PARP14 is a writer, reader, and eraser of mono-ADP-ribosylation.

PARP14/BAL2 is a large multidomain enzyme involved in signaling pathways with relevance to cancer, inflammation, and infection. Inhibition of its mono-ADP-ribosylating PARP homology domain and its three ADP-ribosyl binding macro domains has been regarded as a potential means of therapeutic intervention. Macrodomains-2 and -3 are known to stably bind to ADP-ribosylated target proteins, but the function of macrodomain-1 has remained somewhat elusive.

14-3-3 Activated Bacterial Exotoxins AexT and ExoT Share Actin and the SH2 Domains of CRK Proteins as Targets for ADP-Ribosylation.

Bacterial exotoxins with ADP-ribosyltransferase activity can be divided into distinct clades based on their domain organization. Exotoxins from several clades are known to modify actin at Arg177; but of the 14-3-3 dependent exotoxins only exoenzyme T (AexT) has been reported to ADP-ribosylate actin. Given the extensive similarity among the 14-3-3 dependent exotoxins, we initiated a structural and biochemical comparison of these proteins.

New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action.

Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series.

Simultaneous early surgical repair of post-cholecystectomy major bile duct injury and complex abdominal evisceration: A case report.

Background: Major bile duct injuries (BDIs) are hazardous complications during 0.4%-0.6% of laparoscopic cholecystectomies.

Biological Evaluation of New Thienopyridinium and Thienopyrimidinium Derivatives as Human Choline Kinase Inhibitors.

Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values.

Anticancer Activity of the Choline Kinase Inhibitor PL48 Is Due to Selective Disruption of Choline Metabolism and Transport Systems in Cancer Cell Lines.

A large number of different types of cancer have been shown to be associated with an abnormal metabolism of phosphatidylcholine (PC), the main component of eukaryotic cell membranes. Indeed, the overexpression of choline kinase α1 (ChoKα1), the enzyme that catalyses the bioconversion of choline to phosphocholine (PCho), has been found to associate with cell proliferation, oncogenic transformation and carcinogenesis. Hence, ChoKα1 has been described as a possible cancer therapeutic target.

New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity.

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite.

In Silico Engineering of Enzyme Access Tunnels.

Enzyme engineering is a tailoring process that allows the modification of naturally occurring enzymes to provide them with improved catalytic efficiency, stability, or specificity. By introducing partial modifications to their sequence and to their structural features, enzyme engineering can transform natural enzymes into more efficient, specific and resistant biocatalysts and render them suitable for virtually countless industrial processes. Current enzyme engineering methods mostly target the active site of the enzyme, where the catalytic reaction takes place.

Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme.

Rational backbone redesign of a fructosyl peptide oxidase to widen its active site access tunnel.

Fructosyl peptide oxidases (FPOXs) are enzymes currently used in enzymatic assays to measure the concentration of glycated hemoglobin and albumin in blood samples, which serve as biomarkers of diabetes. However, since FPOX are unable to work directly on glycated proteins, current enzymatic assays are based on a preliminary proteolytic digestion of the target proteins. Herein, to improve the speed and costs of the enzymatic assays for diabetes testing, we applied a rational design approach to engineer a novel enzyme with a wider access tunnel to the catalytic site, using a combination of Rosetta design and molecular dynamics simulations.

Insight into GEBR-32a: Chiral Resolution, Absolute Configuration and Enantiopreference in PDE4D Inhibition.

Alzheimer's disease is the most common type of dementia, affecting millions of people worldwide. One of its main consequences is memory loss, which is related to downstream effectors of cyclic adenosine monophosphate (cAMP). A well-established strategy to avoid cAMP degradation is the inhibition of phosphodiesterase (PDE).

Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell-Cell Adhesion.

Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators.

[The first scientific experimentation on a B-BS protocol applied to an Italian factory].

In this work, is presented afield study on application of the Behavior Based Safety (B-BS) to an Italian industry, a glassware in the north Italy. This experimental study was directed to the analysis of the actual effectiveness of the B-BS, creating a baseline of workers' safety behavior, followed, after a few months from process's implementation, by a Comparative line (Evaluation Line). Data analysis was conducted through the application of the C test by Young, using the modifications proposed by Tryon, to verify the consistency of the results obtained.

[Locally recurrent rectal cancer. Our experience].

The aim of this study was to describe the personal experience in the treatment of 31 patients (19 males, 12 females) with local recurrence following surgery for rectal adenocarcinoma. The exeresis of recurrence was possible in 17 patients (6 Miles, 9 Hartmann, 1 re-resection, 1 transanal resection); of these, only 6 patients reported an improvement of the quality of life. Patients surgically treated and patients with recurrence inoperable and submitted to palliative treatment (colostomy, pain control, radio- and/or chemotherapy) showed similar survival rates.

[Gastrointestinal stromal tumors: five case reports and review of the literature].

Being a rare entity, GISTs represents the most common subset of mesenchymal tumours that arise from the digestive tract. Their immunohistochemical and histopathologic features distinguish them from other gastrointestinal mesenchymal neoplasms. These tumours have been the matter of considerable debate in the literature regarding their histogenesis, criteria for diagnosis, prognostic features and treatment.

[Gastric carcinoid: case report and review of the literature].

Carcinoids are rare tumour of neuroendocrin origin, characterized by argyrophylic silver stain reaction, positive immunohistochemical reaction with neuron-specific markers, a typical growth pattern; they can express different peptides and biogenic amines. Gastric carcinoid tumours have been classified on the basis of susceptibility to gastric trophic stimulus and characteristics mucosal surrounding into 3 different types. This classification is important with respect to therapeutic strategy (type adapted treatment), but the option of endoscopic or surgical treatment is influenced by the impossibility to distinguish clearly the benignity or malignity of these lesions.

Peritoneal mesothelioma in a case of inguinal hernia. A review of the literature.

The peritoneal mesothelioma (PM) is a rare, benign or malignant, primary tumour, arising from the peritoneal membrane. The most frequent histological form is the malignant one with an incidence of 2-2.6 new cases per million per year.

[Abdominal Wells rectopexy with patch micromesh PTFE (Goretex)].

The aim of this study is to discuss the surgical treatment of rectal prolapse. The surgical therapy offers many different options. Beginning from 1970 the anterior rectopexy has been considered a technique with good results, also in the elderly patient, when the general conditions allow it.

[The megacolon in myotonic dystrophy: case report and review of the literature].

Myotonic dystrophy (MD) is an autosomal dominant inherit disease, slowly progressive, involving multiple organ systems. Disorders at any level of the gastrointestinal tract are relatively common and manifest as disturbances in motility, such as impaired esophageal transport, delayed gastric emptying, and megacolon. A 51 years-old man was admitted to our surgical department with obstructive symptoms.

[Compatibility, indications, and limits of nerve sparing technique in lateral pelvic lymphadenectomy for advanced rectal carcinoma].

The aim of radical surgical treatment of rectal cancer is to control the spread and prevent recurrence of the disease. In an attempt to improve the results of treatment of locally advanced rectal cancer, we advocate an extended surgical approach consisting of total mesorectal excision, lateral pelvic lymphadenectomy and the nerve sparing technique with resection of autonomic nerves whenever these fibers are affected by locally advanced tumor. Nine cases (9.

Evaluation of anal function after surgery for rectal cancer.

Background And Objectives: Sphincter-saving surgical procedures for rectal cancer have been legitimized if executed respecting the criteria of oncological radicalness. Our objective was to evaluate anal sphincteric continence after rectal cancer surgery.

Methods: A detailed questionnaire regarding continence was administered to 3 groups of patients.

[Synchronous and metachronous colorectal cancers: a case series contribution].

The Authors, on the basis of their experience with neoplastic colorectal pathology and after a review of the Literature, report a reappraisal of the problems related to colorectal multiple carcinomas. They emphasize the importance of routine preoperative pancolonoscopy for the identification of possible synchronous tumors (both benign and malignant) and periodic endoscopic follow-up (ideally a life-long one) for the detection and removal of all adenomatous polyps as well as early stage metachronous carcinomas, especially for patients with HNPCC. Besides, they stress the importance of sensibilization of the population about the heritability of colorectal carcinomas.

[Traditional cholecystectomy in a patient with situs viscerum inversus partialis].

The authors discuss the etiology of situs viscerum inversus partialis (SVIP), the associated anomalies and the malformations and the relative clinical problems, reviewing the international literature. The present a case of a 51 years old female with a diagnosis of umbilical hernia and cystocele. During hospitalization the patient complained a typical acute cholecystitis pain.

Radiotherapy versus radiotherapy enhanced by cisplatin in stage III non-small cell lung cancer.

Between January 1987 and June 1991, 173 patients with inoperable non-small cell lung cancer, Stage III, were entered into a randomized trial comparing radiotherapy only (RT) (45 Gy/15 fractions/3 weeks) (arm A) versus RT and a daily low dose of cDDP (6 mg/m2) (arm B). An overall response rate of 58.9% was observed in arm A and 50.