Finger-attachment device for the feedback of gripping and pulling force in a manipulating system for brain tumor resection

Purpose: Development and evaluation of an effective attachment device for a bilateral brain tumor resection robotic surgery system based on the sensory performance of the human index finger in order to precisely detect gripping- and pulling-force feedback. Methods: First, a basic test was conducted to investigate the performance of the human index finger in the gripping- and pulling-force feedback system. Based on the test result, a new finger-attachment device was designed and constructed. Then, discrimination tests were conducted to assess the pulling force and the feedback on the hardness of the gripped material. Results: The results of the basic test show the application of pulling force on the side surface of the finger has an advantage to distinguish the pulling force when the gripping force is applied on the finger-touching surface. Based on this result, a finger-attachment device that applies a gripping force on the finger surface and pulling force on the side surface of the finger was developed. By conducting a discrimination test to assess the hardness of the gripped material, an operator can distinguish whether the gripped material is harder or softer than a normal brain tissue. This will help in confirming whether the gripped material is a tumor. By conducting a discrimination test to assess the pulling force, an operator can distinguish the pulling-force resistance when attempting to pull off the soft material. Pulling-force feedback may help avoid the breaking of blood pipes when they are trapped in the gripper or attached to the gripped tissue. Conclusion: The finger-attachment device that was developed for detecting gripping- and pulling-force feedback may play an important role in the development of future neurosurgery robotic systems for precise and safe resection of brain tumors. © 2017 CARSEmbargo Period 12 month

Prospective randomized study for optimal insulin therapy in type 2 diabetic patients with secondary failure

<p>Abstract</p> <p>Background</p> <p>The large clinical trials proved that Basal-Bolus (BB) insulin therapy was effective in the prevention of diabetic complications and their progression. However, BB therapy needs multiple insulin injections per a day. In this regard, a biphasic insulin analogue needs only twice-daily injections, and is able to correct postprandial hyperglycemia. Therefore it may achieve the blood glucose control as same as that of BB therapy and prevent the diabetic complications including macroangiopathy.</p> <p>Methods</p> <p>In PROBE (Prospective, Randomized, Open, Blinded-Endpoint) design, forty-two type 2 diabetic patients (male: 73.8%, median(inter quartile range) age: 64.5(56.8~71.0)years) with secondary failure of sulfonylurea (SU) were randomly assigned to BB therapy with a thrice-daily insulin aspart and once-daily basal insulin (BB group) or to conventional therapy with a twice-daily biphasic insulin analogue (30 Mix group), and were followed up for 6 months to compare changes in HbA1c, daily glycemic profile, intima-media thickness (IMT) of carotid artery, adiponectin levels, amounts of insulin used, and QOL between the two groups.</p> <p>Results</p> <p>After 6 months, HbA1c was significantly reduced in both groups compared to baseline (30 Mix; 9.3(8.1~11.3) → 7.4(6.9~8.7)%, p < 0.01, vs BB;8.9(7.7~10.0) → 6.9(6.2~7.3)%, p < 0.01), with no significant difference between the groups in percentage change in HbA1c (30 Mix; -14.7(-32.5~-7.5)% vs BB -17.8(-30.1~-11.1)%, p = 0.32). There was a significant decrease in daily glycemic profile at all points except dinner time in both groups compared to baseline. There was a significant increase in the amount of insulin used in the 30 Mix group after treatment compared to baseline (30 Mix;0.30(0.17~0.44) → 0.39(0.31~0.42) IU/kg, p = 0.01). There was no significant difference in IMT, BMI, QOL or adiponectin levels in either group compared to baseline.</p> <p>Conclusion</p> <p>Both BB and 30 mix group produced comparable reductions in HbA1c in type 2 diabetic patients with secondary failure. There was no significant change in IMT as an indicator of early atherosclerotic changes between the two groups. The basal-bolus insulin therapy may not be necessarily needed if the type 2 diabetic patients have become secondary failure.</p> <p>Trial registration</p> <p>Current Controlled Trials number, NCT00348231</p

Ossified peripheral middle cerebral artery aneurysm in a 30-year-old man

金沢大学附属病院脳神経外科A 30-year-old man presented with a history of several convulsive episodes. A CT scan showed a calcified focus in the right temporal lobe. Cerebral angiography yielded no abnormal findings. At craniotomy, the M3 portion of the middle cerebral artery was found to terminate with a blind end at the junction with the calcified mass. A pathological diagnosis of an ossified cerebral aneurysm was made. Calcified cerebral aneurysms are not rare; they are thought to be the result of intra-aneurysmal thrombosis or degenerative changes in the aneurysmal wall. However, complete mural ossification of a cerebral aneurysm is seldom seen, and ossified peripheral middle cerebral artery aneurysms are extremely rare in young individuals. The ossified aneurysm that we report developed over a prolonged period and may have arisen during childhood. © 2008 Elsevier Ltd. All rights reserved

An emerging strategy for cancer treatment targeting aberrant glycogen synthase kinase 3β

金沢大学がん研究所分子標的がん医療研究開発センターImprovement in the outcome of cancer patients who are refractory to currently available treatments relies on the development of target-directed therapies. One group of molecular targets with potential clinical relevance is a set of protein tyrosine kinases encoded mostly by proto-oncogenes and that are frequently deregulated in cancer. Glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, has emerged as a therapeutic target for common chronic diseases including type 2 diabetes mellitus, neurodegenerative disorders, inflammation and osteoporosis. This is based on its currently known functions and primary pathologic causalities. GSK3β has well characterized roles in the regulation of gene transcription and in oncogenic signaling. We have shown that deregulated GSK3β promotes gastrointestinal, pancreatic and liver cancers and glioblastomas. Furthermore, we have demonstrated that inhibition of GSK3β attenuates cancer cells survival and proliferation, induces cell senescence and apoptosis and sensitizes tumor cells to chemotherapeutic agents and ionizing radiation. This has led us to propose GSK3β as a potential therapeutic target in cancer. The anti-tumor effects of GSK3β inhibition are mediated by changes in the expression and phosphorylation of molecules critical to the regulation of cell cycling, proliferation and apoptosis and underlie the pathological role for GSK3β in cancer. Investigation of the mechanisms responsible for deregulation of GSK3β and the consequent downstream pathologic effects in cancer cells has shed light on the molecular pathways leading to tumorigenesis. This will allow exploration of novel therapeutic strategies for cancer that target aberrant GSK3β. © 2009 Bentham Science Publishers Ltd

Inhibition of GSK-3β activity attenuates proliferation of human colon cancer cells in rodents

The authors\u27 recent discovery that glycogen synthase kinase-3β (GSK-3β) participates in colon cancer cells\u27 survival and proliferation prompted us to investigate whether GSK-3β inhibition alters proliferation of colon cancer cells in vivo. Groups of four or five athymic mice (Balb/c, nu/nu) with subcutaneous xenografts of SW480 human colon cancer cells were treated with dimethyl sulfoxide (DMSO) or different doses (1, 2 and 5mg/kg body weight) of either small-molecule GSK-3β inhibitor (SB-216763 and AR-A014418) by intraperitoneal injection three times per week for 5 weeks. Compared with DMSO (a diluent of the GSK-3β inhibitors) as a control, either GSK-3β inhibitor significantly inhibited proliferation of cancer cell xenografts in the rodents in a dose-dependent manner. Histochemical and immunohistochemical analysis of tumor xenografts demonstrated a significant, dose-dependent decrease in fractions of proliferating cells and an increase in the incidence of apoptosis of cancer cells in mice treated with either GSK-3β inhibitor. No adverse events or effects were observed in the rodents during the course of treatment, except for rare lethal accidents due to intraperitoneal injection. Morphological examination showed no apparent pathologic changes in major organs including the lungs, liver, pancreas, kidneys, spleen and large bowel of rodents treated with DMSO and the GSK-3β inhibitors. The results indicate that the GSK-3β inhibitors would be a novel class of therapeutic agent for colon cancer. © 2007 Japanese Cancer Association

Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy

Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes. © 2016 Japanese Cancer Association.(Please refer to a different file for the Supporting information of this article.

Deregulated GSK3β sustains gastrointestinal cancer cells survival by modulating human telomerase reverse transcriptase and telomerase

金沢大学がん研究所分子標的がん医療研究開発センターPurpose: Glycogen synthase kinase-3β (GSK3β) regulates multiple cell signaling pathways and has been implicated in glucose intolerance, neurodegenerative disorders, and inflammation. We investigated the expression, activity, and putative pathologic role of GSK3β in gastrointestinal, pancreatic, and liver cancers. Experimental Design: Colon, stomach, pancreatic, and liver cancer cell lines; nonneoplastic HEK293 cells; and matched pairs of normal and tumor tissues of stomach and colon cancer patients were examined for GSK3β expression and its phosphorylation at serine 9 (inactive form) and tyrosine 216 (active form) by Western immunoblotting and for GSK3β activity by in vitro kinase assay. The effects of small-molecule GSK3β inhibitors and of RNA interference on cell survival, proliferation, and apoptosis were examined in vitro and on human colon cancer cell xenografts in athymic mice. The effects of GSK3β inhibition on human telomerase reverse transcriptase (hTERT) expression and telomerase activity were compared between colon cancer and HEK293 cells. Results: Cancer cell lines and most cancer tissues showed increased GSK3β expression and increased tyrosine 216 phosphorylation and activity but decreased serine 9 phosphorylation compared with HEK293 cells and nonneoplastic tissues. Inhibition of GSK3β resulted in attenuated cell survival and proliferation and increased apoptosis in most cancer cell lines and in HT-29 xenografts in rodents but not in HEK293 cells. GSK3β inhibition in colon cancer cells was associated with decreased hTERT expression and telomerase activity. Conclusion: The results indicate that deregulated GSK3β sustains gastrointestinal cancer cells survival through modulation of hTERT and telomerase. © 2009 American Association for Cancer Research

Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex

Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3′ untranslated region (3′-UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3′-UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3′-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node