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

COMPARATIVE ANALYSIS OF THE EXOSOMAL CARGO OF THE ESTROGEN-RESISTANT BREAST CANCER CELLS

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

Exosomes and development of cancer cell resistance to metformin: pilot study

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

p53 Affects Zeb1 Interactome of Breast Cancer Stem Cells

P53 is a critical tumor suppressor that protects the integrity of genome and prevents cells from malignant transformation, including metastases. One of the driving forces behind the onset of metastases is the epithelial to mesenchymal transition (EMT) program. Zeb1 is one of the key transcription factors that govern EMT (TF-EMT). Therefore, the interaction and mutual influence of p53 and Zeb1 plays a critical role in carcinogenesis. Another important feature of tumors is their heterogeneity mediated by the presence of so-called cancer stem cells (CSCs). To this end, we have developed a novel fluorescent reporter-based approach to enrich the population of CSCs in MCF7 cells with inducible expression of Zeb1. Using these engineered cell lines, we studied the effect of p53 on Zeb1 interactomes isolated from both CSCs and regular cancer cells. By employing co-immunoprecipitations followed by mass spectrometry, we found that the composition of Zeb1 interactome was affected not only by the p53 status but also by the level of Oct4/Sox2 expression, indicating that stemness likely affects the specificity of Zeb1 interactions. This study, together with other proteomic studies of TF-EMT interactomes, provides a framework for future molecular analyses of biological functions of Zeb1 at all stages of oncogenesis

[Mass-spectrometric analysis of proteasomal subunits possessing endoribonuclease activity]

Proteasomes act as the main apparatus of non-lysosomal intracellular proteolysis and participate in the regulation of most important cellular processes. Despite considerable progress in the understanding of proteasome's functioning, some issues, in particular, RNase activity of these ribonucleoprotein complexes and its regulation remain scarcely explored. In this paper we found several proteins corresponding by electrophoretic mobility to subunits of the complex 20S proteasome to possess endoribonuclease activity with respect to both sense and antisense sequences of the c-myc mRNA 3'-UTR. Mass-spectrometric analysis of tryptic hydrolysates of these proteins revealed in the samples the presence of 20S proteasome subunits--αl (PSMA6), α5 (PSMA5), α6 (PSMA1) and α7 (PSMA3). A number of novel phosphorylation sites in subunits αl (PSMA6) and α7 (PSMA3), and the form of subunit α5 (PSMA5) with a deletion of N-terminal 20 amino acid residues detected. The observed differences of individual subunits in the possession endonuclease activity could be apparently explained by postranslational modifications of these proteins, in particular--by phosphorylation. It is shown that the specificity of the proteasomal RNase activity varies after dephosphorylation and also influenced by Ca and Mg cations. The conclusions made about the impact of the PTM status of proteasome subunits on the specificity of their RNase activity

New putative phenol oxidase in ascidian blood cells

The phenol oxidase system is ancient and ubiquitously distributed in all living organisms. In various groups it serves for the biosynthesis of pigments and neurotransmitters (dopamine), defence reactions and tissue hardening. Ascidians belong to subphylum Tunicata, which is considered the closest living relative to Vertebrates. Two phenol oxidases previously described for ascidians are vertebrate-like and arthropod-like phenol oxidases. In our present study, we described a new ascidian protein, Tuphoxin, with putative phenol oxidase function, which bears no sequence similarity with two enzymes described previously. The closest related proteins to Tuphoxin are mollusc haemocyanins. Unlike haemocyanins, which are oxygen transporting plasma proteins, Tuphoxin is synthesised in ascidian blood cells and secreted in the extracellular matrix of the tunic—ascidian outer coverings. Single mature transcript coding for this phenol oxidase can give several protein products of different sizes. Thus limited proteolysis of the initial protein is suggested. A unique feature of Tuphoxins and their homologues among Tunicata is the presence of thrombospondin first type repeats (TSP1) domain in their sequence which is supposed to provide interaction with extracellular matrix. The finding of TSP1 in the structure of phenol oxidases is new and we consider this to be an innovation of Tunicata evolutionary lineage