Cyanoacrylate mesh fixation for laparoscopic inguinal hernia repair: a prospective, multicenter, single-arm study.

BACKGROUND: Inguinal hernia repair is among the most frequently performed surgical procedures. Alternatives to penetrating mesh fixation, such as surgical glue, are being investigated for their potential benefit in reducing chronic pain. The aim of this study was to assess the efficacy of the n-hexyl cyanoacrylate glue Ifabond™ for mesh fixation in laparoscopic inguinal hernia repair. METHODS: This prospective, multicenter, single-arm study collected data from laparoscopic inguinal hernia repairs using Ifabond™ (Peters Surgical, Boulogne-Billancourt Cedex, France) and a standard [Promesh® SURG ST (Peters Surgical)/Biomesh® P1 (Cousin Biotech, Wervicq-Sud, France)] or lightweight [Promesh® SURG LI (Peters Surgical)/Premium® Implant (Cousin Biotech)] polypropylene mesh. The primary endpoint was postoperative pain [100-scale Visual Analog Scale (VAS)]. Secondary endpoints were complications, hernia recurrences, and quality of life (QoL) (EQ-5D-3L health index and EQ-VAS). Patients were followed up at 5 weeks and 12 months after surgery. RESULTS: Six-hundred and thirteen patients underwent laparoscopic inguinal hernia repair. Postoperative pain decreased at 5-week (3.97 ± 10.04; p < 0.0001) and 12-month (3.83 ± 11.26; p < 0.0001) follow-up compared with before surgery (26.96 ± 19.42). One hundred and fifteen patients (13.74%) experienced chronic pain in the groin at 12-month follow-up, of whom 14 (2.67%) required analgesics. There were 6 patients with major morbidities and one patient died of an unrelated cause. Two hernia recurrences occurred within 12-month follow-up. Patients' QoL increased from an EQ-5D-3L index score of 0.82 ± 0.19 preoperatively to 0.90 ± 0.15 at 5 weeks (p < 0.0001) and 0.92 ± 0.15 at 12 months after surgery (p < 0.0001). The EQ-VAS general health scoring increased from 79.03 ± 12.69 preoperatively to 84.31 ± 9.97 at 5-week (p < 0.0001) and 84.16 ± 14.48 at 12-month follow-up (p < 0.0001). CONCLUSIONS: Ifabond™ (Peters Surgical) is a safe, reliable, and feasible fixation method for laparoscopic inguinal hernia repair with a very high surgeon satisfaction score, improved patients' QoL, and comparable risk of developing chronic pain and postoperative complications as described in the literature.

De Novo Mutations Affecting the Catalytic Cα Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders.

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

Durability and efficacy of the ELVeS® Radial® 2ring slim fiber for multiple ablations.

OBJECTIVES: To prove that the ELVeS® Radial® 2ring slim fiber (Biolitec AG, Wien, Austria) is safe and effective, with a reliable fiber durability. METHODS: This prospective, non-randomized, registry recruited patients with venous incompetence of the great saphenous vein, with or without concomitant incompetence of the small, anterior accessory and posterior accessory saphenous veins. Anatomic success, clinical success and pain were assessed. RESULTS: 150 patients (410 veins) underwent endovenous laser ablation (EVLA). Mean number of veins treated was 2.7 (1-7) with a mean total length of 80.7 cm. 98.3% occlusions were observed after 12 months. Clinical improvement was significant with reduced venous clinical severity scores at 1 month (1.7 ±1.9; p < .0001) and 12 months (0.7 ±1.3; p < .0001) versus pre-operation (4.4 ± 2.2). Mean pain level after 1-week was 5.8/100. No major surgery- or device-related complications occurred. CONCLUSIONS: 1470-nm EVLA with the 2ring slim fiber is a highly effective treatment option well tolerated by patients. Despite intensive use, fiber integrity was preserved. CLINICAL REGISTRATION: The study protocol was registered in clinicaltrials.gov (NCT03810677).

Laparoscopic Adjustable Gastric Banding with the Adhesix® Bioring® for Weight Regain or Insufficient Weight Loss After a Roux-en-Y Gastric Bypass: Midterm Data from the Pronto Registry.

PURPOSE: Although Roux-en-Y gastric bypass (RYGB) is one of the most common bariatric procedures, insufficient weight loss is described to be as high as 20-35%. To treat weight regain/inadequate weight loss, laparoscopic adjustable gastric banding (LAGB) could be a feasible revisional strategy. MATERIALS AND METHODS: We report on a prospective study which included 35 patients who presented inadequate weight loss or significant weight regain after primary RYGB (percentage excess weight loss [%EWL] at revision < 50%). All patients underwent revisional LAGB with the placement of an Adhesix® Bioring® adjustable gastric band (Cousin Biotech, Wervicq-Sud, France). Patients' weight loss, complications, frequency of revisions and quality of life were evaluated. RESULTS: Follow-up data at 24 months are available for 80% of the included patients. The mean BMI before RYGB was 43.6 ± 5.4 kg/m2 and before revisional LAGB was 38.8 ± 4.3kg/m2. The %EWL before revisional surgery was 23.3 ± 24.8%. The average time between both procedures was 6.7 (mean) ± 3.6 (SD) years. Twenty-four months after revisional LAGB, the average BMI calculated from the weight at RYGB dropped to 32.0 ± 4.5 kg/m2, with an additional %EWL of 49.9 ± 30.3% resulting in a total %EWL of 60.7 ± 28%. The reoperation rate for complications related to LAGB was 21.2%. No band erosions occurred, but two bands needed to be removed during the study. CONCLUSION: Revisional LAGB may be considered a valid salvage procedure in patients with weight regain or inadequate weight loss after RYGB, though band- and port-related complications remain a notable concern.

Endovascular treatment of atherosclerotic lesions in the superficial femoral artery and proximal popliteal artery using the sinus-SuperFlex-635 stent: twelve-month results from the HERO Registry.

BACKGROUND: The aim of this study was to evaluate the safety and performance of the sinus-SuperFlex-635 self-expandable nitinol stent (Optimed GmbH) for the treatment of steno-occlusive lesions in the superficial femoral artery (SFA) and proximal popliteal artery (PPA). METHODS: The prospective, multicenter, observational HERO study recruited 117 eligible patients (83 men; mean age 69.4±9.7y) from 7 centers in Belgium. RESULTS: A total of 129 stents were successfully deployed in 121 lesions in 117 patients (100%). The patients presented with symptomatic ≥50% stenosis or chronic total occlusion (CTO) (30.6%). Mean lesion length was 71.4±56.3 mm. Moderate to severe calcification was present in 82.6% of the lesions. Acute lesion success (<30% residual stenosis) was achieved in 96.0%. There were no in-hospital serious adverse events. Duplex ultrasound-driven primary patency at 12 months was recorded in 84 of 107 (78.5%) lesions. The overall target lesion revascularization (TLR) rate was 8.4% at 12 months; the target extremity revascularization (TER) rate was 4.7%. Clinical assessment at 12 months demonstrated improvement by at least 1 Rutherford class, without the need for TLR (i.e. primary sustained clinical improvement) in 83.9% of patients and with the need for TLR in 90.6% of patients (i.e. secondary sustained clinical improvement). CONCLUSIONS: Based on the high primary patency, low stent fracture rate and significant clinical improvement, combined with refined stent design and long stent availability, the sinus-SuperFlex-635 self-expandable nitinol stent proves its value in the treatment of complex femoropopliteal lesions.

PP2A Inactivation Mediated by PPP2R4 Haploinsufficiency Promotes Cancer Development.

Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here, we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4 Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared with wild-type mice. In addition, chemical-induced skin carcinogenesis was accelerated in PTPA+/gt compared with wild-type mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer. Cancer Res; 77(24); 6825-37. ©2017 AACR.

Fructose-1,6-bisphosphate couples glycolytic flux to activation of Ras.

Yeast and cancer cells share the unusual characteristic of favoring fermentation of sugar over respiration. We now reveal an evolutionary conserved mechanism linking fermentation to activation of Ras, a major regulator of cell proliferation in yeast and mammalian cells, and prime proto-oncogene product. A yeast mutant (tps1∆) with overactive influx of glucose into glycolysis and hyperaccumulation of Fru1,6bisP, shows hyperactivation of Ras, which causes its glucose growth defect by triggering apoptosis. Fru1,6bisP is a potent activator of Ras in permeabilized yeast cells, likely acting through Cdc25. As in yeast, glucose triggers activation of Ras and its downstream targets MEK and ERK in mammalian cells. Biolayer interferometry measurements show that physiological concentrations of Fru1,6bisP stimulate dissociation of the pure Sos1/H-Ras complex. Thermal shift assay confirms direct binding to Sos1, the mammalian ortholog of Cdc25. Our results suggest that the Warburg effect creates a vicious cycle through Fru1,6bisP activation of Ras, by which enhanced fermentation stimulates oncogenic potency.Yeast and cancer cells both favor sugar fermentation in aerobic conditions. Here the authors describe a conserved mechanism from yeast to mammals where the glycolysis intermediate fructose-1,6-bisphosphate binds Cdc25/Sos1 and couples increased glycolytic flux to increased Ras proto-oncoprotein activity.

Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth.

Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3ß, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3ß phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. ©2016 AACR.

B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability.

Here we report inherited dysregulation of protein phosphatase activity as a cause of intellectual disability (ID). De novo missense mutations in 2 subunits of serine/threonine (Ser/Thr) protein phosphatase 2A (PP2A) were identified in 16 individuals with mild to severe ID, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures. PP2A comprises catalytic (C), scaffolding (A), and regulatory (B) subunits that determine subcellular anchoring, substrate specificity, and physiological function. Ten patients had mutations within a highly conserved acidic loop of the PPP2R5D-encoded B56δ regulatory subunit, with the same E198K mutation present in 6 individuals. Five patients had mutations in the PPP2R1A-encoded scaffolding Aα subunit, with the same R182W mutation in 3 individuals. Some Aα cases presented with large ventricles, causing macrocephaly and hydrocephalus suspicion, and all cases exhibited partial or complete corpus callosum agenesis. Functional evaluation revealed that mutant A and B subunits were stable and uncoupled from phosphatase activity. Mutant B56δ was A and C binding-deficient, while mutant Aα subunits bound B56δ well but were unable to bind C or bound a catalytically impaired C, suggesting a dominant-negative effect where mutant subunits hinder dephosphorylation of B56δ-anchored substrates. Moreover, mutant subunit overexpression resulted in hyperphosphorylation of GSK3ß, a B56δ-regulated substrate. This effect was in line with clinical observations, supporting a correlation between the ID degree and biochemical disturbance.

The Basic Biology of PP2A in Hematologic Cells and Malignancies.

Reversible protein phosphorylation plays a crucial role in regulating cell signaling. In normal cells, phosphoregulation is tightly controlled by a network of protein kinases counterbalanced by several protein phosphatases. Deregulation of this delicate balance is widely recognized as a central mechanism by which cells escape external and internal self-limiting signals, eventually resulting in malignant transformation. A large fraction of hematologic malignancies is characterized by constitutive or unrestrained activation of oncogenic kinases. This is in part achieved by activating mutations, chromosomal rearrangements, or constitutive activation of upstream kinase regulators, in part by inactivation of their anti-oncogenic phosphatase counterparts. Protein phosphatase 2A (PP2A) represents a large family of cellular serine/threonine phosphatases with suspected tumor suppressive functions. In this review, we highlight our current knowledge about the complex structure and biology of these phosphatases in hematologic cells, thereby providing the rationale behind their diverse signaling functions. Eventually, this basic knowledge is a key to truly understand the tumor suppressive role of PP2A in leukemogenesis and to allow further rational development of therapeutic strategies targeting PP2A.

Structure, regulation, and pharmacological modulation of PP2A phosphatases.

Protein phosphatases of the type 2A family (PP2A) represent a major fraction of cellular Ser/Thr phosphatase activity in any given human tissue. In this review, we describe how the holoenzymic nature of PP2A and the existence of several distinct PP2A composing subunits allow for the generation of multiple structurally and functionally different PP2A complexes, explaining why PP2A is involved in the regulation of so many diverse cell biological and physiological processes. Moreover, in human disease, most notably in several cancers and Alzheimer's Disease, PP2A expression and/or activity have been found significantly decreased, underscoring its important functions as a major tumor suppressor and tau phosphatase. Hence, several recent preclinical studies have demonstrated that pharmacological restoration of PP2A activity, as well as pharmacological PP2A inhibition, under certain conditions, may be of significant future therapeutic value.

The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity.

Protein phosphatase type 2A (PP2A) enzymes constitute a large family of Ser/Thr phosphatases with multiple functions in cellular signaling and physiology. The composition of heterotrimeric PP2A holoenzymes, resulting from the combinatorial assembly of a catalytic C subunit, a structural A subunit, and regulatory B-type subunit, provides the essential determinants for substrate specificity, subcellular targeting, and fine-tuning of phosphatase activity, largely explaining why PP2A is functionally involved in so many diverse physiological processes, sometimes in seemingly opposing ways. In this review, we highlight how PP2A holoenzyme biogenesis and enzymatic activity are controlled by a sophisticatedly coordinated network of five PP2A modulators, consisting of α4, phosphatase 2A phosphatase activator (PTPA), leucine carboxyl methyl transferase 1 (LCMT1), PP2A methyl esterase 1 (PME-1) and, potentially, target of rapamycin signaling pathway regulator-like 1 (TIPRL1), which serve to prevent promiscuous phosphatase activity until the holoenzyme is completely assembled. Likewise, these modulators may come into play when PP2A holoenzymes are disassembled following particular cellular stresses. Malfunctioning of these cellular control mechanisms contributes to human disease. The potential therapeutic benefits or pitfalls of interfering with these regulatory mechanisms will be briefly discussed.