The toxic effect of R350P mutant desmin in striated muscle of man and mouse.

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.

Circulating microRNAs in Cerebrospinal Fluid and Plasma: Sensitive Tool for Detection of Secondary CNS Involvement, Monitoring of Therapy and Prediction of CNS Relapse in Aggressive B-NHL Lymphomas.

Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin's lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1-4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma.

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.

Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.

Vigor of survival determinism: subtle evolutionary gradualism interspersed with robust phylogenetic leaping.

Discussions of the survival determinism concept have previously focused on its primary role in the evolution of early unicellular organisms in the light of findings which have been reported on a number of diseases. The rationale for such parallel was in the view according to which multicellular organisms could be regarded as sophisticated colonies of semi-autonomous, single-celled entities, whereby various diseases were described as conditions arising upon the activation of the respective survival mechanisms in a milieu unsuitable for such robust stress response. The cellular mechanisms that were discussed in these contexts have been known to play various roles in other biological processes. The proposed notion could thereby be further extended to discussion on mechanisms for the implementation of the respective survival pathways in the development of metazoa, considering that they would have been propagated in their evolution for so long. This manuscript first presents a concise overview of the model previously discussed, followed by the discussion on the role of respective mechanism(s) in origins and development of metazoa. Finally, a reflection on the concept in relation to the prominent evolutionary models is put forward to illustrate a broader context of what is being discussed.

Fundamental paradox of survival determinism: the ur-etiology disease paradigm.

Following a common practice in medicine, biomedical researches tend to view various disease conditions as direct results of preceding, disease-causing events. Such events are commonly those that could have been previously detected and which have given the history of studies of particular diseases, been previously recognized as playing an important role in an onset and/or progression of the disease in question. Although such practice is justified from the very principles of experimental investigation and scientific observation, it comes short of finding the fundamental causes behind these disease conditions. This manuscript proposes a different view to the origin of some types of diseases as well as some other biological phenomena. Namely, the focus of the concept relates to a notion of survival determinism, proposed to have been in the very core of evolution of primordial organisms. Thereby, as various disease models are discussed in the light of the proposed mechanisms for adaptation, they could be seen as relicts of the early evolutionary history of life on Earth.

Ontological hypothesis of the cancer etiology: discord between cells' survival determinism and their disposition to biological altruism.

During the last decades, scientific community has implicitly viewed cancer as a number of different diseases with the same underlying phenotype. Such a view was justified for the fact that some of the genetic and phenotypic similarities, observed in different types of tumors, were perpetuated via some distinct mechanisms. Nevertheless, this manuscript aims to interpret all of these differences in a context of the same underlying cause. To do so, the epigenetic and genetic alterations observed in cancers are initially interpreted in the context of their advantage for the evolution of the early eukaryotic organisms. Subsequently, the proposed premises are further discussed with respect to their propagation in the subsequent generations of the new eukaryotic species, as well as their role in the development of the higher organisms. In the subsequent section, the role of the proposed mechanism is discussed in the context of cancer, which is proposed to originate due to the analogous underlying mechanisms. Finally, the proposed mechanism is briefly discussed in parallel with some other contemporary theories of carcinogenesis, aiming to further support its validity. Thereby, the model presents an alternative interpretation of multiple cancer-related biomedical phenomena from the aspect of a proposed evolutionary mechanism.