Identification of the growth arrest and DNA damage protein GADD34 in the normal human heart and demonstration of alterations in expression following myocardial ischaemia

Growth arrest and DNA damage protein 34 (GADD34) is a multifunctional protein upregulated in response to cellular stress and is believed to mediate DNA repair and restore protein synthesis. In the present study we have examined GADD34 immunoreactivity in human myocardial tissue at defined survival times following cardiac arrest and determined alterations in expression following ischaemia. In the normal human heart, GADD34 immunoreactivity was generally intense and present within most cells. GADD34 immunoreactivity was downregulated in tissue displaying ischaemic damage and remained intense in adjacent non-infarcted tissue. Unlike brain, GADD34 was not found to be upregulated in the peri-infarct zone. Cells displaying apoptotic changes were located in regions displaying reduced GADD34 immunoreactivity. In the brain, it is thought that GADD34 supports re-initiation of protein synthesis following ischaemia. Similarly, GADD34 may perform important functions in cardiac tissue in response to ischaemia

Prolonged expression of the γ-H2AX DNA repair biomarker correlates with excess acute and chronic toxicity from radiotherapy treatment

The normal tissue tolerance levels to fractionated radiotherapy have been appreciated by a century of careful clinical observations and radiobiological studies in animals. During clinical fractionated radiotherapy, these normal tissue tolerance levels are respected, and severe sequelae of radiotherapy are avoided in the majority of patients. Notwithstanding, a minority of patients experience unexpectedly severe normal tissue reactions. The ability to predict which patients might form this minority would be important. We have conducted a study to develop a rapid and reliable diagnostic test to predict excessive normal tissue toxicity (NTT) in radiotherapy patients. A flow cytometric immunocytochemical assay was used to measure DNA damage in peripheral blood lymphocytes (PBL) from cancer patients exposed to 2-Gy gamma radiation. DNA damage and repair was measured by induction of cellular γ-H2AX in unirradiated and exposed cells at specific time points following exposure. In 12 cancer patients that experienced severe atypical NTT following radiotherapy, there was a failure to repair DNA double-strand breaks (DSB) as measured by γ-H2AX induction and persistence. In ten cancer patients that experienced little or no NTT and in seven normal (noncancer controls), efficient repair of DNA DSB was observed in the γ-H2AX assay. We conclude that a flow cytometric assay based on γ-H2AX induction in PBL of radiotherapy patients may represent a robust, rapid and reliable biomarker to predict NTT during radiotherapy. Further research is required with a larger patient cohort to validate this important study

Serum levels of matrix metalloproteinases-2 and-9 and their tissue inhibitors in inflammatory neuromuscular disorders

We monitored serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) before and during intravenously applied immunoglobulin (IVIG) therapy in 33 patients with chronic immune-mediated neuropathies and myopathies and 15 controls. Baseline MMP-2 and TIMP-2 serum levels were lower and MMP-9 and TIMP-1 serum levels higher in all patients compared to age-matched controls. Eight days after IVIG treatment, MMP-2, TIMP-2, and TIMP-1 serum levels increased, while MMP-9 serum levels decreased, indicating tissue repair. After 60 days, MMP-9 levels increased, MMP-2 approached normal levels, while TIMP-1 and TIMP-2 serum levels were below day 8 levels, indicating relapsing tissue damage. Comparing the MMP/TIMP results with the clinical courses, IVIG treatment tended to change MMP/TIMP levels in a way that paralleled clinical improvement and relapse. In sum, during a distinct time period, IVIG therapy seems to be able to modulate VIMP-mediated tissue repair. Copyright (c) 2006 S. Karger AG, Basel

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

Adult tissue homeostasis requires a tight balance between the removal of old or damaged cells and the production of new ones. Such processes are usually driven by dedicated stem cells that reside within specific tissue locations or niches. The intestinal epithelium has a remarkable regenerative capacity, which has made it a prime paradigm for the study of stem cell-driven tissue self-renewal. The discovery of the presence of stem cells in the adult midgut of the fruit fly Drosophila melanogaster has significantly impacted our understanding of the role of stem cells in intestinal homeostasis. Here we will review the current knowledge of the main mechanisms involved in the regulation of tissue homeostasis in the adult Drosophila midgut, with a focus on the role of stem cells in this process. We will also discuss processes involving acute or chronic disruption of normal intestinal homeostasis such as damage-induced regeneration and ageing

Struktur Insang Ikan Ompok Hypophthalmus (Bleeker 1846) Dari Perairan Sungai Siak Kota Pekanbaru

This study aimed to observe the pathology of fish gill tissue Ompok hypophthalmus from Siak River around Siak I and Siak II bridge, Pekanbaru. The research was conducted from December 2013 to April 2014. The samples were prepared for histological observation using paraffin method and stained with Hematoxylin-Eosin (HE). Data were analyzed descriptively and quantitatively based on the histopathological evaluation and the value of the damage scoring. The results showed that the gill tissue structure of O.hypophthalmus fish changed. The damage in gill tissue found at Station I were 8,4% hyperplasia, 5,9% lamella fusion, 2,9% odema and 0,9% necrosis with total damage of gill tissue was 18,1%. Meanwhile, the damage in gill tissue found at Station II were 7,1% hyperplasia, 6,1% lamela fusion, 2,4% odema and 0,9% necrosis with total damage of gill tissue was 16,5%. The results of histopathological scoring below ≤25% indicated that the condition of the gill tissue was considered normal

Tumor detection and elimination by a targeted gallium corrole

Sulfonated gallium(III) corroles are intensely fluorescent macrocyclic compounds that spontaneously assemble with carrier proteins to undergo cell entry. We report in vivo imaging and therapeutic efficacy of a tumor-targeted corrole noncovalently assembled with a heregulin-modified protein directed at the human epidermal growth factor receptor (HER). Systemic delivery of this protein-corrole complex results in tumor accumulation, which can be visualized in vivo owing to intensely red corrole fluorescence. Targeted delivery in vivo leads to tumor cell death while normal tissue is spared. These findings contrast with the effects of doxorubicin, which can elicit cardiac damage during therapy and required direct intratumoral injection to yield similar levels of tumor shrinkage compared with the systemically delivered corrole. The targeted complex ablated tumors at >5 times a lower dose than untargeted systemic doxorubicin, and the corrole did not damage heart tissue. Complexes remained intact in serum and the carrier protein elicited no detectable immunogenicity. The sulfonated gallium(III) corrole functions both for tumor detection and intervention with safety and targeting advantages over standard chemotherapeutic agents

Advances in the design and development of oncolytic measles viruses.

A successful oncolytic virus is one that selectively propagates and destroys cancerous tissue without causing excessive damage to the normal surrounding tissue. Oncolytic measles virus (MV) is one such virus that exhibits this characteristic and thus has rapidly emerged as a potentially useful anticancer modality. Derivatives of the Edmonston MV vaccine strain possess a remarkable safety record in humans. Promising results in preclinical animal models and evidence of biological activity in early phase trials contribute to the enthusiasm. Genetic modifications have enabled MV to evolve from a vaccine agent to a potential anticancer therapy. Specifically, alterations of the MV genome have led to improved tumor selectivity and delivery, therapeutic potency, and immune system modulation. In this article, we will review the advancements that have been made in the design and development of MV that have led to its use as a cancer therapy. In addition, we will discuss the evidence supporting its use, as well as the challenges associated with MV as a potential cancer therapeutic

ECoG-based short-range recurrent stimulation techniques to stabilize tissue at risk of progressive damage: Theory based on clinical observations

We introduce theoretical concepts based on chaos control to stabilize in acute stroke the tissue at risk of progressive damage by preventing adverse effects of waves of mass neuronal depolarization. Moreover, we present clinical electrocorticography (ECoG) recordings of relevant signals suggested for the feedback control. The recordings are performed in combination with novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry in patients with aneurysmal subarachnoid haemorrhage (aSAH). In aSAH patients waves of spreading depolarization (SD) have a high incidence and cause hypoxia in tissue at risk, and, importantly, the haemodynamic response is the inverse of that seen in healthy tissue. In previous clinical studies, clusters of prolonged SDs have been measured in aSAH patients in close proximity to structural brain damage as assessed by neuroimaging, and, in theoretical studies, a mechanism was presented, suggesting how a failure of internal feedback could be a putative mechanism of such SD cluster patterns in acute stroke. 

This failing internal feedback control is now suggested to be replaced by ECoG-based short-range recurrent functional stimulation that initiates the normal hyperperfusion haemodynamic response in a demand-controlled way and stabilizes the tissue at risk during the critical phase of SD passage. The suggested method has three key features: (i) it is short-range, i.e., in the order of the distance of the ECoG electrode strip, (ii) it is demand-controlled, and (iii) it uses no prior knowledge of the target state, in particular, it adapts to conditions in the healthy physiological range. On-demand type stimulation provides minimal invasive feedback as the control force is off when the target state is reached, i.e., the tissue at risk is without SD or it is back to the physiological range (out of risk). These last two features (ii-iii) are shared with classical methods of chaos control, where major progress was made in the last years with respect to extensions for spatio-temporal wave patterns. A detailed bifurcation analysis of the nonlinear model is presented, in particular, the SD cluster forming cortical state is suggested to be caused by a delay-induced saddle-node bifurcation.
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Truncation of POC1A associated with short stature and extreme insulin resistance

We describe a female proband with primordial dwarfism, skeletal dysplasia, facial dysmorphism, extreme dyslipidaemic insulin resistance and fatty liver associated with a novel homozygous frameshift mutation in POC1A, predicted to affect two of the three protein products of the gene. POC1A encodes a protein associated with centrioles throughout the cell cycle and implicated in both mitotic spindle and primary ciliary function. Three homozygous mutations affecting all isoforms of POC1A have recently been implicated in a similar syndrome of primordial dwarfism, although no detailed metabolic phenotypes were described. Primary cells from the proband we describe exhibited increased centrosome amplification and multipolar spindle formation during mitosis, but showed normal DNA content, arguing against mitotic skipping, cleavage failure or cell fusion. Despite evidence of increased DNA damage in cells with supernumerary centrosomes, no aneuploidy was detected. Extensive centrosome clustering both at mitotic spindles and in primary cilia mitigated the consequences of centrosome amplification, and primary ciliary formation was normal. Although further metabolic studies of patients with POC1A mutations are warranted, we suggest that POC1A may be added to ALMS1 and PCNT as examples of centrosomal or pericentriolar proteins whose dysfunction leads to extreme dyslipidaemic insulin resistance. Further investigation of links between these molecular defects and adipose tissue dysfunction is likely to yield insights into mechanisms of adipose tissue maintenance and regeneration that are critical to metabolic health