Identification of rare and novel PHEX variants in X-linked hypophosphatemia.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare metabolic bone disease caused by inactivation mutations in the PHEX gene. Despite the extensive number of reported PHEX variants, only a few cases of chromosomal abnormalities have been documented. OBJECTIVE: We aimed to identify the pathogenic variants in six unrelated families with a clinical diagnosis of XLH and to propose a genetic workflow for hypophosphatemia patients suspected of XLH. METHODS: Multiple genetic testing assays were used to analyze the six families' genetic profiles, including whole exome sequencing, multiplex ligation-dependent probe amplification, whole genome sequencing, reverse transcript polymerase chain reaction, Sanger sequencing, and karyotyping. RESULTS: The study identified six novel pathogenic variants, including one mosaic variant (exon 16-22 deletion), three chromosomal abnormalities (46, XN, inv[X][pter→p22.11::q21.31→p22.11::q21.31 →qter], 46, XN, inv[X][p22.11p22.11], and XXY), a nonclassical intron variant (NM_000444.6, c.1701_31A > G), and a deletion variant (NM_000444.6, c.64_5464-186 del5215) of PHEX. Additionally, a genetic testing workflow was proposed to aid in diagnosing patients suspected of XLH. CONCLUSION: Our research expands the mutation spectrum of PHEX and highlights the significance of utilizing multiple genetic testing methods to diagnose XLH.

Hypoxia macrophage-derived exosomal miR-26b-5p targeting PTEN promotes the development of keloids.

Background: Hypoxia is the typical characteristic of keloids. The development of keloids is closely related to the abnormal phenotypic transition of macrophages. However, the role of exosomal microRNAs (miRNAs) derived from hypoxic macrophages in keloids remains unclear. This study aimed to explore the role of hypoxic macrophage-derived exosomes (HMDE) in the occurrence and development of keloids and identify the critical miRNA. Methods: The expression of CD206+ M2 macrophage in keloids and normal skin tissues was examined through immunofluorescence. The polarization of macrophages under a hypoxia environment was detected through flow cytometry. The internalization of macrophage-derived exosomes in human keloid fibroblasts (HKFs) was detected using a confocal microscope. miRNA sequencing was used to explore the differentially expressed miRNAs in exosomes derived from the normoxic and hypoxic macrophage. Subsequently, the dual-luciferase reporter assay verified that phosphatase and tension homolog (PTEN) was miR-26b-5p's target. The biological function of macrophage-derived exosomes, miR-26b-5p and PTEN were detected using the CCK-8, wound-healing and Transwell assays. Western blot assay was used to confirm the miR-26b-5p's underlying mechanisms and PTEN-PI3K/AKT pathway. Results: We demonstrated that M2-type macrophages were enriched in keloids and that hypoxia treatment could polarize macrophages toward M2-type. Compared with normoxic macrophages-derived exosomes (NMDE), HMDE promote the proliferation, migration and invasion of HKFs. A total of 38 differential miRNAs (18 upregulated and 20 downregulated) were found between the NMDE and HMDE. miR-26b-5p was enriched in HMDE, which could be transmitted to HKFs. According to the results of the functional assay, exosomal miR-26b-5p produced by macrophages facilitated HKFs' migration, invasion and proliferation via the PTEN-PI3K/AKT pathway. Conclusions: The highly expressed miR-26b-5p in HMDE promotes the development of keloids via the PTEN-PI3K/AKT pathway.

Association of serum osteocalcin with bone microarchitecture and muscle mass in Beijing community-dwelling postmenopausal women.

BACKGROUND: Osteoporosis is a systemic skeletal disease with increasing bone fragility and prone to fracture. Osteocalcin (OC), as the most abundant non collagen in bone matrix, has been extensively used in clinic as a biochemical marker of osteogenesis. Two forms of OC were stated on circulation, including carboxylated osteocalcin (cOC) and undercarboxylated osteocalcin (ucOC). OC was not only involved in bone mineralization, but also in the regulation of muscle function. OBJECTIVE: This study explored the relationship between serum OC, cOC, ucOC levels and bone mineral density (BMD), bone microarchitecture, muscle mass and physical activity in Chinese postmenopausal women. METHOD: 216 community-dwelling postmenopausal women were randomized enrolled. All subjects completed biochemical measurements, including serum ß-isomer of C-terminal telopeptides of type I collagen (ß-CTX), N-terminal propeptide of type 1 procollagen (P1NP), alkaline phosphatase (ALP), OC, cOC and ucOC. They completed X-ray absorptiometry (DXA) scan to measure BMD, appendicular lean mass (ALM) and trabecular bone score (TBS). They completed high resolution peripheral quantitative CT (HR-pQCT) to assess peripheral bone microarchitectures. RESULTS: Serum OC, cOC and ucOC were elevated in osteoporosis postmenopausal women. In bone geometry, serum ucOC was positively related with total bone area (Tt.Ar) and trabecular area(Tb.Ar). In bone volumetric density, serum OC and ucOC were negatively associated with total volume bone mineral density (Tt.vBMD) and trabecular volume bone mineral density (Tb.vBMD). In bone microarchitecture, serum OC and ucOC were negatively correlative with Tb.N and Tb.BV/TV, and were positively correlated with Tb.Sp. Serum OC and ucOC were positively associated with Tb.1/N.SD. Serum OC was negatively related with Tb.Th. Serum ucOC was positively associated with ALM. The high level of serum OC was the risk factor of osteoporosis. ALM was the protective factor for osteoporosis. CONCLUSION: All forms of serum OC were negatively associated with BMD. Serum OC and ucOC mainly influenced microstructure of trabecular bone in peripheral skeletons. Serum ucOC participated in modulating both bone microstructure and muscle mass.

Influence of distracted driving of online car-hailing drivers on overall driving performance.

The distraction affects driving performance and induces serious safety issues. To better understand distracted driving, this study examines the influence of distracted driving on overall driving performance. This paper analyzes the distraction behavior (mobile phone use, entertainment activities, and passenger interference) under three driving tasks. The statistical results show that viewing or sending messages is common during driving. Smoking, phone calls, and talking to passengers are evident in cruising, ride request and drop-off, respectively. Then, overall driving performance is proposed based on velocity, longitudinal acceleration (longacc) and yaw_rate. It is divided into three categories, high, medium, and low, by k-means algorithms. The average speed increases from low to high performance; however, the longacc and yaw_rate decrease. Finally, the influence of distracted driving on overall driving performance is analyzed using C4.5 algorithm. The result shows that when time is peak, the probability of high performance (HP) is higher than off-peak. The possibility of HP increases with the increase of duration; the number of, talking to passengers, listening to music or radio, eating; the duration of, viewing or sending messages, phone calls; but reduces with the increase of the number of phone calls. These findings provide theoretical support for driving performance evaluation.

Influence of Obesity and Changes in Weight or BMI on Incident Fractures in Postmenopausal Women: From Peking Vertebral Fracture Study.

This study aims to investigate the influence of overweight/obesity and change in weight or body mass index (BMI) on incident fractures among Chinese postmenopausal women. According to BMI, 754 postmenopausal women were categorized into normal weight (NW), overweight (OW), and obesity (OB) groups, respectively. We used data from the baseline and the second survey for statistical analysis, including anthropometric data, clinical fractures, and morphometric vertebral fractures (MVFs) assessed by X-rays. The prevalence of previous MVFs was 32.7% and 21.8% in the OB and NW groups, respectively (p < 0.05). All incident fractures and incident MVFs accounted for 10.7 and 6.3% among all participants within five years. Overweight/obesity and increase in weight or BMI during the follow-up had no associations with all incident fractures, incident MVFs, and incident clinical non-VFs among all participants. However, after multivariate adjustment, the increased BMI at baseline was the risk factor of incident MVFs in the OW group (odds ratio, OR 2.06, 95% confidence interval, 95% CI 1.16-3.66, p = 0.014), and increase in weight (OR 0.89, 95% CI 0.79-0.99, p = 0.036) or BMI (OR 0.77, 95% CI 0.59-0.99, p = 0.045) during the follow-up were the protective factors of all incident fractures in the NW group. Overweight/obesity and change in weight or BMI do not correlate with fracture risk in postmenopausal women, but an increase in weight is the protective factor against incident fractures in normal-weight participants. Overweight postmenopausal women with a higher BMI should pay attention to the risk of MVFs.

Incident vertebral fracture and longitudinal BMD change in Chinese postmenopausal women with early CKD: Peking Vertebral Fracture Study.

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/1.73m2 for stage 2 (n = 511) and 30-59 mL/min/1.73m2 for stage 3 (n = 92). The non-CKD group included individuals with an eGFR greater than or equal to 90 mL/min/1.73m2. 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.

miR-656-3p inhibits melanomas in vitro and in vivo by inducing senescence via inhibiting LMNB2.

BACKGROUND: Ultra-Violet Radiation (UVR) is the most significant exogenous contributor to skin aging. UVB causes the senescence of melanocytes, which results in a permanent arrest in the proliferative process. Senescence is also regarded as a physiological tumor-suppressing mechanism of normal cells. However, the mechanism of the relationship between melanocyte senescence and melanoma was not sufficiently clarified. METHODS: Melanocytes and melanoma cells were irradiated with UVB for the indicated time. The miRNA expression profile of melanocytes were obtained by miRNA sequencing and confirmed by real-time PCR. Cell count kit-8 assays, cell cycle assays were also employed to explore the effect of miR-656-3p and LMNB2 on senescence. Dual-luciferase reporter assays were applied to determine the miRNA targets. Finally, a xenograft model and a photoaging model of mice were conducted to verified the function of miR-656-3p in vivo. RESULTS: Melanoma cells did not alter into a senescence stage and the expressions of miR-656-3p had no significant changes under the same intensity of UVB radiation. miR-656-3p appeared to be upregulated in melanocytes rather than melanoma cells after UVB radiation. miR-656-3p could promote the photoaging of human primary melanocytes by targeting LMNB2. Finally, overexpression of miR-656-3p significantly induced senescence and inhibited the growth of melanomas in vitro and in vivo. CONCLUSION: Our work not only demonstrated the mechanism by which miR-656-3p induced the senescence of melanocytes but also proposed a treatment strategy for melanomas by using miR-656-3p to induce senescence.

Comparison of bone microstructure and strength in the distal radius and tibia between the different types of primary hypertrophic osteoarthropathy: an HR-pQCT study.

Primary hypertrophic osteoarthropathy (PHO) is a hereditary bone disease that is grouped into PHO autosomal recessive 1 (PHOAR1) and PHO autosomal recessive 2 (PHOAR2) due to different causative genes. Data comparing bone microstructure between the two subtypes are scarce. This is the first study to find that PHOAR1 patients had inferior bone microstructure compared with PHOAR2 patients. PURPOSE: The primary goal of this study was to assess bone microarchitecture and strength in PHOAR1 and PHOAR2 patients and to compare them with age- and sex-matched healthy controls (HCs). The secondary goal was to assess the differences between PHOAR1 and PHOAR2 patients. METHODS: Twenty-seven male Chinese PHO patients (PHOAR1 = 7; PHOAR2 = 20) were recruited from Peking Union Medical College Hospital. The areal bone mineral density (aBMD) was assessed by dual-energy X-ray absorptiometry (DXA). Peripheral bone microarchitecture at the distal radius and tibia were evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Biochemical markers of PGE2, bone turnover, and Dickkopf-1 (DKK1) were investigated. RESULTS: Compared with HCs, PHOAR1 and PHOAR2 patients had distinctively larger bone geometry, substantially lower vBMD at the radius and tibia, and compromised cortical microstructure at the radius. For trabecular bone, PHOAR1 and PHOAR2 patients showed different changes at the tibia. PHOAR1 patients had significant deficits in the trabecular compartment, resulting in lower estimated bone strength. Conversely, PHOAR2 patients showed a higher trabecular number, narrower trabecular separation, and lower trabecular network inhomogeneity than HCs, translating into preserved or slightly high estimated bone strength. CONCLUSION: PHOAR1 patients had inferior bone microstructure and strength compared with PHOAR2 patients and HCs. Additionally, this study was the first to find differences in the bone microstructure between PHOAR1 and PHOAR2 patients.

Shift in Calcium From Peripheral Bone to Axial Bone After Tumor Resection in Patients With Tumor-Induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. After successful tumor resection, patients can recover from hypophosphatemia quicky. However, data on the changes in bone mineral density (BMD) and microstructure in the short term after surgery remained unclear. OBJECTIVE: This work aimed to investigate the postoperative changes in BMD and microstructure both in peripheral and axial bone in TIO patients. METHODS: We evaluated BMD and microarchitecture in 22 TIO patients using high-resolution peripheral quantitative computed tomography (HR-pQCT) and dual-energy x-ray absorptiometry (DXA) before and 3 months after surgery in this retrospective study. RESULTS: In this study, a total of 22 TIO patients who had recovered serum phosphate levels postoperatively were enrolled. After surgery, areal BMD (aBMD) increased by 21.6% in the femoral neck, by 18.9% in the total hip, and by 29.5% in the lumbar spine. Moreover, TBS increased by 14.1% (all P < .001). In contrast, trabecular or cortical volumetric BMD (vBMD), and microstructure of trabecular bone (trabecular number, separation and bone volume ratio) and cortical bone (cortical thickness and porosity) at the distal radius or tibia were further deteriorated. Correlation analyses found that changes in femoral neck and total hip aBMD were both conversely associated with changes in trabecular vBMD and bone volume ratio, while positively correlated with change in trabecular separation at the distal radius. CONCLUSION: Although aBMD and microstructure in the axial bone were improved, vBMD and microstructure in the peripheral bone were further impaired shortly after surgery. Correlation of improvement of aBMD in the total hip and femoral neck with deterioration of vBMD and microstructure at the distal radius indicated a shift in calcium from the peripheral bone to the axial bone in the short term after tumor resection in TIO patients.

SUMOylation mediates the disassembly of the Smad4 nuclear export complex via RanGAP1 in KELOIDS.

Sentrin/small ubiquitin-like modifier (SUMO) has emerged as a powerful mediator regulating biological processes and participating in pathophysiological processes that cause human diseases, such as cancer, myocardial fibrosis and neurological disorders. Sumoylation has been shown to play a positive regulatory role in keloids. However, the sumoylation mechanism in keloids remains understudied. We proposed that sumoylation regulates keloids via a complex. RanGAP1 acted as a synergistic, functional partner of SUMOs in keloids. Nuclear accumulation of Smad4, a TGF-ß/Smad pathway member, was associated with RanGAP1 after SUMO1 inhibition. RanGAP1*SUMO1 mediated the nuclear accumulation of Smad4 due to its impact on nuclear export and reduction in the dissociation of Smad4 and CRM1. We clarified a novel mechanism of positive regulation of sumoylation in keloids and demonstrated the function of sumoylation in Smad4 nuclear export. The NPC-associated RanGAP1*SUMO1 complex functions as a disassembly machine for the export receptor CRM1 and Smad4. Our research provides new perspectives for the mechanisms of keloids and nucleocytoplasmic transport.

A Chinese case of CHST3-related skeletal dysplasia and a systematic review.

PURPOSE: We reported a case with carbohydrate sulfotransferase 3 (CHST3) spondyloepiphyseal dysplasia and made a systematic review of all previously reported cases. METHODS: A 14.8-year-old boy underwent clinical, radiological, and genetic evaluations. The patients and five age-matched healthy boys accepted high-resolution peripheral quantitative computed tomography evaluation. All CHST3-related skeletal dysplasia cases from PubMed and Embase were collected and summarized. The genotype-phenotype correlation was analyzed. RESULTS: The proband complained of aggravated joint pain and had a compression fracture of L2 during his second decade. Physical examination showed a height Z score of -4.94, short limbs, and restricted movement of the elbows and knees. X-rays showed carpal epiphyseal dysplasia, enlargement of elbow and knee joints, and subluxation of the left hip. Echocardiography showed abnormal cardiac valves. Compared with the norm, his total and trabecular volumetric bone mineral density (BMD), and the microarchitecture of the trabecular bone had trends to be worse at the distal radius and tibia. Two novel missense variants of c.1343T>G and c.761C>G in CHST3 were inherited from his father and mother, respectively. In the systematic review, short stature, limited joint extension, joint pain, and joint dislocation were the most common characteristics of this disorder. Height Z score and the proportion of hearing impairment had no significant differences between the missense and nonmissense mutations groups. CONCLUSION: Progressive joint pain and movement restriction are the main characteristics of CHST3-related skeletal dysplasia. BMD and bone microarchitecture of this disorder needs further exploration. There is no apparent genotype-phenotype correlation in this disorder.

Ultra-High Performance Liquid Chromatography-Mass Spectrometry-based Serum Metabolomics for Early Diagnosis of Refractory Tumor-induced Osteomalacia: A Case-control Study.

CONTEXT: Nearly 20% patients with tumor-induced osteomalacia (TIO) experienced recurrence or nonrecovery after surgery. Serum fibroblast growth factor 23 and phosphate concentrations are not sufficient for prognosis in such cases. Despite its importance for understanding of prognosis and underlying pathogenesis, the alteration of systemic metabolism in refractory TIO remains unclear. OBJECTIVE: We aimed to find the metabolomic characteristics of refractory TIO and establish a novel predictive model for early discriminating refractory TIO based on their serum metabolomics. DESIGN AND SETTING: Cross-section study for comparison of metabolomic profile between TIO and normal control and longitudinal study for identifying prognostic model. METHODS: Based on liquid chromatography-tandem mass spectrometry, we analyzed the global metabolomes of preoperative sera from 86 samples (32 TIO recovery patients, 11 nonremission patients, and 43 matched controls). Statistical analyses, pathway enrichment, and receiver operating characteristic analysis were performed to identified and evaluate potential markers. RESULTS: Sparse partial least squares discriminant analysis indicated a clear separation of metabolomic profiles between healthy controls (HC) and TIO patients. The serum metabolites altered in different prognostic groups. L-pipecolic acid, 2-dodecylbenzenesulfonic acid, and 2-deoxygalactopyranose were the top 3 metabolites that were significantly perturbed. A combination of L-pipecolic acid and 2-dodecylbenzenesulfonic acid demonstrated a high-performance panel for TIO prognosis evaluated by random forest algorithm (area under the curve = 0.921, 95% CI, 0.787-0.995). CONCLUSIONS: We investigate the global metabolomes of refractory TIO and identify potential prognostic biomarkers preliminarily. A high sensitivity and specificity panel were identified as promising discriminating predictors, which need to be verified in more patients. This work may demonstrate novel insights into TIO prognosis and pathogenesis.

Evaluation of Volumetric Bone Mineral Density, Bone Microarchitecture, and Bone Strength in Patients with Achondroplasia Caused by FGFR3 c.1138G > A Mutation.

Achondroplasia (ACH) is a skeletal disorder caused by fibroblast growth factor receptor 3 (FGFR3) variants. Volumetric bone mineral density (vBMD), bone microarchitecture, and strength have not been evaluated in these patients previously. This study aims to evaluate vBMD, bone microarchitecture, and strength in ACH patients. Seventeen patients underwent clinical and biochemical evaluations, and genetic testing. High-resolution peripheral quantitative computed tomography was performed in 10 ACH patients and 21 age- and sex-matched healthy subjects. All individuals had the hotspot mutation of c.1138G > A in FGFR3. Linear growth retardation, disproportionate short stature, and genu varum are the most common manifestations. The mean height was 108.82 ± 24.08 cm (Z score: - 5.72 ± 0.96). Total vBMD in the ACH and the control groups was 427.08 ± 49.29 mg HA/cm3 versus 300.35 ± 69.92 mg HA/cm3 (p < 0.001) at the radius and 336.90 ± 79.33 mg HA/cm3 versus 292.20 ± 62.35 mg HA/cm3 (p = 0.098) at the tibia; both at the radius and tibia, vBMD of trabecular bones was significantly lower in the ACH group than in the control group, but vBMD of cortical bones was slightly higher in the ACH group. Trabecular separation and cortical thickness in the ACH group were significantly higher than those in the control group, but trabecular number was significantly decreased in the ACH group. Stiffness and failure load were only better at the radius in the ACH group. ACH patients have higher total and cortical vBMD, lower trabecular vBMD, worse trabecular bone microarchitecture, thicker cortical bone thickness, and better estimated bone strength.

Hyperparathyroidism in a Large Cohort of Chinese Patients With Tumor-induced Osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by excessive production of fibroblast growth factor 23 (FGF23) by a tumor. Hyperparathyroidism (HPT) including secondary HPT (SHPT) and tertiary HPT (THPT) in TIO patients, which is believed to be associated with phosphate supplementation, has not been well documented. OBJECTIVES: To clarify the prevalence, clinical characteristics, and risk factors for HPT in a large cohort of Chinese patients with TIO in our hospital. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study enrolled 202 patients with TIO. MAIN OUTCOME MEASUREMENTS: Occurrence of HPT in patients with TIO. RESULTS: HPT was observed in 91 patients (91/202, 45.1%): 84 patients (41.6%) with SHPT and 7 patients (3.5%) with THPT. All patients with THPT underwent parathyroidectomy and only 1 patient experienced recurrence. Compared with patients without HPT, patients with SHPT had longer disease duration, higher rate of phosphate and calcitriol supplementation, lower serum calcium, lower urine calcium excretion, and higher urine phosphate excretion. Compared with patients with SHPT, patients with THPT had even longer disease duration and a higher rate of phosphate and calcitriol supplementation. PTH levels showed positive correlation with intact FGF23 and 1,25-dihydroxyvitamin D levels, but not 25-hydroxy vitamin D level in patients with TIO. Multivariate logistic regression analysis showed that long disease duration and phosphate supplementation were independently associated with occurrence of HPT in patients with TIO. Further logistic regression analysis and restricted cubic spline model revealed dose-response relationship between cumulative dose of phosphate supplementation and PTH levels. CONCLUSIONS: HPT is common in patients with TIO. To avoid the occurrence of HPT in patients with TIO, timely diagnosis and tumor resection is necessary and an excessive dose of phosphate supplementation is not suggested before surgery.

The First Compound Heterozygous Mutations of DMP1 Causing Rare Autosomal Recessive Hypophosphatemic Rickets Type 1.

CONTEXT: Hereditary hypophosphatemic rickets (HR) consists of a group of inherited hypophosphatemia due to mutations of different genes, which need genetic analysis to make a differential diagnosis. Among them, autosomal recessive hypophosphatemic rickets type 1 (ARHR1), caused by a homozygous mutation of dentin matrix protein 1 (DMP1), is extremely rare, with only 30 reported patients. To date, there has been no case with compound heterozygous DMP1 mutations. OBJECTIVE: To report the first compound heterozygous mutations of DMP1 causing ARHR1 and confirm the effect of the mutation on DMP1 protein. METHODS: We report the clinical features of a Chinese patient with HR. Whole-exome sequencing (WES) was performed on the proband. Then, Cytoscan HD array, Sanger sequencing, and genomic quantitative PCR (qPCR) were used to confirm the mutations. A cell experiment was conducted to explore the effect of the mutation. RESULTS: The proband is a 4-year-old boy, who developed genu varum when he was able to walk at age 1 year and tooth loss after a mild hit at age 3.5 years. Physical examination, biochemical measurement, and imaging finding indicated HR. Family history was negative. WES performed on the proband revealed a novel start codon mutation (c.1A > T, p.Met1Leu) in DMP1 and a large deletion involving most of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family gene, including DSPP, DMP1, IBSP, and MEPE. The novel paternally inherited start codon mutation, which resulted in decreased expression of DMP1 protein with smaller molecular weight and cleavage defect, was confirmed by Sanger sequencing. The maternally inherited deletion was validated by Cytoscan and qPCR, and the breakpoint was finally identified by long-range PCR and Sanger sequencing. Manifestation of dentin dysplasia (DD) or dentinogenesis imperfecta (DGI) caused by DSPP mutations was absent in the patient and his mother, confirming that haploinsufficiency could not lead to DD or DGI. CONCLUSION: We report for the first time compound heterozygous DMP1 mutations consisting of a large deletion and a novel start codon mutation (c.1A > T, p.Met1Leu) in a Chinese patient with ARHR1.

Discovery of novel anti-tumor compounds targeting PARP-1 with induction of autophagy through in silico and in vitro screening.

Poly (ADP-ribose) polymerase 1 (PARP-1) is a critical enzyme involved in DNA damage repair and recombination, and shows great potential for drug development in the treatment of cancers with defective DNA repair. The anti-tumor activities of PARP-1 inhibitors are regulated by both inhibition activities and allosteric mechanisms of PARP-1, and may also be involved in an autophagy-mediated process. Screening PARP-1 inhibitors with potential allosteric mechanisms and induced autophagy process could achieve elevated potency toward cancer cell killing. In this study, we tried to discover novel anti-tumor compounds targeting PARP-1 by computer simulations and in vitro screening. In order to filter PARP-1 inhibitors that could affect the folding state of the helix domain (HD) on PARP-1, the free energy contribution of key residues on HD were systematically analyzed using the ligand-binding crystal structures and integrated into in silico screening workflow for the selection of 20 pick-up compounds. Four compounds (Chemdiv codes: 8012-0567, 8018-6529, 8018-7168, 8018-7603) were proved with above 40% inhibitory ratio targeting PARP-1 under 20 µM, and further performed binding mode prediction and dynamic effect evaluation by molecular dynamics simulation. Further in vitro assays showed that compounds 8018-6529 and 8018-7168 could inhibit the growth of the human colorectal cancer cell (HCT-116) with IC50 values of 4.30 and 9.29 µM and were accompanied with an induced autophagy process. Taken together, we discover two novel anti-tumor compounds that target PARP-1 with an induced autophagy process and provide potential hit compounds for the anti-cancer drug development.

Tumor-induced osteomalacia combined with acromegaly: A case report.

Both acromegaly and tumor-induced osteomalacia (TIO) are rare diseases caused by an excess hormone secreted by neuroendocrine neoplasms, which are growth hormone (GH) and fibroblast growth factor 23 (FGF23), respectively. GH elevates phosphate reabsorption via the effect of insulin-like factor 1 (IGF-1), while FGF23 inhibits phosphate reabsorption and reduces serum phosphate level markedly. A patient who developed a typical acromegaly appearance but was accompanied with height loss and hypophosphatemia for 2 years visited our hospital. Laboratory investigations showed GH and IGF-1 hypersecretion, as well as hypophosphatemia caused by renal phosphate wasting. Magnetic resonance image revealed a pituitary somatotroph adenoma. Octreoscan scintigraphy also found a causative tumor on the right foot for hypophosphatemia. Then, he underwent resection of the tumor on the right foot. His serum phosphate returned to normal immediately but elevated gradually. Then, we removed the pituitary adenoma of the patient, and the GH and phosphate levels returned to the normal range. Here, we report the first case with acromegaly combined with TIO, the changing process of his phosphate concentration suggests an interesting concurrent effect of excess GH and FGF23 in this rare condition.

Repetitive DNA Sequences in the Human Y Chromosome and Male Infertility.

The male-specific Y chromosome, which is well known for its diverse and complex repetitive sequences, has different sizes, genome structures, contents and evolutionary trajectories from other chromosomes and is of great significance for testis development and function. The large number of repetitive sequences and palindrome structure of the Y chromosome play an important role in maintaining the stability of male sex determining genes, although they can also cause non-allelic homologous recombination within the chromosome. Deletion of certain Y chromosome sequences will lead to spermatogenesis disorders and male infertility. And Y chromosome genes are also involved in the occurrence of reproductive system cancers and can increase the susceptibility of other tumors. In addition, the Y chromosome has very special value in the personal identification and parentage testing of male-related cases in forensic medicine because of its unique paternal genetic characteristics. In view of the extremely high frequency and complexity of gene rearrangements and the limitations of sequencing technology, the analysis of Y chromosome sequences and the study of Y-gene function still have many unsolved problems. This article will introduce the structure and repetitive sequence of the Y chromosome, summarize the correlation between Y chromosome various sequence deletions and male infertility for understanding the repetitive sequence of Y chromosome more systematically, in order to provide research motivation for further explore of the molecules mechanism of Y-deletion and male infertility and theoretical foundations for the transformation of basic research into applications in clinical medicine and forensic medicine.

Bone Microarchitecture in Obese Postmenopausal Chinese Women: The Chinese Vertebral Osteoporosis Study (ChiVOS).

Background: Obesity is associated with improved bone mass and microarchitecture in Caucasian individuals, but evidence in obese Asian individuals is lacking. Objective: To analyze the areal bone mineral density (aBMD) and bone microarchitecture in normal-weight, overweight, and obese postmenopausal Chinese women. Methods: A total of 243 postmenopausal women from the Chinese Vertebral Osteoporosis Study (ChiVOS) were included and were divided into three groups (OB, obese group; OW, overweight group; NW, normal weight group) by BMI level. aBMD, trabecular bone score (TBS), and appendicular lean mass (ALM) were measured by dual-energy X-ray absorptiometry (DXA). Bone microarchitecture was measured by HR-pQCT at the distal radius and tibia. X-ray was performed to confirm vertebral fractures (VFs). Multiple linear regression was used to evaluate the correlations between bone parameters and ALM after adjusting for confounding variables. Results: The prevalence of VFs and clinical fractures were similar among the groups. Participants in the OB group showed a lower level of osteocalcin with comparable levels of other bone turnover markers (BTMs). The aBMD at several skeletal sites was higher in the OB group than in the NW group after adjusting for age (p<0.01 for all comparisons). At the radius, the OB group had a higher Ct.Ar, Tb.vBMD, Tb.BV/TV, Tb.N, Tb.Th, and Ct.Th than the NW group after adjusting for covariates (p<0.05 for all). Differences of a similar magnitude were found at the distal tibia. There was a trend of decreasing trend in Tb.Sp, Tb.1/N/SD, and Ct.Po among groups at both sites. However, the bone microarchitecture did not differ between participants with severe obesity (BMI≥35.0kg/m2) and those with 30.0≤BMI<35 kg/m2. Multiple linear regression revealed that the associations between ALM and most of the bone microarchitecture parameters at both sites were much stronger than the association between body weight and bone parameters. Conclusion: We have observed significant improvements in aBMD, bone geometry, and bone microarchitecture in obese postmenopausal Chinese women. Except for a lower level of osteocalcin in the OB group, no significant differences in BTMs were found among the groups. Compared with body weight, ALM may explain greater variance in the improvement of bone microarchitecture parameters.