bluuebunny/crossref_metadata_2025 huggingface dataset:
On-wafer monitoring of electron and ion energy distribution at the bottom of contact hole
Authors: Ohtake Hiroto , Jinnai Butsurin , Suzuki Yuya , Soda Shinnosuke , Shimmura Tadashi , Samukawa Seiji
Published: April 2007

In situ on-wafer monitoring of the electron and ion energies at the contact-hole bottom is primarily achieved in Ar ultrahigh-frequency plasma. The on-wafer probe reveals a lower electron density and higher electron temperature at the contact-hole bottom due to the electron-shading effect, as compared with that in the bulk plasma. The on-wafer probe also shows the ion energy distribution function (IEDF) at the contact-hole bottom. The peak energy of IEDF corresponded to the sheath potential. Accordingly, the authors found that the on-wafer probe is a very effective tool for investigating the electron and ion energies in real SiO2 contact structures.
Electron-beam focusing characteristics of double-gated carbon nanofiber based field emission sources
Authors: Yang X. , Gardner W. L. , Baylor L. R. , Cui H. , Lowndes D. H. , Joy D. C. , Simpson M. L.
Published: April 2007

Recently, vertically aligned carbon nanofiber based dual-gate field emission structures have been fabricated for use in parallel electron-beam lithography, and their electron-beam focus adjustment capability has been demonstrated. This article summarizes the results of a numerical investigation of device behavior due to geometry variation in an effort to better understand device characteristics and performance. The effect of electrode thickness on minimum beam diameter and depth of field (DOF) were investigated for axially symmetric structures using a two-dimensional simulation package. The results indicate both a decrease in minimum spot size from ∼30to∼20nm, and an increase in DOF from ∼1to∼6μm when the focus electrode thickness is increased from 100to500nm. The impact of misalignments of the focus electrode and the carbon nanofiber on the beam behavior was investigated with a three-dimensional simulation package. Results show that reasonably well-converged beams can be achieved even with considerable offset to either the focus electrode or carbon nanofiber, though large beam deflections are produced. In addition, the deflections due to these offsets appear to be linear.
Field emitter array with a memory function for ultrahigh luminance field emission display
Authors: Nagao M. , Yasumuro C. , Taniguchi M. , Itoh S. , Kanemaru S. , Itoh J.
Published: April 2007

By adding a memory function to each pixel of a field emission display (FED), an ultrahigh luminance FED with a luminance of more than 10000cd∕m2 can be realized. For this purpose, the authors fabricated a field emitter array (FEA) with a memory function, in which a FEA, emission-control thin-film transistor (TFT), memory capacitor, and write-control TFT are monolithically integrated. They used an HfC-coated Si tip for the FEA because it enables a long emission lifetime. The TFT structure was optimized to control the emission current. The memory-function FEA was demonstrated in a vacuum chamber. The data holding time of the memory function was also measured. It was sufficiently long for display applications.
Sublithographic vertical gold nanogap for label-free electrical detection of protein-ligand binding
Authors: Jang Dong-Yoon , Kim Young-Pil , Kim Hak-Sung , Ko Park Sang-Hee , Choi Sung-Yool , Choi Yang-Kyu
Published: April 2007

Label-free electrical detection of protein-ligand binding using a vertical gold nanogap is presented. A sublithographic nanogap was created using a sacrificial ultrathin film deposited by atomic layer deposition (ALD) in a process similar to the formation of a cantilever in microelectromechanical system processing. Due to the atomic precision of the sacrificial Al2O3 thickness by ALD, a 7nm nanogap was successfully fabricated. After binding streptavidin to biotin on the gold surface, an electrical current was measured for various voltages. A dramatic current increase was observed in the case of biotin-streptavidin binding in comparison with the other two cases: a control group filled with air and a biotin-only binding group. There was a minimal current change in the cases of the biotin-PBST group, the biotin-BSA group, and the biotin-saturated streptavidin group, as compared with the biotin-streptavidin group. At a 0.1μg∕ml concentration of streptavidin (1.5nM), the current difference before and after the protein binding was amplified by approximately 3000-fold with 17nm nanogap. Also, the detection sensitivity of the vertical nanogap as the gap size varied was investigated. As the size of biotin-streptavidin binding is the most comparable to 12nm nanogap, the highest sensitivity was shown in the 12nm gap device. 7nm nanogap can be used to detect smaller size of biomolecule than that of biotin streptavidin. This arrayable, two-terminal microdevice could be tested for use on a wide range of other biomolecules.
Nanopatterning with 248nm photolithography by photostabilizing bilayer photoresists
Authors: Tsai F.-Y. , Jhuo S.-J. , Lee J.-T.
Published: April 2007

The authors demonstrated patterning of 35nm isolated lines with 248nm photolithography by photostabilizing a bilayer photoresist structure with a postdevelopment UV exposure. Overcoming the limitations of the conventional single-layer resist structure, the bilayer structure allowed the resist lines to drastically shrink in dimensions by ∼70% upon photostabilization, while maintaining their critical attributes including sidewall profile, dry etch resistance, and ability to be stripped, and eliminating the need for high-temperature baking during the process. Comparing two types of photoresists, environmentally stable chemically amplified positive (ESCAP) and acetal, as the top layer in the bilayer structure, the ESCAP-type resist’s shrinkage was ∼67% that of the acetal-type resist, as a result of its lower free-volume reduction and extent of cross-linking. C13 solid-state nuclear magnetic resonance spectra indicated that the photostabilized resists were cross-linked through bonding between the polymer backbones and between the backbones and the phenol side groups. The applicability of this photostabilization technique to device processing was confirmed with the fabrication of a ∼35nm insulator-metal-insulator junction, a structure similar to that of a typical giant magnetoresistive reader. Their technique may be readily extendable to other applications requiring nanopatterning.
Synthesis of germanium nanowires on insulator catalyzed by indium or antimony
Authors: Sun Xuhui , Calebotta Gabe , Yu Bin , Selvaduray Guna , Meyyappan M.
Published: April 2007

Chemically synthesized one dimensional germanium nanowires on insulator offer a viable nanomaterial platform for high-performance and low-power electronics. The use of noncontaminating metal catalysts and growth of nanowires on an insulator layer facilitate the direct integration of nanowire components into future nanoelectronic chips. Indium and antimony were used as catalysts for germanium nanowire growth in a simple thermal evaporation process. The self-assembly of germanium nanowire on insulator follows the vapor-liquid-solid process. Results show that the nanowires, 10–20nm in diameter and tens of microns in length are single crystals with a diamond cubic lattice structure and grow preferentially along the ⟨111⟩ crystallographic direction.
Hydrothermal synthesis and visible light photocatalysis of metal-doped titania nanoparticles
Authors: Han Tao-Yun , Wu Chu-Fu , Hsieh Chien-Te
Published: April 2007

A hydrothermal treatment was employed to implant three types of metal ions (Fe, Co, and Ni) into commercial TiO2 photocatalysts for improving the photocatalytic reactivity of methylene blue (MB) under visible light irradiation. Nitrogen physisorption measurement indicated that surface areas and porosities of metal-doped titania powders still maintain an identical value, compared to the starting material. The diffuse reflection spectra of metal-doped titania reflected a light absorption edge, shifting to the visible light range of approximately 400–700nm. According to the Kubelka-Munk plot, the optical band gaps were found to have the following order: Fedoping(2.98eV)>Codoping(2.88eV)>Nidoping(2.63eV), based on the fixed dopant concentration. A Langmuir-Hinshelwood model was used to investigate the photocatalytic activity for removing MB from the liquid phase. It was found that the photodegradation activity has an increasing trend with the decreasing optical band gap.
Residual gas analysis based on carbon nanotube field emission display
Authors: Wang Jinchan , Zhang Xiaobing , Lei Wei , Xiao Mei , Cui Yunkang , Di Yunsong , Mao Fuming
Published: April 2007

The authors measured the residual gas spectrum of a field emission display (FED) with carbon nanotube (CNT) emitters and found that the main residual gases inside a sealed CNT FED, containing an evaporated Ba getter, are H2, CH4, CO, Ar, and CO2, all of which are typical residual gases of electronic vacuum tubes. Additionally they also measured the electron stimulated desorption of gases by operating their field emission devices.
Characterization of all-Nb nanodevices fabricated by electron beam lithography and ion beam oxidation
Authors: Im Hyunsik , Pashkin Yu. A. , Yamamoto T. , Astafiev O. , Nakamura Y. , Tsai J.-S.
Published: April 2007

The authors present a reliable process that allows them to fabricate all-niobium nanodevices in a reproducible and well controlled way. Deposition of niobium thin films is done through a suspended mask formed in a Ge layer supported by a thermally stable polymer called phenylene-ether-sulfone, while the tunnel barrier is formed by ion beam oxidation of Nb surface. They study the effect of the fabrication conditions on the quality of narrow Nb stripes by measuring their transition temperature. Using dc transport measurements, they characterize tunnel junctions as well as single-electron transistors (SETs) and extract basic junction parameters, such as the barrier height, width, and specific capacitance. Low-frequency charge noise of all-Nb SETs at 50mK has a 1∕f power spectrum and the value of ∼4×10−3e∕Hz1∕2 at 1Hz.
Novel gun of rf power amplifier based on always-on cold cathode
Authors: Wang Qilong , Di Yunsong , Lei Wei , Zhang Xiaobing , Wang Jinchan , Mu Hui
Published: April 2007

A novel gun double hop gun of rf power amplifier based on an always-on ringed cold cathode is suggested. Double hopping electron funnels, including a metal funnel and a glass funnel, are fabricated in. MgO film is deposited around the walls of the funnels by electron beam evaporation. Secondary electrons or backscatters (elastic and inelastic) escape from the dielectric film (MgO) under the bombardment of accelerated electrons and are driven to the exit window of the glass funnel by a modulated voltage. Among the escaping electrons, the ratios of secondary emission electrons, elastic scatters, and inelastic scatters are 90%, 9%, and 1%, respectively. Most of the escaping electrons at the exit window have low energy (<50eV) and can be easily controlled by the modulated voltage with low amplitude (∼100V) applied on the electrode of the glass funnel. The average velocity in the Z direction of the escaping electrons increases as the amplitude of the modulated voltage (Vgate) increases. The distributions of the velocities in the X and Y directions are found to be symmetrical.
Emission current scaling in nanodiamond lateral field emission devices
Authors: Subramanian K. , Kang W. P. , Davidson J. L.
Published: April 2007

Batch-fabricated lateral fingerlike nanodiamond emitters with sharp apexes were characterized for emission current scaling to examine the scaling effect of the number of emitters with respect to the forward emission current. Three nanodiamond lateral device configurations were evaluated: 6- 125- and 2000-finger emitter structures. Current scaling behavior was observed for a given electric field, e.g., 10V∕μm, demonstrating emission current of 1.1, 11.3, and 109μA, respectively. The augmentation in overall emission current of the multifingered lateral emitters is attributed to the increase in the emitter area and thereby the number of potential emission sites in the cathode. Deviation from ideal scaling, factors contributing to deviation, and the design/process developments addressed to mitigate the nonideality are discussed.
Alteration in human defensin-5 expression following gastric bypass surgery
Authors: Sundbom M , Elphick D A , Mahida Y R , Cunliffe R N , Midtvedt T , Engstrand L , Rubio C , Axelsson L Göran
Published: April 2007

Background:Roux-en-Y gastric bypass surgery provides a novel human model to investigate small bowel mucosal innate immunity, in which there is loss of gastric acid-mediated protection against orally-acquired microorganisms.

Aim:To study changes in jejunal mucosal immunoreactivity of human defensin (HD)-5, an antimicrobial peptide normally produced by Paneth cells.

Methods:Mucosal samples were obtained from 18 female patients (24–54 years), from the same segment of jejunum during and after gastric bypass surgery. Samples were used for bacterial culture and immunohistochemistry using anti-HD-5 antibody. The number of immunoreactive cells per crypt and villus were determined and expressed as mean (SD).

Results:No bacteria were cultured from any of the perioperative jejunal samples but colonies of bacteria normally present in the pharynx were identified during culture of all postoperative jejunal biopsy specimens (1–>100 colonies). Paneth cell numbers per crypt were unchanged after gastric bypass (4.16 (0.71) vs 4.24 (0.78)). However, following surgery, there was an increase in HD-5-positive intermediate cells per crypt (0.25 (0.41) vs 1.12 (0.66), p<0.01), HD-5 staining enterocytes per crypt (0.03 (0.09) vs 1.38 (1.10), p<0.01), HD-5 staining material in the crypt lumen (crypt lumens: 5.0% (10.9%) vs 68.1% (27.9%), p<0.01) and HD-5 immunoreactivity coating the luminal surface of villus enterocytes (villi sampled: 15.0% (31.0%) vs 67.5% (42.0%), p<0.01).

Conclusions:Bacteria normally resident in the pharynx were present in the proximal jejunal mucosa following Roux-en-Y gastric bypass surgery. After gastric bypass, there was increased secretion of HD-5 and an increase in HD-5 expressing intermediate cells and enterocytes in the crypt. The increase in HD-5 expression in the jejunal mucosa following gastric bypass surgery is likely to be secondary to exposure to orally-acquired microorganisms.
Laboratory costs of a hospital-based blood transfusion service in Malawi
Authors: Lara Antonieta Medina , Kandulu James , Chisuwo Laphiod , Kashoti Andrew , Mundy Catherine , Bates Imelda
Published: April 2007

Background:

Despite policies advocating centralised transfusion services based on voluntary donors, the hospital-based replacement donor system is widespread in sub-Saharan Africa.

Aims:

To evaluate the cost of all laboratory resources needed to provide a unit of safe blood in rural Malawi using the family replacement donor system

Methods:

Full economic costs of all laboratory tests used to screen potential donors and to perform cross-matching were documented in a prospective, observational study in Ntcheu district hospital laboratory.

Results:

1729 potential donors were screened and 11 008 tests were performed to ensure that 1104 units of safe blood were available for transfusion. The annual cost of all transfusion-related tests (in 2005 US$) was $17 976, equivalent to $16.28 per unit of transfusion-ready blood. Transfusion-related tests used 53% of the laboratory’s total annual expenditure of $33 608.

Conclusions:

This is the first study to provide prospective economic costs of all laboratory tests associated with the family replacement donor system in a district hospital in Africa. Results show that despite potential economies of scale, a unit of blood from the centralised system costs about three times as much as one from the hospital-based “replacement” system. Factors affecting these relative costs are complex but are in part due to the cost of donor recruitment in centralised systems. In the replacement system the cost of donor recruitment is entirely borne by families of patients needing a blood transfusion.
Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: assessment of test sensitivity and impact of chromosome 17 polysomy
Authors: Hofmann M , Stoss O , Gaiser T , Kneitz H , Heinmöller P , Gutjahr T , Kaufmann M , Henkel T , Rüschoff J
Published: April 2007

Aims:

To investigate the correlation between centrally assessed human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) results and response to treatment of patients with metastatic breast cancer enrolled in a first-line, phase II, open-label, 3-weekly trastuzumab (Herceptin) monotherapy trial (WO16229).

Methods:

Samples from participants in the WO16229 trial were collected and tumour HER2 status determined by IHC and FISH. HER2 test results were interpreted according to manufacturers’ test kit protocols. Responders were defined as patients showing either partial or complete responses.

Results:

Response data were available for 103/105 patients; centrally confirmed HER2 status was available for 95 patients. Intra-laboratory concordance for central IHC and FISH results was 93%. Complete responses were seen in two patients; their samples were IHC 3+ and FISH positive. Partial responses were seen in 17 patients; all were IHC 3+ and 14 were FISH positive. IHC and FISH showed 100% and 84.2% sensitivity, respectively, in determining response to trastuzumab. Polysomy was observed in 27% of patients; six responded to trastuzumab treatment. All six responders showed HER2 overexpression (IHC 3+) and HER2 gene amplification; two were FISH negative due to chromosome 17 polysomy.

Conclusions:

HER2 determination by IHC and FISH correlates with clinical response data in the WO16229 trial with high concordance of IHC and FISH results. Polysomy is the major cause of response in FISH-negative cases; polysomic cases should be retested by strictly standardised IHC.
Hepatocyte growth factor promotes colonic epithelial regeneration via Akt signaling
Authors: Kanayama Masami , Takahara Terumi , Yata Yutaka , Xue Feng , Shinno Eiji , Nonome Kazunobu , Kudo Hiroshi , Kawai Kengo , Kudo Takahiko , Tabuchi Yoshiaki , Watanabe Akiharu , Sugiyama Toshiro
Published: April 2007

Hepatocyte growth factor (HGF) can promote the regeneration of injured organs, including HGF gene therapy by electroporation (EP) for liver injury. In this study, we investigated the effect of HGF on dextran sulfate sodium-induced colitis and tried to clarify the regenerative mechanisms of colonic epithelial cells and the signaling pathway involved. Colitis was induced by dextran sulfate sodium in mice, together with HGF gene transfer by EP. On day 10, the colitis was evaluated histologically and by Western blot analysis. The colonic epithelial cell line MCE301 was exposed to HGF protein, and its proliferation and activated signaling pathway were analyzed. In vivo, the histological score improved and the number of Ki-67-positive epithelial cells increased in the HGF-treated mice compared with the controls. Western blot analysis showed enhanced expression of phospho-Akt in the HGF-treated mice compared with the controls. In vitro, HGF stimulated the proliferation of MCE301 cells. There was enhanced phospho-Akt expression for more than 48 h after HGF stimulation, although phospho-ERK1/2 was enhanced for only 10 min. LY-294002 or Akt small interfering RNA suppressed cell proliferation induced by HGF. Thus HGF induces the proliferation of colonic epithelial cells via the phosphatidylinositol 3-kinase/Akt signaling pathway. HGF gene therapy can attenuate acute colitis via epithelial cell proliferation through the PI3K/Akt pathway. These data suggested that HGF gene therapy by EP may be effective for the regeneration and repair of injured epithelial cells in inflammatory bowel disease.
Persistence of eupnea and gasping following blockade of both serotonin type 1 and 2 receptors in the in situ juvenile rat preparation
Authors: Toppin Veronica A. L. , Harris Michael B. , Kober Anna M. , Leiter J. C. , St.-John Walter M.
Published: April 2007

In severe hypoxia or ischemia, normal eupneic breathing is replaced by gasping, which can serve as a powerful mechanism for “autoresuscitation.” We have proposed that gasping is generated by medullary neurons having intrinsic pacemaker bursting properties dependent on a persistent sodium current. A number of neuromodulators, including serotonin, influence persistent sodium currents. Thus we hypothesized that endogenous serotonin is essential for gasping to be generated. To assess such a critical role for serotonin, a preparation of the perfused, juvenile in situ rat was used. Activities of the phrenic, hypoglossal, and vagal nerves were recorded. We added blockers of type 1 and/or type 2 classes of serotonergic receptors to the perfusate delivered to the preparation. Eupnea continued following additions of any of the blockers. Changes were limited to an increase in the frequency of phrenic bursts and a decline in peak heights of all neural activities. In ischemia, gasping was induced following any of the blockers. Few statistically significant changes in parameters of gasping were found. We thus did not find a differential suppression of gasping, compared with eupnea, following blockers of serotonin receptors. Such a differential suppression had been proposed based on findings using an in vitro preparation. We hypothesize that multiple neurotransmitters/neuromodulators influence medullary mechanisms underlying the neurogenesis of gasping. In greatly reduced in vitro preparations, the importance of any individual neuromodulator, such as serotonin, may be exaggerated compared with its role in more intact preparations.
Experimental quadriceps muscle pain impairs knee joint control during walking
Authors: Henriksen Marius , Alkjær Tine , Lund Hans , Simonsen Erik B. , Graven-Nielsen Thomas , Danneskiold-Samsøe Bente , Bliddal Henning
Published: April 2007

Pain is a cardinal symptom in musculoskeletal diseases involving the knee joint, and aberrant movement patterns and motor control strategies are often present in these patients. However, the underlying neuromuscular mechanisms linking pain to movement and motor control are unclear. To investigate the functional significance of muscle pain on knee joint control during walking, three-dimensional gait analyses were performed before, during, and after experimentally induced muscle pain by means of intramuscular injections of hypertonic saline (5.8%) into vastus medialis (VM) muscle of 20 healthy subjects. Isotonic saline (0.9%) was used as control. Surface electromyography (EMG) recordings of VM, vastus lateralis (VL), biceps femoris, and semitendinosus muscles were synchronized with the gait analyses. During experimental muscle pain, the loading response phase peak knee extensor moments were attenuated, and EMG activity in the VM and VL muscles was reduced. Compressive forces, adduction moments, knee joint kinematics, and hamstring EMG activity were unaffected by pain. Interestingly, the observed changes persisted when the pain had vanished. The results demonstrate that muscle pain modulated the function of the quadriceps muscle, resulting in impaired knee joint control and joint instability during walking. The changes are similar to those observed in patients with knee pain. The loss of joint control during and after pain may leave the knee joint prone to injury and potentially participate in the chronicity of musculoskeletal problems, and it may have clinically important implications for rehabilitation and training of patients with knee pain of musculoskeletal origin.
Stimulation pulse characteristics and electrode configuration determine site of excitation in isolated mammalian skeletal muscle: implications for fatigue
Authors: Cairns Simeon P. , Chin Eva R. , Renaud Jean-Marc
Published: April 2007

We examined whether electrical field stimulation with varying characteristics could excite isolated mammalian skeletal muscle through different sites. Supramaximal (20-V, 0.1-ms) pulse stimulation with transverse wire or parallel plate electrodes evoked similar forces in nonfatigued slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles from mice. d-tubocurarine shifted the twitch force-stimulation strength relationship toward higher pulse strengths with both electrode configurations in soleus muscle, suggesting that weaker pulses excite muscle via neuromuscular transmission. With wire stimulation, movement of the recording electrode along the muscle caused a delay between the stimulus artifact and the peak of the action potential, consistent with action potential propagation along the sarcolemma. TTX abolished all contractions evoked with 20-V, 0.1-ms pulses, suggesting that excitation occurred via voltage-dependent Na+channels and, hence, muscle action potentials. TTX did not prevent force development with ≥0.4-ms pulses in soleus or 1-ms pulses in EDL muscle. Furthermore, myoplasmic Ca2+(i.e., the fura 2 ratio) and sarcomere shortening were greater during tetanic stimulation with 2.0-ms than with 0.5-ms pulses in flexor digitorum brevis fibers from rats. TTX prevented all shortening and Ca2+release with 0.5-ms, but not 2.0-ms, pulses, indicating that longer pulses can directly trigger Ca2+release. Hence, proper interpretation of mechanistic studies requires precise understanding of how muscles are excited; otherwise, incorrect conclusions can be made. Using this new understanding, we showed that disrupted propagation of action potentials along the surface membrane is a major cause of fatigue in soleus muscle that is focally and continuously stimulated at 125 Hz.
Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity
Authors: Eliasson Pernilla , Fahlgren Anna , Pasternak Björn , Aspenberg Per
Published: April 2007

Tendons can function as springs and thereby preserve energy during cyclic loading. They might also have damping properties, which, hypothetically, could reduce risk of microinjuries due to fatigue at sites of local stress concentration within the tendon. At mechanical testing, damping will appear as hysteresis. How is damping influenced by training or disuse? Does training decrease hysteresis, thereby making the tendon a better spring, or increase hysteresis and thus improve damping? Seventy-eight female 10-wk-old Sprague-Dawley rats were randomized to three groups. Two groups had botulinum toxin injected into the calf muscles to unload the left Achilles tendon through muscle paralysis. One of these groups was given doxycycline, as a systemic matrix metalloproteinase inhibitor. The third group served as loaded controls. The Achilles tendons were harvested after 1 or 6 wk for biomechanical testing. An increase with time was seen in tendon dry weight, wet weight, water content, transverse area, length, stiffness, force at failure, and energy uptake in all three groups ( P < 0.001 for each parameter). Disuse had no effect on these parameters. Creep was decreased with time in all groups. The only significant effect of disuse was on hysteresis ( P = 0.004) and creep ( P = 0.007), which both decreased with disuse compared with control, and on modulus, which was increased ( P = 0.008). Normalized glycosaminoglycan content was unaffected by time and disuse. No effect of doxycycline was observed. The results suggest that in growing animals, the tendons continue to grow regardless of mechanical loading history, whereas maintenance of damping properties requires mechanical stimulation.
Cancer Immunologists and Cancer Biologists: Why We Didn't Talk Then but Need to Now
Authors: Prendergast George C. , Jaffee Elizabeth M.
Published: April 2007

What is cancer? Cancer is a disease initiated by a series of cumulative genetic and epigenetic changes that occur in a normal cell. However, in addition to the malignant cell itself, cancer is a disease of microenvironment and immunity. Although genetic and epigenetic alterations drive cellular transformation, genomic plasticity, and evolution, it has become increasingly apparent that multiple signals delivered within the tumor microenvironment by modifier genes, stromal and endothelial cells, and immune cells are critical factors in determining the progression versus dormancy or destruction of an initiated lesion and also whether metastasis may occur. With regard to the important roles of immune cells in cancer, a chasm exists between immunologists and biologists: although sharing a common disease interest, there is little history for workers to draw on based on shared perspectives or understanding. How did this disconnect arise? Here, we look at how these workers became separated in the past and address why it has now become critical to spur greater cross-fertilization. In particular, we highlight three ideas that we believe are important for discussion and debate. The first idea is that therapeutic strategies that fail to harness the immune system will always be defeated by tumor resistance, due to the large “genomic space” that genetically plastic tumor cells can readily access to evolve resistance mechanisms. Because all therapies drive tumor progression by imposing a selection for resistant cells, harnessing the adaptivity of the immune system will be indispensable to ultimately stanching the deadly adaptability of the tumor cell. The second idea is that using molecular targeted agents to reverse tumoral immune suppression may offer a powerful method to leverage the efficacy of most if not all therapeutic agents. We suggest that the mechanisms that support evolution of a “smoldering” inflammatory environment in cancer overlap with those that support evolution of tumoral immune escape. If true, relieving immune suppression will switch the inflammatory state from supportive to destructive for the tumor. The third idea is that by ablating immunosuppression mechanisms, cytotoxic chemotherapy might synergize with, rather than antagonize, active immunotherapy. Provocative preclinical studies in this area prompt clinical attention. We believe that increased efforts to intermingle the perspectives and work of cancer immunologists with cancer biologists and pharmacologists will be needed to realize the National Cancer Institute's goal of managing cancer in the clinic by 2015. [Cancer Res 2007;67(8):3500–4]
S100A6 Is Increased in a Stepwise Manner during Pancreatic Carcinogenesis: Clinical Value of Expression Analysis in 98 Pancreatic Juice Samples
Authors: Ohuchida Kenoki , Mizumoto Kazuhiro , Yu Jun , Yamaguchi Hiroshi , Konomi Hiroyuki , Nagai Eishi , Yamaguchi Koji , Tsuneyoshi Masazumi , Tanaka Masao
Published: April 2007

There are few reports describing the diagnostic significance of S100A6 expression in clinical samples obtained from patients with pancreatic disease. In the present study, we measured S100A6 expression in pancreatic tissues and juice to evaluate its involvement in pancreatic carcinogenesis. We did quantitative real-time reverse transcription-PCR to measure mRNA expression in microdissected cells and pancreatic juice samples. Microdissected invasive ductal carcinoma and intraductal papillary mucinous neoplasm (IPMN) cells expressed significantly higher levels of S100A6 than did microdissected pancreatitis-affected epithelial and normal cells (all comparison; P < 0.008). Median levels of S100A6 in invasive ductal carcinoma were higher than those in IPMN, and those in pancreatitis-affected epithelial cells tended to be higher than those in normal cells, although these differences were not statistically significant. In analyses of pancreatic juice, IPMN and pancreatic cancer samples expressed significantly higher levels of S100A6 than did chronic pancreatitis samples (both; P < 0.017), but levels in pancreatic cancer and IPMN samples did not differ form each other. Receiver operating characteristic (ROC) curve analysis revealed that measurement of S100A6 was useful for discriminating cancer (area under the ROC curve, 0.864) or IPMN (area under the ROC curve, 0.749) from chronic pancreatitis. The present data suggest that expression of S100A6 is increased in a stepwise manner during pancreatic carcinogenesis and may be a biomarker for evaluating malignant potential. Measurement of S100A6 in pancreatic juice may be useful to detect early pancreatic cancer or identify individuals with high-risk lesions that may progress to pancreatic cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(4):649–54)
Extracellular Activity of Cyclic AMP–Dependent Protein Kinase as a Biomarker for Human Cancer Detection: Distribution Characteristics in a Normal Population and Cancer Patients
Authors: Wang Hui , Li Mao , Lin Wenyao , Wang Wenquan , Zhang Zhuo , Rayburn Elizabeth R. , Lu Jian , Chen Deng , Yue Xinsen , Shen Fuming , Jiang Feng , He Jie , Wei Wu , Zeng Xiaofei , Zhang Ruiwen
Published: April 2007

The overexpression of cyclic AMP (cAMP)–dependent protein kinase (PKA) has been reported in patients with cancer, and PKA inhibitors have been tested in clinical trials as a novel cancer therapy. The present study was designed to characterize the population distribution of extracellular activity of cAMP-dependent protein kinase (ECPKA) and its potential value as a biomarker for cancer detection and monitoring of cancer therapy. The population distribution of ECPKA activity was determined in serum samples from a Chinese population consisting of a total of 603 subjects (374 normal healthy volunteers and 229 cancer patients). The serum ECPKA was determined by a validated sensitive radioassay, and its diagnostic values (including positive and negative predictive values) were analyzed. The majority of normal subjects (>70%) have undetectable or very low levels of serum ECPKA. In contrast, the majority of cancer patients (>85%) have high levels of ECPKA. The mean ECPKA activity in the sera of cancer patients was 10.98 units/mL, 5-fold higher than that of the healthy controls (2.15 units/mL; P < 0.001). In both normal subjects and cancer patients, gender and age had no significant influence on the serum ECPKA. Among factors considered, logistic analysis revealed that the disease (cancer) is the only factor contributing to the elevation of ECPKA activity in cancer patients. In conclusion, ECPKA may function as a cancer marker for various human cancers and can be used in cancer detection and for monitoring response to therapy with other screening or diagnostic techniques. (Cancer Epidemiol Biomarkers Prev 2007;16(4):789–95)
Dietary Fiber and Risk of Colorectal Cancer in the Japan Collaborative Cohort Study
Authors: Wakai Kenji , Date Chigusa , Fukui Mitsuru , Tamakoshi Koji , Watanabe Yoshiyuki , Hayakawa Norihiko , Kojima Masayo , Kawado Miyuki , Suzuki Koji , Hashimoto Shuji , Tokudome Shinkan , Ozasa Kotaro , Suzuki Sadao , Toyoshima Hideaki , Ito Yoshinori , Tamakoshi Akiko ,   for the JACC Study Group
Published: April 2007

To examine the association of dietary fiber with the risk of colorectal cancer in a population with a high incidence of cancer and a low fiber intake, we analyzed the data from the Japan Collaborative Cohort Study. From 1988 to 1990, 43,115 men and women aged 40 to 79 years completed a questionnaire on dietary and other factors. Intake of dietary fiber was estimated using a food frequency questionnaire. Rate ratios (RR) were computed by fitting proportional hazards models. During the mean follow-up of 7.6 years, 443 colorectal cancer cases were recorded. In all participants, we found a decreasing trend in risk of colorectal cancer with increasing intake of total dietary fiber; the multivariate-adjusted RRs across quartiles were 1.00, 0.96 [95% confidence interval (95% CI), 0.72-1.27], 0.72 (0.53-0.99), and 0.73 (0.51-1.03; Ptrend = 0.028). This trend was exclusively detected for colon cancer: the corresponding RRs were 1.00, 0.90 (95% CI, 0.64-1.26), 0.56 (0.38-0.83), and 0.58 (0.38-0.88; Ptrend = 0.002). The decrease in RRs with increasing intake of dietary fiber was larger in men than in women. No material differences appeared in the strength of associations with the risk between water-soluble and insoluble dietary fiber. For food sources of fiber, bean fiber intake was somewhat inversely correlated with colorectal cancer risk. This prospective study supported potential protective effects of dietary fiber against colorectal cancer, mainly against colon cancer. The role of dietary fiber in the prevention of colorectal cancer seems to remain inconsistent, and further investigations in various populations are warranted. (Cancer Epidemiol Biomarkers Prev 2007;16(4):668–75)
Health Care Utilization by Adult Long-term Survivors of Hematopoietic Cell Transplant: Report from the Bone Marrow Transplant Survivor Study
Authors: Shankar Sadhna M. , Carter Andrea , Sun Can-Lan , Francisco Liton , Baker K. Scott , Gurney James G. , Weisdorf Daniel G. , Forman Stephen J. , Robison Leslie L. , Grant Marcia , Bhatia Smita
Published: April 2007

The high intensity of therapy and prolonged immune suppression after hematopoietic cell transplantation (HCT) increase the risk of long-term complications and health care needs among survivors. The aim of this study was to evaluate the current status of health care utilization by long-term HCT survivors and to identify factors associated with lack of utilization. A total of 845 individuals who had undergone HCT between 1974 and 1998 at age 21 years or older and survived 2 or more years after HCT participated in the study. Health care utilization was assessed through a mailed questionnaire in three domains: general contact with health care system, general physical examination, and cancer/HCT–related visit. The median age at HCT was 38.2 years, and the median length of follow-up was 6.4 years. Overall, 98% of allogeneic and 94% of autologous HCT survivors reported medical contact 11+ years after HCT. Cancer/HCT–related visits decreased with increasing time from HCT (allogeneic HCT, 98-57%; autologous HCT, 94-63%). The prevalence of general physical examination increased with time (allogeneic HCT, 56-74%; autologous HCT, 72-81%). Primary care physicians provide health care for an increasing number of adult long-term survivors of HCT, emphasizing the need for increased awareness of the long-term follow-up needs of the HCT survivors by the health care providers. (Cancer Epidemiol Biomarkers Prev 2007;16(4):834–9)
Dietary Flavonoids and the Risk of Colorectal Cancer
Authors: Theodoratou Evropi , Kyle Janet , Cetnarskyj Roseanne , Farrington Susan M. , Tenesa Albert , Barnetson Rebecca , Porteous Mary , Dunlop Malcolm , Campbell Harry
Published: April 2007

In vitro and in vivo laboratory data point to chemoprotective effects of flavonoids on colorectal cancer. However, there has been limited epidemiologic research on the dietary intake of flavonoids and risk of colorectal cancer. Recent expansions of dietary databases to include flavonoid data now make such studies feasible. Association between the six main classes of flavonoids and the risk of colorectal cancer was examined using data from a national prospective case-control study in Scotland, including 1,456 incident cases and 1,456 population-based controls matched on age, sex, and residence area. Dietary, including flavonoid data, were obtained from a validated, self-administered food frequency questionnaire. Risk of colorectal cancer was estimated using conditional logistic regression models in the whole sample and stratified by sex, smoking status, and cancer site and adjusted for established and putative risk factors. After energy adjustment, reductions in colorectal cancer risk associated with the highest quartiles of intake (versus the lowest quartile) were 27% for flavonols [odds ratio (OR), 0.73; Ptrend = 0.012], 32% for quercetin (OR, 0.68; Ptrend = 0.001), 32% for catechin (OR, 0.68; Ptrend < 0.0005); 26% for epicatechin (OR, 0.74; Ptrend = 0.019), and 22% for procyanidins (OR, 0.78; Ptrend = 0.031). The significant dose-dependent reductions in colorectal cancer risk that were associated with increased consumption of flavonols, quercetin, catechin, and epicatechin remained robust after controlling for overall fruit and vegetable consumption or for other flavonoid intake. The risk reductions were greater among nonsmokers, but no interaction beyond a multiplicative effect was present. Sex-specific or cancer-type differences were not observed. No risk reductions were associated with intake of flavones (Ptrend = 0.64), flavonones (Ptrend = 0.22), and phytoestrogens (Ptrend = 0.26). This was the first of several a priori hypotheses to be tested in this large study and showed strong and linear inverse associations of flavonoids with colorectal cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(4):684–93)
Age at Menarche and Menopause and Breast Cancer Risk in the International BRCA1/2 Carrier Cohort Study
Authors: Chang-Claude Jenny , Andrieu Nadine , Rookus Matti , Brohet Richard , Antoniou Antonis C. , Peock Susan , Davidson Rosemarie , Izatt Louise , Cole Trevor , Noguès Catherine , Luporsi Elisabeth , Huiart Laetitia , Hoogerbrugge Nicoline , Van Leeuwen Flora E. , Osorio Ana , Eyfjord Jorunn , Radice Paolo , Goldgar David E. , Easton Douglas F. ,   Epidemiological Study of Familial Breast Cancer (EMBRACE), Gene Etude Prospective Sein Ovaire (GENEPSO), Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland (GEO-HEBON), the International BRCA1/2 Carrier Cohort Study (IBCCS) collaborators group
Published: April 2007

Background: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown.

Methods: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach.

Results: Breast cancer risk was not significantly related to age at menopause {hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44]; 35 to 40 years, 1.15 [0.65-2.04]; 45 to 54 years, 1.02 [0.65-1.60]; ≥55 years, 1.12 [0.12-5.02], as compared with premenopausal women}. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56; 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity.

Conclusions: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers. (Cancer Epidemiol Biomarkers Prev 2007;16(4):740–6)
Insulin Resistance-Related Genes and Advanced Left-Sided Colorectal Adenoma
Authors: Gunter Marc J. , Hayes Richard B. , Chatterjee Nilanjan , Yeager Meredith , Welch Robert , Schoen Robert E. , Yakochi Lance , Schatzkin Arthur , Peters Ulrike
Published: April 2007

Background: Insulin resistance has been linked with colorectal neoplasia through a number of mechanistic and observational studies. Allelic variants of genes encoding components of the insulin pathway, including insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 and insulin receptor substrate-2 (IRS1 and IRS2) have been associated with hyperinsulinemia and insulin resistance and may, therefore, predict susceptibility to colorectal neoplasia.

Methods: We investigated whether single nucleotide polymorphisms (SNP) in the INS, INSR, IRS1, and IRS2 genes are associated with risk of advanced left-sided colorectal adenoma, a cancer precursor. We analyzed 20 SNPs in a largely Caucasian study population comprising 766 cases with advanced adenomas of the distal colon and 771 controls, all of whom had undergone flexible sigmoidoscopy as part of the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Results: Overall, we found limited evidence for a role of gene variants of the insulin signaling pathway and prevalence of advanced colorectal adenoma. We observed a statistically significant interaction between INSR genotypes and body mass index (BMI) with colorectal adenoma prevalence (P value for global test = 0.003) and suggestion of an interaction between INSR genotypes and glycemic load (P value for global test = 0.06); however, exploration of the interaction of BMI and glycemic load with the individual SNPs in INSR did not suggest a single SNP that may explain the significance of these global tests of interaction and did not yield any consistent patterns.

Conclusion: These findings do not provide strong evidence for associations between polymorphic variation in genes of the insulin signaling pathway and advanced left-sided colorectal adenoma. Evidence for interaction between INSR variants and BMI and glycemic load for risk of advanced left-sided colorectal adenoma requires independent confirmation, and genotyping of INSR across a broader region and at greater density may be necessary to fully elucidate the nature of these interactions. (Cancer Epidemiol Biomarkers Prev 2007;16(4):703–8)
Clinical and Biological Activity of Soy Protein Powder Supplementation in Healthy Male Volunteers
Authors: Goodin Susan , Shen Francisco , Shih Weichung J. , Dave Nisha , Kane Michael P. , Medina Patrick , Lambert George H. , Aisner Joseph , Gallo Michael , DiPaola Robert S.
Published: April 2007

Purpose: To determine if a commonly used soy protein supplement exhibits biological activity in vivo and in vitro, we evaluated an over-the-counter soy protein powder supplement using blood from healthy male volunteers and in an estrogen receptor in vitro assay.

Subjects and Methods: We recruited healthy male volunteers 18 years of age or older that were in good health. Treatment consisted of consuming two scoops (56 g) of pure soy protein powder (Puritan's Pride, Oakdale, NY) daily for 28 days. Serum testosterone and luteinizing hormone (LH) levels were collected on days −7, 0, 14, and 28 of therapy, and day 42. A reporter estrogen receptor (ER) assay was used to determine the effect on ER-β and ER-α in vitro.

Results: Twelve subjects were enrolled with a mean age of 32.25 years (range 25 to 47). Serum testosterone decreased 19%(±22%) during the 4-week use of soy protein powder (P = 0.021) and increased within 2 weeks after we discontinued soy protein powder. Serum LH concentrations decreased during the 4-week use of soy protein powder then increased within 2 weeks after we stopped the soy protein powder, but the changes did not reach statistical significance (P = 0.20). Soy protein powder was found to induce agonist activity to ER-β using a reporter estrogen receptor assay in yeast.

Conclusion: Soy protein powder decreases serum testosterone levels in healthy men and acts as an ER-β agonist; the significance of this biological effect with respect to cancer prevention needs further study. (Cancer Epidemiol Biomarkers Prev 2007;16(4):829–33)