Connective Tissue Growth Factor: Regulation, Diseases, and Drug Discovery.

In drug discovery, selecting targeted molecules is crucial as the target could directly affect drug efficacy and the treatment outcomes. As a member of the CCN family, CTGF (also known as CCN2) is an essential regulator in the progression of various diseases, including fibrosis, cancer, neurological disorders, and eye diseases. Understanding the regulatory mechanisms of CTGF in different diseases may contribute to the discovery of novel drug candidates. Summarizing the CTGF-targeting and -inhibitory drugs is also beneficial for the analysis of the efficacy, applications, and limitations of these drugs in different disease models. Therefore, we reviewed the CTGF structure, the regulatory mechanisms in various diseases, and drug development in order to provide more references for future drug discovery.

Comparisons of oblique lumbar interbody fusion and transforaminal lumbar interbody fusion for degenerative spondylolisthesis: a prospective cohort study with a 2-year follow-up.

Objective: This study aimed to compare the clinical outcomes between oblique (OLIF) and transforaminal lumbar interbody fusion (TLIF) for patients with degenerative spondylolisthesis during a 2-year follow-up. Methods: Patients with symptomatic degenerative spondylolisthesis who underwent OLIF (OLIF group) or TLIF (TLIF group) were prospectively enrolled in the authors' hospital and followed up for 2 years. The primary outcomes were treatment effects [changes in visual analog score (VAS) and Oswestry disability index (ODI) from baseline] at 2 years after surgery; these were compared between two groups. Patient characteristics, radiographic parameters, fusion status, and complication rates were also compared. Results: In total, 45 patients were eligible for the OLIF group and 47 patients for the TLIF group. The rates of follow-up were 89% and 87% at 2 years, respectively. The comparisons of primary outcomes demonstrated no different changes in VAS-leg (OLIF, 3.4 vs. TLIF, 2.7), VAS-back (OLIF, 2.5 vs. TLIF, 2.1), and ODI (OLIF, 26.8 vs. TLIF, 30). The fusion rates were 86.1% in the TLIF group and 92.5% in the OLIF group at 2 years (P = 0.365). The OLIF group had less estimated blood loss (median, 200 ml) than the TLIF group (median, 300 ml) (P < 0.001). Greater restoration of disc height was obtained by OLIF (mean, 4.6 mm) than the TLIF group (mean, 1.3 mm) in the early postoperative period (P < 0.001). The subsidence rate was lower in the OLIF group than that in the TLIF group (17.5% vs. 38.9%, P = 0.037). The rates of total problematic complications were not different between the two groups (OLIF, 14.6% vs. TLIF, 26.2%, P = 0.192). Conclusion: OLIF did not show better clinical outcomes than TLIF for degenerative spondylolisthesis, except for lesser blood loss, greater disc height restoration, and lower subsidence rate.

Gynecological cancer prognosis using machine learning techniques: A systematic review of the last three decades (1990-2022).

OBJECTIVE: Many Computer Aided Prognostic (CAP) systems based on machine learning techniques have been proposed in the field of oncology. The objective of this systematic review was to assess and critically appraise the methodologies and approaches used in predicting the prognosis of gynecological cancers using CAPs. METHODS: Electronic databases were used to systematically search for studies utilizing machine learning methods in gynecological cancers. Study risk of bias (ROB) and applicability were assessed using the PROBAST tool. 139 studies met the inclusion criteria, of which 71 predicted outcomes for ovarian cancer patients, 41 predicted outcomes for cervical cancer patients, 28 predicted outcomes for uterine cancer patients, and 2 predicted outcomes for gynecological malignancies broadly. RESULTS: Random forest (22.30 %) and support vector machine (21.58 %) classifiers were used most commonly. Use of clinicopathological, genomic and radiomic data as predictors was observed in 48.20 %, 51.08 % and 17.27 % of studies, respectively, with some studies using multiple modalities. 21.58 % of studies were externally validated. Twenty-three individual studies compared ML and non-ML methods. Study quality was highly variable and methodologies, statistical reporting and outcome measures were inconsistent, preventing generalized commentary or meta-analysis of performance outcomes. CONCLUSION: There is significant variability in model development when prognosticating gynecological malignancies with respect to variable selection, machine learning (ML) methods and endpoint selection. This heterogeneity prevents meta-analysis and conclusions regarding the superiority of ML methods. Furthermore, PROBAST-mediated ROB and applicability analysis demonstrates concern for the translatability of existing models. This review identifies ways that this can be improved upon in future works to develop robust, clinically translatable models within this promising field.

Genomic Profiling Reveals the Variant Landscape of Sporadic Parathyroid Adenomas in Chinese Population.

OBJECTIVE: To define somatic variants of parathyroid adenoma (PA) and to provide novel insights into the underlying molecular mechanism of sporadic PA. METHODS: Basic clinical characteristics and biochemical indices of 73 patients with PA were collected. Whole-exome sequencing was performed on matched tumor-constitutional DNA pairs to detect somatic alterations. Functional annotation was carried out by ingenuity pathway analysis afterward. The protein expression of the variant gene was confirmed by immunohistochemistry, and the relationship between genotype and phenotype was analyzed. RESULTS: Somatic variants were identified in 1549 genes, with an average of 69 variants per tumor (range, 13-2109; total, 9083). Several novel recurrent somatic variants were detected, such as KMT2D (15/73), MUC4 (14/73), POTEH (13/73), CD22 (12/73), HSPA2 (12/73), HCFC1 (11/73), MAGEA1 (11/73), and SLC4A3 (11/73), besides the previously reported PA-related genes, including MEN1 (11/73), CASR (6/73), MTOR (4/73), ASXL3 (3/73), FAT1 (3/73), ZFX (5/73), EZH1 (2/73), POT1 (2/73), and EZH2 (1/73). Among them, KMT2D might be the candidate driver gene of PA. Crucially, 5 patients carried somatic mutations in CDC73, showed an aggressive phenotype similar to that of parathyroid carcinoma (PC), and had a decreased expression of parafibromin. Pathway analysis of recurrent potential PA-associated driver variant genes revealed functional enrichments in the signaling pathway of Notch. CONCLUSION: Our study expanded the pathogenic variant spectrum of PA and indicated that KMT2D might be a novel candidate driver gene and be considered as a diagnostic biomarker for PA. Meanwhile, CDC73 mutations might be an early developmental event from PA to PC. The results provided insights into elucidating the pathogenesis of parathyroid tumorigenesis and a certain basis for clinical diagnosis and treatment.

Case report: Clinical characteristics and treatment of secondary osteoporosis induced by X-linked congenital adrenal dysplasia.

Objective: To summarize the clinical features and bone complications in a patient from a large family with X-linked congenital adrenocortical hypoplasia (AHC) and evaluate the efficacy of different treatment regimens on the prognosis of secondary osteoporosis caused by AHC at a 5-year follow-up. Methods: A large family with AHC was recruited, and the causative gene mutation was identified by Sanger sequencing in the proband. Clinical features as well as radiological examinations and laboratory indices of osteoporosis secondary to AHC were analyzed in this study. Meanwhile, the proband was treated with classical antiresorptive drugs (bisphosphonates) for 2 years and switched to a vitamin K2 analogue for another 3 years, during which the efficacy of the drugs was evaluated. Results: The proband was identified as carrying a homozygous insertion mutation (p. Thr193GlyfsX13) in the NR0B1 (nuclear receptor subfamily 0, group B, member 1) gene, resulting in a premature stop codon due to a frameshift mutation. During treatment and follow-up, the proband did not respond well to bisphosphonate and developed atypical femoral fractures. Vitamin K2 improved clinical symptoms. In terms of bone mineral density (BMD), there is no evidence of any effect of vitamin K2 on the neck of femur, though some minor effects on spinal BMD cannot be excluded. Conclusions: Secondary osteoporosis induced by AHC deserves clinical attention. Unlike in primary osteoporosis, the curative effect of bisphosphonates was unsatisfactory and was more likely to cause atypical femoral fractures in long-term treatment. It is suggested that bone anabolic drugs may be better alternatives.

Clinical and genetic characteristics of 29 Chinese patients with X-linked hypophosphatemia.

Objective: The aim of this study was to fully describe the clinical and genetic characteristics, including clinical manifestations, intact fibroblast growth factor 23 (iFGF23) levels, and presence of PHEX gene mutations, of 22 and 7 patients with familial and sporadic X-linked dominant hypophosphatemia (XLH), respectively. Methods: Demographic data, clinical features, biochemical indicators, and imaging data of 29 patients were collected. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced. The serum level of iFGF23 was measured in 15 of the patients. Results: Twenty-nine patients (male/female: 13:16, juvenile/adult: 15:14) with XLH were included. The main symptoms were bowed lower extremities (89.7%), abnormal gait (89.7%), and short stature/growth retardation (78.6%). Hypophosphatemia with a high alkaline phosphatase level was the main biochemical feature and the median value of serum iFGF23 was 55.7 pg/ml (reference range: 16.1-42.2 pg/ml). Eight novel mutations in the PHEX gene were identified by Sanger sequencing, including two missense mutations (p. Gln682Leu and p. Phe312Ser), two deletions (c.350_356del and c.755_761del), one insertion (c.1985_1986insTGAC), and three splice mutations (c.1700+5G>C, c.1966-1G>T, and c.350-14_350-1del). Additionally, the recurrence rate after the first orthopedic surgery was 77.8% (7/9), and five of them had their first surgery before puberty. Conclusion: Our study expanded the clinical phenotypes and gene mutation spectrum of XLH and provided a reference for the optimal timing of orthopedic surgeries.

Clinical characteristics and identification of a novel TGFB1 variant in three unrelated Chinese families with Camurati-Engelmann disease.

BACKGROUND: To investigate the clinical characteristics and molecular diagnosis of Camurati-Engelmann disease (CAEND) in Chinese individuals. METHODS: We recruited six patients aged 14 to 45 years in three unrelated families with CAEND, including five females and one male. Clinical manifestations, biochemical tests, and radiographic examinations were analyzed. The TGFB1 gene variants were further identified by Sanger sequencing. In addition, one female patient was followed up for 5 years. RESULTS: The onset age of the patients ranged from 1 to 6 years. All of them had family histories and consisted of an autosomal dominant inheritance pattern. Gait disturbance, fatigue, progressive bone pain, muscle atrophy, and weakness were the main complaints. Laboratory examinations revealed that the inflammatory markers were at high levels, in addition to the increased bone metabolism indicators. The thickened diaphysis of long bones and the narrowed medullary cavity was observed by radiography. Furthermore, bone scintigraphy detected abnormal symmetrical radioactive concentrations in the affected regions of bone. Sanger sequencing identified a missense heterozygous variant in exon 4 of the TGFB1 gene in families 1 and 2, resulting in Arg218Cys, which confirmed CAEND. Moreover, one novel variant c.669C > G in exon 4 of the TGFB1 gene harboring Cys223Trp was detected in family 3. Subsequent bioinformatics software predicted that the novel variant was pathogenic. Of interest, III:2 in family 3 experienced heart valve defects and tachycardia at birth, which had never been reported in CAEND patients before. Moreover, the response to drug treatment is also full of contradictions and is worthy of further study. CONCLUSION: Besides the typical CAEND manifestations, the new phenotypic characteristics of tachycardia and heart valve defects were first reported in one woman carrying the novel variant p.Cys223Trp in TGFB1 the gene. In addition, we demonstrated that increased bone metabolism indicators and inflammatory markers may possess auxiliary diagnosis for CAEND.

Mutations in Profilin 1 Cause Early-Onset Paget's Disease of Bone With Giant Cell Tumors.

Paget's disease of bone (PDB) is a late-onset chronic progressive bone disease characterized by abnormal activation of osteoclasts that results in bone pain, deformities, and fractures. PDB is very rare in Asia. A subset of PDB patients have early onset and can develop malignant giant cell tumors (GCTs) of the bone (PDB/GCTs), which arise within Paget bone lesions; the result is a significantly higher mortality rate. SQSTM1, TNFRSF11A, OPG, VCP, and HNRNPA2B1 have been identified as pathogenic genes of PDB, and ZNF687 is the only confirmed gene to date known to cause PDB/GCT. However, the molecular mechanism underlying PDB/GCT has not been fully elucidated. Here, we investigate an extended Chinese pedigree with eight individuals affected by early-onset and polyostotic PDB, two of whom developed GCTs. We identified a heterozygous 4-bp deletion in the Profilin 1 (PFN1) gene (c.318_321delTGAC) by genetic linkage analysis and exome sequencing for the family. Sanger sequencing revealed another heterozygous 1-bp deletion in PFN1 (c.324_324delG) in a sporadic early-onset PDB/GCT patient, further proving its causative role. Interestingly, a heterozygous missense mutation of PFN1 (c.335 T > C) was identified in another PDB/GCT family, revealing that not only deletion but also missense mutations in PFN1 can cause PDB/GCT. Furthermore, we established a Pfn1-mutated mouse model (C57BL/6J mice) and successfully obtained Pagetic phenotypes in heterozygous mice, verifying loss of function of PFN1 as the cause of PDB/GCT development. In conclusion, our findings reveal mutations in PFN1 as the pathological mechanism in PDB/GCT, and we successfully established Pfn1-mutated mice as a suitable animal model for studying PDB-associated pathological mechanisms. The identification of PFN1 mutations has great diagnostic value for identifying PDB individuals predisposed toward developing GCTs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Remote Patient Monitoring Using Radio Frequency Identification (RFID) Technology and Machine Learning for Early Detection of Suicidal Behaviour in Mental Health Facilities.

Remote Patient Monitoring (RPM) has gained great popularity with an aim to measure vital signs and gain patient related information in clinics. RPM can be achieved with noninvasive digital technology without hindering a patient's daily activities and can enhance the efficiency of healthcare delivery in acute clinical settings. In this study, an RPM system was built using radio frequency identification (RFID) technology for early detection of suicidal behaviour in a hospital-based mental health facility. A range of machine learning models such as Linear Regression, Decision Tree, Random Forest, and XGBoost were investigated to help determine the optimum fixed positions of RFID reader-antennas in a simulated hospital ward. Empirical experiments showed that Decision Tree had the best performance compared to Random Forest and XGBoost models. An Ensemble Learning model was also developed, took advantage of these machine learning models based on their individual performance. The research set a path to analyse dynamic moving RFID tags and builds an RPM system to help retrieve patient vital signs such as heart rate, pulse rate, respiration rate and subtle motions to make this research state-of-the-art in terms of managing acute suicidal and self-harm behaviour in a mental health ward.

Accuracy and complications of posterior C2 screw fixation using intraoperative three-dimensional fluoroscopy-based navigation.

BACKGROUND: The peculiar and highly variable C2 anatomy can make screw fixation more challenging and prone to potential vertebral artery or neurologic injury. Conventional C-arm fluoroscopy has several drawbacks. The aim of this research was to evaluate the accuracy of posterior C2 screw fixation using intraoperative three-dimensional fluoroscopy-based navigation (ITFN) and assess the perioperative complication rate related to screw placement. METHODS: A retrospective review identified patients who underwent operative management with C2 instruments using ITFN at our hospital between January 2006 and December 2012. Clinical data were obtained from medical records and final screw positions were graded according to a modified classification of Gertzbein and Robbins. Grade A and B screws were considered well positioned. RESULTS: The study included 99 patients (53 males and 46 females) who underwent posterior C2 screw fixation using ITFN. The mean Japan Orthopedic Association score improved from (6.7 ± 1.9) points before surgery to (12.5 ± 2.7) points at 6-month follow-up (z = +8.628, P < 0.01). The mean visual analogue scale improved from (4.1 ± 1.2) points before surgery to (0.7 ± 0.9) points at 6-month follow-up, with an improvement of 83.7% (z = 8.638, P < 0.01). Of the 196 screws analyzed using computed tomography and chart review, 126 transarticular, 64 pedicle, and 6 pars screws were placed with 82.5% (104/126), 89.1% (57/64), and 100% (6/6) accuracy (grade A), respectively; 98.5% (193/196) of screws were grade A or B (grade C, 1.5% (3/196)), and no neurologic injuries occurred. In normal C2 cases, 93 transarticulars and 47 pedicles were placed with high accuracy rates of 90.3% (84/93) and 93.6% (44/47) (grade A), respectively. However, in cases with C2 deformity, 33 transarticular, 17 pedicle, and 6 pars screws were placed with only 60.6% (20/33), 76.5% (13/17), and 100% (6/6) accuracy (grade A), respectively. CONCLUSION: ITFN is a safe, accurate, and effective tool for posterior C2 fixation.

A novel anti-human DR5 monoclonal antibody with tumoricidal activity induces caspase-dependent and caspase-independent cell death.

Like anti-Fas monoclonal antibodies, some monoclonal antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors have tumoricidal activity too. In this article we report a novel mouse anti-human DR5 monoclonal antibody, AD5-10, that induces apoptosis of various tumor cell lines in the absence of second cross-linking in vitro and showed strong tumoricidal activity in vivo. AD5-10 does not compete with TRAIL for binding to DR5 and synergizes with TRAIL to induce apoptosis of tumor cells. AD5-10 induces both caspase-dependent and caspase-independent cell death in Jurkat cells, whereas TRAIL induces only caspase-dependent cell death. We show for the first time that DR5 can mediate caspase-independent cell death, and DR5 can mediate distinct cell signals when interacting with different extracellular proteins. Studies on AD5-10 help us to understand more on the functions of DR5 and may provide new ideas for cancer immunotherapy.