TLR9 Agonist Protects Mice from Radiation-Induced Gastrointestinal Syndrome

Radiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.Male C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4-10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.Mice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).TLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies

Клиническое наблюдение редкого варианта поражения лабиринта: опухоль эндолимфатического мешка

Endolymphatic sac tumors are rare neoplasms originating from the endolymphatic epithelium of the intraosseous part of the endolymphatic duct and sac, typically characterized by slow growth and local destructive changes. We present a case of an endolymphatic sac tumor in a 28-year-old man who consulted an otoneurologist with complaints of progressive hearing loss and dizziness attacks and was referred for a CT scan of the temporal bones and MRI of the inner ear with delayed contrast enhancement. The data of otoneurological and radiological examinations before and after surgical treatment and the results of surgical treatment with histological verification of the tumor are presented. The objective of this case presentation is to demonstrate the usefulness of CT and MRI methods in detecting an endolymphatic sac tumor, to compare the results of otoneurological and radiological examinations and intraoperative and histological data followed by surgery. Radiological examination revealed a neoplasm of the right temporal bone with typical imaging characteristics of endolymphatic sac tumor. Surgery was performed, the mass was removed completely, and the endolymphatic sac tumor was histologically verified. Radiologic presentation includes a typically located area of bone destruction in the petrous part of the temporal bone in the area of the vestibular aqueduct, possibly with the spread of the tumor into the cerebellopontine angle, with a heterogeneous structure, with uneven contrast enhancement. Due to the rarity of this pathology, diagnosis in the early stages is often difficult, and for the correct interpretation of radiologic findings in patients with hearing loss and dizziness, knowledge of the normal anatomy of the temporal bone and awareness of rare variants of its lesions are of key importance. Timely examination of patients with suspected temporal bone lesions and correct diagnosis are the key to successful treatment and maintaining the quality of life in this group of patients.Опухоли эндолимфатического мешка — это редкие новообразования, исходящие из эндолимфатического эпителия внутрикостной части эндолимфатического протока и мешка, типичными для них являются медленный рост и локальные деструктивные изменения. Нами представлено наблюдение опухоли эндолимфатического мешка у мужчины 28 лет, который обратился к отоневрологу с жалобами на прогрессирующее снижение слуха и приступы головокружения и был направлен на лучевое обследование в объеме МСКТ височных костей и МРТ внутреннего уха с отсроченным контрастированием. Приведены данные отоневрологического, лучевого обследования до и после оперативного лечения и результаты оперативного лечения с гистологической верификацией опухоли. Цель данного наблюдения — продемонстрировать возможности лучевой диагностики (КТ и МРТ) в выявлении опухоли эндолимфатического мешка, сопоставить результаты отоневрологического и лучевого обследования и интраоперационные и гистологические данные. При лучевом обследовании выявлено новообразование височной кости с типичными визуализационными характеристиками опухоли эндолимфатического мешка. Проведено оперативное лечение, образование удалено, верифицирована опухоль эндолимфатического мешка. Лучевая семиотика ОЭМ включает наличие типично расположенной зоны остеодеструкции в каменистой части височной кости в зоне расположения водопровода преддверия, возможно распространение опухолевого компонента в область мостомозжечкового угла, гетерогенной структуры, с неравномерным накоплением контрастного препарата. В связи с редкостью данной патологии диагностика на ранних стадиях часто затруднена, а для верной интерпретации изменений при лучевом обследовании пациентов со снижением слуха и головокружением, знание нормальной лучевой анатомии височной кости и информированность о редких вариантах ее патологии имеют ключевое значение. Своевременное обследование пациентов с подозрением на образование височной кости и правильная постановка диагноза являются залогом успешного лечения и сохранения качества жизни у данной группы пациентов

Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells.Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.Peer reviewedBiochemistry and Molecular Biolog

BENIGN PAROXYSMAL POSITIONAL VERTIGO IN THE PRACTICE OF AMBULANCE DOCTOR

The article contains information on benign paroxysmal positional vertigo, which is one of the most common causes of dizziness. Data on etiology, epidemiology, clinical manifestations, diagnosis, differential diagnosis and treatment of this disease are presented.</jats:p

Factors of Influence on the Energy Efficiency of Exothermal Transformations in a Controlled High-Voltage Electrochemical Explosion

The analysis of the results of experimental studies of the influence of changes in the initial conditions on the energy characteristics of a controlled high-voltage electrochemical explosion (HVECE) is carried out, the main factors affecting the specific energy efficiency of chemical transformations of a water-filled exothermic medium (WFEM) in its discharge channel are determined. The range of rational changes in the main factors has been established in which an increase in the specific energy efficiency of exothermic transformations of the WFEM in the channel of the controlled HVECE is ensured. This will make it possible to reduce the weight and size characteristics and power consumption of the pulse current generator to ensure the necessary energy characteristics of the controlled HVECE, specified by a specific discharge-pulse technology.</jats:p