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Galapagos Research Centre d. o. o., is a private research organization, active in the field of chemistry, biology, biomedicine, veterinary science and pharmacy. This article is devoted to the Internationa Year of Chemistry; this review includes the areas of study undertaken by the chemists in the research centre. Also presented are the current techniques and technologies applied in the implementation of research and development projects.The main activities of chemists are directed to the synthesis of new organic compounds resulting in potentially new medicines, their subsequent identification, structural characterization, purification process, magnification (scale up), the applied analysis of biological materials (DMPK – Drug Metabolism and Pharmacokinetics) and the pharmaceutical development of preclinical candidates.Project teams at Galapagos incorporate researchers of all relevant professions to explore the potential of new medicines. These include chemists (chemical engineers and technologists), biologists, medical doctors, veterinarians and pharmacists. The ultimate goal of each of the projects is to establish an effective, well-defined preclinical candidate, which is further developed in other parts of the organization (Belgium, France, Great Britain), otherwise in the development laboratories of large partner organizations.This research article includes research and technology supported by concrete examples, and the results published in previous articles.

Copyright of Kemija u Industriji is the property of Croatian Society of Chemical Engineers and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Agronomy Journal / Agronomski Glasnik (0002-1954) is the property of Croatian Society of Agronomists and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Although parenteral nutrition (PN) significantly improves mortality rates in pediatric short bowel syndrome (SBS), long-term PN has many possible complications and impacts quality of life. Bowel lengthening procedures (BLPs) increase the contact surface of food and the intestinal mucosa and enable the better absorption of nutrients and liquids, possibly leading to a PN decrease., Methods: We retrospectively reviewed the data of patients with short bowel syndrome who underwent BLPs in the period from January 2016 to January 2022. Overall, eight patients, four male, five born prematurely, underwent BLPs., Results: There was a significant decrease in the percentage of total caloric intake provided via PN and PN volume after the BLPs. The more evident results were seen 6 months after the procedure and at the last follow-up, which was, on average, 31 months after the procedure. Two patients were weaned off PN after their BLPs. Patients remained well nourished during the follow-up., Conclusions: The BLP led to a significant decrease in PN needs and an increase in the food intake; however, significant changes happened more than 6 months after the procedure.

The process of identifying the protein targets and off-targets of a biologically active compound is of great importance in modern drug discovery. Various chemical proteomics approaches have been established for this purpose. To compare the different approaches, and to understand which method would provide the best results, we have chosen the EGFR inhibitor lapatinib as an example molecule. Lapatinib derivatives were designed using linkers with motifs, including amino (amidation), alkyne (click chemistry) and the diazirine group (photo-affinity). These modified lapatinib analogues were validated for their ability to inhibit EGFR activity in vitro and were shown to pull down purified recombinant EGFR protein. In all of the approaches evaluated here, we identified EGFR as the main protein target from the lysate of immortalised cell line expressing EGFR, thus validating its potential use to identify unknown protein targets. Taken together, the results reported here give insight into the cellular activities of lapatinib.

Polyelectrolyte multilayers are coatings formed by the alternate deposition of polycations and polyanions on a charged surface. In this study we examined how the type of substrate affects a multilayer prepared from poly(allylamine hydrochloride) and poly(acrylic acid). Silicon and titanium wafers were used as substrates. Their properties were systematically studied using ellipsometry, tensiometry, atomic force microscopy and streaming potential measurements. Multilayers were built up at pH = 7 with tetramethylammonium chloride as the background salt. The growth of films was monitored by ellipsometry, while the morphology and surface roughness were determined by atomic force microscopy. It was found that the thickness of multilayers containing 10 layers on silicon is 10 nm, whereas the thickness of the same film on titanium is three times higher. It was shown that multilayers formed on silicon display a grain-like structure, which was not the case for a film formed on titanium. Such morphological properties are also reflected in the surface roughness. Finally, it was shown that, in addition to the electrostatic interactions, the hydrophobicity of the substrate also plays an important role in the polyelectrolyte multilayer formation process and influences its thickness and properties.

Aim: Blunt abdominal trauma is the major cause of abdominal injury in children. No clear guidelines exist for the initial management of blunt pancreatic trauma in children. The aim of this study was to perform a systematic review and meta-analysis of initially non-operative versus initially operative treatment in children with blunt pancreatic injury., Methods: Studies including children (<18 years) with blunt pancreatic injuries published in any language after year 1990 were included. Total of 849 studies were identified by searching PubMed, Scopus, CINAHL and Cochrane Database. After review, 42 studies met inclusion criteria and were included in this systematic review. There were 1754 patients, of whom 1095 were initially managed non-operatively (NOM), and 659 operatively (OM). Primary outcome was non-operative management success rate, and secondary outcomes were mortality, complications (including specifically pseudocysts and pancreatic fistulas), percent of patients and days on total parenteral nutrition (TPN), length of hospital stay and readmissions., Results: There was no difference in mortality between NOM and OM groups. The incidence of pseudocysts was significantly higher in NOM group compared to OM (P<0.001), especially for AAST grade III or higher (P<0.00001). Overall incidence of pancreatic fistulas was significantly lower for NOM group (p = 0.02) but no difference was observed for AAST grades III or higher (p = 0.49). There was no difference in the length of hospital stay (P = 0.31). Duration of total parenteral nutrition was not different for all AAST grades (P = 0.35), but was significantly shorter for OM group for AAST grades III and higher (p = 0.0001). There was no overall difference in readmissions (P = 0.94). Overall success rate of initial non-operative treatment was 87%., Conclusions: Most patients with pancreatic trauma can initially be treated non-operatively, while early surgical treatment may benefit patients with lesions of the main pancreatic duct. ERCP offers both highly accurate diagnosis and potential treatment of ductal injuries., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability).

Purpose: Management of hydrocolpos in cloaca patients is of clinical importance. We report a nonoperative method for the management of hydrocolpos in the form of initial catheter decompression, followed by an endoscopy with catheters placement into both the bladder and vagina, and leaving these catheters for 9 and 14days respectively., Methods: The medical records of six cloaca patients with hydrocolpos in the last 12years were reviewed. The outcomes measured were the renal function, bladder emptying, the presence/resolution of hydronephrosis, and the recurrence of hydrocolpos., Results: Complete drainage of hydrocolpos was achieved in four out of six cases and partial drainage in two. On common channel endoscopy, in four patients the structures were identified and balloon catheters inserted. After catheter removal, the vagina and urinary tract remained adequately drained through the natural cloacal opening with no post-micturition residual urine, resolution of hydroneprosis within 60days, preserved renal function, and no hydrocolpos reaccumulation., Conclusion: Initial decompression and short time catheterization can be the definite solution for some cloaca patients with hydrocolpos. Our case-series showed a success rate in two-thirds of patients by achieving the three main goals; permanent hydrocolpos derivation, undisturbed voiding, and preservation of renal function., Level of Evidence: Study can be classified as a Treatment Study, LEVEL IV Case series with no comparison group., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To present a case of a 6-month-old infant with melanotic neuroectodermal tumor of infancy (MNTI) in the upper arm., Clinical Presentation and Intervention: A 6-month-old female presented with a well-circumscribed lesion of the upper arm at the Children's Hospital Zagreb. A biopsy was performed and microscopy revealed 2 cell populations consisting of small neuroblastic cells and larger melanin-containing epithelial cells. An excisional biopsy performed 1 month later confirmed the initial diagnosis of MNTI, but the tumor had increased in size since the initial biopsy. After complete surgical excision the patient recovered well with no recurrence., Conclusion: The MNTI located in the upper arm was diagnosed on first biopsy and surgically excised completely. The patient recovered without recurrence in a follow-up of 2.5 years., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

The aim of the study was to assess diagnostic accuracy (sensitivity and specificity) of Fenyö-Lindberg and Teicher scores for distinguishing patients that need immediate surgical treatment from the others, in a female population from an urban setting. The study prospectively included 130 female patients admitted to the emergency department with abdominal pain indicating acute appendicitis. The scores and parameters of validity were calculated and compared to definitive diagnosis. For Fenyö-Lindberg score of -17 or less, 84.5% sensitivity, 55.6% specificity, 87.9% positive predictive value (PPV) and 48.4% negative predictive value (NPV) were recorded. For cut-off value greater or equal to -2, there was 59.2% sensitivity, 77.8% specificity, 91% PPV and 33.3% NPV. The Receiver Operating Characteristic (ROC) curve analysis of Fenyö-Lindberg score showed that the best single cut-off value for discriminating acute appendicitis in the study population was -15. For Teicher score, values greater than -3 yielded 89.3% sensitivity and 22.2% specificity, 81.4% PPV and 35.3% NPV. In conclusion, Fenyö-Lindberg score could be used as an additional tool to exclude appendicitis and avoid unnecessary appendectomies. Teicher score may help in recognizing patients with appendicitis. None of the two scores can indicate or decline appendectomy in all cases. Scoring systems may be useful for pointing to important clinical signs and symptoms in specific subpopulations.

Inflammatory myofibroblastic tumor (IMT) is a rare benign neoplasm, mainly involving the lungs of the children. It represents 0.7% of all lung tumors. It was first described by Brunn in 1939.2 Diagnosis is very difficult and often only possible after resection of the tumor. We would like to present a case of pulmonary IMT in a 13-year-old girl who presented with symptoms like cough, shortness of breath, and chest discomfort. Chest X ray and computed tomography revealed the presence of a right lower lobe lung mass. Its clinical and radiological findings were diverse and non specific. The mass was removed in toto, histopathology confirmed the inflammatory myofibroblastic tumor of the lung. Intraoperative and postoperative courses were uneventful. The patient has been without any signs of relapse 2 years after the surgery.

Cystic lymphangiomas of the small bowel mesentery are rare manifestations of intra-abdominal tumors. Usually, they are discovered incidentally during examination for an unrelated abdominal illness. We present a case of a 4-year-old boy who was admitted to our hospital because of the right lower quadrant acute abdominal pain suspect of acute appendicitis. At laparotomy, a giant, cystic, encapsulated and lipomatous mesenterial mass was found, 15 x 15 x 10 cm in size, infiltrating the jejunum. The tumor was located 70 cm from Treitz's ligament. Extirpation of tumor mass with intestinal resection of the involved loops was necessary. Pathologic examination confirmed the diagnosis of mesenteric cystic lymphangioma. Although they are rare, cystic mesenteric lymphangiomas should be considered as a possible cause of acute abdomen and treated with surgical resection. Prognosis after surgical removal is excellent.

A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Central gas station of the natural gas borehole system Podravina is located near the village Molve. It delivers more than a quarter of total energy used in Croatia to its consumers. Over the years, adapting technology to increasingly demanding and rigorous standards in environmental protection has become paramount. Yet, despite all the industry has undertaken to address the risk of harmful substances entering the food chain, a multidisciplinary research team of independent scientists monitors the content of specific substances in all components of the ecosystem. This paper presents measurements of total sulphur contents in soil surface [(0 to 3) cm] and subsurface [(3 to 8) cm] layers (study period: autumn 2006 - spring 2010) and in plants (study period: spring 2000 - spring 2010), and the concentration of gaseous sulphur compounds in the air. Concentrations of hydrogen sulphide (H2S) and mercaptans (RSH) were measured from the summer of 2002 until the autumn of 2010, while concentrations of sulphur dioxide (SO2) were measured from the spring of 2008 until the autumn of 2010. The paper also shows total annual atmospheric sulphur (S-SO4) deposition at Bilogora measuring station (study period: 2001 - 2010). Average monthly concentrations of H2S in air varied between 0.2 μg m-3 and 2.0 μg m-3, RSH between 0.1 μg m-3 and 24.5 μg m-3, and SO2 between 0.4 μg m-3 and 2.8 μg m-3 depending on the location and the season of sampling. Mean values of total sulphur in soil and in Plantago lanceolata plant ranged between 610 mg kg-1 and 1,599 mg kg-1 and between 3,614 mg kg-1 and 4,342 mg kg-1, respectively, depending on the soil type, location, and sampling depth. Average values of total sulphur mass ratio for all examined single soil samples (n=80) were 1,080 mg kg-1 for both studied layers, and 4,108 mg kg-1 for all analysed plant samples (n=85). Average total annual atmospheric sulphur deposition at Bilogora measuring station was 6.3 kg of S-SO4 per hectare.

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

Spatial and temporal distribution of arsenic levels in soil during the 9 year monitoring period was investigated on four different soil types in the area of the gas borehole system Podravina in Croatia. Arsenic levels in the PM(10) particle fraction were measured periodically at the same locations for 3 years. Arsenic levels in soil significantly depended on soil types. Elevated levels were found on gleysol vertic, at two sampling sites, with values exceeding 30 mg/kg of arsenic in soil. Arsenic levels in air were low and they were not significantly different between sampling sites, suggesting that gas borehole activities have no influence on arsenic levels in the environment., (© Springer Science+Business Media, LLC 2011)

The stability in aqueous solution of five classes of coumarin dimers (I-V, compounds 1-29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A conjugate of pyridine-4-aldoxime and atropine (ATR-4-OX) was synthesized and its antidotal efficiency was tested in vitro on tabun- or paraoxon-inhibited acetylcholinesterase (AChE) of human erythrocytes as well as in vivo using soman-, tabun- or paraoxon-poisoned mice. Its genotoxic profile was assessed on human lymphocytes in vitro and was found acceptable for further research. ATR-4-OX showed very weak antidotal activity, inadequate for soman or tabun poisoning. Conversely, it was effective against paraoxon poisoning both in vitro and in vivo. All animals treated with 5 % or 25 % LD(50) doses of the new oxime survived after administration of 10.0 or 16.0 LD(50) doses of paraoxon, respectively. Based on the persistence of toxicity symptoms in mice, the atropine moiety had questionable effects in attenuating such symptoms. It appears that ATR-4-OX has a therapeutic effect related to the reactivation of phosphylated AChE, but not to receptor antagonization.

Popliteal cyst, also called Baker's cyst, is a popliteal fossa enlargement filled with synovial fluid. Baker's cysts can be symptomatic and cause considerable pathologies such as thrombophlebitis, compartment syndrome and even nerve entrapment. It is the most common nonvascular pathology seen in the popliteal fossa but clinically indistinguishable from deep vein thrombosis. The aim of the present study was to evaluate venous duplex scanning in detecting and distinguishing complicated Baker's cyst and deep vein thrombosis in outpatient setting. Medical records of all patients undergoing venous duplex scanning during 2008 and 2009 to rule out deep vein thrombosis were reviewed. Ten patients having undergone ultrasonography examination were found to have complicated Baker's cyst. Baker's cysts are a rather common condition. When presenting with swollen and painful calf, it is impossible to differentiate it from deep vein thrombosis by simple clinical examination. Venous duplex scanning of lower extremity was found to be a useful imaging modality for detection of Baker's cysts, deep vein thrombosis and associated pathology.

Purpose: We have assessed the use of an ultrasonic nebulization system (UNS), composed of ultrasonic nebulizer and diffusion dryer filled with charcoal, for the effective delivery of beclomethasone to the airways in a murine asthma model., Methods: Solution of beclomethasone in ethanol was aerosolized using an ultrasonic nebulizer. Passage of the aerosol through a drying column containing charcoal and deionizer produced dry beclomethasone particles. Particles were delivered to BALB/c mice placed in a whole-body exposition chamber 1 h before intranasal challenge with ovalbumine. Efficacy of beclomethasone delivery was evaluated by examining bronchoalveolar lavage fluid (BALF) cytology., Results: Effect of three UNS system parameters on aerosol particle size was investigated. The critical parameter affecting the size of dry particles was beclomethasone concentration in aerosolized solution and solution flow rate while power level of ultrasonic nebulizer generator had no effect. Administration of beclomethasone at calculated dose of 150 microg/kg to mice significantly decreased total cell number and relative eosinophil number in BALF., Conclusions: The UNS system produces a monodisperse aerosol that can be used for inhalative delivery of poorly water soluble substances to experimental animals. The UNS system minimizes formulation requirements and allows rapid and relatively simple efficacy and toxicity testing in animals.