The competitive mechanism of EZH1 and EZH2 in promoting oral squamous cell carcinoma.

Enhancer of Zeste Homolog 1 (EZH1) and Enhancer of Zeste Homolog 2 (EZH2) are the key components of polycomb repressive complex 2 (PRC2); however, the roles of these proteins in oral squamous cell carcinoma (OSCC) have yet to be elucidated. In this study, we aimed to determine the respective roles of these proteins in OSCC by investigating the expression levels of EZH1 and EZH2 in OSCC tissues (N = 63) by immunohistochemistry. In addition, we used lentiviruses to construct stable OSCC cell lines that overexpressed EZH1 and EZH2. Then, we investigated these cell lines for cell viability, colony formation capacity, stemness, and epithelial-mesenchymal transition (EMT). Binding competition between EZH1 and EZH2 with PRC2 was further evaluated using Co-immunoprecipitation (Co-IP). Compared with normal tissues, the expression levels of EZH2 in OSCC tissues was up-regulated, while the expression of EZH1 was down-regulated. EZH2 enhanced cell viability, colony formation capacity, stemness, and EMT, while EZH1 did not. Furthermore, analysis indicated that EZH1 and EZH2 bound competitively to PRC2 and influenced the methylation status of H3K27. In conclusion, our findings verified that EZH1 and EZH2 play opposing roles in OSCC and that EZH1 and EZH2 compete as the key component of PRC2, thus affecting the characteristics of OSCC via the methylation of H3K27.

Acellular dermal matrix for one-stage treatment of lower extremity full-thickness skin defect: a case series.

BACKGROUND: Self-repair of lower limb wounds has always been one of the research hotspots. Flaps and skin graft are the preferred treatment for lower extremity wound reconstruction. However, these treatments have many disadvantages, such as secondary damage, poor healing quality. In recent years, the use of acellular dermal matrix has emerged as an alternative treatment option for extremity ulcers. METHODS: This study aimed to explore whether acellular dermal matrix can be used as a single treatment to promote wound healing. 7 patients with lower extremities cutaneous deficiency exposing bone or tendon, were covered by Pelnac, which was an acellular dermal matrix product approved by China Food and Drug Administration. All the wound was treated by Pelnac without flaps and skin graft. The external dressing was changed every 10 days. RESULTS: After a maximum of 20 weeks, all the wounds were completely healed. During the 12 months follow-up period none of the patients developed skin wear on the treatment area. All patients maintained their postoperative ambulatory ability. All patients were satisfied with the appearance and feeling after wound healing. CONCLUSION: These findings may mean acellular dermal matrix is a novel method offering opportunity for treatment of lower extremities cutaneous deficiency exposing bone or tendon. It also has the potential to close wounds of all uninfected, non-ischemic, full-thickness cutaneous deficiency.

Preliminary study on the molecular features of mutation in multiple primary oral cancer by whole exome sequencing.

Multiple primary cancers (MPCs) refer to cancers that occur simultaneously or metachronously in the same individual. The incidence of MPC has increased recently, as the survival time of malignant tumor patients has been greatly prolonged. It is difficult to differentiate MPC from primary cancers (PCs) in the same anatomical region from the clinical manifestation alone. However, their biological behaviors appear to be distinct. In this study, we show that the prognosis of multiple primary oral cancers (MP-OCs) is worse than primary oral cancers (P-OCs). To better understand the molecular mechanisms of MP-OC, we used whole exome sequencing (WES) to analyze samples from 9 patients with MP-OC and 21 patients with P-OC. We found more somatic mutations in MP-OC than in P-OC. MP-OC had more complicated mutation signatures, which were associated with age-related and Apolipoprotein B mRNA Editing Catalytic Polypeptide-like (APOBEC) activity-related signatures. Tumor mutational burden (TMB) and mutant-allele tumor heterogeneity (MATH) of MP-OC trended higher compared to P-OC. KEGG and GO analysis showed the differential pathways of MP-OC versus P-OC. In addition, MP-OC took amplification, not loss, as the main pattern of copy number variation (CNV), while P-OC took both. Lastly, we did not find significantly different mutant germline genes, but MSH-6 mutation may be a potential MP-OC driver. In short, our preliminary results show that MP-OC and P-OC have different molecular characteristics.

Development and validation of a ferroptosis-related lncRNAs signature to predict prognosis and microenvironment for melanoma.

Ferroptosis plays an important role in cancer. However, studies about ferroptosis-related lncRNAs (FRLs) in skin cutaneous melanoma (SKCM) are scarce. Moreover, the relationship between prognostic FRLs and tumor microenvironment (TME) in melanoma remains unclear. This study investigates the potential prognostic value of FRLs and their association with TME in SKCM. The RNA-sequencing data of SKCM were downloaded from The Cancer Genome Atlas (TCGA) database. Melanoma patients were randomly divided into training and testing groups in a 1:1 ratio. A signature composed of 19 FRLs was developed by the least absolute shrinkage and selection operator (LASSO) regression analysis to divide patients into a low-risk group with a better prognosis and a high-risk group with a poor prognosis. Multivariate Cox regression analysis suggested that the risk score was an independent prognostic factor. The Area Under Curve (AUC) value of the risk score reached 0.768 in the training group and 0.770 in the testing group. Subsequent analysis proved that immune-related signaling pathways were significantly enriched in the low-risk group. The tumor immune cell infiltration analysis demonstrated that melanoma in the high-risk group tended to be immunologically "cold". We identified a novel FRLs signature which could accurately predict the prognosis of patients with melanoma.

General anesthesia in children and long-term neurodevelopmental deficits: A systematic review.

Background: Millions of children experienced surgery procedures requiring general anesthesia (GA). Any potential neurodevelopmental risks of pediatric anesthesia can be a serious public health issue. Various animal studies have provided evidence that commonly used GA induced a variety of morphofunctional alterations in the developing brain of juvenile animals. Methods: We conducted a systematic review to provide a brief overview of preclinical studies and summarize the existing clinical studies. Comprehensive literature searches of PubMed, EMBASE, CINAHL, OVID Medline, Web of Science, and the Cochrane Library were conducted using the relevant search terms "general anesthesia," "neurocognitive outcome," and "children." We included studies investigating children who were exposed to single or multiple GA before 18, with long-term neurodevelopment outcomes evaluated after the exposure(s). Results: Seventy-two clinical studies originating from 18 different countries published from 2000 to 2022 are included in this review, most of which are retrospective studies (n = 58). Two-thirds of studies (n = 48) provide evidence of negative neurocognitive effects after GA exposure in children. Neurodevelopmental outcomes are categorized into six domains: academics/achievement, cognition, development/behavior, diagnosis, brain studies, and others. Most studies focusing on children <7 years detected adverse neurocognitive effects following GA exposure, but not all studies consistently supported the prevailing view that younger children were at greater risk than senior ones. More times and longer duration of exposures to GA, and major surgeries may indicate a higher risk of negative outcomes. Conclusion: Based on current studies, it is necessary to endeavor to limit the duration and numbers of anesthesia and the dose of anesthetic agents. For future studies, we require cohort studies with rich sources of data and appropriate outcome measures, and carefully designed and adequately powered clinical trials testing plausible interventions in relevant patient populations.

Deep learning models for predicting the survival of patients with chondrosarcoma based on a surveillance, epidemiology, and end results analysis.

Background: Accurate prediction of prognosis is critical for therapeutic decisions in chondrosarcoma patients. Several prognostic models have been created utilizing multivariate Cox regression or binary classification-based machine learning approaches to predict the 3- and 5-year survival of patients with chondrosarcoma, but few studies have investigated the results of combining deep learning with time-to-event prediction. Compared with simplifying the prediction as a binary classification problem, modeling the probability of an event as a function of time by combining it with deep learning can provide better accuracy and flexibility. Materials and methods: Patients with the diagnosis of chondrosarcoma between 2000 and 2018 were extracted from the Surveillance, Epidemiology, and End Results (SEER) registry. Three algorithms-two based on neural networks (DeepSurv, neural multi-task logistic regression [NMTLR]) and one on ensemble learning (random survival forest [RSF])-were selected for training. Meanwhile, a multivariate Cox proportional hazards (CoxPH) model was also constructed for comparison. The dataset was randomly divided into training and testing datasets at a ratio of 7:3. Hyperparameter tuning was conducted through a 1000-repeated random search with 5-fold cross-validation on the training dataset. The model performance was assessed using the concordance index (C-index), Brier score, and Integrated Brier Score (IBS). The accuracy of predicting 1-, 3-, 5- and 10-year survival was evaluated using receiver operating characteristic curves (ROC), calibration curves, and the area under the ROC curves (AUC). Results: A total of 3145 patients were finally enrolled in our study. The mean age at diagnosis was 52 ± 18 years, 1662 of the 3145 patients were male (53%), and mean survival time was 83 ± 67 months. Two deep learning models outperformed the RSF and classical CoxPH models, with the C-index on test datasets achieving values of 0.832 (DeepSurv) and 0.821 (NMTLR). The DeepSurv model produced better accuracy and calibrated survival estimates in predicting 1-, 3- 5- and 10-year survival (AUC:0.895-0.937). We deployed the DeepSurv model as a web application for use in clinical practice; it can be accessed through https://share.streamlit.io/whuh-ml/chondrosarcoma/Predict/app.py. Conclusions: Time-to-event prediction models based on deep learning algorithms are successful in predicting chondrosarcoma prognosis, with DeepSurv producing the best discriminative performance and calibration.

Identification and validation of a ferroptosis-related gene signature for predicting survival in skin cutaneous melanoma.

PURPOSE: Ferroptosis plays a crucial role in the initiation and progression of melanoma. This study developed a robust signature with ferroptosis-related genes (FRGs) and assessed the ability of this signature to predict OS in patients with skin cutaneous melanoma (SKCM). METHODS: RNA-sequencing data and clinical information of melanoma patients were extracted from TCGA, GEO, and GTEx. Univariate, multivariate, and LASSO regression analyses were conducted to identify the gene signature. A 10 FRG signature was an independent and strong predictor of survival. The predictive performance was assessed using ROC curve. The functions of this gene signature were assessed by GO and KEGG analysis. The statuses of low-risk and high-risk groups according to the gene signature were compared by GSEA. In addition, we investigated the possible relationship of FRGs with immunotherapy efficacy. RESULTS: A prognostic signature with 10 FRGs (CYBB, IFNG, FBXW7, ARNTL, PROM2, GPX2, JDP2, SLC7A5, TUBE1, and HAMP) was identified by Cox regression analysis. This signature had a higher prediction efficiency than clinicopathological features (AUC = 0.70). The enrichment analyses of DEGs indicated that ferroptosis-related immune pathways were largely enriched. Furthermore, GSEA showed that ferroptosis was associated with immunosuppression in the high-risk group. Finally, immune checkpoints such as PDCD-1 (PD-1), CTLA4, CD274 (PD-L1), and LAG3 were also differential expression in two risk groups. CONCLUSIONS: The 10 FRGs signature were a strong predictor of OS in SKCM and could be used to predict therapeutic targets for melanoma.

Free Flap Reconstruction of Extremity Defects in Pediatric Patients.

BACKGROUND: Microsurgical reconstruction of extremity defects with free flaps has been carried out for many years. The aim of this retrospective study is to characterize free flap surgery on children of 1 to 7 years old by evaluating a series of 20 cases of free flap surgeries that have been performed in pediatric patients. METHODS: From February 2014 to January 2018, 20 patients, 10 boys and 10 girls aged from 1 to 7 years (average, 4.6 years), were engaged in this study. Several types of free flaps were used, including anterolateral thigh flaps (ALT), inferior ulnar collateral artery flap, latissimus dorsi flap, medial plantar flap, fibular osteocutaneous flap and hallux toenail flap. After operations, follow-up period was at least for 2 years and the average follow-up period was 48.5 months. The long-term outcomes were estimated by questionnaires derived from the American Academy of Orthopaedic Surgeons Pediatric Outcomes Data Collection Instrument (PODCI). RESULTS: A total of 21free-flap reconstructions were performed on 20patients, including 15 ALT, 3 composite flaps, and 3 other cutaneous flaps. The size of the tissue flap ranged from 1.5 to 280 cm2 (average, 74.1cm2). The diameter of the anastomosed artery of the flap ranged from 0.7 to 1.2 mm. Among the 21 flaps, 20 survived and the success rate was about 95 %. Contour adaption was achieved in all flaps. Fifteen children received a secondary operation for debulking or functional improvement. Secondary deformity was present in 3 children, among which ankle joint valgus was seen in two children and a flexion deformity of injured toe occurred in one child. The mean global functioning score of PODCI was 94 (ranging from 81 to 98, maximum 100). CONCLUSION: The success rate of free-flap surgery in pediatric patients was comparable to that achieved in adults. Post-operative caring for pediatric patients was easier than expected. For pediatric patients, the final outcomes were not varied remarkably from different types of free tissue transfer.

Identification and Validation of Immune-Related lncRNA Signature as a Prognostic Model for Skin Cutaneous Melanoma.

PURPOSE: Skin cutaneous melanoma (SKCM) is the most aggressive skin cancer that results in high morbidity and mortality rate worldwide. Immune-related long non-coding RNAs (IRlncRs) play an important role in regulating gene expression in tumors. Therefore, in this study, we aimed to identify IRlncRs signature that could predict prognosis and therapeutic targets for melanoma irrespective of the gene expression levels. METHODS: RNA-sequencing data were obtained from The Cancer Genome Atlas (TCGA). IRlncRs were identified using co-expression analysis and recognized using univariate analysis. The impact of IRlncRs on survival was analyzed using a modified least absolute shrinkage and selection operator (Lasso) regression model. A 1-year survival receiver operating characteristic curve was constructed, and the area under the curve was calculated to identify the optimal cut-off point to distinguish between high and low-risk groups in patients with SKCM. Furthermore, integrative analysis was performed to identify the impact of clinicopathological features, chemotherapeutic treatment, tumor-infiltrating immune cells, and mutant genes on survival. RESULTS: A total of 28 IRlncRs significantly associated with survival were identified. Seventeen IRlncRs pairs were used to build a survival risk model that could be used to distinguish between low and high-risk groups. The high-risk group was negatively associated with tumor-infiltrating immune cells and had a higher half inhibitory centration for chemotherapeutic agents such as cisplatin and vinblastine. Additionally, the high-risk group had a positive correlation with the expression of specific mutant genes such as BRAF and KIT. CONCLUSION: Our findings demonstrate that some IRlncRs have a significant correlation with survival and therapeutic targets for SKCM patients and may provide new insight into the clinical diagnosis and treatment strategies for SKCM patients.

Opening wedge phalangeal osteotomy for correction of Wassel type IV-D thumb duplication.

BACKGROUND: Thumb duplication is one of common anomalies of the hand. Among of Wassel type IV subtypes, type IV-D duplication with a zigzag deformity is most challenging for reconstructing. Several factors may affect the surgical outcomes. This study aimed to present an opening wedge osteotomy at proximal phalangeal neck for treating type IV-D duplication. METHODS: Data from 14 patients are presented in this study. Eight patients had duplication of the right thumb, and six left thumb. After removal of radial supernumerary thumb, a snug collateral ligament was repaired to correct angular deformity of metacarpophalangeal joint (MCP). Angular deformity of the interphalangeal (IP) joint was corrected by an opening wedge osteotomy at the proximal phalangeal neck. A wedge bone from ablated thumb was grafted to correct the malalignment. IP joint was further stabilized by plication of the ulnar capsule. The relocation of radial part of FPL to the center of distal phalangeal base by use of pull-out suture technique RESULTS: After surgery, the angulations of the IP joints and the MCP joints were improved. Bone union was observed in all patients. According to the Japanese Society for Surgery of the Hand evaluation form, twelve cases were rated good, 2 cases fair. Stability of IP and MCP joints was good in all cases. The active ROM of IP was less in residual thumb than in normal thumb. Small nails were observed in some patients. CONCLUSIONS: Although the reconstructed thumbs were smaller than normal counterparts, they were aligned and with stable joints. The opening wedge osteotomy at proximal phalangeal neck could improve realignment of IP joint and prevent reoccurrence of deformity over time.

Skin Epidermis and Adnexa Regrowth Induced by Treatment With Artificial Dermal Template After Full-Thickness Skin Wound.

Full-thickness skin wounds are common accidents. Although healing can be achieved by treatments like autologous skin grafts, donor site morbidity is hardly evitable. In this article, we provide compelling evidence demonstrating that artificial dermal template (ADT)-treated wound healing is achieved by regrowth of skin epidermis as well as adnexa without skin grafts by use of rodent models. First, by fixating a chamber to the wound edge, we confirmed that wound healing was achieved by regeneration instead of contracture. We found highly proliferative cells in adnexa in the newly formed skin. In the distal edge of newly formed skin, we identified immature hair follicles at early developing stages, suggesting they were newly regenerated. Second, we observed that the Lgr5-positive hair follicle stem cells contributed to formation of new hair follicles through a lineage tracing model. Also, Lgr6-positive cells were enriched in distal edge of newly developed skin. Finally, WNT signaling pathway mediators were highly expressed in the new skin epidermis and adnexa, implying a potential role of WNT signaling during ADT treatment-stimulated skin regrowth. Taken together, our findings demonstrated that full skin regrowth can be induced by ADT treatment alone, thus arguing for its wide clinical application in skin wound treatment.

A novel chronic nerve compression model in the rat.

Current animal models of chronic peripheral nerve compression are mainly silicone tube models. However, the cross section of the rat sciatic nerve is not a perfect circle, and there are differences in the diameter of the sciatic nerve due to individual differences. The use of a silicone tube with a uniform internal diameter may not provide a reliable and consistent model. We have established a chronic sciatic nerve compression model that can induce demyelination of the sciatic nerve and lead to atrophy of skeletal muscle. In 3-week-old pups and adult rats, the sciatic nerve of the right hind limb was exposed, and a piece of surgical latex glove was gently placed under the nerve. N-butyl-cyanoacrylate was then placed over the nerve, and after it had set, another piece of glove latex was placed on top of the target area and allowed to adhere to the first piece to form a sandwich-like complex. Thus, a chronic sciatic nerve compression model was produced. Control pups with latex or N-butyl-cyanoacrylate were also prepared. Functional changes to nerves were assessed using the hot plate test and electromyography. Immunofluorescence and electron microscopy analyses of the nerves were performed to quantify the degree of neuropathological change. Masson staining was conducted to assess the degree of fibrosis in the gastrocnemius and intrinsic paw muscles. The pup group rats subjected to nerve compression displayed thermal hypoesthesia and a gradual decrease in nerve conduction velocity at 2 weeks after surgery. Neuropathological studies demonstrated that the model caused nerve demyelination and axonal irregularities and triggered collagen deposition in the epineurium and perineurium of the affected nerve at 8 weeks after surgery. The degree of fibrosis in the gastrocnemius and intrinsic paw muscles was significantly increased at 20 weeks after surgery. In conclusion, our novel model can reproduce the functional and histological changes of chronic nerve compression injury that occurs in humans and it will be a useful new tool for investigating the mechanisms underlying chronic nerve compression.

One-stage Pelnac Reconstruction in Full-thickness Skin Defects with Bone or Tendon Exposure.

Dermal regeneration template, such as Integra and Pelnac, was originally designed for treating large area burn injury by inducing regeneration of dermis. To date, it has been widely applied in various acute and chronic wound sites. The present study demonstrated that application of artificial dermis alone induced 1-stage wound healing for wounds with bone or tendon exposure that should usually be repaired by flap surgery. Eight patients who presented with skin defects with bone and/or tendon exposure were treated by 1-stage Pelnac approach. All wounds healed within 20 weeks without skin graft or flap surgery. The wound area was reconstructed by nearly normal skin structure and linear scar. In the case of scalp defect, evidence of hair follicle cell migration and regeneration during healing process was observed. Thereby, the 1-stage Pelnac reconstitution can be considered as a novel method for inducing regrowth of epidermis and hair follicles to cure large full-thickness skin defect with bone and tendon exposure in 1 stage.

Differentiation of bone marrow stromal cells into schwann-like cells using dihydrotestosterone combined with a classical induction method.

OBJECTIVE: To investigate the effect of dihydrotestosterone (DHT) combined with Dezawa's method on the differentiation of bone marrow stromal cells (BMSCs) into schwann-like cells. RESULTS: Compared to the Dezawa's method, schwann-like cells obtained from our modified method were longer and thinner and exhibited a typical bipolar or tripolar shape. These cells had a higher mRNA expression of S100 and myelin protein zero (P0), about 1.7- and 2.5-fold respectively, while the glial fibrillary acidic protein (GFAP) mRNA level was decreased about 92 %. No significant difference in peripheral myelin protein 22 (PMP22) mRNA expression was found. Immunofluorescence and Western blot showed the similar results. CONCLUSION: DHT in combination with Dezawa's method to induce a BMSCs to differentiate into schwann-like cells with higher expression of P0, which might be more effective in clinical application than previous method for nerve regeneration.

Regeneration in the Pituitary After Cell-Ablation Injury: Time-Related Aspects and Molecular Analysis.

We recently showed that the mouse pituitary holds regenerative competence. Young-adult GHCre/iDTR mice, expressing diphtheria toxin (DT) receptor in GH-producing cells, regenerate the GH(+) cells, as ablated by 3-day DT treatment (3DT), up to 60% after 5 months. The pituitary's stem cells participate in this restoration process. Here, we characterized this regenerative capacity in relation to age and recovery period and started to search for underlying molecular mechanisms. Extending the recovery period (up to 19 mo) does not result in higher regeneration levels. In addition, the regenerative competence disappears at older age, coinciding with a reduction in pituitary stem cell number and fitness. Surprisingly, prolonging DT treatment of young-adult mice to 10 days (10DT) completely blocks the regeneration, although the stem cell compartment still reacts by promptly expanding, and retains in vitro stem cell functionality. To obtain a first broad view on molecular grounds underlying reparative capacity and/or failure, the stem cell-clustering side population was analyzed by whole-genome expression analysis. A number of stemness factors and components of embryonic, epithelial-mesenchymal transition, growth factor and Hippo pathways are higher expressed in the stem cell-clustering side population of the regenerating pituitary (after 3DT) when compared with the basal gland and to the nonregenerating pituitary (after 10DT). Together, the regenerative capacity of the pituitary is limited both in age-related terms and final efficacy, and appears to rely on stem cell-associated pathway activation. Dissection of the molecular profiles may eventually identify targets to induce or boost regeneration in situations of (injury-related) pituitary deficiency.

A Modified Approach to Inducing Bone Marrow Stromal Cells to Differentiate into Cells with Mature Schwann Cell Phenotypes.

Marrow stromal cells (MSCs) can be induced to differentiate into Schwann-like cells under classical induction conditions. However, cells derived from this method are unstable, exhibiting a low neurotrophin expression level after the induction conditions are removed. In Schwann cell (SC) culture, progesterone (PROG) enhances neurotrophic synthesis and myelination, specifically regulating the expression of the myelin protein zero (P0)- and peripheral myelin protein 22 (PMP22)-encoding genes by acting in concert or in synergy with insulin and glucocorticoids (GLUCs). In the present study, we investigated whether combined PROG, GLUC, and insulin therapy induced MSCs to differentiate into modified SC-like cells with phenotypes similar to those of mature SCs. After being cultured for 2 weeks in modified differentiation medium, the modified SC-like cells showed increased expression of P0 and PMP22. In addition, morphological and phenotypic characterizations were conducted over a period of over 2 weeks, and functional characteristics persisted for more than 3 weeks after the induction reagents were withdrawn. The transplantation of green fluorescent protein-labeled, modified SC-like cells into transected sciatic nerves with a 10-mm gap significantly increased the proliferation of the original SCs and improved axon regeneration and myelination compared with original BM-SCs. Immunostaining for P0 revealed that more of the transplanted modified SC-like cells retained the phenotypic characteristics of SCs. Taken together, these results reveal that the combined application of PROG, GLUC, and insulin induces MSCs to differentiate into cells with phenotypic, molecular, and functional properties of mature SCs.

Pituitary tumors contain a side population with tumor stem cell-associated characteristics.

Pituitary adenomas cause significant endocrine and mass-related morbidity. Little is known about the mechanisms that underlie pituitary tumor pathogenesis. In the present study, we searched for a side population (SP) in pituitary tumors representing cells with high efflux capacity and potentially enriched for tumor stem cells (TSCs). Human pituitary adenomas contain a SP irrespective of hormonal phenotype. This adenoma SP, as well as the purified SP (pSP) that is depleted from endothelial and immune cells, is enriched for cells that express 'tumor stemness' markers and signaling pathways, including epithelial-mesenchymal transition (EMT)-linked factors. Pituitary adenomas were found to contain self-renewing sphere-forming cells, considered to be a property of TSCs. These sphere-initiating cells were recovered in the pSP. Because benign pituitary adenomas do not grow in vitro and have failed to expand in immunodeficient mice, the pituitary tumor cell line AtT20 was further used. We identified a SP in this cell line and found it to be more tumorigenic than the non-SP 'main population'. Of the two EMT regulatory pathways tested, the inhibition of chemokine (C-X-C motif) receptor 4 (CXCR4) signaling reduced EMT-associated cell motility in vitro as well as xenograft tumor growth, whereas the activation of TGFß had no effect. The human adenoma pSP also showed upregulated expression of the pituitary stem cell marker SOX2. Pituitaries from dopamine receptor D2 knockout (Drd2(-/-)) mice that bear prolactinomas contain more pSP, Sox2(+), and colony-forming cells than WT glands. In conclusion, we detected a SP in pituitary tumors and identified TSC-associated characteristics. The present study adds new elements to the unraveling of pituitary tumor pathogenesis and may lead to the identification of new therapeutic targets.

Pituitary stem cells: where do we stand?

Some 5 years ago, the stem cells of the adult pituitary gland were discovered. Subsequent in-depth characterization revealed expression of several stemness markers and embryo-typical factors. Now, the quest is open to decipher their role in the gland. When and how pituitary stem cells differentiate to contribute to the mature hormone-producing cell populations is not known. New research models support their involvement in cell regeneration after injury in the gland, and suggest a possible role in pituitary tumor formation. From their expression phenotype, pituitary stem cells seem to re-use embryonic developmental programs during the creation of new hormonal cells. Here, we will review the latest progression in the domain of pituitary stem cells, including the uncovering of some new molecular flavors and of the first potential functions. Eventually, we will speculate on their differentiation programs towards hormonal cells, with a particular focus on gonadotropes.

A new modified Tsuge suture for flexor tendon repairs: the biomechanical analysis and clinical application.

PURPOSE: This study is to develop a new suturing technique for flexor tendon repair by modifying the extant Tsuge repair techniques and to use biomechanical analysis to compare the new method with four established repair techniques and evaluate its clinical efficacy in the repair of 47 flexor tendons in 22 patients. METHODS: The biomechanical analysis relied on 50 flexor digitorum profundus tendons harvested from fresh cadavers. The tendons were randomly divided into five groups, transected, and repaired by use of a 1. double-loop suture, 2. double modified locking Kessler, 3. four-strand Savage, 4. modified six-strand Savage, and 5. the new technique. The tensile force and breaking force of all repaired tendons were measured by static loading trials. For clinical application, 22 patients with acute flexor tendon injuries were treated with the new modified Tsuge suture and follow-up for more than 12 months. RESULTS: While differences in the tensile force and breaking force in the modified Tsuge sutures and modified six-strand Savage sutures were not statistically significant, static loading trials showed the tensile force, in the form of a 2-mm gap formation, and the breaking force of the new modified Tsuge sutures were, statistically, both higher than the ones characteristic of double-loop sutures, double modified locking Kessler, and four-strand Savage sutures. After 12 months, restored functions were observed in all the patients during the postoperative 12 months. Total active motion (TAM) score demonstrated that more than 90% fingers were estimated as excellent or good. CONCLUSION: The new modified Tsuge sutures described here have evident higher tensile and breaking forces compared to other four-strand core suture techniques, suggesting, in turn, that this new technique is a good alternative for flexor tendon repairs in clinical applications.

Common genetic variants in the microRNA biogenesis pathway are associated with malignant peripheral nerve sheath tumor risk in a Chinese population.

PURPOSE: The role of microRNAs (miRNAs) in tumorigenesis has been well established. Genetic variants in the miRNA biogenesis pathway genes may modify cancer development and survival by affecting the miRNA biogenesis. Our aim is to investigate the association of polymorphisms in the miRNA biogenesis pathway genes and malignant peripheral nerve sheath tumor (MPNST) risk among neurofibromatosis type 1 (NF1) patients. METHODS: A case-control study was performed to analyze 53 SNPs in 11 miRNA biogenesis pathway genes in 356 patients (200 patients with NF1 and 156 patients with both NF1 and MPNST) in China. Association analysis was performed in an additive genetic model by logistics regression. RESULTS: Four SNPs (DDX5 rs1991401, OR=1.79, 95% CI, 1.34-2.38, P=7.90 × 10(-5); DROSHA rs10719, OR=1.64, 95% CI, 1.23-2.20, P=8.76 × 10(-4); AGO2 rs7005286, OR=0.48, 95% CI, 0.32-0.72, P=3.46 × 10(-4); GEMIN4 rs7813, OR=0.50, 95% CI, 0.34-0.72, P=2.65 × 10(-4)) were significantly associated with MPNST risk. A strong gene-dose effect with increased MPNST risk (P for trend<0.001) was observed. CONCLUSIONS: Genetic variants in the miRNA biogenesis pathway genes may modify MPNST risk both individually and jointly.