СРАВНИТЕЛЬНЫЙ АНАЛИЗ ЭКЗОСОМ КЛЕТОК ЭСТРОГЕН-РЕЗИСТЕНТНОГО РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ

The exosomes involvement in the pathogenesis of tumors is based on their property to incorporate into the recipient cells resulting in the both genomic and epigenomic changes.  Earlier we have shown that exosomes from different types of estrogen-independent breast  cancer cells (MCF-7/T developed by long-term tamoxifen treatment, and MCF-7/M)  developed by metformin treatment were able to transfer resistance to the parent MCF-7  cells. To elucidate the common features of the both types of resistant exosomes, the  proteome and microRNA cargo of the control and both types of the resistant exosomes were  analyzed. Totally, more than 400 proteins were identified in the exosome samples. Of these  proteins, only two proteins, DMBT1 (Deleted in Malignant Brain Tumors 1) and THBS1  (Thrombospondin-1), were commonly expressed in the both resistant exosomes (less than  5% from total DEPs) demonstrating the unique protein composition of each type of the resistant exosomes. The comparative analysis of the miRNA differentially expressed in  the both MCF-7/T and MCF-7/M resistant exosomes revealed 180 up-regulated and 202  down-regulated miRNAs. Among them, 4 up-regulated and 8 down-regulated miRNAs were  associated with progression of hormonal resistance of breast tumors. The bioinformatical  analysis of 4 up-regulated exosomal miRNAs revealed 2 miRNAs, mir- 101and mir-181b, which up-regulated PI3K signaling  supporting the key role of PI3K/Akt in the development of the resistant phenotype of breast cancer cells.Участие экзосом в патогенезе злокачественных опухолей основано на их способности проникать внутрь  клеток-реципиентов, вызывая в последних каскад генетических и эпигенетических изменений. Ранее мы  показали, что экзосомы, продуцируемые различными вариантами эстроген-независимых сублиний клеток  рака молочной железы (MCF-7/T, полученной в результате длительного культивирования клеток в  присутствии антиэстрогена тамоксифена, и MCF-7/M, полученной в результате культивирования клеток с  метформином), способны индуцировать резистентность в родительских клетках MCF-7. В настоящей работе  для исследования характерных особенностей состава экзосом резистентных клеток был проведен  сравнительный анализ протеома и профиля микроРНК контрольных экзосом и экзосом, полученных от  резистентных сублиний. В целом в образцах экзосом было идентифицировано более 400 белков, из которых  только 2 белка, DMBT1 (Deleted in Malignant Brain Tumors 1) и THBS1 (Thrombospondin-1), были  гиперэкспрессированы в обоих типах резистентных экзосом (менее 5 % от общего количества белков,  дифференциально экспрессированных в экзосомах резистетных клеток), что свидетельствует об уникальном  составе экзосомальных белков для каждого типа резистентных клеток. Сравнительный анализ  состава микроРНК, дифференциально экспрессированных в обоих вариантах экзосом резистентных клеток,  выявил 180 гиперэкспрессированных микроРНК и 202 микроРНК с пониженной экспрессией. Среди них 4  гиперэкспрессированных и 8 гипоэкспрессированных микроРНК оказались ассоциированы с развитием  гормональной резистентности клеток рака молочной железы. Биоинформатический анализ 4  гиперэкспрессированных микроРНК выявил 2 микроРНК, mir-101и mir-181b, участвующих в стимуляции PI3K  сигналинга, свидетельствуя о важной роли последнего в развитии гормональной резистентности  клеток рака молочной железы.

Are mild head injuries as mild as we think? Neurobehavioral concomitants of chronic post-concussion syndrome

BACKGROUND: Mild traumatic brain injury (MTBI) can sometimes lead to persistent postconcussion symptoms. One well accepted hypothesis claims that chronic PCS has a neural origin, and is related to neurobehavioral deficits. But the evidence is not conclusive. In the attempt to characterise chronic MTBI consequences, the present experiment used a group comparison design, which contrasted persons (a) with MTBI and PCS, (b) MTBI without PCS, and (c) matched controls. We predicted that participants who have experienced MTBI but show no signs of PCS would perform similar to controls. At the same time, a subgroup of MTBI participants would show PCS symptoms and only these volunteers would have poorer cognitive performance. Thereby, the performance deficits should be most noticeable in participants with highest PCS severity. METHOD: 38 patients with a single MTBI that had occurred at least 12 month prior to testing, and 38 matched controls, participated in the experiment. A combination of questionnaires and neuropsychological test batteries were used to assess the extent of PCS and related deficits in neurobehavioral performance. RESULTS: 11 out of 38 MTBI participants (29%) were found to suffer from PCS. This subgroup of MTBI patients performed poorly on neuropsychological test batteries. Thereby, a correlation was found between PCS symptom severity and test performance suggesting that participants with more pronounced PCS symptoms performed worse in cognitive tasks. In contrast, MTBI patients with no PCS showed performed similar to matched control. We further found that loss of consciousness, a key criterion for PCS diagnosis, was not predictive of sustained PCS. CONCLUSION: The results support the idea that MTBI can have sustained consequences, and that the subjectively experienced symptoms and difficulties in everyday situations are related to objectively measurable parameters in neurocognitive function

Impaired executive function in male MDMA ("ecsatsy") users.

Rationale: Long-term users of ecstasy have shown impaired performance on a multitude of cognitive abilities (most notably memory, attention, executive function). Research into the pattern of MDMA effects on executive functions remains fragmented, however. Objectives: To determine more systematically what aspects of executive function are affected by a history of MDMA use, by using a model that divides executive functions into cognitive flexibility, information updating and monitoring, and inhibition of pre-potent responses. Methods: MDMA users and controls who abstained from ecstasy and other substances for at least 2 weeks were tested with a computerized cognitive test battery to assess their abilities on tasks that measure the three submodalities of executive function, and their combined contribution on two more complex executive tasks. Because of sex-differential effects of MDMA reported in the literature, data from males and females were analyzed separately. Results: Male MDMA users performed significantly worse on the tasks that tap on cognitive flexibility and on the combined executive function tasks; no differences were found on the other cognitive tasks. Female users showed no impairments on any of the tasks. Conclusions: The present data suggest that a history of MDMA use selectively impairs executive function. In male users, cognitive flexibility was impaired and increased perseverative behavior was observed. The inability to adjust behavior rapidly and flexibly may have repercussions for daily life activities

Экзосомы и развитие резистентности опухолевых клеток к метформину: пилотное исследование

Objective: to study the role of the intercellular interactions in the progression of the cancer cells resistance to metformin, a biguanide antidiabetic drug exhibited the marked anti-tumor activity.Results. Earlier we have demonstrated the effect of horizontal transferring of hormonal resistance of breast cancer cells  from cell to cell, and showed the key role of exosomes on the transferring of the resistance. Here we have shown the effect of the horizontal transferring of metformin resistance in breast cancer cells – similar to the progression of hormonal resistance. We found that horizontal transferring of the metformin resistance is mediated via exosomes secreted by the resistant cells. The proteome analysis of the exosomes revealed several proteins differentially expressed in the exosomes of metformin-resistant cells and associated with the regulation of cell response to apoptotic drugs.Conclusions. Totally, the data presented demonstrate the new mechanism of the development of the cancer cell resistance based on the intercellular interactions, opening the new insights in the target therapy of breast cancer.Цель работы – исследование роли межклеточных взаимодействий в развитии резистентности клеток рака молочной железы к метформину – антидиабетическому препарату из группы бигуанидов, обладающему выраженным противоопухолевым эффектом.Результаты. В основу работы легли данные, полученные нами ранее при изучении гормональной резистентности клеток рака молочной железы и продемонстрировавшие возможность передачи резистентного фенотипа горизонтальным путем, от клетки к клетке, в том числе с участием экзосом. В настоящей работе мы показали возможность развития устойчивости к метформину горизонтальным путем, как и в случае гормональной резистентности. Установлено, что решающим фактором в подобном горизонтальном пути передачи резистентности являются межклеточные взаимодействия, реализуемые в том числе с участием экзосом, продуцируемых метформинрезистентными клетками. Анализ протеома экзосом подтвердил присутствие в экзосомах резистентных клеток белков, регулирующих ответ клеток на действие апоптотических агентов.Заключение. Полученные данные подтверждают существование неизвестного ранее механизма распространения резистентности, основанного на межклеточных взаимодействиях, и открывают новые возможности в поиске мишеней противоопухолевой терапии

Magnetic resonance imaging after most common form of concussion

<p>Abstract</p> <p>Background</p> <p>Until now there is a lack of carefully controlled studies with conventional MR imaging performed exclusively in concussion with short lasting loss of consciousness (LOC).</p> <p>Methods</p> <p>A MR investigation was performed within 24 hours and after 3 months in 20 patients who had suffered a concussion with a verified loss of consciousness of maximally 5 minutes. As a control group, 20 age- and gender matched patients with minor orthopaedic injuries had a MR investigation using the same protocol.</p> <p>Results</p> <p>In a concussion population with an average LOC duration of 1. 4 minutes no case with unequivocal intracranial traumatic pathology was detected.</p> <p>Conclusion</p> <p>An ordinary concussion with short lasting LOC does not or only seldom result in a degree of diffuse axonal injury (DAI) that is visualized by conventional MR with field strength of 1.0 Tesla (T). Analysis of earlier MR studies in concussion using field strength of 1.5 T as well as of studies with diffusion tensor MR imaging (MR DTI) reveal methodological shortcomings, in particular use of inadequate control groups. There is, therefore, a need for carefully controlled studies using MR of higher field strength and/or studies with MR DTI exclusively in common concussion with LOC of maximally 5 minutes.</p

Traumatic-event headaches

BACKGROUND: Chronic headaches from head trauma and whiplash injury are well-known and common, but chronic headaches from other sorts of physical traumas are not recognized. METHODS: Specific information was obtained from the medical records of 15 consecutive patients with chronic headaches related to physically injurious traumatic events that did not include either head trauma or whiplash injury. The events and the physical injuries produced by them were noted. The headaches' development, characteristics, duration, frequency, and accompaniments were recorded, as were the patients' use of pain-alleviative drugs. From this latter information, the headaches were classified by the diagnostic criteria of the International Headache Society as though they were naturally-occurring headaches. The presence of other post-traumatic symptoms and litigation were also recorded. RESULTS: The intervals between the events and the onset of the headaches resembled those between head traumas or whiplash injuries and their subsequent headaches. The headaches themselves were, as a group, similar to those after head trauma and whiplash injury. Thirteen of the patients had chronic tension-type headache, two had migraine. The sustained bodily injuries were trivial or unidentifiable in nine patients. Fabrication of symptoms for financial remuneration was not evident in these patients of whom seven were not even seeking payments of any kind. CONCLUSIONS: This study suggests that these hitherto unrecognized post-traumatic headaches constitute a class of headaches characterized by a relation to traumatic events affecting the body but not including head or whiplash traumas. The bodily injuries per se can be discounted as the cause of the headaches. So can fabrication of symptoms for financial remuneration. Altered mental states, not systematically evaluated here, were a possible cause of the headaches. The overall resemblance of these headaches to the headaches after head or whiplash traumas implies that these latter two headache types may likewise not be products of structural injuries

Oculo-visual changes and clinical considerations affecting older patients with dementia

Purpose: Dementia is associated with various alterations of the eye and visual function. Over 60% of cases are attributable to Alzheimer's disease, a significant proportion of the remainder to vascular dementia or dementia with Lewy bodies, while frontotemporal dementia, and Parkinson's disease dementia are less common. This review describes the oculo-visual problems of these five dementias and the pathological changes which may explain these symptoms. It further discusses clinical considerations to help the clinician care for older patients affected by dementia. Recent findings: Visual problems in dementia include loss of visual acuity, defects in colour vision and visual masking tests, changes in pupillary response to mydriatics, defects in fixation and smooth and saccadic eye movements, changes in contrast sensitivity function and visual evoked potentials, and disturbance of complex visual functions such as in reading ability, visuospatial function, and the naming and identification of objects. Pathological changes have also been reported affecting the crystalline lens, retina, optic nerve, and visual cortex. Clinically, issues such as cataract surgery, correcting the refractive error, quality of life, falls, visual impairment and eye care for dementia have been addressed. Summary: Many visual changes occur across dementias, are controversial, often based on limited patient numbers, and no single feature can be regarded as diagnostic of any specific dementia. Nevertheless, visual hallucinations may be more characteristic of dementia with Lewy bodies and Parkinson's disease dementia than Alzheimer's disease or frontotemporal dementia. Differences in saccadic eye movement dysfunction may also help to distinguish Alzheimer's disease from frontotemporal dementia and Parkinson's disease dementia from dementia with Lewy bodies. Eye care professionals need to keep informed of the growing literature in vision/dementia, be attentive to signs and symptoms suggestive of cognitive impairment, and be able to adapt their practice and clinical interventions to best serve patients with dementia