High-Dose Lanreotide in the Treatment of Poorly Differentiated Pancreatic Neuroendocrine Carcinoma: A Case Report

Pancreatic neuroendocrine tumors (NETs), including poorly differentiated carcinomas (NECs), are rarely encountered. The majority of these tumors do not secrete excess hormones, but functioning NETs produce large amounts of vasoactive peptides and may cause carcinoid syndrome. Synthetic somatostatin analogs (SSAs) have been widely used in NETs for control of hormonal syndromes. Here, we present a case of poorly differentiated, grade 3 pancreatic NEC associated with carcinoid syndrome, for which adequate symptom control was achieved for 2 years and 4 months using the long-acting SSA lanreotide Autogel®. In February 2009, a 55-year-old woman presented with episodes of flushing, diarrhea and epigastric pain. Imaging techniques revealed the presence of a metabolically active mass expressing somatostatin receptors in the hilar area of the liver. Histopathological examination confirmed the malignant nature of the mass, which was identified as a poorly differentiated grade 3 pancreatic NEC (TNM staging: T4NxM0). Therapeutic options were limited for the patient because of the extent of the primary mass involving the celiac axis, severe gastrointestinal toxicity experienced as a side effect of chemotherapy with cisplatin-etoposide and, later in the course of the disease, extensive liver metastases and carcinoid heart syndrome. Along with a palliative debulking surgery and right portal vein embolization, biotherapy with a high dose of lanreotide Autogel (120 mg/14 days) contributed to alleviation of symptoms caused by hormone overproduction, even after the development of liver metastases. These results suggest that patients with poorly differentiated NECs who exhibit signs of carcinoid syndrome can benefit from treatment with somatostatin analogs

A high-throughput target-based screening approach for the identification and assessment of Mycobacterium tuberculosis mycothione reductase inhibitors

Abstract: The World Health Organization\u2019s goal to combat tuberculosis (TB) is hindered by the emergence of anti-microbial resistance, therefore necessitating the exploration of new drug targets. Multidrug regimens are indispensable in TB therapy as they provide synergetic bactericidal effects, shorten treatment duration, and reduce the risk of resistance development. The research within our European RespiriTB consortium explores Mycobacterium tuberculosis energy metabolism to identify new drug candidates that synergize with bedaquiline, with the aim of discovering more efficient combination drug regimens. In this study, we describe the development and validation of a luminescence-coupled, target-based assay for the identification of novel compounds inhibiting Mycobacterium tuberculosis mycothione reductase (Mtr Mtb ), an enzyme with a role in the protection against oxidative stress. Recombinant Mtr Mtb was employed for the development of a highly sensitive, robust high-throughput screening (HTS) assay by coupling enzyme activity to a bioluminescent readout. Its application in a semi-automated setting resulted in the screening of a diverse library of ~130,000 compounds, from which 19 hits were retained after an assessment of their potency, selectivity, and specificity. The selected hits formed two clusters and four fragment molecules, which were further evaluated in whole-cell and intracellular infection assays. The established HTS discovery pipeline offers an opportunity to deliver novel Mtr Mtb inhibitors and lays the foundation for future efforts in developing robust biochemical assays for the identification and triaging of inhibitors from high-throughput library screens

The Adjustment of International Institutions to Global Power Shifts: A Framework for Analysis

As powers such as China and India rise, and powers such as the US or the UK decline, international institutions such as the United Nations Security Council, the World Trade Organization and the International Monetary Fund come under pressure to adapt to new power realities. In the wake of global power shifts, both emerging and established powers may challenge the institutional status quo. Contrary to what most power transition and power shift theories assume, challengers do not always draw on power bargaining to pursue institutional adjustment. In some issue areas, they do, but in others they employ alternative strategies including strategic cooptation, rhetorical coercion and principled persuasion. In order to contribute to a better understanding of institutional adjustments to global power shifts, the introduction to this special issue theorizes these various strategies. First, we conceptualize power bargaining, strategic cooptation, rhetorical coercion and principled persuasion as distinct strategies for institutional adjustment. Second, we elaborate on the conditions under which challengers choose particular strategies. Third, we specify the conditions under which challengers are able to achieve institutional adaptation through a particular strategy. Finally, we discuss broader implications for the future of the international order and the management of global power shifts

HL-LHC Computing Review: Common Tools and Community Software

International audienceCommon and community software packages, such as ROOT, Geant4 and event generators have been a key part of the LHC's success so far and continued development and optimisation will be critical in the future. The challenges are driven by an ambitious physics programme, notably the LHC accelerator upgrade to high-luminosity, HL-LHC, and the corresponding detector upgrades of ATLAS and CMS. In this document we address the issues for software that is used in multiple experiments (usually even more widely than ATLAS and CMS) and maintained by teams of developers who are either not linked to a particular experiment or who contribute to common software within the context of their experiment activity. We also give space to general considerations for future software and projects that tackle upcoming challenges, no matter who writes it, which is an area where community convergence on best practice is extremely useful