Two novel mutations of CAII gene were identified by mutational analysis: A nonsense mutation in exon 4 (c.T381C p.Y127X) in both families; a splice mutation at the splice donor site of intron 3 (c.350+2T>C, IVS3+2T>C) in one family. The splice-site mutation causes exon 3 skipping in patient's mRNA resulting in an in-frame deletion and a novel premature stop codon. These mutations were predicted to result in a loss of function of CAII. This is the first report of CAII deficiency syndrome in Chinese population. Our findings extent the spectrum of CAII mutations observed in patients with CAII deficiency syndrome.

Background: The occurrence of seroma formation after axillary lymphadenectomy for breast cancer cannot be ignored. Various approaches have been used in an effort to reduce it, but these results are still controversial. We aimed to describe a new method of application of OK-432 (Sapylin, heat-treated Su strain of Streptococcus) to reduce seroma formation after axillary lymphadenectomy for breast cancer and to verify the safety and efficacy of it as a beneficial supplement for conventional surgery., Methods: A prospective, randomized analysis of consecutive quadrantectomy or mastectomy plus axillary lymphadenectomy using or not using OK-432 was designed. From July 2010 to November 2011, a total of 111 patients were enrolled in this prospective, randomized study and completed the follow-up. OK-432 applied to the axillary fossa plus placement of closed suction drainage was used in 54 patients (the experimental group); placement of closed suction drainage was used in 57 patients (the control group)., Results: There were no statistical significance between the two groups in terms of age, body mass index, treatment received, tumor size, number of removed lymph nodes, and lymph node status. Postoperative drainage magnitude and duration were significantly reduced in the experimental group (P = 0.008 and 0.003, respectively). One week after hospital discharge, fewer patients developed a palpable seroma in the experimental group: 10 in the experimental group versus 28 in the control group (P = 0.001). Fewer seromas needed aspiration (mean 1 [range 0-3] in the experimental group vs. mean 4 [range 1-5] in the control group; P < 0.001). There were no significant differences in terms of the incidence of complications associated with axillary lymphadenectomy (P = 0.941)., Conclusions: OK-432 is a feasible and safe option for axillary lymphadenectomy for breast cancer. The use of it does not always prevent seroma formation, but it can reduce drainage magnitude and duration, as well as decrease the incidence of seroma after the removal of drainage. It may be increasingly conducted in day surgery clinics.

Fructose-1,6-diphosphate (FDP) is a glycolytic intermediate which has been used an intervention in various ischemic conditions for two decades. Yet whether FDP can enter the cell is under constant debate. In this study we examined membrane permeability of FDP in artificial membrane bilayers and in endothelial cells. To examine passive diffusion of FDP through the membrane bilayer, L-alpha-phosphatidylcholine from egg yolk (Egg PC) (10 mM) multi-lamellar vesicles were created containing different external concentrations of FDP (0, 0.5, 5 and 50 mM). The passive diffusion of FDP into the vesicles was followed spectrophotometrically. The results indicate that FDP diffuses through the membrane bilayer in a dose-dependent fashion. The movement of FDP through Egg PC membrane bilayers was confirmed by measuring the conversion of FDP to dihydroxyacetone-phosphate and the formation of hydrozone. FDP (0, 0.5, 5 or 50 mM) was encapsulated in Egg PC multilamellar vesicles and placed in a solution containing aldolase. In the 5 and 50 mM FDP groups there was a significant increase in dihydroxyacetone/hydrazone indicating that FDP crossed the membrane bilayer intact. We theorized that the passive diffusion of FDP might be due to disruption of the membrane bilayer. To examine this hypothesis, small unilamellar vesicles composed of Egg PC were created in the presence of 60 mM carboxyfluorescein, and the leakage of the sequestered dye was followed upon addition of various concentrations of FDP, fructose, fructose-6-phosphate, or fructose-1-phosphate (0, 5 or 50 mM). These results indicate that increasing concentrations of FDP increase the leakage rate of carboxyfluorescein. In contrast, no concentration of fructose, fructose-6-phosphate, or fructose-1-phosphate resulted in any significant increase in membrane permeability to carboxyfluorescein. To examine whether FDP could pass through cellular membranes, we examined the uptake of 14C-FDP by endothelial cells cultured under hypoxia or normoxia for 4 or 16 h. The uptake of FDP was dose-dependent in both the normoxia and hypoxia treated cells, and was accompanied by no significant loss in endothelial cell viability. Our results demonstrate that FDP can diffuse through membrane bilayers in a dose-dependent manner.