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Supplementary Video 3 from Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

Supplementary Video 5 from Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

Supplementary Video 6 from Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]

Supplementary Video 1 from Role of the Polarity Determinant Crumbs in Suppressing Mammalian Epithelial Tumor Progression

Atherosclerosis is a chronic disease of arteries, which constitutes the pathological basis of a series of cardiovascular diseases. The inflammatory response of vascular endothelial cells mediated by oxidized low density lipoprotein (ox-LDL) is the early behavior and main signal of atherosclerosis. In this study, the damage model of vascular endothelial cells treated with ox-LDL was used to reproduce the damage process of vascular endothelial cells in the process of atherosclerosis. Cell viability was detected by CCK-8. The release levels of reactive oxygen species, nitric oxide, and superoxide dismutase (SOD) were detected by commercial kits. EdU cell proliferation assay was used to detect cell proliferation, real-time fluorescent quantitative PCR and Western blot were used to detect the expression level of related genes. The results showed we successfully constructed a vascular endothelial injury model by incubating vascular endothelial cells with gradient concentrations of ox-LDL. The incubation of safflor yellow A (SYA) partially restored the loss of viability of vascular endothelial cells mediated by ox-LDL, and SYA could promote the proliferation of injured vascular endothelial cells. In addition, SYA may transmit related signals through the AMPK pathway to protect vascular endothelial cells from ox-LDL-mediated damage. All these results provide a further understanding of the occurrence and development of atherosclerosis, provide a theoretical basis for the use of SYA-related drugs in the treatment of cardiovascular diseases, and provide a reference paradigm for studying the pharmacology, toxicology, and mechanism of action of key active substances in TCM.

To palliate suffering, understanding the circumstances leading to suffering and its amelioration could be helpful. Our study aimed to explore contributing and relieving factors of suffering in palliative care. Adult palliative care stage III or IV cancer in-patients were recruited from University of Malaya Medical Centre. Participants recorded their overall suffering score from 0 to 10 three times daily, followed by descriptions of their contributing and relieving factors. Factors of suffering were thematically analysed with NVIVO. Descriptive data were analysed with SPSS. 108 patients participated. The most common contributing factor of suffering was health factor (96.3%), followed by healthcare factor (78.7%), psychological factor (63.0%) and community factor (20.4%). The most common relieving factor was health factor (88.9%), followed by psychological factor (78.7%), community factor (75.9%) and healthcare factor (70.4%). Self-reported assessment of suffering offers a rapid approach to detect bothering issues that require immediate attention and further in-depth exploration.

Purpose To validate a 10-point scoring system for the prediction of successful treatment modality in patients with cesarean scar pregnancy (CSP). Patients and methods Data were collected from women seen between April 1, 2018, and June 30, 2019, at the Second Affiliated Hospital of Army Medical University of China who were diagnosed with CSP and underwent evacuation, followed by uterine artery embolization (UAE) and successive laparoscopic local resection as salvage treatment if necessary. A score was computed based on clinical and ultrasonographic parameters included in a previously developed scoring system. Treatment indicated by the scoring system was compared with actual treatment received. Receiver operating characteristic (ROC) curves were used to identify cut-off scores for salvage treatment. Results Of 183 women, 108 were successfully treated by evacuation, 57 required UAE, and 18 eventually underwent laparoscopic surgery. Among 97 women scoring 0-4, 89 (91.8%) were treated by evacuation only. Of 69 women scoring between 5 and 7, 44 (63.8%) needed UAE following evacuation. Of 17 women scoring 8-10, 10 women (58.8%) underwent laparoscopic surgery. A cut-off of 4.145 was obtained by ROC curve for prediction of any salvage treatment; this was comparable to the scale's conventional cut-off of 4. The cut-off score for women requiring laparoscopic surgery was 6.580, which was lower than 8 obtained in the scale's initial validation. Conclusion The overall performance of the 10-point scoring system was moderate for predicting successful treatment modalities of women with CSP, but the scale showed good predictive ability in recognizing women needing only evacuation before recovery.

Background and objectives: Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia, and can be divided into amnestic and non-amnestic types. Patients with amnestic MCI present with memory impairments that are often considered as the early manifestation of Alzheimer’s disease. Patients with amnestic MCI are more likely to progress to Alzheimer’s disease than patients with non-amnestic MCI. The U.S. Food and Drug Administration has not yet approved any drug that can treat amnestic MCI. Moxibustion is a common noninvasive traditional oriental intervention, which uses mainly the heat generated by burning herbal preparations containing moxa and mugwort (Artemisia vulgaris) to simulate acupoints for alleviating the symptoms. To date, many clinical studies have investigated the clinical use of moxibustion to improve memory impairments of Alzheimer’s disease, but these have failed to make a distinction between amnestic and non-amnestic MCI. Therefore, this trial has been designed to assess the effectiveness of moxibustion on amnestic MCI using the Montreal Cognitive Assessment Scale. We will also assess the safety of moxibustion in healthy controls, and analyze the variation of brain functional connectivity and effective brain networks in patients with amnestic MCI undergoing moxibustion using function magnetic resonance imaging. Design: This is a prospective, single-center, randomized controlled clinical trial. Methods: This study will enroll 64 patients with amnestic MCI and 48 healthy controls at Baoan People’s Hospital, Shenzhen, China. The first 64 recruited patients with amnestic MCI will be randomly divided into moxibustion, placebo moxibustion, drug, and control groups (n = 16 per group). In the moxibustion group, patients will be given moxa-wool moxibustion for 12 consecutive weeks. The placebo moxibustion group will receive placebo moxibustion on the same acupoints. Patients in the drug group will be given oral administration of donepezil hydrochloride tablets, 5 mg daily, for 12 consecutive weeks. The control group will receive no intervention. Forty-eight healthy controls will also be randomly assigned into moxibustion, placebo moxibustion, and control groups (n = 16 per group). Interventions will be the same as those received by the patients with amnestic MCI. Evaluators will be blind to group allocation. Outcome measures and preliminary results: The primary outcome measure will be the improvement in cognitive function 12 months after treatment. Secondary outcome measures will be the scores on the Montreal Cognitive Assessment Scale, Clinical Dementia Rating Scale, Mini-Mental State Examination Scale, and Activity of Daily Living Scale before treatment, after 12 weeks of treatment, and 6 months after the end of treatment, as well as brain function analysis before treatment and after 12 weeks of treatment and adverse events during treatment and follow-up. A correlation analysis between cognitive function scores and brain function results will be performed. Results of our preliminary study involving 60 patients with amnestic MCI who experienced moxibustion or received no treatment showed that moxibustion on acupoints significantly improved cognitive ability and quality of sleep in patients relative to the baseline and compared with the control group. Moreover, the scores on attention and delayed recall in the moxibustion group after treatment were significantly higher than those at base line. In the control group the scores on visual space, execution, and delayed recall were significantly lower than those at baseline. These findings indicate that moxibustion improves patient’s attention and delayed recall. If not, visual space, execution, and delayed recall in MCI patients tend to be declined over time. No obvious adverse responses to moxibustion treatment occurred in the preliminary study. Discussion: This proposed trial has the potential to uncover that moxibustion will enhance cognitive-related brain function connections and effector brain networks, which is not yet known. If moxibustion is shown to be an effective and safe treatment strategy in patients with amnestic MCI, then this may pave the way for use of this treatment in clinic amnestic MCI. Ethics and dissemination: This study was approved by the Medical Ethics Committee of the Chinese Clinical Trial Registry (approval No. ChiECRCT-2017018) in October 2016, and registered on April 2017. The study was designed in June 2016. Patient recruitment was initialized in October 2016. Data analysis will be completed in December 2019. Results will be disseminated through publication in a peer-reviewed journal. Protocol version: 1.0. Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-POC-17011162).

Dimethylsulfide (DMS) is an important and dominant sulfur compound that is transferred from the ocean to the atmosphere. In this study, the spatiotemporal variations in DMS concentrations and its two closely related compounds, namely, dimethylsulfoniopropionate (DMSP) and acrylic acid (AA), were investigated in the Yangtze (Changjiang) River Estuary and its adjacent waters, where the salinity changed dramatically in June 2014. The concentration ranges (average values) of DMS, DMSP, and AA were 1.10–27.5 (8.53), 5.93–195 (40.1), and 4.2–122.6 (17.9) nmol L −1 in the surface waters, respectively. The DMS and DMSP concentrations were higher in the study area than in its neighboring regions because of the high levels of nutrients originating in the Yangtze and Qiantang Rivers. However, the AA concentration was lower in the study area. Although no significant correlations were found between DMS, DMSP, or AA and salinity, high concentrations of DMS, AA, and DMSP were recorded between the salinity levels of 26‰ and 31‰. DMS and AA concentrations were positively correlated with chlorophyll a . The average AA/(DMSP+AA) and DMS/(DMSP+AA) ratios were 36.9% and 17.1%, respectively. The vertical profiles of DMSP and DMS presented similar variation patterns, and high concentrations of both compounds were mostly detected in the surface waters. By contrast, AA showed a different variation pattern compared with those of DMSP and DMS because AA could have other potential sources. The low average sea-to-air flux of DMS (that is, 6.55 μmol m −2 d −1 ) was mainly attributed to the low wind speed in early summer.

Based on the density functional theory, we investigate the structural, electronic, and magnetic properties of graphene sheet with substitutional Ge atoms in both single and double vacancies, and graphene sheet with Ge-chain impurity. We find the substitutional Ge is chemically bonded to graphene, and is more stable in the double vacancy site. The electronic properties indicate that metallic and semiconductor states with a range of band gaps from 0 to 0.87 eV could be obtained depending on different substitution sites, concentrations, and vacancy types. Magnetic moment is observed in graphene with single vacancy. Tunable electronic behaviors are also observed in graphene sheet with Ge-chain impurity, and a magnetic moment of 2.9 μB is observed in single Ge-chain incorporated 4 × 4 graphene supercell. From these investigations, we conclude that by doping of Ge in vacancy-contained graphene, it could provide great advantages for its application in future nanoscale devices.

ContextNumerous studies have shown that gratitude can reduce stress and improve quality of life.ObjectiveOur study aimed to examine the effect of mindful gratitude journaling on suffering, psychological distress and quality of life of patients with advanced cancer.MethodsWe conducted a parallel-group, blinded, randomised controlled trial at the University of Malaya Medical Centre, Malaysia. Ninety-two adult patients with advanced cancer, and an overall suffering score ≥4/10 based on the Suffering Pictogram were recruited and randomly assigned to either a mindful gratitude journaling group (N=49) or a routine journaling group (N=43).ResultsAfter 1 week, there were significant reductions in the overall suffering score from the baseline in both the intervention group (mean difference in overall suffering score=−2.0, 95% CI=−2.7 to −1.4, t=−6.125, p=0.000) and the control group (mean difference in overall suffering score=−1.6, 95% CI=−2.3 to −0.8, t=−4.106, p=0.037). There were also significant improvements in the total Hospital Anxiety and Depression Scale score (mean difference=−3.4, 95% CI=−5.3 to −1.5, t=−3.525, p=0.000) and the total Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being score (mean difference=7.3, 95% CI=1.5 to 13.1, t=2.460, p=0.014) in the intervention group after 7 days, but not in the control group.ConclusionThe results provide evidence that 7 days of mindful gratitude journaling could positively affect the state of suffering, psychological distress and quality of life of patients with advanced cancer.Trial registration numberThe trial was registered with the Australian and New Zealand Clinical Trials Registry (ACTRN1261800172191) and conducted in accordance with the Declaration of Helsinki.

Functional magnetic resonance imaging has been widely used to investigate the effects of acupuncture on neural activity. However, most functional magnetic resonance imaging studies have focused on acute changes in brain activation induced by acupuncture. Thus, the time course of the therapeutic effects of acupuncture remains unclear. In this study, 32 patients with amnestic mild cognitive impairment were randomly divided into two groups, where they received either Tiaoshen Yizhi acupuncture or sham acupoint acupuncture. The needles were either twirled at Tiaoshen Yizhi acupoints, including Sishencong (EX-HN1), Yintang (EX-HN3), Neiguan (PC6), Taixi (KI3), Fenglong (ST40), and Taichong (LR3), or at related sham acupoints at a depth of approximately 15 mm, an angle of ± 60°, and a rate of approximately 120 times per minute. Acupuncture was conducted for 4 consecutive weeks, five times per week, on weekdays. Resting-state functional magnetic resonance imaging indicated that connections between cognition-related regions such as the insula, dorsolateral prefrontal cortex, hippocampus, thalamus, inferior parietal lobule, and anterior cingulate cortex increased after acupuncture at Tiaoshen Yizhi acupoints. The insula, dorsolateral prefrontal cortex, and hippocampus acted as central brain hubs. Patients in the Tiaoshen Yizhi group exhibited improved cognitive performance after acupuncture. In the sham acupoint acupuncture group, connections between brain regions were dispersed, and we found no differences in cognitive function following the treatment. These results indicate that acupuncture at Tiaoshen Yizhi acupoints can regulate brain networks by increasing connectivity between cognition-related regions, thereby improving cognitive function in patients with mild cognitive impairment.

The general modular management theory takes organizational structure, work flow and product design and production as the core. In practice, it only pays attention to a certain aspect of modularization, and does not establish a comprehensive and unified modular management system. In this context, this article, guided by modular thinking, constructs a comprehensive management model based on modular thinking, and elaborates on the basic management structure of the modular management system. Meanwhile, this paper discusses the practical requirements of promoting modular management mode from the perspective of system, stability and moderation. It is hoped that this research can promote the theoretical innovation of comprehensive modular management and also provide a reference for the innovative practice of enterprise business models.

Animal manure waste is considered as an environmental challenge especially in farming areas mainly because of gaseous emission and water pollution. Among all the pollutants emitted from manure waste, ammonia is of greatest concern as it could contribute to formation of aerosols in the air and could hardly be controlled by traditional disposal methods like landfill or composting. On the other hand, manure waste is also a renewable source for energy production. In this work, an environmental friendly animal waste disposal process with combined ammonia recovery and energy production was proposed and investigated both experimentally and economically. Lab-scale feasibility study results showed that 70% of ammonia in the manure waste could be converted to struvite as fertilizer, while solid manure waste was successfully gasified in a 10kW downdraft fixed-bed gasifier producing syngas with the higher heating value of 4.9MJ/(Nm3). Based on experimental results, economic study for the system was carried out using a cost-benefit analysis to investigate the financial feasibility based on a Singapore case study. In addition, for comparison, schemes of gasification without ammonia removal and incineration were also studied for manure waste disposal. The results showed that the proposed gasification-based manure waste treatment process integrated with ammonia recovery was most financially viable.

This paper established a multi-level extension model for function effects post-evaluation of substation construction project, the model not only reduces the influence of subjective factors on the evaluation results, but also can determines the key factors which affect the quality of the evaluation results and overall developing trend of the project and provides some suggestions for the project late operation. Taking into account the fact that the element of the judgment matrix formed by traditional AHP is a certain value and may lead to a big difference from the judgment matrix formed by the different group of experts, thus reduces the credibility of the evaluation results; In order to overcome the problem, this paper introduces the concept of interval number, the maximum and minimum of judgment matrix elements relative importance comparison are used as the upper and lower limits of interval number respectively. Interval number are used as the elements of judgment matrix to make the evaluation result more rational. At the end, a practical 220kV substation construction project is taken as an example to verify the validity and rationality of the established model.

With the development of modern aircraft, and the increasing aircraft performance day by day, the pilot need gain more and more information. The application of the large screen makes a lot of flight information on one display monitors. The large screen display picture is composed of several child pictures, which need several displayers formerly, but the display operation is not as convenient as traditional independent operating monitors. This paper proposes a method based on sprite in large screen display contrast and adjustment, through the collection of pilots’ touch screen operation information on the screen. And then it implements the sprite window open and the adjustment of the contrast in the FPGA. Using the proposed approach, the pilot can easily adjust the contrast of sprite in the large screen display, meeting the modern aircraft in all aspects of the mission requirements.

The polarization effect introduced by electric field deformation is the most important bottleneck of CdZnTe detector in x-ray imaging. Currently, most of studies focus on electric field deformation caused by trapped carriers; the perturbation of electric field due to drifting carriers has been rarely reported. In this study, the effect of transient space–charge perturbation on carrier transport in a CdZnTe semiconductor is evaluated by using the laser-beam-induced current (LBIC) technique. Cusps appear in the current curves of CdZnTe detectors with different carrier transport performances under intense excitation, indicating the deformation of electric field. The current signals under different excitations are compared. The results suggest that with the increase of excitation, the amplitude of cusp increases and the electron transient time gradually decreases. The distortion in electric field is independent of carrier transport performance of detector. Transient space–charge perturbation is responsible for the pulse shape and affects the carrier transport process.

We have prepared amorphous hydrogenated germanium carbon (a-Ge1−xCx:H) films by radio frequency (RF) reactive magnetron sputtering and their composition, optical, electrical and chemical bonding properties are investigated as a function of RF power. The results show that the deposition rate increases and the optical gap of the a-Ge1−xCx:H films decreases as RF power increases from 30 to 90 W. The decrease of the optical gap is mainly due to the decrease in the carbon content. As increasing RF power, the refractive index of the films increases and the absorption edge shifts to long wavelength region. Besides, the room temperature dark conductivity increase with RF power is due to the decrease of the activation energy connected with the increase of Ge content. Through the analysis of X-ray photoelectron spectroscopy (XPS), we found that the formation of Ge–C bonds in the films is promoted by high RF power connected with relatively high self-bias and Ge content.

A first-principles study based on the density functional theory has been carried out to investigate the electronic and optical properties of zinc-blende GeC 1− x B x with various boron concentrations. The calculated lattice parameters of zinc-blende GeC are in good agreement with the previous computations, and the substitution of C with B in GeC induces an increase in the lattice parameters. The calculated results show that the band gap of GeC transforms from indirect band gap to direct band gap and shrinks after C atom is replaced by B atom. The static dielectric constants of B-doped GeC are found to be remarkably large, so it may act as a new dielectric material. Furthermore, after B doping, a new absorption peak appears in the infrared band (0–2 eV) and will intensify with the increase of doping concentration. All the calculated optical properties show a red shift property.

Based on the first-principles density-functional theory, the electronic structures and optical properties of monoclinic HfO2 and Ti-doped m-HfO2 are comparatively investigated. The calculated lattice parameters of m-HfO2 are in good agreement with the experimental values and the previous works, and the incorporation of Ti into HfO2 induces a decrease in the lattice parameters. Electronic structures of m-HfO2 and Ti-doped HfO2 are studied through the densities of states (DOS) and band structures. The results indicate that the Ti substitution of Hf sites modifies the conduction band structure of HfO2, which leads to a reduction of the band gap of HfO2. The complex dielectric function and refractive index are calculated and the peak position distributions of imaginary parts of the complex dielectric function have been explained. The calculated optical properties are consistent with the experimental measurements for m-HfO2.

An increasing web services run in mobile context. Context may influence customer potential needs and buying behaviors in some specific situation. However existent customer segmentation method do not attach importance to context factors, which weakly support the development of context-sensitive mobile service . Therefore a mobile customer segmentation method based on context is proposed and validated by a case. The further research is mentioned in the end of the paper.

The knowledge of preference drift is important to maintain the user’s preference accurate. With the swift development of mobile service the recognition of such knowledge has attracted immense attention in recent times. However, existing research based on clustering is inadequate for the description of item objects with weak N-ary associations. This paper, through the analysis of contextual recommendation, proposes a “hypergraph model” for contextual items. Furthermore, similarities between pair of items, item clusters and the degree of user preference drift are defined. Based on above definitions, a method to discover user preference drift is proposed. In addition two experiments are being carried out to validate its significance.

Clinical and experimental data now clearly indicate that chronic inflammation significantly contributes to cancer development. Emerging out of these studies is an appreciation that persistent humoral immune responses exacerbate recruitment and activation of innate immune cells in neoplastic microenvironments where they regulate tissue remodeling, pro-angiogenic and pro-survival pathways that together potentiate cancer development. Population-based studies examining individuals with chronic inflammatory disorders have revealed that states of suppressed cellular immunity, in combination with enhanced humoral immunity and humoral immunity-associated cytokines, cooperate and effectively suppress anti-tumor immune responses while simultaneously enhancing angiogenesis and presumably overall cancer risk in afflicted tissue. In addition, studies in transgenic mouse models of de novo organ-specific cancer development have revealed that inflammation mediated by immunoglobulins and immune complexes might be functionally significant parameters of tumor promotion and progression. These recent advances support the hypothesis that enhanced states of local humoral and innate immune activation, in combination with suppressed cellular immunity and failed cytotoxic T cell anti-tumor immunity, alter cancer risk and therefore represent powerful targets for anti-cancer immunotherapeutics.

Genomic instability is a hallmark of cancer development and progression, and characterizing the stresses that create and the mechanisms by which cells respond to genomic perturbations is essential. Here we demonstrate that antiapoptotic BCL-2 family proteins promoted tumor formation of transformed baby mouse kidney (BMK) epithelial cells by antagonizing BAX- and BAK-dependent apoptosis. Cell death in vivo correlated with hypoxia and induction of PUMA (p53 up-regulated modulator of apoptosis). Strikingly, carcinomas formed by transformed BMK cells in which apoptosis was blocked by aberrant BCL-2 family protein function displayed prevalent, highly polyploid, tumor giant cells. Examination of the transformed BMK cells in vivo revealed aberrant metaphases and ploidy changes in tumors as early as 9 d after implantation, which progressed in magnitude during the tumorigenic process. An in vitro ischemia system mimicked the tumor microenvironment, and gain of BCL-2 or loss of BAX and BAK was sufficient to confer resistance to apoptosis and to allow for accumulation of polyploid cells in vitro. These data suggest that in vivo, even in cells in which p53 function is compromised, apoptosis is an essential response to hypoxia and ischemia in the tumor microenvironment and that abrogation of this response allows the survival of cells with abnormal genomes and promotes tumorigenesis.

Genetic aberrations were examined to assess the possible roles that p53 and retinoblastoma susceptibility genes might have played in the development of small cell cervical carcinomas. Cervical cancer tissues from 12 patients with small cell cervical carcinoma that were free of human papillomavirus were analyzed. The presence of mutational alterations were examined by polymerase chain reaction-single-strand conformation polymorphism and by direct DNA sequencing. None of 12 small cell cervical carcinomas were found to contain mutations in regions of p53 and retinoblastoma susceptibility genes that were functionally important and where most mutations in human tumors have been found. Furthermore, there was no evidence indicative of loss of heterozygosity of chromosome region 17p13 (in which p53 is located) in these tumors. These data seem to suggest that whereas mutant type of p53 and retinoblastoma susceptibility genes may exhibit “oncogenic” function in many human tumors, mutational inactivation of these genes may not be an important feature in the carcinogenic development of human papillomavirus-negative small cell cervical carcinomas. © 1994 Wiley-Liss, Inc.

Most tumors are epithelial-derived, and although disruption of polarity and aberrant cellular junction formation is a poor prognosticator in human cancer, the role of polarity determinants in oncogenesis is poorly understood. Using in vivo selection, we identified a mammalian orthologue of the Drosophila polarity regulator crumbs as a gene whose loss of expression promotes tumor progression. Immortal baby mouse kidney epithelial cells selected in vivo to acquire tumorigenicity displayed dramatic repression of crumbs3 (crb3) expression associated with disruption of tight junction formation, apicobasal polarity, and contact-inhibited growth. Restoration of crb3 expression restored junctions, polarity, and contact inhibition while suppressing migration and metastasis. These findings suggest a role for mammalian polarity determinants in suppressing tumorigenesis that may be analogous to the well-studied polarity tumor suppressor mechanisms in Drosophila. [Cancer Res 2008;68(11):4105–15]

Defects in apoptosis that evolve during the course of cancer progression not only provide cancer cells with intrinsic survival advantage, but also provide inherent resistance to chemotherapeutic agents. Thus, modulation of apoptosis by targeting components of the apoptotic machinery and its regulators to restore apoptotic function is a rational approach for treating cancer. With our increasing knowledge of the mechanisms of apoptosis regulation and of how apoptosis is disabled in cancer cells, numerous novel approaches targeting apoptotic pathways can now be exploited for cancer therapy. While most of these therapies are still in preclinical development, some have shown considerable promise and progressed into the clinic. This chapter summarizes the current knowledge of the apoptotic pathways and provides a selective review on the development of drugs that target the apoptotic machinery.

Defects in apoptosis that evolve during the course of cancer progression not only provide cancer cells with intrinsic survival advantage, but also provide inherent resistance to chemotherapeutic agents. Thus, modulation of apoptosis by targeting components of the apoptotic machinery and its regulators to restore apoptotic function is a rational approach for treating cancer. With our increasing knowledge of the mechanisms of apoptosis regulation and of how apoptosis is disabled in cancer cells, numerous novel approaches targeting apoptotic pathways can now be exploited for cancer therapy. While most of these therapies are still in preclinical development, some have shown considerable promise and progressed into the clinic. This chapter summarizes the current knowledge of the apoptotic pathways and provides a selective review on the development of drugs that target the apoptotic machinery.

SummaryDefective apoptosis not only promotes tumorigenesis, but also can confound chemotherapeutic response. Here we demonstrate that the proapoptotic BH3-only protein BIM is a tumor suppressor in epithelial solid tumors and also is a determinant in paclitaxel sensitivity in vivo. Furthermore, the H-ras/mitogen-activated protein kinase (MAPK) pathway conferred resistance to paclitaxel that was dependent on functional inactivation of BIM. Whereas paclitaxel induced BIM accumulation and BIM-dependent apoptosis in vitro and in tumors in vivo, the H-ras/MAPK pathway suppressed this BIM induction by phosphorylating BIM and targeting BIM for degradation in proteasomes. The proteasome inhibitor Velcade (P-341, Bortezomib) restored BIM induction, abrogated H-ras-dependent paclitaxel resistance, and promoted BIM-dependent tumor regression, suggesting the potential benefits of combinatorial chemotherapy of Velcade and paclitaxel.

To study the clinical manifestation, angiographic features, and prognosis of myocardial bridge.A retrospective analysis was made on the data of the clinical manifestation, coronary angiography, and prognosis of 35 patients with myocardial bridge, 29 males and 6 females, with an average age of 52.0 +/- 9.5 years, out of 2 871 patients undergoing coronary angiography 1 January 1996 - 20 February 2001.The detection rate of myocardial bridge, mostly in the middle or distal parts of left anterior descending branch and 24 being isolated myocardial bridge, was 1.22% in coronary angiography. There was a significant difference in the extent of diameter stenosis during systolic stage between the group with atherosclerosis (68% +/- 15%, n = 15) and the group without atherosclerosis (54% +/- 14%, n = 20) in the vessel proximal to myocardial bridge (P0.01). The systolic diameter stenosis was more severe in the abnormal ECG group (63% +/- 13%, n = 12) than in the normal ECG group (54% +/- 14%, n = 12), P0.05. However, the systolic stenosis extent of myocardial bridge in the patients with typical angina pectoris (58% +/- 15%, n = 11) was not significantly different from that in the patients with atypical angina pectoris (54% +/- 15%, n = 13). The systolic stenosis extent of myocardial bridge were 69% +/- 9% (n = 7) and 58% +/- 16% (n = 26) in the patients with and without left ventricular wall hypertrophy respectively (P = 0.09). No malignant event occurred during the follow-up period of 3 - 50 months.(1) The more severe the extent of systolic diameter stenosis, the more severe the myocardial ischemia and the more the possibility of abnormal ECG. (2) Myocardial bridge tends to promote or accelerate the atherosclerosis of the vessels proximal to it. (3) Left ventricular wall hypertrophy may promote the formation of myocardial bridge clinically. (4) The prognosis of myocardial bridge is good.

Cu/HfOx/n+Si devices are fabricated to investigate the influence of technological parameters including film thickness and Ar/O2 ratio on the resistive switching (RS) characteristics of HfOx films, in terms of switch ratio, endurance properties, retention time and multilevel storage. It is revealed that the RS characteristics show strong dependence on technological parameters mainly by altering the defects (oxygen vacancies) in the film. The sample with thickness of 20 nm and Ar/O2 ratio of 12:3 exhibits the best RS behavior with the potential of multilevel storage. The conduction mechanism of all the films is interpreted based on the filamentary model.

Resistive switching characteristics of hafnium oxide are studied for possible nonvolatile memory device applications. The HfOx films with different oxygen contents are deposited by rf magnetron sputtering under different O2 flow rates. The films are amorphous, and the stoichiometric of the film is improved by increasing the O2 flow rate. Current-voltage characteristics of the TiN/HfOx/ITO device are investigated with 1 mA compliance. The bipolar resistive switching behavior is observed for the TiN/HfOx/ITO structure, and the resistive switching mechanism of the TiN/HfOx/ITO structure is explained by trap-controlled space charge limit current conduction.