Duodenal papilla radiomics-based prediction model for post-endoscopic retrograde cholangiopancreatography pancreatitis using machine learning: a retrospective multicohort study.

BACKGROUND AND AIMS: The duodenal papillae are the primary and essential pathway for ERCP, greatly determining its complexity and outcome. We aimed to investigate the association between papilla morphology and post-ERCP pancreatitis (PEP), and to construct a robust model for PEP prediction. METHODS: We enrolled retrospectively patients underwent ERCP in 2 centers from January 2019 and June 2022. Radiomic features of papilla were extracted from endoscopic images with deep learning. Potential predictors and their importance were evaluated with three machine learning algorithms. A predictive model was developed using best subset selection by logistic regression, and its performance was evaluated in terms of discrimination, calibration, and clinical utility based on area under curve (AUC) of receiver operation characteristics (ROC), calibration and clinical decision curve, respectively. RESULTS: A total of 2038 and 334 ERCP patients from 2 centers were enrolled in this study with PEP rates of 7.9% and 9.6%, respectively. The R-score was significantly associated with PEP and showed great diagnostic value (AUC, 0.755-0.821). Six hub predictors were selected to conduct a predictive model. The radiomics-based model demonstrated excellent discrimination (AUC, 0.825-0.857) and therapeutic benefits in the training, testing, and validation cohorts. The addition of the R-score significantly improved diagnostic accuracy of the predictive model (NRI, 0.151-0.583, p<0.05; IDI, 0.097-0.235, p<0.001). CONCLUSIONS: Radiomic signature of papilla is a crucial independent predictor of PEP. The papilla-radiomics-based model performs well for the clinical prediction of PEP.

Dexamethasone promotes osteoblast apoptosis through the Chk2/p53 signaling pathway.

BACKGROUND: Glucocorticoids (GCs) are widely used to treat inflammatory or autoimmune diseases. However, several studies have reported that the use of GCs can lead to numerous complications, the most serious of which are osteoporosis and osteonecrosis of the femoral head (ONFH). Osteoblast apoptosis has been identified as an important event in the development of GC-induced osteoporosis and ONFH. However, the mechanisms underlying the regulation of these processes have not yet been explored. OBJECTIVES: To observe the effect of dexamethasone (Dex) on the apoptosis of osteoblasts and explore its mechanism, as well as provide a new therapeutic idea for GC­induced osteoporosis and ONFH. MATERIAL AND METHODS: Cell proliferation and apoptosis of MC3T3-E1 cells after Dex treatment were determined using the CellTiter-Glo® Luminescent Cell Viability Assay kit and Annexin V-FITC/PI Double Staining Apoptosis Detection Kit, respectively. The expression of caspase-3/cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP)/cleaved PARP in MC3T3-E1 cells after Dex treatment was determined with western blotting. The expression of p53 and checkpoint kinase 2 (Chk2) in MC3T3-E1 cells after Dex treatment was analyzed using western blotting and polymerase chain reaction (PCR). The effects of p53 knockdown and Chk2 knockdown on Dex-induced apoptosis of MC3T3-E1 cells were also characterized. RESULTS: Dexamethasone remarkably inhibited cell growth and induced the apoptosis of MC3T3-E1 cells. We also observed that Dex induced osteoblast apoptosis by promoting p53 expression. The regulatory effect of Dex on p53 expression is mediated by the upregulation of Chk2, which interacted with p53 and inhibited p53 degradation. The knockdown of p53 alleviated Dex-induced MC3T3-E1 cell apoptosis by decreasing the expression of cleaved caspase-3 and cleaved PARP. CONCLUSIONS: We demonstrated that Dex increased Chk2 protein expression, which stabilized the protein expression of p53, and in turn promoted osteoblast apoptosis.

Potential influence of factors for genu valgus with hereditary multiple exostoses.

Genu valgus is one of the most common limb deformities in hereditary multiple exostoses (HME). However, it is easily concealed and may account for subsequent osteoarthritis of the knee. The knees of 56 patients (33 men and 23 women) with HME were investigated bilaterally. Knee valgus was described by the mechanical axis deviation (MAD), mechanical lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA). We investigated sex, age, BMI, total number of palpable osteochondromas, number of radiographic osteochondromas around the knee, forearm deformities, morphology and distribution of lesions, and correlations between these factors and genu valgus. The measurement of LDFA and MPTA was performed to identify the sources of genu valgus deformity. Based on the measurement of the mechanical axis, limbs were classified as genu valgus (n = 22) or normal mechanical axis groups (n = 90). The different severities of the genu valgus patients were classified by MAD. By bivariate logistic regression, genu valgus was significantly associated with more sessile and flared metaphyseal lesions. However, only the number of flared metaphyseal lesions had a significant influence on the severity of genu valgus. By analyzing the LDFA and MPTA, it was found that abnormalities of both proximal tibia and distal femur play important roles in genu valgus. Early detection of sessile and flared metaphyseal knee lesions in patients with HME can contribute to early intervention of genu valgus. Level of relevance: Level 2.

miR-143 is implicated in growth plate injury by targeting IHH in precartilaginous stem cells.

Precartilaginous stem cells (PCSCs) are able to initiate chondrocyte and bone development. The present study aimed to investigate the role of miR-143 and the underlying mechanisms involved in PCSC proliferation. In a rat growth plate injury model, tissue from the injury site was collected and the expression of miR-143 and its potential targets was determined. PCSCs were isolated from the rabbits' distal epiphyseal growth plate. Cell viability, DNA synthesis, and apoptosis were determined with MTT, BrdU, and flow cytometric analysis, respectively. Real time PCR and western blot were performed to detect the mRNA and protein expression of the indicated genes. Indian hedgehog (IHH) was identified as a target gene for miR-143 with luciferase reporter assay. Decreased expression of miR-143 and increased expression of IHH gene were observed in the growth plate after injury. miR-143 mimics decreased cell viability and DNA synthesis and promoted apoptosis of PCSCs. Conversely, siRNA-mediated inhibition of miR-143 led to increased growth and suppressed apoptosis of PCSCs. Transfection of miR-143 decreased luciferase activity of wild-type IHH but had no effect when the 3'-UTR of IHH was mutated. Furthermore, the effect of miR-143 overexpression was neutralized by overexpression of IHH. Our study showed that miR-143 is involved in growth plate behavior and regulates PCSC growth by targeting IHH, suggesting that miR-143 may serve as a novel target for PCSC-related diseases.

Open reduction and internal fixation for displaced Salter-Harris type II fractures of the distal tibia: a retrospective study of sixty-five cases in children.

BACKGROUND: The treatment for displaced Salter-Harris II (S-H II) distal tibia fractures remains controversial. The purpose of this study was to review S-H II distal tibia fractures and evaluate the rate of premature physeal closure (PPC) treated by open reduction and internal fixation (ORIF). METHODS: We reviewed the charts and radiographs of S-H II fractures of the distal tibia with displacement > 3 mm between 2012 and 2019 treated by ORIF. Patients were followed up for a minimum of 6 months. CT scans of injured side or contralateral ankle radiograph were obtained if there was any evidence of PPC. Any angular deformity or shortening of the involved leg was documented. Multivariable logistic regression was performed to identify risk factors for the occurrence of PPC. RESULTS: A total of 65 patients with a mean age of 11.8 years were included in this study. The mean initial displacement was 8.0 mm. All patients but one were treated within 7 days after injury and the mean interval was 3.7 days. Supination-external rotation injuries occurred in 50 patients, pronation-eversion external rotation in 13, and supination-plantar flexion in two. The residual gap was less than 1 mm in all patients following ORIF and all fractures healed within 4-6 weeks. Superficial skin infection developed in one patient. Ten patients complained of the cosmetic scar. The rate of PPC was 29.2% and two patients with PPC developed a varus deformity of the ankle. Patients with associated fibular fracture had 7 times greater odds of developing PPC. Age, gender, injured side, mechanism of injury, amount of initial displacement, interval from injury to surgery, or energy of injury did not significantly affect the rate of PPC. CONCLUSIONS: ORIF was an effective choice of treatment for S-H II distal tibia fractures with displacement > 3 mm to obtain a satisfactory reduction. PPC is a common complication following ORIF. The presence of concomitant fibula fracture was associated with PPC.

Preventive and therapeutic significance of octreotide combined with lansoprazole on post-ERCP pancreatitis and its effect on serum amylase, inflammatory factors and immune function.

The study aimed to investigate the preventive and therapeutic significance of octreotide combined with lansoprazole on post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and its effects on serum amylase (AMS), inflammatory factors and immune function. A total of 132 patients who underwent ERCP in Shaoxing People's Hospital (Shaoxing, China) were enrolled in the study and allocated into two groups: The study group (octreotide plus lansoprazole, 68 cases) and the control group (octreotide alone, 64 cases). The incidence of PEP and post-ERCP hyperamylasemia (PEH), the concentrations of serum AMS, interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α), as well as the T-lymphocyte population in peripheral blood were detected. The AMS levels in the study group were significantly lower than those in the control group at 6 and 24 h after treatment (P<0.001). The incidence of PEP and PEH, symptom disappearance time and hospital stay in the study group were significantly lower than those in the control group after treatment (P<0.05). The levels of IL-17 and TNF-α in the study group were significantly lower than those in the control group after treatment (all P<0.05). The percentage of CD3+, CD4+, CD8+ cells and the ratio of CD4+/CD8+ in the study group were significantly higher than those in the control group after treatment (all P<0.05). The results indicated that octreotide combined with lansoprazole reduces AMS levels and the incidence of PEP, alleviates inflammation and improves the immune function.

Concurrent ipsilateral Tillaux fracture and medial malleolar fracture in adolescents: management and outcome.

BACKGROUND: The concurrent ipsilateral Tillaux fracture with medial malleolar fracture in adolescents commonly suffer from high-energy injury, making treatment more difficult. The aim of this study was to discuss the mechanism on injury, diagnosis, and treatment of this complex fracture pattern. METHODS: The charts and radiographs of six patients were reviewed. The function was assessed by the American Orthopedic Foot and Ankle Society ankle-hindfoot scores. RESULTS: The mean age at operation was 12.8 years. The mean interval from injury to operation was 7.7 days. Five Tillaux fractures and all medial malleolar fractures were shown on AP plain radiographs. One Tillaux fracture and two cases with avulsion of posterolateral tibial aspect were confirmed in axial computerized tomography. There was talar subluxation laterally with medial space widening in three and syndesmotic disruption in one. There were five patients sustaining ipsilateral distal fibular fractures. All fractures, except nonunion in two medial malleolar fractures and in one Tillaux fracture, healed within 6-8 weeks. There was one case of osteoarthritis of ankle joint. The average AOFAS score was 88.7. CONCLUSIONS: Computerized tomography is helpful in identifying the fracture pattern. Anatomic reduction and internal fixation of Tillaux and medial malleolar fracture was recommended to restore the articular surface congruity and ankle stability.

MiR-132/212 promotes the growth of precartilaginous stem cells (PCSCs) by regulating Ihh/PTHrP signaling pathway.

Precartilaginous stem cells (PCSCs) are adult stem cells that can initiate chondrocytes and bone development. In the present study, we explored whether miR-132/212 was involved in the proliferation of PCSCs via Hedgehog signaling pathway. PCSCs were isolated and purified with the fibroblast growth factor receptor-3 (FGFR-3) antibody. Cell viability, DNA synthesis and apoptosis were measured using MTT, BrdU and flow cytometric analysis. The mRNA and protein expression were detected by real-time PCR and Western blot, respectively. The target gene for miR-132/212 was validated by luciferase reporter assay. Results showed that transfection with miR-132/212 mimic significantly increased cell viability and DNA synthesis, and inhibited apoptosis of PCSCs. By contrast, miR-132/212 inhibitor could suppress growth and promote apoptosis of PCSCs. Luciferase reporter assays indicated that transfection of miR-132/212 led to a marked reduction of luciferase activity, but had no effect on PTCH1 3'-UTR mutated fragment, suggesting that Patched1 (PTCH1) is a target of miR-132/212. Furthermore, treatment with miR-132/212 mimics obviously increased the protein expression of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP), which was decreased after treatment with Hedgehog signaling inhibitor, cyclopamine. We also found that inhibition of Ihh/PTHrP signaling by cyclopamine significantly suppressed growth and DNA synthesis, and induced apoptosis in PCSCs. These findings demonstrate that miR-132/212 promotes growth and inhibits apoptosis in PCSCs by regulating PTCH1-mediated Ihh/PTHrP pathway, suggesting that miR-132/212 cluster might serve as a novel target for bone diseases.

A hybrid technique for treating multilevel cervical myelopathy: Cervical artificial disc replacement combined with fusion.

Clinical and radiographic outcomes of multilevel cervical myelopathy (MCM) patients treated with a hybrid technique combining cervical anterior corpectomy and fusion (ACF) with cervical artificial disc replacement (C-ADR) were evaluated. A total of 23 patients including 14 females and 9 males (mean age, 48.3 years) were treated with the hybrid technique and they were followed up for an average time of 35 months (range from 24 to 40 months). Arm- and neck-pain visual analogue scale (VAS) scores, neck disability index (NDI) scores and C2-7 range of motion (ROM) preoperation and 6 weeks, 3 and 24 months postoperation were assessed and compared. Fusion success and system failure based on anteroposterior (AP), lateral and flexion/extension X-rays were examined by an independent reviewer. Postoperative VAS, NDI and ROM were decreased significantly at all the time-points examined, as compared to preoperative scores (P<0.05). The results revealed that this hybrid technique is both technically feasible and effective for the treatment of MCM. However, future comparative studies will be required to determine the potential benefits and pitfalls of this hybrid technique.

Whole genome sequencing of pairwise human subjects reveals DNA mutations specific to developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening.

Upregulation of RASAL2 promotes proliferation and metastasis, and is targeted by miR-203 in hepatocellular carcinoma.

RAS protein activator like 2 (RASAL2) has been reported to be dysregulated in various types of cancer. It has previously been demonstrated that RASAL2 is hypomethylated in hepatocellular carcinoma (HCC). However, the expression pattern of RASAL2 and its potential role in HCC remain to be elucidated. The present study demonstrated that the expression of RASAL2 was upregulated in HCC tissues, compared with in normal liver tissues, by using immunohistochemistry. In addition, Cell Counting Kit-8 assay and invasion assay revealed that knockdown of RASAL2 inhibited the growth and invasion of HCC cells. Western blotting results indicated that the inhibition of RASAL2 reduced the levels of phosphorylated-AKT. Notably, RASAL2 was observed to be a direct target of miR-203 in HCC in luciferase activity assays. Furthermore, overexpression of miR-203 exhibited a similar effect to RASAL2 knockdown in HCC cells. These results indicated that RASAL2 serves a tumor oncogenic role in HCC and may be considered a potential target in HCC.

The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical osteosarcoma models.

In the present study, we investigated the activity of XL388, a novel mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, in preclinical osteosarcoma (OS) models. XL388 was cytotoxic, cytostatic and pro-apoptotic to multiple established OS cell lines and primary human OS cells. XL388 blocked mTORC1/2 activation and downregulated cyclin D1/B1 expressions in OS cells, leaving AKT Thr-308 phosphorylation un-affected. Intriguingly, AKT1 T308A mutation potentiated XL388-induced cytotoxicity in OS cells. XL388 activated cytoprotective autophagy in OS cells. Autophagy inhibition, either pharmacologically or genetically, augmented XL388-induced anti-OS activity. Further, XL388 oral administration inhibited U2OS xenografts growth in severe combined immuno-deficient (SCID) mice. Such activity was enhanced with co-administration of the autophagy inhibitor 3-methyladenine (3-MA). Similarly, Beclin-1-silenced U2OS xenografts were remarkably more sensitive to XL388. Thus, concurrent blockage of mTORC1/2 with XL388 may have therapeutic value for OS.

Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection.

BACKGROUND AND AIMS: There is no prognostic model that is reliable and practical for patients who have received curative liver resection (CLR) for hepatocellular carcinoma (HCC). This study aimed to establish and validate a Surgery-Specific Cancer of the Liver Italian Program (SSCLIP) scoring system for those patients. METHODS: 668 eligible patients who underwent CLR for HCC from five separate tertiary hospitals were selected. The SSCLIP was constructed from a training cohort by adding independent predictors that were identified by Cox proportional hazards regression analyses to the original Cancer of the Liver Italian Program (CLIP). The prognostic performance of the SSCLIP at 12 and 36-months was compared with data from existing models. The patient survival distributions at different risk levels of the SSCLIP were also assessed. RESULTS: Four independent predictors were added to construct the SSCLIP, including age (HR = 1.075, 95%CI: 1.019-1.135, P = 0.009), albumin (HR = 0.804, 95%CI: 0.681-0.950, P = 0.011), prothrombin time activity (HR = 0.856, 95%CI: 0.751-0.975, P = 0.020) and microvascular invasion (HR = 19.852, 95%CI: 2.203-178.917, P = 0.008). In both training and validation cohorts, 12-month and 36-month prognostic performance of the SSCLIP were significantly better than those of the original CLIP, model of end-stage liver disease-based CLIP, Okuda and Child-Turcotte-Pugh score (all P < 0.05). The stratification of risk levels of the SSCLIP showed an enhanced ability to differentiate patients with different outcomes. CONCLUSIONS: A novel SSCLIP to predict survival of HCC patients who received CLR based on objective parameters may provide a refined, useful prognosis algorithm.

Activity of the novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 against osteosarcoma.

Recent studies have identified that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important feature of osteosarcoma, where it promotes cell proliferation, survival, and chemo-resistance. Here, we studied the therapeutic potential of NVP-BEZ235, a novel dual PI3K/mTOR dual inhibitor, on osteosarcoma cells in vivo and in vitro. NVP-BEZ235 was cytotoxic and cytostatic to a panel of osteosarcoma lines (MG-63, U2OS and SaOs-2), where it induce apoptosis and cell-cycle arrest. At the molecular level, NVP-BEZ235 inhibited PI3K-AKT-mTORC1 activation and downregulated cyclin D1/cyclin B1 expressions, while increasing MEK/Erk phosphorylation in osteosarcoma cells. MEK/Erk inhibitors PD98059 and MEK-162 increased NVP-BEZ235 activity on osteosarcoma cells. In vivo, oral NVP-BEZ235 inhibited U2OS xenograft in SCID mice, and its anti-tumor efficiency was further enhanced by MEK-162 co-administration. Taken together, our findings indicate that dual inhibition of PI3K and mTOR with NVP-BEZ235, either alone or in combination with MEK/Erk inhibitors, may be an efficient treatment for osteosarcoma.

[Mid-term outcomes of unilateral pedicle screw fixation with lumbar interbody fusion for lumber degenerative diseases].

OBJECTIVE: To evaluate the mid-term clinical outcomes of unilateral pedicle screw fixation with lumbar interbody fusion for lumber degenerative diseases. METHODS: From October 2008 to December 2010, unilateral pedicle screw fixation with lumbar interbody fusion was performed for a consecutive cohort of 42 patients. There were 18 males and 24 females with an average age of 52 (38-69) years. The operation level at L3-4 (n = 2), L4-5 (n = 19), L5-S1 (n = 21) and multilevel (n = 0). Their clinical outcomes were assessed by Oswestry (ODI) scores and Japanese Orthopedics Association (JOA) questionnaires before and after operation. Operative duration, intraoperative blood loss, incision status and complications were recorded. Radiological examination was performed to assess the height of intervertebral space, the postoperative intervertebrai fusion conditions and the degeneration of adjacent segments. RESULTS: The mean operative duration was 90 minutes and mean blood loss 150 ml. All incisions healed primarily. The mean follow-up period was 40 (36-58) months. The ODI scores decreased significantly from 59.1 ± 9.6 preoperatively to 8.5 ± 2.7 postoperatively (P < 0.05). The JOA scores improved markedly from 8.3 ± 2.7 preoperatively to 23.3 ± 2.1 postoperatively (P < 0.05). And the proportion of optimal outcomes was 88.1%. The ventral and dorsal heights of intervertebal disc were significantly higher than those before operation. The fusion rate was 95.2% and the incidence of adjacent segment degeneration 9.5%. There was no occurrence of such complications as secondary scoliosis, screw loosening, internal fixation failure and cage slippage. CONCLUSION: Unilateral pedicle screw fixation with lumbar interbody fusion is efficacious for lumber degenerative diseases with little surgical trauma.

Bufotalin-induced apoptosis in osteoblastoma cells is associated with endoplasmic reticulum stress activation.

The search for novel and more efficient chemo-agents against malignant osteoblastoma is important. In this study, we examined the potential anti-osteoblastoma function of bufotalin, and studied the underlying mechanisms. Our results showed that bufotalin induced osteoblastoma cell death and apoptosis in dose- and time-dependent manners. Further, bufotalin induced endoplasmic reticulum (ER) stress activation in osteoblastoma cells, the latter was detected by the induction of C/EBP homologous protein (CHOP), phosphorylation of inositol-requiring enzyme 1 (IRE1) and PKR-like endoplasmic reticulum kinase (PERK), as well as caspase-12 activation. Conversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP depletion by shRNA significantly inhibited bufotalin-induced osteoblastoma cell death and apoptosis. Finally, by using a mice xenograft model, we demonstrated that bufotalin inhibited U2OS osteoblastoma cell growth in vivo. In summary, our results suggest that ER stress contributes to bufotalin-induced apoptosis in osteoblastoma cells. Bufotalin might be investigated as a novel anti-osteoblastoma agent.