Feasibility, safety and oncological short-term outcome of laparoscopic pancreaticoduodenectomy for periampullary cancer: Findings from a large sample from Vietnam.

Laparoscopic pancreaticoduodenectomy (LPD) is an alternative to open pancreaticoduodenectomy (OPD) for treatment of periampullary cancer in selected patients. However, this is a difficult procedure with a high complication rate. We conducted a prospective cohort study of 85 patients with suspected periampullary cancer who underwent LPD from February 2017 to January 2022 at University Medical Center at Ho Chi Minh City, Vietnam. Among these, 15 patients were excluded from the data analysis because of benign disease confirmed by postoperative pathological examination. Among 70 patients, the mean age was 58.9 ±â€…8.9 years old and 51.4% were female. The conversion rate to open surgery was 7.1% (n = 5). Among those underwent LPD, the mean operating time and estimated blood loss were 509 ±â€…94 minutes and 267 ±â€…102 mL, respectively. The median length of hospital stay was 8 days, interquartile range (IQR) 7-12 days. The percentage of cumulative morbidity, pancreatic fistula and major complication was 35.4%, 12.3%, and 13.8%, respectively. The median of comprehensive complication index (CCI) was 26.2 (IQR 20.9-29.6). Three patients required reoperation due to severe pancreatic fistula (n = 2) and necrotizing pancreatitis (n = 1). There was no death after ninety-day. The average number of harvested lymph nodes was 16.6 ±â€…5.1. The percentage of R0 resection was 100%. With properly selected patients, LPD can be a feasible, safe and effective approach with acceptable short-term outcomes.

KTt-45, a T-type calcium channel blocker, acts as an anticancer agent by inducing apoptosis on HeLa cervical cancer cell line.

The abnormal expression in the T-type calcium channels is involved in various cancer types, thus inhibiting T-type calcium channels is one of approaches in cancer treatment. The fact that KTt-45 acted as a T-type calcium channel inhibitor as well as a pain-relief agent prompts us to address if KTt-45 plays any role against cancer cells. The results showed that KTt-45 caused cytotoxic effects towards HeLa cervical, Raji lymphoma, MCF-7 breast cancer, and A549 lung cancer cell lines with IC50 values less than 100 µM, in which highly selective toxicity was against HeLa cells (IC50 = 37.4 µM, SI > 3.2). Strikingly, the KTt-45 induced an accumulation of cytoplasmic vacuoles after 48 h treatment and mitochondrial-dependent apoptosis activation as evidenced by morphological features, chromatin condensation, nuclear fragmentation, and significant activation of caspase-9 as well as caspase-3. In conclusion, KTt-45 could inhibit cell growth and trigger mitochondrial-dependent apoptosis in HeLa cervical cancer cells. The results, taken together, strongly demonstrated that KTt-45 is a potential agent for further study on anticancer drug development which not only targets cancer cells but also helps to relieve neuropathic pain in cancer patients.

Cytotoxicity, anti-diabeticity, and phytocomposition investigation of Vietnamese Euphorbia tithymaloides Linn. (Euphorbiaceae).

In this study, the aerial parts of mature Vietnamese Euphorbia tithymaloides plants were put through cytotoxic, anti-diabetic, and phytocompositional evaluations. Specifically, four extracts (petroleum ether (PE), ethyl acetate (EA), methanol (Me), and aqueous (W)) were prepared by maceration at room temperature. All extracts, together with some isolated compounds, were investigated for cytotoxicity against some human normal and cancer cell lines (fibroblasts, HeLa, NCI-H460, HepG2, MCF-7, and Jurkat) using the standardized modified sulforhodamine B (SRB) assay. Additionally, the anti-diabetic activity of extracts and compounds was evaluated via their α-glucosidase inhibitory capacity. The obtained results indicated that Vietnamese E. tithymaloides extracts exhibited moderate cytotoxic activity, among which the PE extract possessed the highest values, on the NCI-H460 cell line. Second, the aqueous extract was revealed to possess very high α-glucosidase inhibitory activity (IC50 = 113.75 ± 14.02 µg ml-1). From the PE extract, three new jatrophane diterpenoids (named tithymal A, tithymal B, and tithymal C) and two known ones were isolated and structurally elucidated using NMR and MS spectroscopies. Noticeably, tithymal A exhibited significantly high inhibitory activity against α-glucosidase (IC50 = 10.71 ± 0.52 µg ml-1). These observations have significantly highlighted the medicinal potential of Vietnamese E. tithymaloides and expanded its scientific fascination.

EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes.

NUT carcinoma is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of progrowth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NUT carcinoma that can impede BRD4-NUT's ability to activate genes, but the efficacy of BETi as monotherapy is limited. Here, we demonstrated that enhancer of zeste homolog 2 (EZH2), which silences genes through establishment of repressive chromatin, is a dependency in NUT carcinoma. Inhibition of EZH2 with the clinical compound tazemetostat potently blocked growth of NUT carcinoma cells. Epigenetic and transcriptomic analysis revealed that tazemetostat reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NUT carcinoma cells. CDKN2A was identified as the only gene among all tazemetostat-derepressed genes to confer resistance to tazemetostat in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes, resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In preclinical models, combined tazemetostat and BETi synergistically blocked tumor growth and prolonged survival of NUT carcinoma-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NUT carcinoma substantiates the reliance of NUT carcinoma tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NUT carcinoma growth. SIGNIFICANCE: Repression of tumor suppressor genes, including CDKN2A, by EZH2 provides a mechanistic rationale for combining EZH2 and BET inhibitors for the clinical treatment of NUT carcinoma. See related commentary by Kazansky and Kentsis, p. 3827.

EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes.

NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) impede BRD4-NUT's ability to activate genes and are thus a promising treatment but limited as monotherapy. The role of gene repression in NC is unknown. Here, we demonstrate that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark, and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4- NUT-regulated genes. CDKN2A was identified as the only gene amongst all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined EZH2 inhibition and BET inhibition synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked growth and prolonged survival of NC-xenografted mice, with all mice cured in one cohort. STATEMENT OF SIGNIFICANCE: Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary chromatin regulatory pathways to maintain NC growth. In particular, repression of CDKN2A expression by EZH2 provides a mechanistic rationale for combining EZH2i with BETi for the clinical treatment of NC.

Effects of Nitisinone on Oxidative and Inflammatory Markers in Alkaptonuria: Results from SONIA1 and SONIA2 Studies.

Nitisinone (NTBC) was recently approved to treat alkaptonuria (AKU), but there is no information on its impact on oxidative stress and inflammation, which are observed in AKU. Therefore, serum samples collected during the clinical studies SONIA1 (40 AKU patients) and SONIA2 (138 AKU patients) were tested for Serum Amyloid A (SAA), CRP and IL-8 by ELISA; Advanced Oxidation Protein Products (AOPP) by spectrophotometry; and protein carbonyls by Western blot. Our results show that NTBC had no significant effects on the tested markers except for a slight but statistically significant effect for NTBC, but not for the combination of time and NTBC, on SAA levels in SONIA2 patients. Notably, the majority of SONIA2 patients presented with SAA > 10 mg/L, and 30 patients in the control group (43.5%) and 40 patients (58.0%) in the NTBC-treated group showed persistently elevated SAA > 10 mg/L at each visit during SONIA2. Higher serum SAA correlated with lower quality of life and higher morbidity. Despite no quantitative differences in AOPP, the preliminary analysis of protein carbonyls highlighted patterns that deserve further investigation. Overall, our results suggest that NTBC cannot control the sub-clinical inflammation due to increased SAA observed in AKU, which is also a risk factor for developing secondary amyloidosis.

Growth parameters in children with achondroplasia: A 7-year, prospective, multinational, observational study.

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

Processing and Mechanical Properties of Basalt Fibre-Reinforced Thermoplastic Composites.

Basalt fibre is derived from volcanic rocks and has similar mechanical properties as glass fibre. However, poor fibre-matrix compatibility and processing issues are the main factors that have restricted the mechanical performance of basalt fibre-reinforced thermoplastic composites (BFRTP). In this work, basalt continuous fibre composites with polypropylene (PP) and polycarbonate (PC) matrices were studied. The composites were processed by compression moulding, and a processing study was conducted to achieve good quality composites. For the BF-PC composites, the optimisation of material preparation and processing steps allowed the polymer to impregnate the fibres with minimal fibre movements, hence improving impregnation and mechanical properties. For BF-PP composites, a compatibiliser was required to improve fibre-matrix compatibility. The compatibiliser significantly improved the tensile and impact strength values for short BF-PP composites and continued to increase at 40 wt%. Furthermore, the analytical modelling of the Young's moduli indicated that the induced fibre orientation during processing for short BF-PP composites and unidirectional (UD) BF-PC composites had better stress transfer than that of UD BF-PP composites.

Duodenal Obstruction Due to Giant Gallstone: A Case Report.

BACKGROUND: Duodenal obstruction due to a gallstone, also known as Bouveret's syndrome, is one type of gallstone ileus. This is a rare complication of cholelithiasis. Among gallstone ileus cases, duodenal obstruction is alsorare. Apart from rareness, diagnosis is challenging due to unspecific clinical manifestation. Treatment options have benefits and drawbacks with each as well. Therefore, setting an appropriate option in a certain patient is an important issue. CASE REPORT: An 85-year-old woman presented clinically with a gastric outlet obstruction. Upper gastrointestinal (GI) endoscopy was attempted but endoscopic exploration was limited because of duodenum filled by fluid. Rigler's triad was detected on abdominal enhanced CT scan: duodenal obstruction, ectopic gallstone within duodenum lumen, pneumobilia. The stone was very large (9 cm long). The diagnosis was duodenal obstruction due to giant gallstone and cholecysto-duodenum fistula. The patient was treated with a radical one-stage procedure: fistulotomy for gallstone removal, cholecystectomy, side-to-side Roux-en-Y duodenojejunostomy. There were no complications related to surgery during the follow-up period. CONCLUSION: Surgery plays an important role in management of duodenal obstruction due to a gallstone, especially a large and impacted stone. Radical one-stage surgery is one of the feasible, safe, and efficient procedures in selected patients.

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Growth charts in Kabuki syndrome 1.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.

Recent advances in the engineering and application of streptavidin-like molecules.

Streptavidin (SA), and other related proteins, has been isolated from a wide range of organisms, including bacteria, fungi, frogs, fish, and birds. Although their original function is not well understood, they have found an important place in biotechnology based on their unique ability to bind biotin molecules with high affinity and specificity. The SA-biotin interaction is robust and easy to incorporate into different designs, and as such, it is used when reliable molecule interaction is needed under poorly controlled experimental conditions. There are continued efforts to engineer these proteins to modulate their size, valency, and affinity, since the optimum molecular properties vary depending on individual applications. This review will describe recent developments in streptavidin engineering to meet these requirements, including those that form novel oligomeric states, e.g., a monomer, have fewer functional biotin-binding sites, or bind biotin with reduced affinity. We also examine various reported applications of both natural or engineered SA constructs in cell biology, biochemistry, genetics, synthetic chemistry, cancer therapy, drug delivery, and nanotechnology to illustrate the breadth of modern science that is advanced by the endogenous and engineered SA-biotin interactions.

C-Type Natriuretic Peptide Analogue Therapy in Children with Achondroplasia.

BACKGROUND: Achondroplasia is a genetic disorder that inhibits endochondral ossification, resulting in disproportionate short stature and clinically significant medical complications. Vosoritide is a biologic analogue of C-type natriuretic peptide, a potent stimulator of endochondral ossification. METHODS: In a multinational, phase 2, dose-finding study and extension study, we evaluated the safety and side-effect profile of vosoritide in children (5 to 14 years of age) with achondroplasia. A total of 35 children were enrolled in four sequential cohorts to receive vosoritide at a once-daily subcutaneous dose of 2.5 µg per kilogram of body weight (8 patients in cohort 1), 7.5 µg per kilogram (8 patients in cohort 2), 15.0 µg per kilogram (10 patients in cohort 3), or 30.0 µg per kilogram (9 patients in cohort 4). After 6 months, the dose in cohort 1 was increased to 7.5 µg per kilogram and then to 15.0 µg per kilogram, and in cohort 2, the dose was increased to 15.0 µg per kilogram; the patients in cohorts 3 and 4 continued to receive their initial doses. At the time of data cutoff, the 24-month dose-finding study had been completed, and 30 patients had been enrolled in an ongoing long-term extension study; the median duration of follow-up across both studies was 42 months. RESULTS: During the treatment periods in the dose-finding and extension studies, adverse events occurred in 35 of 35 patients (100%), and serious adverse events occurred in 4 of 35 patients (11%). Therapy was discontinued in 6 patients (in 1 because of an adverse event). During the first 6 months of treatment, a dose-dependent increase in the annualized growth velocity was observed with vosoritide up to a dose of 15.0 µg per kilogram, and a sustained increase in the annualized growth velocity was observed at doses of 15.0 and 30.0 µg per kilogram for up to 42 months. CONCLUSIONS: In children with achondroplasia, once-daily subcutaneous administration of vosoritide was associated with a side-effect profile that appeared generally mild. Treatment resulted in a sustained increase in the annualized growth velocity for up to 42 months. (Funded by BioMarin Pharmaceutical; ClinicalTrials.gov numbers, NCT01603095, NCT02055157, and NCT02724228.).

Introduction of Novel Surgical Techniques: A Survey on Knowledge, Attitude, and Practice of Surgeons.

Purpose. To investigate the knowledge, attitude, and practice of surgeons toward introducing novel surgical techniques in Egypt, Palestine, and Vietnam. Summary Background Data. Despite the recent advances in modern surgical care and its role in advancing the quality and the length of lives, surgery in the developing world has stagnated or even regressed. Methods. A survey was undertaken among the surgeons in 9 hospitals belonging to the 3 countries. Questions were categorized into knowledge, attitude, and practice questions. Meta-analyses were performed to estimate the event rate and compare between knowledge and practice, senior and junior surgeons. Results. A total of 244 responses, with a response rate of 79.7%, were included in the analysis. Regarding knowledge and attitude, the results were satisfactory except that only 55.8% of surgeons appraised their level of education and 43.3% wanted to earn money from the novel procedure. There was a significant difference between knowledge and practice regarding getting informed consent from the patients (P = .024), discussing the novelty of the procedure (P < .001), discussing the alternative procedures (P < .001), discussing the surgeons' experience and level of skills (P < .001), discussing the risk of the new procedure (P < .001), and monitoring the outcomes after the new procedure (P < .001). Conclusions. Most surgeons have sufficient knowledge and are motivated regarding adopting novel surgical techniques in order to provide the best care for the patients. However, there was a gap between knowledge and practice. Training programs and evidence-based guidelines regarding the introduction of novel surgical techniques are needed to overcome these challenges.

A facile method for fabricating a three-dimensional aligned fibrous scaffold for vascular application.

Vascular graft replacement remains the optimal treatment option for many vascular diseases despite advances in endovascular surgery. In this study, we proposed the use of surface topographical cues to align and maintain the phenotype of vascular smooth muscle cells (vSMCs) which were reported as one of the vital limitations for successful graft replacement. An auxiliary electrospinning setup has been developed to collect circumferentially aligned fibres on a 3D tubular format; this micro-architecture was found to be similar to the tunica media layer of blood vessels. The presence of aligned fibres served as a signaling modality to induce cell alignment and the maintenance of the contractile phenotype. vSMCs cultured on the 3D aligned fibrous substrate were found to exhibit better cell proliferation ability and enhanced cell-shape directionality. The functional expression of the two representative intracellular contractile proteins (i.e. α-SMA and MHC) was found to exhibit definitive markers that are orderly organized as microfilament bundles. Collectively, the result suggests a possibility of adapting the 3D aligned tubular scaffold to enhance and regulate cell function along with the additional tunability of scaffold diameter and thicknesses for tailoring to the needs of individual patients or future ex vivo studies.

Inflammatory and oxidative stress biomarkers in alkaptonuria: data from the DevelopAKUre project.

OBJECTIVE: The aim of this work was to assess baseline serum levels of established biomarkers related to inflammation and oxidative stress in samples from alkaptonuric subjects enrolled in SONIA1 (n = 40) and SONIA2 (n = 138) clinical trials (DevelopAKUre project). METHODS: Baseline serum levels of Serum Amyloid A (SAA), IL-6, IL-1ß, TNFα, CRP, cathepsin D (CATD), IL-1ra, and MMP-3 were determined through commercial ELISA assays. Chitotriosidase activity was assessed through a fluorimetric method. Advanced Oxidation Protein Products (AOPP) were determined by spectrophotometry. Thiols, S-thiolated proteins and Protein Thiolation Index (PTI) were determined by spectrophotometry and HPLC. Patients' quality of life was assessed through validated questionnaires. RESULTS: We found that SAA serum levels were significantly increased compared to reference threshold in 57.5% and 86% of SONIA1 and SONIA2 samples, respectively. Similarly, chitotriosidase activity was above the reference threshold in half of SONIA2 samples, whereas CRP levels were increased only in a minority of samples. CATD, IL-1ß, IL-6, TNFα, MMP-3, AOPP, thiols, S-thiolated protein and PTI showed no statistically significant differences from control population. We provided evidence that alkaptonuric patients presenting with significantly higher SAA, chitotriosidase activity and PTI reported more often a decreased quality of life. This suggests that worsening of symptoms in alkaptonuria (AKU) is paralleled by increased inflammation and oxidative stress, which might play a role in disease progression. CONCLUSIONS: Monitoring of SAA may be suggested in AKU to evaluate inflammation. Though further evidence is needed, SAA, chitotriosidase activity and PTI might be proposed as disease activity markers in AKU.

Neural stem cell therapy for subacute and chronic ischemic stroke.

Neural stem cells (NSCs) play vital roles in brain homeostasis and exhibit a broad repertoire of potentially therapeutic actions following neurovascular injury. One such injury is stroke, a worldwide leading cause of death and disability. Clinically, extensive injury from ischemic stroke results from ischemia-reperfusion (IR), which is accompanied by inflammation, blood-brain barrier (BBB) damage, neural cell death, and extensive tissue loss. Tissue plasminogen activator (tPA) is still the only US Food and Drug Administration-approved clot-lysing agent. Whereas the thrombolytic role of tPA within the vasculature is beneficial, the effects of tPA (in a non-thrombolytic role) within the brain parenchyma have been reported as harmful. Thus, new therapies are needed to reduce the deleterious side effects of tPA and quickly facilitate vascular repair following stroke. The Stroke Treatment Academic Industry Roundtable (STAIR) recommends that stroke therapies "focus on drugs/devices/treatments with multiple mechanisms of action and that target multiple pathways". Thus, based on multifactorial ischemic cascades in various stroke stages, effective stroke therapies need to focus on targeting and ameliorating early IR injury as well as facilitating angiogenesis, neurogenesis, and neurorestorative mechanisms following stroke. This review will discuss the preclinical perspectives of NSC transplantation as a promising treatment for neurovascular injury and will emphasize both the subacute and chronic phase of ischemic stroke.

Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study.

BACKGROUND: Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS: Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. CONCLUSION: Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2.

Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.

Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia.

AIMS/HYPOTHESIS: Sirtuin 1 (Sirt1) has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear. METHODS: This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas. RESULTS: We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r) as well as a marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP) cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas. CONCLUSIONS/INTERPRETATION: This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted.