Resensitising proteasome inhibitor-resistant myeloma with sphingosine kinase 2 inhibition.

The introduction of the proteasome inhibitor bortezomib into treatment regimens for myeloma has led to substantial improvement in patient survival. However, whilst bortezomib elicits initial responses in many myeloma patients, this haematological malignancy remains incurable due to the development of acquired bortezomib resistance. With other patients presenting with disease that is intrinsically bortezomib resistant, it is clear that new therapeutic approaches are desperately required to target bortezomib-resistant myeloma.

A Phase II Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Arbaclofen Administered for the Treatment of Social Function in Children and Adolescents With Autism Spectrum Disorders: Study Protocol for AIMS-2-TRIALS-CT1.

Autism Spectrum Disorder (ASD or autism) is characterized by difficulties in social communication and interaction, which negatively impact on individuals and their families' quality of life. Currently no pharmacological interventions have been shown to be effective for improving social communication in autism. Previous trials have indicated the potential of arbaclofen for improving social function among autistic children and adolescents with fluent speech.

Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer.

The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM).

Access to Dental Visits and Correlates of Preventive Dental Care in Children with Autism Spectrum Disorder.

Dental care received by children in the Autism Speaks Autism Treatment Network (ATN) was compared to National Survey of Children's Health (NSCH) data for children without special healthcare needs and children with parent-reported ASD. Correlates of obtained preventive dental services were examined within the ATN sample. Participants included 375 families of children ages 4 to 17 enrolled in the ATN.

The mutational burden of therapy-related myeloid neoplasms is similar to primary myelodysplastic syndrome but has a distinctive distribution.

Therapy-related myeloid neoplasms (T-MN) are poorly characterized secondary hematological malignancies following chemotherapy/radiotherapy exposure. We compared the clinical and mutational characteristics of T-MN (n = 129) and primary myelodysplastic syndrome (P-MDS, n = 108) patients. Although the somatic mutation frequency was similar between T-MN and P-MDS patients (93% in both groups), the pattern was distinct.

Arbaclofen in Children and Adolescents with Autism Spectrum Disorder: A Randomized, Controlled, Phase 2 Trial.

Several lines of emerging data point to an imbalance between neuronal excitation and inhibition in at least a subgroup of individuals with autism spectrum disorder (ASD), including in those with fragile X syndrome (FXS), one of the most common genetic syndromes within ASD. In animal models of FXS and of ASD, GABA-B agonists have improved both brain and behavioral phenotypes, including social behavior. A phase 2 randomized, placebo-controlled, crossover trial found that the GABA-B agonist arbaclofen improved social avoidance symptoms in FXS.

BAM-matcher: a tool for rapid NGS sample matching.

Unlabelled: The standard method used by high-throughput genome sequencing facilities for detecting mislabelled samples is to use independently generated high-density SNP data to determine sample identity. However, as it has now become commonplace to have multiple samples sequenced from the same source, such as for analysis of somatic variants using matched tumour and normal samples, we can directly use the genotype information inherent in the sequence data to match samples and thus bypass the need for additional laboratory testing. Here we present BAM-matcher, a tool that can rapidly determine whether two BAM files represent samples from the same biological source by comparing their genotypes.

STX209 (arbaclofen) for autism spectrum disorders: an 8-week open-label study.

STX209 (arbaclofen), a selective GABA-B agonist, is hypothesized to modulate the balance of excitatory to inhibitory neurotransmission, and has shown preliminary evidence of benefit in fragile X syndrome. We evaluated its safety, tolerability, and efficacy in non-syndromic autism spectrum disorders, in an 8-week open-label trial enrolling 32 children and adolescents with either Autistic Disorder or Pervasive Developmental Disorder-Not Otherwise Specified, and a score ≥17 on the Aberrant Behavior Checklist (ABC)-Irritability subscale. STX209 was generally well-tolerated.

Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial.

Research on animal models of fragile X syndrome suggests that STX209, a γ-aminobutyric acid type B (GABA(B)) agonist, might improve neurobehavioral function in affected patients. We evaluated whether STX209 improves behavioral symptoms of fragile X syndrome in a randomized, double-blind, placebo-controlled crossover study in 63 subjects (55 male), ages 6 to 39 years, with a full mutation in the FMR1 gene (>200 CGG triplet repeats). We found no difference from placebo on the primary endpoint, the Aberrant Behavior Checklist-Irritability (ABC-I) subscale.

Family size and turnover rates among several classes of small non-protein-coding RNA genes in Caenorhabditis nematodes.

It is important to understand the forces that shape the size and evolutionary histories of gene families. Here, we investigated the evolution of non-protein-coding RNA genes in the genomes of Caenorhabditis nematodes. We specifically focused on nested arrangements, that is, cases in which an RNA gene is entirely contained in an intron of another gene.

Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial.

Objective: To evaluate the efficacy and safety of ziprasidone adjunctive to a mood stabilizer for the maintenance treatment of bipolar mania.

Method: Subjects with DSM-IV bipolar I disorder with a Mania Rating Scale score > or = 14 were enrolled. Subjects achieving > or = 8 consecutive weeks of stability with open-label ziprasidone (80-160 mg/d) and lithium or valproate (period 1) were randomly assigned in the 6-month, double-blind maintenance period (period 2) to ziprasidone plus mood stabilizer or placebo plus mood stabilizer.

Computational prediction of Caenorhabditis box H/ACA snoRNAs using genomic properties of their host genes.

Identification of small nucleolar RNAs (snoRNAs) in genomic sequences has been challenging due to the relative paucity of sequence features. Many current prediction algorithms rely on detection of snoRNA motifs complementary to target sites in snRNAs and rRNAs. However, recent discovery of snoRNAs without apparent targets requires development of alternative prediction methods.

Thoracic spinal cord compression by intramedullary hamartomatous tissue in a young boy: case report.

Objective: Spinal cord hamartomas are a rare occurrence characterized by well- differentiated mature elements located in an irregular position in the spinal cord.

Clinical Presentation: The authors present the unique case of a 12-year-old boy who originally presented to our center for treatment of a right thalamic astrocytoma. One year after his initial presentation, the child developed progressive bilateral leg weakness with decreased sensation.

Case of microarteriovenous malformation-induced trigeminal neuralgia treated with radiosurgery.

Radiosurgery to the right fifth cranial nerve was performed with the Gamma Knife on a 39- year-old patient who presented with classic symptoms of trigeminal neuralgia (TN), but was found on imaging studies to harbour a small intrinsic vascular malformation within the nerve. Based on size and drainage, the arteriovenous malformation (AVM) was Spetzler-Martin Grade III and no previous history of bleeding was reported. The patient had failed a trial of carbamazepine, and no surgical procedures had been performed.

Intracranial delivery of the nitric oxide donor diethylenetriamine/nitric oxide from a controlled-release polymer: toxicity in cynomolgus monkeys.

Objective: Diethylenetriamine/nitric oxide (DETA/NO) has been shown to be an effective treatment for delayed posthemorrhagic vasospasm when released abluminally from ethylene-vinyl acetate copolymer (EVAc). However, the observed mortality associated with this drug warrants further investigation. To establish a maximum tolerable dose, this study evaluated the toxicity of DETA/NO released from EVAc in a dose-escalation series in cynomolgus monkeys (Macaca fascicularis).

Acute intracranial subdural hematoma following a lumbar CSF leak caused by spine surgery.

Study Design: Case report.

Objective: To report a case of an acute intracranial subdural hematoma that formed due to cerebrospinal fluid (CSF) leak following lumbar surgery.

Summary Of Background Data: Intracranial hypotension may occur when CSF is removed from the subarachnoid space.

Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model.

Introduction: Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer), and the efficacy of Paclimer was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer in a canine dose escalation toxicity study to prepare its translation into clinical scenarios.

Language development in preschool-age children adopted from China.

This study examined the language development of 55 preschool-age children adopted from China who had resided in their permanent homes for approximately 2 years or longer. Slightly over 5% of the children scored below average on 2 or more measures from a battery of standardized speech-language tests normed on monolingual English speakers. However, the vast majority scored within or well above the average range on 2 or more measures.

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region.

Distal ventriculoperitoneal shunt failure caused by silicone allergy. Case report.

The placement of a ventriculoperitoneal (VP) shunt is the most common form of treatment for hydrocephalus. Although allergic reactions to the silicone in shunt hardware are very rare, the authors describe a case of silicone allergy causing multiple ventricular shunt revisions. A 24-year-old man, who had undergone multiple VP shunt revisions, presented with shunt malfunction caused by allergic reaction of the tissues surrounding the shunt tubing.

Delayed intracranial delivery of a nitric oxide donor from a controlled-release polymer prevents experimental cerebral vasospasm in rabbits.

Objective: Decreased local availability of nitric oxide (NO) may mediate chronic vasospasm after aneurysmal subarachnoid hemorrhage (SAH). Previous reports have shown that early treatment with NO prevents vasospasm in animals. We evaluated the efficacy of controlled-release polymers that contain the NO donor diethylenetriamine (DETA-NO) for the delayed treatment of vasospasm in a rabbit model of SAH.

Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome.

Objective: The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for schizophrenia. These behavioral manifestations of 22q11.