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Mitochondrial Hsp90s suppress calcium-mediated stress signals propagating from mitochondria to the ER in cancer cells

Background: Resistance to cell death in the presence of stressful stimuli is one of the hallmarks of cancer cells acquired during multistep tumorigenesis, and knowledge of the molecular mechanism of stress adaptation can be exploited to develop cancer-selective therapeutics. Mitochondria and the endoplasmic reticulum (ER) are physically interconnected organelles that can sense and exchange various stress signals. Although there have been many studies on stress propagation from the ER to mitochondria, reverse stress signals originating from mitochondria have not been well reported.Methods: After inactivation of the proteins by pharmacologic and genetic methods, the signal pathways were analyzed by fluorescence microscopy, flow cytometry, MTT assay, and western blotting. A mouse xenograft model was used to examine synergistic anticancer activity and the action mechanism of drugs in vivo.Results: We show in this study that mitochondrial heat shock protein 90 (Hsp90) suppresses mitochondria-initiated calcium-mediated stress signals propagating into the ER in cancer cells. Mitochondrial Hsp90 inhibition triggers the calcium signal by opening the mitochondrial permeability transition pore and, in turn, the ER ryanodine receptor, via calcium-induced calcium release. Subsequent depletion of ER calcium activates unfolded protein responses in the ER lumen, thereby increasing the expression of a pro-apoptotic transcription factor, CEBP homologous protein (CHOP). Combined treatment with the ER stressor thapsigargin and the mitochondrial Hsp90 inhibitor gamitrinib augmented interorganelle stress signaling by elevating CHOP expression, and showed synergistic cytotoxic activity exclusively in cancer cells in vitro and in vivo.Conclusions: Collectively, mitochondrial Hsp90s confer cell death resistance to cancer cells by suppressing the mitochondria-initiated calcium-mediated interorganelle stress response.open0

Shear-wave elastography in breast ultrasonography: the state of the art

Shear-wave elastography (SWE) is a recently developed ultrasound technique that can visualize and measure tissue elasticity. In breast ultrasonography, SWE has been shown to be useful for differentiating benign breast lesions from malignant breast lesions, and it has been suggested that SWE enhances the diagnostic performance of ultrasonography, potentially improving the specificity of conventional ultrasonography using the Breast Imaging Reporting and Data System criteria. More recently, not only has SWE been proven useful for the diagnosis of breast cancer, but has also been shown to provide valuable information that can be used as a preoperative predictor of the prognosis or response to chemotherapy

Inflammatory Responses Are Not Sufficient to Cause Delayed Neuronal Death in ATP-Induced Acute Brain Injury

BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc) and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+) and Iba-1(+) cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+) cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side) did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular components (microglia, astrocytes, monocytes, and neutrophils) and different factors (proinflammatory and neurotrophic) could be produced in inflammatory processes depending on the nature of the injury. The results in this study suggest that the inflammatory responses of microglia and monocytes in response to ATP-induced acute injury could not be neurotoxic

Application of computer-aided diagnosis in breast ultrasound interpretation: improvements in diagnostic performance according to reader experience

Purpose The purpose of this study was to evaluate the usefulness of applying computer-aided diagnosis (CAD) to breast ultrasound (US), depending on the reader's experience with breast imaging. Methods Between October 2015 and January 2016, two experienced readers obtained and analyzed the grayscale US images of 200 cases according to the Breast Imaging Reporting and Data System (BI-RADS) lexicon and categories. They additionally applied CAD (S-Detect) to analyze the lesions and made a diagnostic decision subjectively, based on grayscale US with CAD. For the same cases, two inexperienced readers analyzed the grayscale US images using the BI-RADS lexicon and categories, added CAD, and came to a subjective diagnostic conclusion. We then compared the diagnostic performance depending on the reader's experience with breast imaging. Results The sensitivity values for the experienced readers, inexperienced readers, and CAD (for experienced and inexperienced readers) were 91.7%, 75.0%, 75.0%, and 66.7%, respectively. The specificity values for the experienced readers, inexperienced readers, and CAD (for experienced and inexperienced readers) were 76.6%, 71.8%, 78.2%, and 76.1%, respectively. When diagnoses were made subjectively in combination with CAD, the specificity significantly improved (76.6% to 80.3%) without a change in the sensitivity (91.7%) in the experienced readers. After subjective combination with CAD, both of the sensitivity and specificity improved in the inexperienced readers (75.0% to 83.3% and 71.8% to 77.1%). In addition, the area under the curve improved for both the experienced and inexperienced readers (0.84 to 0.86 and 0.73 to 0.80) after the addition of CAD. Conclusion CAD is more useful for less experienced readers. Combining CAD with breast US led to improved specificity for both experienced and inexperienced readers

Nanostructured, Self-Assembling Peptide K5 Blocks TNF-α and PGE2 Production by Suppression of the AP-1/p38 Pathway

Nanostructured, self-assembling peptides hold promise for a variety of regenerative medical applications such as 3D cell culture systems, accelerated wound healing, and nerve repair. The aim of this study was to determine whether the self-assembling peptide K5 can be applied as a carrier of anti-inflammatory drugs. First, we examined whether the K5 self-assembling peptide itself can modulate various cellular inflammatory responses. We found that peptide K5 significantly suppressed the release of tumor-necrosis-factor- (TNF-) α and prostaglandin E2 (PGE2) from RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS). Similarly, there was inhibition of cyclooxygenase- (COX-) 2 mRNA expression assessed by real-time PCR, indicating that the inhibition is at the transcriptional level. In agreement with this finding, peptide K5 suppressed the translocation of the transcription factors activator protein (AP-1) and c-Jun and inhibited upstream inflammatory effectors including mitogen activated protein kinase (MAPK), p38, and mitogen-activated protein kinase kinase 3/6 (MKK 3/6). Whether this peptide exerts its effects via a transmembrane or cytoplasmic receptor is not clear. However, our data strongly suggest that the nanostructured, self-assembling peptide K5 may possess significant anti-inflammatory activity via suppression of the p38/AP-1 pathway

Cell-free synthesis of functional phospholipase A1 from Serratia sp.

Additional file 1: Figure S1 Gas chromatography analysis of sesame oil incubated with cell-free synthesized PLA1