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Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.

Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state. Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus. Upon specific signal recognition cues, some PM-bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. However, lipid-anchored PM-bound proteins enter the nucleus in their full length for depalmitoylation. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. Moreover, targeting intracellular movement pathways of disease-associated MTFs may significantly improve the survival of patients.

RAS GTPases are frequently mutated in human cancer. H- and NRAS isoforms are distributed over both plasma-membrane and endomembranes, including the Golgi complex, but how this organizational context contributes to cellular transformation is unknown. Here we show that RAS at the Golgi is selectively activated by apoptogenic stimuli and antagonizes cell survival by suppressing ERK activity through the induction of PTPRκ, which targets CRAF for dephosphorylation. Consistently, in contrast to what occurs at the plasma-membrane, RAS at the Golgi cannot induce melanoma in zebrafish. Inactivation of PTPRκ, which occurs frequently in human melanoma, often coincident with TP53 inactivation, accelerates RAS-ERK pathway-driven melanomagenesis in zebrafish. Likewise, tp53 disruption in zebrafish facilitates oncogenesis driven by RAS from the Golgi complex. Thus, RAS oncogenic potential is strictly dependent on its sublocalization, with Golgi complex-located RAS antagonizing tumor development.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal disease due, in large part, to a high rate of second primary tumor (SPT) formation. The 4-nitroquinoline 1-oxide (4-NQO) mouse model of oral carcinogenesis provides a robust system in which to study chemopreventive agents in the context of chemically induced HNSCC tumors. STAT3 is a potent oncogene that is hyperactivated by tyrosine phosphorylation early in HNSCC carcinogenesis and is a rational therapeutic target. We recently reported that loss-of-function of the STAT3 phosphatase PTPRT promotes STAT3 activation in HNSCC tumors and preclinical models and may serve as a predictive biomarker of response to STAT3 inhibitors, including the small-molecule Stattic. We therefore investigated the hypothesis that Ptprt-knockout (KO) mice would be more susceptible to 4-NQO-induced oral carcinogenesis and more sensitive to Stattic-mediated chemoprevention compared with wild-type (WT) mice. Herein, we demonstrate that Ptprt WT and KO mice develop similar spectra of HNSCC disease severity upon 12 weeks of 4-NQO administration, with no apparent effect of Ptprt genotype on carcinogenesis or treatment outcome. Targeting of STAT3 with Stattic resulted in a chemopreventive effect against 4-NQO-induced oral cancer (P = 0.0402). While these results do not support a central role for PTPRT in 4-NQO-induced HNSCC carcinogenesis, further investigation of STAT3 as a chemoprevention target in this cancer is warranted. Cancer Prev Res; 9(8); 657-63. ©2016 AACR.

Signal transducer and activator of transcription 3 (STAT3) overactivation is a common event in many cancers, including head and neck squamous cell carcinoma (HNSCC), where STAT3 represents a promising therapeutic target. HNSCC is not characterized by frequent kinase mutations, in contrast to some malignancies where mutational activation of kinases upstream of STAT3 is common. Instead, STAT3 may be activated by loss-of-function of negative regulators of STAT3, including by promoter hypermethylation of PTPRT. Here we first analyzed The Cancer Genome Atlas data and determined that the PTPRT promoter is frequently hypermethylated in several cancers, including HNSCC (60.1% of tumors analyzed) in association with downregulation of PTPRT mRNA expression and upregulation of pSTAT3 expression. These findings were confirmed in an independent cohort of HNSCC tumors by methylation-specific PCR and immunohistochemistry. We demonstrate that PTPRT promoter methylation and gene silencing is reversible in HNSCC cells, leading to PTPRT-specific downregulation of pSTAT3 expression. We further show that PTPRT promoter methylation is significantly associated with sensitivity to STAT3 inhibition in HNSCC cells, suggesting that PTPRT promoter methylation may serve as a predictive biomarker for responsiveness to STAT3 inhibitors in clinical development.

ObjectiveIn rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple pathways involving protein tyrosine phosphorylation, we sought to identify protein tyrosine phosphatases (PTPs) regulating the invasiveness of RA FLS. We describe that the transmembrane receptor PTPκ (RPTPκ), encoded by the transforming growth factor (TGF) β-target gene, PTPRK, promotes RA FLS invasiveness.MethodsGene expression was quantified by quantitative PCR. PTP knockdown was achieved using antisense oligonucleotides. FLS invasion and migration were assessed in transwell or spot assays. FLS spreading was assessed by immunofluorescence microscopy. Activation of signalling pathways was analysed by Western blotting of FLS lysates using phosphospecific antibodies. In vivo FLS invasiveness was assessed by intradermal implantation of FLS into nude mice. The RPTPκ substrate was identified by pull-down assays.ResultsPTPRK expression was higher in FLS from patients with RA versus patients with osteoarthritis, resulting from increased TGFB1 expression in RA FLS. RPTPκ knockdown impaired RA FLS spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumour necrosis factor and interleukin 1 stimulation. Furthermore, RPTPκ deficiency impaired the in vivo invasiveness of RA FLS. Molecular analysis revealed that RPTPκ promoted RA FLS migration by dephosphorylation of the inhibitory residue Y527 of SRC.ConclusionsBy regulating phosphorylation of SRC, RPTPκ promotes the pathogenic action of RA FLS, mediating cross-activation of growth factor and inflammatory cytokine signalling by TGFβ in RA FLS.

Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy. RPTPσ is reciprocally regulated by interactions with chondroitin sulfate or heparan sulfate containing extracellular proteoglycans in a mechanism called the proteoglycan switch. We show that the proteoglycan switch regulates FLS function. Incubation of FLS with a proteoglycan-binding RPTPσ decoy protein inhibited cell invasiveness and attachment to cartilage by disrupting a constitutive interaction between RPTPσ and the heparan sulfate proteoglycan syndecan-4. RPTPσ mediated the effect of proteoglycans on FLS signaling by regulating the phosphorylation and cytoskeletal localization of ezrin. Furthermore, administration of the RPTPσ decoy protein ameliorated in vivo human FLS invasiveness and arthritis severity in the K/BxN serum transfer model of RA. Our data demonstrate that FLS are regulated by an RPTPσ-dependent proteoglycan switch in vivo, which can be targeted for RA therapy. We envision that therapies targeting the proteoglycan switch or its intracellular pathway in FLS could be effective as a monotherapy or in combination with currently available immune-targeted agents to improve control of disease activity in RA patients.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias.

BackgroundProtein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC). STAT3 is a frequently hyperactivated oncogene in HNSCC. As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC.MethodsWe analyzed data from The Cancer Genome Atlas (TCGA) and our previous whole-exome sequencing study and summarized the mutation, methylation, and copy number status of PTPRD in HNSCC and other cancers. In vitro studies involved standard transfection and MTT protocols, as well as methylation-specific PCR.ResultsOur findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC. We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3. Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells. We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC.ConclusionPTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine-substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.

Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.

BackgroundThe neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.ResultsHere we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and beta-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.ConclusionOur data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.

Objective: To determine the effect of delayed start of light polymerization of a dual-cured composite base on the microleakage of Class 2 open-sandwich composite restorations. Method and Materials: Fifty extracted human molars were used to prepare Class 2 mesio-occlusal and disto-occlusal slot preparations. Teeth were randomly divided into 2 groups and restored with a base of dual-cured composite in the proximal box and a top layer of light-cured composite. Group I was restored with a 1-step dual-cured bonding agent; group II was restored with a 2-step dual-cured bonding agent. Five subgroups were created according to the method of polymerization of the dual-cured composite: (A) selfcured, (B) light-cured immediately, (C) light-cured 30 seconds after placement, (D) lightcured 60 seconds after placement, and (E) light-cured 120 seconds after placement. Restorations were stored for 1 week at 37°C and 100% relative humidity, thermocycled (2,000 times, 5°C to 55°C, 15-second dwell), and immersed in a 1% aqueous solution of methylene blue for 24 hours at 37°C. Samples were sectioned mesiodistally, and dye penetration at enamel, dentin, and cementum margins was scored under a stereomicroscope using an ordinal scoring system. Results: Statistical analysis using analysis of variance (ANOVA) on ranks showed that the dual-cured composite light polymerized 1 minute after placement exhibited the lowest microleakage (P < .05) in both bonding agent groups. Conclusion: Delayed, rather than immediate, light polymerization of the dual-cured composite base reduced microleakage in Class 2 open-sandwich restorations. [ABSTRACT FROM AUTHOR]

The formation and plasticity of synaptic connections rely on regulatory interactions between pre- and postsynaptic cells. We show that the Drosophila heparan sulfate proteoglycans (HSPGs) Syndecan (Sdc) and Dallylike (Dlp) are synaptic proteins necessary to control distinct aspects of synaptic biology. Sdc promotes the growth of presynaptic terminals, whereas Dlp regulates active zone form and function. Both Sdc and Dlp bind at high affinity to the protein tyrosine phosphatase LAR, a conserved receptor that controls both NMJ growth and active zone morphogenesis. These data and double mutant assays showing a requirement of LAR for actions of both HSPGs lead to a model in which presynaptic LAR is under complex control, with Sdc promoting and Dlp inhibiting LAR in order to control synapse morphogenesis and function.

Let n be a positive integer greater than 1, ℤn the ring of integer modulo n, f an endomorphism on ℤn and Un the set of all units in ℤn. The unitary endo-Cayley digraph, denoted by endo-Cayf (ℤn, Un), is the digraph whose vertex set is ℤn and a vertex u is adjacent to v if v = f(u) + u ∈ Un for some u ∈ Un. We study about the edge coloring properties of undirected unitary endo-Cayley graphs, endo-Cayf (ℤn, Un). Their edge chromatic number are disclosed. We also determine what class they are of. Moreover, some basic properties involving edge coloring are investigated. [ABSTRACT FROM AUTHOR]

This case report presents the use of custom-made temporomandibular joint prostheses in the treatment of a class 2 malocclusion secondary to juvenile idiopathic arthritis. The patient had degeneration of the mandibular condyles with associated arthropathy and dentofacial deformity. Conventional orthognathic treatment was considered, but would not address the arthropathy. The orthognathic movements were accounted for in the design of the prosthesis and the patient’s arthralgia, functional limitations and aesthetics were addressed. [ABSTRACT FROM AUTHOR]

The purpose of the study was to demonstrate the use of photographs taken in the natural head position (NHP) as a tool to evaluate the effects of functional appliances on clinical soft tissue profile configuration. It was further aimed to evaluate the interrelation between changes in hard and soft tissue structures. Our maternai consisted of photo graphs, lateral cephalometric and hand-wrist radiographs of 8 (5 girls and 3 boys) skeletal Class 2 children treated by activator. Material was collected at.preobservation, pretreatment, Angle Class I molar relationship and posttreatment periods. Repeated measure analyses and Duncan’s tests were used to evaluate the changes in cephalometric and photographic parameters at different periods. Pearson’s correlation coefficients were used to test the associations between hard and soft tissue changes during treatment. It was concluded that, use of photographs taken in the NHP may have significant advantages in the evaluation of soft tissue profile configuration. As expected, statistically significant changes were obtained both in cephalometric and photographice measurements during treatment. A correction of skeletal Class 2 discrepancy was observed together with a reduction in clinical soft tissue profile convexity and an improvement in labiomental curvature. However, these changes in hard and soft tissue structures were not found to be related to each other.

Abstract: Experimental retinal injury threshold data from the literature and computer model data were used to quantitatively characterize the risk of retinal thermal injury for visible laser radiation that exceeds the exposure limit defined by IEC 60825-1 and the European Directive on Artificial Optical Radiation (AOR). This discussion is of particular relevance for medical laser aiming beams with powers of up to 5mW. Exposure to 1mW (Class 2 emissions) does not appear to be able to cause retinal injury for exposure durations of up to about 5s. Even though there is uncertainty in the experimental threshold data for collimated beams, experience with laser pointers up to 5mW shows that there is little risk from accidental momentary exposure to these Class 3R lasers. However, injury threshold data indicate that exposure to some pulsed emission Class 3R lasers as well as extended-source Class 3R lasers with powers above 5mW could induce retinal injury. Recommendations for amendment of the standards IEC 60825-1 and IEC 60601-2-22 are given that should facilitate an agreement of the involved stakeholders on the necessary user safety precautions of Class 3R laser products and medical aiming beams. [Copyright &y& Elsevier]

Abstract: Objective: Elevated growth hormone (GH) levels lead to increased circulating insulin-like growth factor-I (IGF-I), but the effects on localised muscle IGF-I splice variant expression is not known. The effects of rhGH administration, with or without an acute bout of high resistance exercise, were measured on serum IGF-I and on the mRNA levels of IGF-I splice variants in the vastus lateralis muscle of healthy young men. Design: The study was a randomised double blind trial with a crossover design. Seven subjects were randomly assigned to a group receiving daily injections of rhGH (0.075IUkg−1 day−1) or placebo for a two week period. Following a one month washout, the groups were reversed. Results: Administration of rhGH increased circulating IGF-I from 31.8±3.2 to 109±5.4nmol/L (p <0.05). There was no effect of the exercise bout. RNA was extracted from muscle biopsies obtained from exercised and non-exercised legs 2.5h after the cessation of the exercise. Transcript expression was measured using Real-time QPCR. There was no effect of either exercise or rhGH administration on IGF-I 5′ (Class 1 or Class 2) or 3′ (IGF-IEa, or MGF) transcripts. Conclusion: Although rhGH administration has an effect on liver IGF-I expression, as shown by increase in circulating IGF-I, muscle IGF-I expression is unaffected in young healthy subjects with normal GH profile. The findings contrast with those of a previous study in which GH deficient elderly men showed higher muscle IGF-I 3′ splice variant levels following rhGH administration with and without resistance training. Unlike in the liver, muscle Class1 and 2 IGF-I expression do not change significantly following administration of rhGH. [Copyright &y& Elsevier]

The two major principles in silicon neuron implementations are phenomenological and conductance-based. The former reproduces some properties perceived by the designers and does not claim mechanisms are consistent. The latter reproduces the dynamics of the ion channels on the nerve membranes. Although it makes the silicon neurons more similar to biological ones, the implementations tend to be complicated because it attempts to replicate the detailed dynamics of the biological components. In previous work [1], we proposed a simple and biologically realistic MOSFET-based Class 2 silicon nerve membrane. It reproduced basic mathematical structures that produce resting potential and threshold in the Hodgkin-Huxley equations [2,3]. In this paper, we focus on a method of designing such a silicon nerve membrane, which is based on mathematical analyses that have been applied to biological neuron models. The concept of the method is to reproduce the topological structure in phase portraits of biological nerve membrane models utilizing the characteristic curves of basic MOSFET circuitries as the elements of these for silicon nerve membranes. The design method also revealed how to tune their parameters up. [ABSTRACT FROM AUTHOR]

In this paper, a systematic way is described for the construction of all irreducible characters and irreducible representations of finite p-groups of class 2. [ABSTRACT FROM AUTHOR]

Uveal melanoma is a common intraocular malignant tumor that is uniformly fatal once metastatic. No effective adjuvant therapy currently exists to reduce the risk of distant metastasis after definitive treatment of the primary lesion. Immunotherapy has been used effectively in the adjuvant setting in locally advanced cutaneous melanoma. We performed a Phase I/II clinical trial of adjuvant ipilimumab in high-risk primary uveal melanoma with distant metastasis-free survival (DMFS) as the primary objective. A total of 10 patients with genomically high-risk disease were treated: three at a dose of 3 mg/kg and seven at 10 mg/kg. Two of the seven patients at the higher dose had to discontinue therapy secondary to grade 3 toxicity. At 36 months follow-up, 80% of patients had no evidence of distant disease (95% CI, 58.7–100). With recent advancements in CTLA-4 inhibition, PD-1 inhibition, and combined checkpoint blockade, immunotherapy is a promising avenue of treatment in uveal melanoma. Further clinical trials are needed to elucidate the role of immunotherapy in the adjuvant setting. [ABSTRACT FROM AUTHOR]

In the present study to investigate the regions of compensation mechanisms in dento-maxillo-facial system involved for the prevention of anterior open-bite in high-angle skeletal class 2 growing cases, 17 subjects with skeletal and dental open-bite were compared with 17 subjects showing skeletal open-bite but a mean overbite of 2.12 ± 0.50 mm. In cephalometric comparison of two groups in regard with maxillo-facial morphology and dentoalveolar structural characteristics; among the cranial, maxillary, mandibular, maxillo-mandibuhr, facial height and dental parameters, gonial angle, cant of ramus, effective length of the mandible, lower anterior facial height, and anterior facial height, posterior facial height, overbite, upper and lower posterior vertical dentoalveolar height, upper anterior vertical dentoalveolar height and inclination of the upper incisors showed statistically significant differences between the groups.