Prognostic value of staging laparotomy in supradiaphragmatic clinical stage I and II Hodgkin\u27s disease

In the period 1974-1989, 219 patients with supradiaphragmatic clinical stage I and II Hodgkin\u27s disease were treated at the Institute of Oncology in Ljubljanaof these 95 (43%) patients underwent staging laparotomy. Of laparotomized patients, those with pathological stage III-IV, and of non-laparotomized, those with unfavorable prognostic factors (B-symptoms, bulky mediastinum) received chemotherapy: the remaining patients were treated by irradiation. No statistically significant difference in the survival and disease-free survival between laparotomized and nonlaparotomized patients could be found

Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering

Acetyl-4'-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency

CITATION: Di Meo, I., et al. 2017. Acetyl-4′-phosphopantetheine is stable in serum and prevents phenotypes induced by pantothenate kinase deficiency. Scientific Reports, 7:11260, doi:10.1038/s41598-017-11564-8.The original publication is available at https://www.nature.comCoenzyme A is an essential metabolite known for its central role in over one hundred cellular metabolic reactions. In cells, Coenzyme A is synthesized de novo in five enzymatic steps with vitamin B5 as the starting metabolite, phosphorylated by pantothenate kinase. Mutations in the pantothenate kinase 2 gene cause a severe form of neurodegeneration for which no treatment is available. One therapeutic strategy is to generate Coenzyme A precursors downstream of the defective step in the pathway. Here we describe the synthesis, characteristics and in vivo rescue potential of the acetyl-Coenzyme A precursor S-acetyl-4′-phosphopantetheine as a possible treatment for neurodegeneration associated with pantothenate kinase deficiency.https://www.nature.com/articles/s41598-017-11564-8Publisher's versio

Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds

The invention relates to (S)-acyl-4'-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment of neurodegenerative diseases, such as PKAN

Stable pantetheine derivatives for the treatment of pantothenate kinase associated neurodegeneration (PKAN) and methods for the synthesis of such compounds

The invention relates to (S)-acyl-4'-phosphopantetheine derivatives, methods of their synthesis, and related medical uses of such compounds. Preferred medical uses relate to the treatment of neurodegenerative diseases, such as PKAN

Identification of the chelocardin biosynthetic gene cluster from Amycolatopsis sulphurea : a platform for producing novel tetracycline antibiotics

Tetracyclines (TCs) are medically important antibiotics from the polyketide family of natural products. Chelocardin (CHD), produced by Amycolatopsis sulphurea, is a broad-spectrum tetracyclic antibiotic with potent bacteriolytic activity against a number of Gram-positive and Gram-negative multi-resistant pathogens. CHD has an unknown mode of action that is different from TCs. It has some structural features that define it as 'atypical' and, notably, is active against tetracycline-resistant pathogens. Identification and characterization of the chelocardin biosynthetic gene cluster from A. sulphurea revealed 18 putative open reading frames including a type II polyketide synthase. Compared to typical TCs, the chd cluster contains a number of features that relate to its classification as 'atypical': an additional gene for a putative two-component cyclase/aromatase that may be responsible for the different aromatization pattern, a gene for a putative aminotransferase for C-4 with the opposite stereochemistry to TCs and a gene for a putative C-9 methylase that is a unique feature of this biosynthetic cluster within the TCs. Collectively, these enzymes deliver a molecule with different aromatization of ring C that results in an unusual planar structure of the TC backbone. This is a likely contributor to its different mode of action. In addition CHD biosynthesis is primed with acetate, unlike the TCs, which are primed with malonamate, and offers a biosynthetic engineering platform that represents a unique opportunity for efficient generation of novel tetracyclic backbones using combinatorial biosynthesis