The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

AbstractThe inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca2+-release channel located on the endoplasmic reticulum (ER). IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca2+. Furthermore, IP3R2 is modulated by various protein kinases. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca2+ channel with exquisite properties for setting up intracellular Ca2+ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca2+ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs

DLBCL cells with acquired resistance to venetoclax are not sensitized to BIRD-2 but can be resensitized to venetoclax through Bcl-XL inhibition

Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax

Percutaneous endoscopic gastrostomy in children

PurposePercutaneous endoscopic gastrostomy (PEG) can improve nutritional status and reduce the amount of time needed to feed neurologically impaired children. We evaluated the characteristics, complications, and outcomes of neurologically impaired children treated with PEG.MethodsWe retrospectively reviewed the records of 32 neurologically impaired children who underwent PEG between March 2002 and August 2008 at our medical center. Forty-two PEG procedures comprising 32 PEG insertions and 10 PEG exchanges, were performed. The mean follow-up time was 12.2 (6.6) months.ResultsMean patient age was 9.4 (4.5) years. The main indications for PEG insertion were swallowing difficulty with GI bleeding due to nasogastric tube placement and/or the presence of gastroesophageal reflux disease (GERD). The overall rate of complications was 47%, with early complications evident in 25% of patients and late complications in 22%. The late complications included one gastro-colic fistula, two cases of aggravated GERD, and four instances of wound infection. Among the 15 patients with histological evidence of GERD before PEG, 13 (87%) had less severe GERD, experienced no new aspiration events, and showed increased body weight after PEG treatment.ConclusionPEG is a safe, effective, and relatively simple technique affording long-term enteral nutritional support in neurologically impaired children. Following PEG treatment, the body weight of most patients increased and the levels of vomiting, GI bleeding, and aspiration fell. We suggest that PEG with post-procedural observation be considered for enteral nutritional support of neurologically impaired children

Exploring and exploiting Bcl-2'S anti-apoptotic function in diffuse large B-cell lymphoma: BH4 domain versus the hydrophobic cleft

This project aspires 1. to demonstrate cancer cells dual addiction to anti-apoptotic Bcl-2 by exploiting the properties of BH3 mimetics and BH4-targeting tools 2. to screen and/or develop novel, in vivo applicable petidomimetics and TAT-IDPs peptide derivatives targeting Bcl-2 via its BH4-domain via a Celltox-TM Green Cytotoxicity Assay 3. to establish the effect of TAT-IDPs and derivatives on the survival and function of platelets from healthy volunteers and cancer patients.nrpages: 128status: publishe

Antagonizing Bcl-2's BH4 domain in cancer

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Recent advances in uncovering the mechanisms contributing to BIRD-2-induced cell death in B-cell cancer cells

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The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) type 2 (IP3R2) is an intracellular Ca²⁺-release channel located on the endoplasmic reticulum (ER). IP3R2 is characterized by a high sensitivity to both IP3 and ATP and is biphasically regulated by Ca²⁺. Furthermore, IP3R2 is modulated by various protein kinases. In addition to its regulation by protein kinase A, IP3R2 forms a complex with adenylate cyclase 6 and is directly regulated by cAMP. Finally, in the ER, IP3R2 is less mobile than the other IP3R isoforms, while its functional properties appear dominant in heterotetramers. These properties make the IP3R2 a Ca²⁺ channel with exquisite properties for setting up intracellular Ca²⁺ signals with unique characteristics. IP3R2 plays a crucial role in the function of secretory cell types (e.g. pancreatic acinar cells, hepatocytes, salivary gland, eccrine sweat gland). In cardiac myocytes, the role of IP3R2 appears more complex, because, together with IP3R1, it is needed for normal cardiogenesis, while its aberrant activity is implicated in cardiac hypertrophy and arrhythmias. Most importantly, its high sensitivity to IP3 makes IP3R2 a target for anti-apoptotic proteins (e.g. Bcl-2) in B-cell cancers. Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca²⁺ release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. These results were the first to unravel the physiological and pathophysiological role of IP3R2 and we anticipate that further progress will soon be made in understanding the function of IP3R2 in various tissues and organs.publisher: Elsevier articletitle: The type 2 inositol 1,4,5-trisphosphate receptor, emerging functions for an intriguing Ca2+-release channel journaltitle: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research articlelink: http://dx.doi.org/10.1016/j.bbamcr.2014.12.006 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe

Cystoscope-guided trans-anal Fistula-tract Laser Closure (FiLaC) of late onset recurrent recto-urethral fistula post anorectal malformation repair: A case report

Introduction: Management of persistent and recurrent rectourethral fistula after primary treatment of anorectal malformations (ARM) is challenging. Various surgical techniques have been proposed and until today there is no consensus on the optimal approach. Case presentation: We describe a case of late onset recurrent rectourethral fistula after neonatal ARM repair, treated with a minimally invasive cystoscope-guided trans-anal Fistula-tract Laser Closure (FiLaC). A male patient suffering from ARM, type recto-bulbar fistula, was treated with an anorectoplasty during the neonatal period. Post-operatively, no reoperations were needed and long term follow-up demonstrated good functional outcome. At the age of 19 years, the patient presented with complaints of anal urinary leakage during micturition. Voiding-cysto-urethrography and perineal Nuclear Magnetic Resonance (NMR) demonstrated a fistula tract between the bulbar urethra and the distal rectum. Given the lack of associated urinary tract infections or fecaluria and the absence of fecal or urinary incontinence in between micturition, we decided to perform a trans-luminal, non-surgical approach. By analogy with the minimally invasive laser treatment of peri-anal fistula in adults, we performed a trans-anal cystoscope-guided FiLaC. We observed a fast post-operative recovery with an excellent one-year follow-up, illustrated by the elimination of symptoms, absence of fistula opening on rectoscopy and disappearance of the fistula-tract continuity on voiding-cysto-urethrography. Conclusion: This case exemplifies the potential benefits of using minimally invasive FiLaC treatment for the management of recurrent and persistent recto-urethral fistula following primary treatment of ARM. Long term follow-up is awaited to confirm the value of FiLaC in this treatment setting