bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase 2 trial of complete resection for stage IV melanoma
Authors: Sosman Jeffrey A. , Moon James , Tuthill Ralph J. , Warneke James A. , Vetto John T. , Redman Bruce G. , Liu P. Y. , Unger Joseph M. , Flaherty Lawrence E. , Sondak Vernon K.
Published: March 2011

BACKGROUND:

On the basis of retrospective experience at individual centers, it appears that patients with stage IV melanoma who undergo complete resection have a favorable outcome compared with patients with disseminated stage IV disease. The Southwest Oncology Group (SWOG) performed a prospective trial in patients with metastatic melanoma who were enrolled before complete resection of their metastatic disease and provided prospective outcomes in the cooperative group setting.

METHODS:

Based on their physical examination and radiologic imaging studies, patients with a stage IV melanoma judged amenable to complete resection underwent surgery within 28 days of enrollment. All eligible patients were followed with scans (computed tomography or positron emission tomography) every 6 months until relapse and death.

RESULTS:

Seventy‐seven patients were enrolled from 18 different centers. Of those, 5 patients were ineligible; 2 had stage III disease alone; and 3 had no melanoma in their surgical specimen. In addition, 8 eligible patients had incompletely resected tumor. Therefore, the primary analysis included 64 completely resected patients. Twenty patients (31%) had visceral disease. With a median follow‐up of 5 years, the median relapse‐free survival was 5 months (95% CI, 3‐7 months) whereas median overall survival was 21 months (95% CI, 16‐34 months). Overall survivals at 3 and 4 years were 36% and 31%, respectively.

CONCLUSIONS:

In a prospective multicenter setting, appropriately selected patients with stage IV melanoma achieved prolonged overall survival after complete surgical resection. Although median relapse‐free survival was only 5 months, patients could still frequently undergo subsequent surgery for isolated recurrences. This patient population is appropriate for aggressive surgical therapy and for trials evaluating adjuvant therapy. Cancer 2011;. © 2011 American Cancer Society.
Phase 2 study of nilotinib as third‐line therapy for patients with gastrointestinal stromal tumor
Authors: Sawaki Akira , Nishida Toshirou , Doi Toshihiko , Yamada Yasuhide , Komatsu Yoshito , Kanda Tatsuo , Kakeji Yoshihiro , Onozawa Yusuke , Yamasaki Makoto , Ohtsu Atsushi
Published: March 2011

BACKGROUND:

Patients with gastrointestinal stromal tumors (GISTs) resistant to both imatinib and sunitinib have a poor prognosis and few therapeutic options. In this study, the efficacy and safety of nilotinib (AMN107) as a third‐line therapy for patients with GISTs was evaluated.

METHODS:

A single‐arm, open‐label trial was conducted in 8 Japanese hospitals. The key eligibility criteria included resistance or intolerance to both imatinib and sunitinib treatment. The primary endpoint was disease control rate, defined as the percentage of patients with complete response, partial response (PR), or stable disease (SD) lasting 24 weeks or longer.

RESULTS:

Thirty‐five patients were enrolled and treated with nilotinib 400 mg twice daily, which generally was well tolerated. Disease control rate at Week 24 was 29% (90% confidence interval, 16.4%‐43.6%). The median progression‐free survival was 113 days, and the median overall survival was 310 days. The objective response rate was 3%, comprising 1 PR in a patient with a GIST possessing both a KIT exon 11 mutation, and an imatinib‐resistant and sunitinib‐resistant KIT exon 17 mutation. Twenty‐three (66%) patients had SD (≥6 weeks) as the best response.

CONCLUSIONS:

These results suggest that nilotinib is generally well tolerated and has encouraging antitumor activity in patients with GIST who failed both imatinib and sunitinib. Cancer 2011;. © 2011 American Cancer Society.
Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy
Authors: Suzuki Akihiro , Xiao Lianchun , Hayashi Yuki , Macapinlac Homer A. , Welsh James , Lin Steven H. , Lee Jeffrey H. , Bhutani Manoop S. , Maru Dipen M. , Hofstetter Wayne L. , Swisher Stephen G. , Ajani Jaffer A.
Published: March 2011

BACKGROUND:

Metabolic imaging is of interest in esophageal cancer; however, the usefulness of initial standardized uptake value (SUV) in positron emission tomography (PET) is unknown in patients with esophageal or gastroesophageal carcinoma treated with definitive chemoradiotherapy. The authors hypothesized that initial SUV would correlate with patient outcome.

METHODS:

The authors retrospectively analyzed esophageal or gastroesophageal carcinoma patients who had baseline PET and endoscopic ultrasonography in addition to other routine staging. All patients received definitive chemoradiotherapy. Multiple statistical methods were used.

RESULTS:

The authors analyzed 209 consecutive esophageal or gastroesophageal carcinoma patients treated with definitive chemoradiation for outcome; of these, 180 had baseline PET for additional analyses. The median overall survival (OS) for all patients was 20.7 months (95% confidence interval, 18.8‐26.3). Patients with clinical complete response (CR) lived longer than those with less than clinical CR (P < .0001). The median initial SUV was 12.7 (range, 0‐51). Higher initial SUV was associated with longer tumors (P = .0001), higher T‐stage status (P < .0001), positive N‐stage status (P = .0001), higher overall stage (P < .0001), lack of clinical CR (P = .0002), and squamous cell histology (P < .0001). In the univariate analysis, initial SUV was associated with OS (Cox model, P = .016; log‐rank test, P = .002). In the multivariate analysis, initial SUV dichotomized by the median value (P = .024) and tumor grade (P = .016) proved to be independent OS prognosticators. Median initial SUV for clinical CR patients was 10.2, compared with 15.3 for less than clinical CR patients (P = .0058).

CONCLUSIONS:

The data indicate that a higher initial SUV is associated with poorer OS in patients with esophageal or gastroesophageal carcinoma receiving definitive chemoradiation. Upon validation, baseline PET may become a useful stratification factor in randomized trials and for individualizing therapy. Cancer 2011;. © 2011 American Cancer Society.
Clinical effect of temozolomide‐based chemotherapy in poorly differentiated endocrine carcinoma after progression on first‐line chemotherapy
Authors: Welin Staffan , Sorbye Halfdan , Sebjornsen Sigrunn , Knappskog Stian , Busch Christian , Öberg Kjell
Published: March 2011

BACKGROUND:

Patients with metastatic poorly differentiated endocrine carcinoma (PDEC) usually have a short survival. The chemotherapy combination of cisplatin and etoposide is frequently used as first‐line palliative chemotherapy. There are, however, no published studies concerning second‐line treatment of the disease. Temozolomide has shown clinical effect in well‐differentiated endocrine carcinomas. This study was performed to evaluate the effect of temozolomide in PDEC patients who had progressed on first‐line treatment.

METHODS:

Twenty‐five patients with PDEC (mainly gastrointestinal) were treated with temozolomide alone or in combination with capecitabine. A subset of patient also received bevacizumab. MGMT methylation was analyzed in tissue specimens. Data were collected retrospectively.

RESULTS:

One patient had a complete response, and 7 patients had partial response (33% response rate). Median duration of response was 19 months. Another 9 (38%) patients had a stable disease, after progression at inclusion, with a median duration of 18 months. Median progression‐free survival for all patients was 6 months, and median overall survival was 22 months. Only 1 patient had a MGMT methylation.

CONCLUSIONS:

Treatment with temozolomide alone or in combination with capecitabine and bevacizumab resulted in objective response or stabilization in 71% of PDEC patients who failed on first‐line chemotherapy. These results indicated that temozolomide may be used as second‐line treatment in PDEC. Cancer 2011;. © 2011 American Cancer Society.
Differential regulation of the expression of neurotrophin receptors in rat extraocular motoneurons after lesion
Authors: Morcuende Sara , Matarredona Esperanza R. , Benítez‐Temiño Beatriz , Muñoz‐Hernández Rocío , Pastor Ángel M. , de la Cruz Rosa R.
Published: March 2011

Neurotrophins acting through high‐affinity tyrosine kinase receptors (trkA, trkB, and trkC) play a crucial role in regulating survival and maintenance of specific neuronal functions after injury. Adult motoneurons supplying extraocular muscles survive after disconnection from the target, but suffer dramatic changes in morphological and physiological properties, due in part to the loss of their trophic support from the muscle. To investigate the dependence of the adult rat extraocular motoneurons on neurotrophins, we examined trkA, trkB, and trkC mRNA expression after axotomy by in situ hybridization. trkA mRNA expression was detectable at low levels in unlesioned motoneurons, and its expression was downregulated 1 and 3 days after injury. Expression of trkB and trkC mRNAs was stronger, and after axotomy a simultaneous, but inverse regulation of both receptors was observed. Thus, whereas a considerable increase in trkB expression was seen about 2 weeks after axotomy, the expression of trkC mRNA had decreased at the same post‐lesion period. Injured extraocular motoneurons also experienced an initial induction in expression of calcitonin gene‐related peptide and a transient downregulation of cholinergic characteristics, indicating a switch in the phenotype from a transmitter‐specific to a regenerative state. These results suggest that specific neurotrophins may contribute differentially to the survival and regenerative responses of extraocular motoneurons after lesion. J. Comp. Neurol. 519:2335–2352, 2011. © 2011 Wiley‐Liss, Inc.
Recovery and aging of serotonergic fibers after single and intermittent MDMA treatment in dark agouti rat
Authors: Ádori Csaba , Andó Rómeó D. , Szekeres Mária , Gutknecht Lise , Kovács Gábor G. , Hunyady László , Lesch Klaus‐Peter , Bagdy György
Published: March 2011

3,4‐Methylenedioxymethamphetamine (MDMA; ecstasy) is a popular party drug known to cause selective serotonergic damage. Here we examined the long‐term recovery and aging of serotonergic fibers and levels of brain‐derived neurotrophic factor (BDNF) after intermittent MDMA administration (15 mg kg−1 i.p. every 7th day for 4 weeks, MDMA ×4) and a single‐dose treatment (15 mg kg−1 i.p., MDMA ×1) in adolescent/young adult male Dark Agouti rats. After MDMA treatment, tryptophan hydroxylase‐immunoreactive fiber density decreased and then recovered in all brain regions. Recovery was more pronounced in the MDMA ×4 group compared with the MDMA ×1 group, but similar long‐term BDNF responses were found after both treatments. Twenty‐two months after treatment, there were fewer clusters of aberrant serotonergic fibers in the parietal cortex in the MDMA ×4 group compared with the MDMA ×1 group. There was no difference in the density of microglial cells or astrocytes in treated groups versus the control 22 months after the treatments. These results indicate that recovery of serotonergic fibers is faster after intermittent MDMA treatment than after single‐dose administration, and differences in BDNF levels per se are unlikely to account for this difference. Moreover, it seems that intermittent MDMA treatment attenuates the morphological signs of aging in serotonergic fibers. In addition, neither intermittent nor single‐dose MDMA exposition of young animals induces accelerated aging processes or neurodegeneration in senescence, as indicated by the unaltered densities of microglial cells and astrocytes in the treated groups compared with the control. J. Comp. Neurol. 519:2353–2378, 2011. © 2011 Wiley‐Liss, Inc.
Mapping of endogenous morphine‐like compounds in the adult mouse brain: Evidence of their localization in astrocytes and GABAergic cells
Authors: Laux Alexis , Muller Arnaud H. , Miehe Monique , Dirrig‐Grosch Sylvie , Deloulme Jean Christophe , Delalande François , Stuber Denise , Sage Dominique , Van Dorsselaer Alain , Poisbeau Pierrick , Aunis Dominique , Goumon Yannick
Published: March 2011

Endogenous morphine, morphine‐6‐glucuronide, and codeine, which are structurally identical to vegetal alkaloids, can be synthesized by mammalian cells from dopamine. However, the role of brain endogenous morphine and its derivative compounds is a matter of debate, and knowledge about its distribution is lacking. In this study, by using a validated antibody, we describe a precise mapping of endogenous morphine‐like compounds (morphine and/or its glucuronides and/or codeine) in the mouse brain. First, a mass spectrometry approach confirmed the presence of morphine and codeine in mouse brain, but also, of morphine‐6‐glucuronide and morphine‐3‐glucuronide representing two metabolites of morphine. Second, light microscopy allowed us to observe immunopositive cell somas and cytoplasmic processes throughout the mouse brain. Morphine‐like immunoreactivity was present in various structures including the hippocampus, olfactory bulb, band of Broca, basal ganglia, and cerebellum. Third, by using confocal microscopy and immunofluroscence co‐localization, we characterized cell types containing endogenous opiates. Interestingly, we observed that morphine‐like immunoreactivity throughout the encephalon is mainly present in γ‐aminobutyric acid (GABA)ergic neurons. Astrocytes were also labeled throughout the entire brain, in the cell body, in the cytoplasmic processes, and in astrocytic feet surrounding blood vessels. Finally, ultrastructural localization of morphine‐like immunoreactivity was determined by electron microscopy and showed the presence of morphine‐like label in presynaptic terminals in the cerebellum and postsynaptic terminals in the rest of the mouse brain. In conclusion, the presence of endogenous morphine‐like compounds in brain regions not usually involved in pain modulation opens the exciting opportunity to extend the role and function of endogenous alkaloids far beyond their analgesic functions. J. Comp. Neurol. 519:2390–2416, 2011. © 2011 Wiley‐Liss, Inc.
Neural cell adhesion molecule ablation in mice causes hippocampal dysplasia and loss of septal cholinergic neurons
Authors: Tereshchenko Yuliya , Morellini Fabio , Dityatev Alexander , Schachner Melitta , Irintchev Andrey
Published: March 2011

The neural cell adhesion molecule (NCAM) is implicated in nervous system development and plasticity. In humans, abnormal NCAM expression has been linked to the pathogenesis of neuropsychiatric and neurodegenerative disorders accompanied by cognitive dysfunctions. Impaired cognition is also observed in NCAM‐deficient (NCAM−/−) mice. Considering the importance of the septal cholinergic nuclei and the hippocampus for cognition, we performed quantitative morphological analyses of these areas in young and adult (2 and 13 months old, respectively) NCAM−/− mice and wild‐type (NCAM+/+) littermates. In young mice, we found lower numbers of septal cholinergic neurons in NCAM−/− than in NCAM+/+ mice. Despite deficient numbers of neurons, total lengths of cholinergic axons and choline acetyltransferase protein levels in the hippocampus of NCAM−/− mice were normal. The hippocampus of NCAM−/− mice was atrophic, notably in the CA3 subfield and the dentate gyrus (DG). The atrophy appeared to have different primary causes in the two subfields: loss of pyramidal cells in CA3 and reduced branching and volume of granule cell dendrites in the DG. The frequency of dendritic spines on dentate granule cells in NCAM−/− mice was normal. Numbers of parvalbumin‐positive (PV+) interneurons were reduced in NCAM−/− mice in proportion to subfield volume loss, and the ratios of principal cells to PV+ interneurons were similar to those of NCAM+/+ mice. None of the observed abnormalities was exaggerated or alleviated in adult NCAM−/− mice. Our observations indicate that NCAM ablation causes structural abnormalities in the hippocampus and the forebrain cholinergic system in adult mice, which may contribute to impaired cognition in NCAM−/− mice. J. Comp. Neurol. 519:2475–2492, 2011. © 2011 Wiley‐Liss, Inc.
Sensory neuroanatomy of Parastrongyloides trichosuri, a nematode parasite of mammals: Amphidial neurons of the first‐stage larva
Authors: Zhu He , Li Jian , Nolan Thomas J. , Schad Gerhard A. , Lok James B.
Published: March 2011

Owing to its ability to switch between free‐living and parasitic modes of development, Parastrongyloides trichosuri represents a valuable model with which to study the evolution of parasitism among the nematodes, especially aspects pertaining to morphogenesis of infective third‐stage larvae. In the free‐living nematode Caenorhabditis elegans, developmental fates of third‐stage larvae are determined in part by environmental cues received by chemosensory neurons in the amphidial sensillae. As a basis for comparative study, we have described the neuroanatomy of the amphidial sensillae of P. trichosuri. By using computational methods, we incorporated serial electron micrographs into a three‐dimensional reconstruction of the amphidial neurons of this parasite. Each amphid is innervated by 13 neurons, and the dendritic processes of 10 of these extend nearly to the amphidial pore. Dendritic processes of two specialized neurons leave the amphidial channel and terminate within invaginations of the sheath cell. One of these is similar to the finger cell of C. elegans, terminating in digitiform projections. The other projects a single cilium into the sheath cell. The dendritic process of a third specialized neuron terminates within the tight junction of the amphid. Each amphidial neuron was traced from the tip of its dendrite(s) to its cell body in the lateral ganglion. Positions of these cell bodies approximate those of morphologically similar amphidial neurons in Caenorhabditis elegans, so the standard nomenclature for amphidial neurons in C. elegans was adopted. A map of cell bodies within the lateral ganglion of P. trichosuri was prepared to facilitate functional study of these neurons. J. Comp. Neurol. 519:2493–2507, 2011. © 2011 Wiley‐Liss, Inc.
Ontogeny of sex differences in response to novel objects from adolescence to adulthood in lister‐hooded rats
Authors: Cyrenne De‐Laine M. , Brown Gillian R.
Published: March 2011

In humans, novelty‐seeking behavior peaks in adolescence and is higher in males than females. Relatively, little information is available regarding age and sex differences in response to novelty in rodents. In this study, male and female Lister‐hooded rats were tested at early adolescence (postnatal day, pnd, 28), mid‐adolescence (pnd 40), or early adulthood (pnd 80) in a novel object recognition task (n = 12 males/females per age group). Males displayed a higher preference for the novel object than females at mid‐adolescence, with no sex difference at early adolescence. Adult females interacted with the novel object more than adult males, but not when side biases were removed. Sex differences at mid‐adolescence were not found in other measures, suggesting that the difference at this age was specific to situations involving choice of novelty. The results are considered in the context of age‐ and sex‐dependent interactions between gonadal hormones and the dopamine system. © 2011 Wiley Periodicals, Inc. Dev Psychobiol 53:670–676, 2011.
Control of pelvic girdle development by genes of the Pbx family and Emx2
Authors: Capellini Terence D. , Handschuh Karen , Quintana Laura , Ferretti Elisabetta , Di Giacomo Giuseppina , Fantini Sebastian , Vaccari Giulia , Clarke Shoa L. , Wenger Aaron M. , Bejerano Gill , Sharpe James , Zappavigna Vincenzo , Selleri Licia
Published: March 2011

Genes expressed in the somatopleuric mesoderm, the embryonic domain giving rise to the vertebrate pelvis, appear important for pelvic girdle formation. Among such genes, Pbx family members and Emx2 were found to genetically interact in hindlimb and pectoral girdle formation. Here, we generated compound mutant embryos carrying combinations of mutated alleles for Pbx1, Pbx2, and Pbx3, as well as Pbx1 and Emx2, to examine potential genetic interactions during pelvic development. Indeed, Pbx genes share overlapping functions and Pbx1 and Emx2 genetically interact in pelvic formation. We show that, in compound Pbx1;Pbx2 and Pbx1;Emx2 mutants, pelvic mesenchymal condensation is markedly perturbed, indicative of an upstream control by these homeoproteins. We establish that expression of Tbx15, Prrx1, and Pax1, among other genes involved in the specification and development of select pelvic structures, is altered in our compound mutants. Lastly, we identify potential Pbx1‐Emx2–regulated enhancers for Tbx15, Prrx1, and Pax1, using bioinformatics analyses. Developmental Dynamics 240:1173–1189, 2011. © 2011 Wiley‐Liss, Inc.
Loss of Lrp2 in zebrafish disrupts pronephric tubular clearance but not forebrain development
Authors: Kur Esther , Christa Anna , Veth Kerry N. , Gajera Chandresh R. , Andrade‐Navarro Miguel A. , Zhang Jingjing , Willer Jason R. , Gregg Ronald G. , Abdelilah‐Seyfried Salim , Bachmann Sebastian , Link Brian A. , Hammes Annette , Willnow Thomas E.
Published: March 2011

Low‐density lipoprotein receptor‐related protein 2 (LRP2) is a multifunctional cell surface receptor conserved from nematodes to humans. In mammals, it acts as regulator of sonic hedgehog and bone morphogenetic protein pathways in patterning of the embryonic forebrain and as a clearance receptor in the adult kidney. Little is known about activities of this LRP in other phyla. Here, we extend the functional elucidation of LRP2 to zebrafish as a model organism of receptor (dys)function. We demonstrate that expression of Lrp2 in embryonic and larval fish recapitulates the patterns seen in mammalian brain and kidney. Furthermore, we studied the consequence of receptor deficiencies in lrp2 and in lrp2b, a homologue unique to fish, using ENU mutagenesis or morpholino knockdown. While receptor‐deficient zebrafish suffer from overt renal resorption deficiency, their brain development proceeds normally, suggesting evolutionary conservation of receptor functions in pronephric duct clearance but not in patterning of the teleost forebrain. Developmental Dynamics 240:1567–1577, 2011. © 2011 Wiley‐Liss, Inc.
Recent Advances in the Synthesis of Fluorinated Amino Acids
Authors: Qiu Xiao‐Long , Qing Feng‐Ling
Published: March 2011

Introduction of fluorine atoms or fluorine‐containing groups into amino acids has attracted much attention from bioorganic and medicinal chemists because the resulting fluorinated amino acids have found wide application as potential enzyme inhibitors and antitumor (antibacterial) agents. Additionally, it is well known that replacement of naturally occurring amino acid(s) in some peptide chains with their fluorinated counterparts can significantly increase specific protein–ligand or protein–protein interactions, leading to increases in the proteolytic and thermal stabilities of peptide compounds and, as a result, promote their therapeutic properties. This microreview summarizes important advances in the synthesis of fluorinated amino acids since 2005. The contents are simply divided into three groups on the basis of amino acid types: fluorinated α‐amino acids (F‐αAAs), fluorinated β‐amino acids (F‐βAAs), and fluorinated cyclic amino acids (F‐CAAs).
Controlling retention, selectivity and magnitude of EOF by segmented monolithic columns consisting of octadecyl and naphthyl monolithic segments – applications to RP‐CEC of both neutral and charged solutes
Authors: Karenga Samuel , Rassi Ziad El
Published: March 2011

Monolithic capillaries made of two adjoining segments each filled with a different monolith were introduced for the control and manipulation of the electroosmotic flow (EOF), retention and selectivity in reversed phase‐capillary electrochromatography (RP‐CEC). These columns were called segmented monolithic columns (SMCs) where one segment was filled with a naphthyl methacrylate monolith (NMM) to provide hydrophobic and π‐interactions, while the other segment was filled with an octadecyl acrylate monolith (ODM) to provide solely hydrophobic interaction. The ODM segment not only provided hydrophobic interactions but also functioned as the EOF accelerator segment. The average EOF of the SMC increased linearly with increasing the fractional length of the ODM segment. The neutral SMC provided a convenient way for tuning EOF, selectivity and retention in the absence of annoying electrostatic interactions and irreversible solute adsorption. The SMCs allowed the separation of a wide range of neutral solutes including polycyclic aromatic hydrocarbons (PAHs) that are difficult to separate using conventional alkyl‐bonded stationary phases. In all cases, the k′ of a given solute was a linear function of the fractional length of the ODM or NMM segment in the SMCs, thus facilitating the tailoring of a given SMC to solve a given separation problem. At some ODM fractional length, the fabricated SMC allowed the separation of charged solutes such as peptides and proteins that could not otherwise be achieved on a monolithic column made from NMM as an isotropic stationary phase due to the lower EOF exhibited by this monolith.
Variation in aroma release between panellists consuming different types of confectionary
Authors: Blee Nicola , Linforth Robert , Yang Nicole , Brown Keith , Taylor Andrew
Published: March 2011

Variation in in vivo volatile release was studied using atmospheric pressure chemical ionization–mass spectrometry. The extent of variation in in vivo flavour release was related to the partitioning behaviour of the compound. Compounds with highest air/water partition coefficients (Kaw) showed more variation in release than those with low Kaw values. Sample matrix components (such as lipid) have the potential to influence the air/product partition coefficient. If they reduce the partition coefficient they can reduce the variation in volatile release. Variation in release was assessed for menthone from a series of five different sample types. Chewing gum gave the most consistent release, which was attributed to the consistency of chewing in oral processing and volatile delivery. The least consistent release intensity was associated with the boiled sweet, which may have resulted in substantial variation in oral processing and hence volatile delivery. A study of a panel of 50 people showed that there were strong correlations in the intensity of volatile release across sample types. Panellists who released high concentrations of volatiles into their breath from one sample type would typically do so for another. Equally, panellists who released lower amounts from one sample type would also release less from others. Some differences in the intensity of aroma release were observed between sample types. These appear to be related to textural differences between samples, which would affect oral processing. Copyright © 2011 John Wiley & Sons, Ltd.
Im Reich des Steinbocks
Authors: Klimscha Florian , Siegel Ulrike , Eichmann Ricardo , Schmidt Klaus
Published: March 2011

Fern der bekannten Ausgrabungsstätten legen internationale Archäologenteams im jordanischen Tall Hujayrat al‐Ghuzlan die Überreste chalkolithischer Siedlungen frei. Ihre Funde sind voller Überraschungen – sie zeigen, wie Kulturen und Techniken von den Metropolen in die Provinz ausstrahlten.
Spontaneous blood oxygenation level‐dependent fMRI signal is modulated by behavioral state and correlates with evoked response in sensorimotor cortex: A 7.0‐T fMRI study
Authors: Donahue Manus J. , Hoogduin Hans , Smith Stephen M. , Siero Jeroen C.W. , Chappell Michael , Petridou Natalia , Jezzard Peter , Luijten Peter R. , Hendrikse Jeroen
Published: March 2011

Synchrony measurements of spontaneous low‐frequency blood oxygenation level‐dependent (BOLD) fluctuations are increasingly being used to investigate spatial regions of functional connectivity. Although information regarding BOLD–BOLD synchrony between different regions is frequently reported, the relationship between spontaneous activity and behavioral state, and the association of spontaneous signal synchrony and evoked response, are less well characterized. The purpose of this study is to exploit the higher signal‐to‐noise ratio and in turn available spatial resolution at 7.0 T to understand the relationship between synchrony, measured as Pearson's R value, and amplitude, measured as signal standard deviation over time, in sensorimotor cortex for four separate behavioral states: eyes closed resting (EC), eyes open fixation (EO), EO with constant right hand fist clench (EO‐F) and EO with 6 s off/6 s on (0.083 Hz) right hand finger tapping (EO‐T). BOLD (TE/TR = 25/3,000 ms; 100 time points) scans were performed in healthy volunteers (7.0 T; 4 M/3 F; right‐handed) at high spatial resolution = 1.6 × 1.6 × 1.6 mm3. Results (z > 5; P < 0.05; low‐pass filtering <0.067 Hz) reveal that synchrony is highest in the EC state (R = 0.35 ± 0.07) and reduces for EO (R = 0.26 ± 0.07), EO‐F (R = 0.23 ± 0.07; P < 0.05), and EO‐T (R = 0.12 ± 0.04; P < 0.05) conditions. Amplitude was highest in the EC condition and only reduced significantly (P < 0.05) for the EO‐T condition. Synchrony within sensorimotor cortex correlated with evoked finger‐tapping response magnitude (R = 0.81; P = 0.03), suggesting that spontaneous signal synchrony may be a predictor of evoked BOLD response magnitude and may account for intersubject variability in sensorimotor cortex. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Comparison of the neural correlates of retrieval success in tests of cued recall and recognition memory
Authors: Okada Kayoko , Vilberg Kaia L. , Rugg Michael D.
Published: March 2011

The neural correlates of successful retrieval on tests of word stem recall and recognition memory were compared. In the recall test, subjects viewed word stems, half of which were associated with studied items and half with unstudied items, and for each stem attempted to recall a corresponding study word. In the recognition test, old/new judgments were made on old and new words. The neural correlates of successful retrieval were identified by contrasting activity elicited by correctly endorsed test items. Old > new effects common to the two tasks were found in medial and lateral parietal and right entorhinal cortex. Common new > old effects were identified in medial and left frontal cortex, and left anterior intra‐parietal sulcus. Greater old > new effects were evident for cued recall in inferior parietal regions abutting those demonstrating common effects, whereas larger new > old effects were found for recall in left frontal cortex and the anterior cingulate. New > old effects were also found for the recall task in right lateral anterior prefrontal cortex, where they were accompanied by old > new effects during recognition. It is concluded that successful recall and recognition are associated with enhanced activity in a common set of recollection‐sensitive parietal regions, and that the greater activation in these regions during recall reflects the greater dependence of that task on recollection. Larger new > old effects during recall are interpreted as reflections of the greater opportunity for iterative retrieval attempts when retrieval cues are partial rather than copy cues. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Optimizing preprocessing and analysis pipelines for single‐subject fMRI. I. Standard temporal motion and physiological noise correction methods
Authors: Churchill Nathan W. , Oder Anita , Abdi Hervé , Tam Fred , Lee Wayne , Thomas Christopher , Ween Jon E. , Graham Simon J. , Strother Stephen C.
Published: March 2011

Subject‐specific artifacts caused by head motion and physiological noise are major confounds in BOLD fMRI analyses. However, there is little consensus on the optimal choice of data preprocessing steps to minimize these effects. To evaluate the effects of various preprocessing strategies, we present a framework which comprises a combination of (1) nonparametric testing including reproducibility and prediction metrics of the data‐driven NPAIRS framework (Strother et al. [2002]: NeuroImage 15:747–771), and (2) intersubject comparison of SPM effects, using DISTATIS (a three‐way version of metric multidimensional scaling (Abdi et al. [2009]: NeuroImage 45:89–95). It is shown that the quality of brain activation maps may be significantly limited by sub‐optimal choices of data preprocessing steps (or “pipeline”) in a clinical task‐design, an fMRI adaptation of the widely used Trail‐Making Test. The relative importance of motion correction, physiological noise correction, motion parameter regression, and temporal detrending were examined for fMRI data acquired in young, healthy adults. Analysis performance and the quality of activation maps were evaluated based on Penalized Discriminant Analysis (PDA). The relative importance of different preprocessing steps was assessed by (1) a nonparametric Friedman rank test for fixed sets of preprocessing steps, applied to all subjects; and (2) evaluating pipelines chosen specifically for each subject. Results demonstrate that preprocessing choices have significant, but subject‐dependant effects, and that individually‐optimized pipelines may significantly improve the reproducibility of fMRI results over fixed pipelines. This was demonstrated by the detection of a significant interaction with motion parameter regression and physiological noise correction, even though the range of subject head motion was small across the group (≪ 1 voxel). Optimizing pipelines on an individual‐subject basis also revealed brain activation patterns either weak or absent under fixed pipelines, which has implications for the overall interpretation of fMRI data, and the relative importance of preprocessing methods. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
β‐catenin as a potential key target for tumor suppression
Authors: Fu Yuejun , Zheng Shuhua , An Na , Athanasopoulos Takis , Popplewell Linda , Liang Aihua , Li Ke , Hu Changchen , Zhu Yajing
Published: March 2011

β‐catenin is a multifunctional protein identified to be pivotal in embryonic patterning, organogenesis and adult homeostasis. It plays a critical structural role in mediating cadherin junctions and is also an essential transcriptional co‐activator in the canonical Wnt pathway. Evidence has been documented that both the canonical Wnt pathway and cadherin junctions are deregulated or impaired in a plethora of human malignancies. In the light of this, there has been a recent surge in elucidating the mechanisms underlying the etiology of cancer development from the perspective of β‐catenin. Here, we focus on the emerging roles of β‐catenin in the process of tumorigenesis by discussing novel functions of old players and new proteins, mechanisms identified to mediate or interact with β‐catenin and the most recently unraveled clinical implications of β‐catenin regulatory pathways toward tumor suppression.
Cancer risk in patients with allergic rhinitis, asthma and atopic dermatitis: A nationwide cohort study in Taiwan
Authors: Hwang Chian‐Yaw , Chen Yi‐Ju , Lin Ming‐Wei , Chen Tzeng‐Ji , Chu Szu‐Ying , Chen Chih‐Chiang , Lee Ding‐Dar , Chang Yun‐Ting , Wang Wen‐Jen , Liu Han‐Nan
Published: March 2011

It has long been a debate that whether atopy is a risk factor or protective factor for cancer. However, no large‐scale study of different cancers in patients with atopic diseases has been conducted among Asians. Here, we conducted a nationwide study to evaluate the cancer risk in patients with allergic rhinitis (AR), asthma and atopic dermatitis (AD). Drawing on Taiwan's National Health Insurance Research Database, 225,315 patients with AR, 107,601 patients with asthma and 34,263 patients with AD without prior cancers were identified in the period from 1996 to 2008. The standard incidence ratio (SIR) of each cancer was calculated. Although the overall cancer risks in patients with atopic symptoms were not increased, the risks were slightly elevated in female patients with AR or asthma (SIR: 1.13 and 1.08, AR and asthma, respectively) and slightly decreased in males patients with AR. Those aged 20–39 years‐old possessed the highest risk. A higher risk of developing brain cancer was found in patients with atopic diseases, and patient with AR or asthma also had an elevated risk of developing cancer of kidney and urinary bladder. In contrast, the risk of nonmelanoma skin cancer was lower in patients with AR and asthma. Compared to patients with only one atopic disease, those with more than one atopic disease had lower cancer risks. Our data suggests that the association between atopy and cancer is site‐specific.
Growth‐inhibitory and chemosensitizing effects of the glutathione‐S‐transferase‐π‐activated nitric oxide donor PABA/NO in malignant gliomas
Authors: Kogias Evangelos , Osterberg Nadja , Baumer Brunhilde , Psarras Nikolaos , Koentges Christoph , Papazoglou Anna , Saavedra Joseph E. , Keefer Larry K. , Weyerbrock Astrid
Published: March 2011

Glutathione‐S‐transferases (GSTs) are upregulated in malignant gliomas and contribute to their chemoresistance. The nitric oxide (NO) donor PABA/NO (O2‐{2,4‐dinitro‐5‐[4‐(N‐methylamino)benzoyloxy]phenyl} 1‐(N,N‐dimethylamino)diazen‐1‐ium‐1,2‐diolate) generates NO upon selective enzymatic activation by GST‐π‐inducing selective biological effects in tumors. Tumor cell killing and chemosensitization were observed in a variety of tumors after exposure to GST‐activated NO donor drugs. In our project, cytotoxic and chemosensitizing effects of PABA/NO in combination with carboplatin (CPT) and temozolomide (TMZ) were studied in human U87 glioma cells in vitro and in vivo. U87 glioma cells were exposed to PABA/NO alone or in combination with CPT or TMZ for 24 hr. Cell viability was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay after 24‐hr incubation and 48 hr after drug removal. The antiproliferative effect of PABA/NO was assessed in an intracranial U87 glioma nude rat model comparing subcutaneous administration and intratumoral delivery by convection‐enhanced delivery. PABA/NO monotherapy showed a strong dose‐dependent growth‐inhibitory effect in U87 glioma cells in vitro, and a strong synergistic effect was observed after concomitant treatment with TMZ, but not with CPT. Systemic and intratumoral PABA/NO administration significantly reduced cell proliferation, but this did not result in prolonged survival in nude rats with intracranial U87 gliomas. PABA/NO has potent antiproliferative effects, sensitizes U87 glioma cells to TMZ in vitro and shows some in vivo efficacy. Further studies are still required to consolidate the role of NO donor therapy in glioma treatment.
Expression of microRNA 210 associates with poor survival and age of tumor onset of soft‐tissue sarcoma patients
Authors: Greither T. , Würl P. , Grochola L. , Bond G. , Bache M. , Kappler M. , Lautenschläger C. , Holzhausen H.‐J. , Wach S. , Eckert A.W. , Taubert H.
Published: March 2011

Expression of microRNAs can affect age of tumor onset and prognosis of cancer patients. However, nothing is known about the effects of microRNAs on altered age of cancer onset and disease‐specific survival of soft‐tissue sarcoma (STS) patients. The levels of miR‐210, also known as hypoxia‐regulated microRNA, were analyzed by quantitative real‐time (RT)‐PCR in the tumors of 78 STS patients. The patients were stratified according to their microRNA levels with low, intermediate and high expression levels and the association of microRNA expression and patients' survival was analyzed using multivariate Cox's regression hazard analyses. A significant correlation between an intermediate miR‐210 expression and disease‐specific death of STS patients [relative risk (RR) = 3.19; p = 0.018] was observed compared with patients with high expression levels in their tumors. Interestingly, the association between an intermediate expression of miR‐210 and a poor prognosis was only significant in female STS patients (RR = 11.28; p = 0.010), but not observed in male individuals. Furthermore, the expression of miR‐210 showed a significant association with the age of tumor onset in a gender‐specific manner. Specifically, male patients with an intermediate expression of miR‐210 associated with a 9.6‐year later age of tumor onset (p = 0.017) compared with males with a low expression of miR‐210 in their tumors. However, no significant differences in the female patients were observed. This study provides the first evidence of a correlation of expression levels of a single microRNA (miR‐210) with the prognosis and age of tumor onset in a gender‐specific manner in STS patients.
A new hybrid algorithm for finding the lowest minima of potential surfaces: Approach and application to peptides
Authors: Goldstein Moshe , Fredj Erick , Gerber R. Benny
Published: March 2011

A new algorithm is presented for finding the global minimum, and other low‐lying minima, of a potential energy surface (PES) of biological molecules. The algorithm synergetically combines three well‐known global optimization methods: the diffusion equation method (DEM), which involves smoothing the PES; a simulated annealing (SA) algorithm; and evolutionary programming (EP), whose population‐oriented approach allows for a parallel search over different regions of the PES. Tests on five peptides having between 6 and 9 residues show that the code implementing the new combined algorithm is efficient and is found to outperform the constituent methods, DEM and SA. Results of the algorithm, in the gas phase and with the GBSA implicit solvent model, are compared with crystallographic data for the test peptides; good accord is found in all cases. Also, for all but one of the examples, our hybrid algorithm finds a minimum deeper than those obtained by a very extensive scan. TINKERs implementation of the OPLS‐AA force field is employed for the structure prediction. The results show that the new algorithm is a powerful structure predictor, when a reliable potential function is available. Our implementation of the algorithm is time‐efficient, and requires only modest computational resources. Work is underway on applications of the new algorithm to structural prediction of proteins and other biological macro‐molecules. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Enantioselective organocatalytic diels–Alder reactions: A density functional theory and kinetic isotope effects study
Authors: Omar Nasr Y.M. , Rahman Noorsaadah A. , Zain Sharifuddin MD
Published: March 2011

The mechanism and enantioselectivity of the organocatalytic Diels–Alder reaction were computationally investigated by density functional theory at the B3LYP/6‐31G(d) level of theory. The uncatalyzed Diels–Alder reaction was also studied to explore the effect of the organocatalyst on this reaction in terms of energetics, selectivity, and mechanism. The catalyzed reaction showed improved endo/exo selectivity, and the free energy of activation was significantly lowered in the presence of the catalyst. Both uncatalyzed and catalyzed reactions exhibited concerted asynchronous reaction mechanism with the degree of asynchronicity being more evident in the presence of the catalyst. The Corey's experimentally derived predictive selection rules for the outcome of the organocatalytic Diels–Alder reaction were also theoretically analyzed, and an excellent agreement was found between experiment and theory. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Electronic and chelation effects on the unusual C2‐methylation of N‐(para‐substituted)phenylaziridines with lithium organocuprates
Authors: Kim Jongtaek , Yoo Eunjung , Chang Sukbok , Lee Yoon Sup
Published: March 2011

Density functional theory calculations with the B3LYP functional were performed for the title ring‐opening reaction to understand the intrinsic activating and directing effects of the N‐substituents, as well as the electron donating effect of the para‐substituted (Y = Cl, H, Me) phenyl group at the more hindered benzylic C2 atom. The N‐tosyl group (i.e., N‐Tos) or the N‐(2‐pyridyl)sulfonyl group (i.e., N‐Py) was introduced to activate the ring nitrogen atom (N1) and the para‐substituted (Y = Cl, H, Me) phenyl group for the activation of the C2 atom. Conformational searches and geometry optimizations were performed for the N‐(para‐substituted)phenylaziridines (1∼6). Calculations indicate that the aziridine 6 (i.e., Py/Me) has the most elongated C2N1 bond intrinsically due to the electronic activating effects, implying the aziridine 6 to be the most potent candidate for the more‐hindered C2 opening. Transition states (TSs) were investigated for the prospective ring‐opening paths (I∼IV), considering the types of intermolecular push–pull interactions between the N‐activated phenylaziridines and the cuprate. The N‐Py group provides an unique C2‐favored TS along the path IV, which the N‐Tos group cannot afford, due to the less charge transfer from the nucleophilic CH of the cuprate into the electrophilic C2 atom. Furthermore, the e‐donating effect of the para‐substituents (Y = Cl, H, Me) enhances the C2 opening for the path IV. This study enables us to understand the unusual ring‐opening phenomena in terms of electronic and directing effects and hence may serve as a tool to design substrates for highly regioselective ring openings. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Regeneration of amphioxus oral cirri and its skeletal rods: implications for the origin of the vertebrate skeleton
Authors: Kaneto Satoshi , Wada Hiroshi
Published: March 2011

The oral cirri of amphioxus function as the first filter during feeding by eliminating unwanted large or noxious particulates. In this study, we were able to regenerate cirri following artificial amputation. This is the first firm observation of regeneration in amphioxus. Using this regeneration system, we studied skeletogenesis of the cellular skeleton of amphioxus oral cirri. During regeneration, the skeletal cells showed expression of fibrillar collagen and SoxE genes. These observations suggest that an evolutionarily conserved genetic regulatory system is involved in amphioxus cirrus and vertebrate cartilage skeletogenesis. In addition, Runx and SPARC/osteonectin expression were observed in regenerating cirral skeletal cells, indicating that cirral skeletogenesis is similar to vertebrate osteogenesis. We propose that the common ancestors of chordates possessed a genetic regulatory system that was the prototype of chondrogenesis and osteogenesis in vertebrates. Genome duplications caused divergence of this genetic regulatory system resulting in the emergence of cartilage and mineralized bone. The development of the vertebrate skeleton is an example of the functional segregation and subsequent recruitment of unique genetic materials that may account for the evolutionary diversification of novel cell types. J. Exp. Zool. (Mol. Dev. Evol.) 316:409–417, 2011. © 2011 Wiley‐Liss, Inc.
Pyrazoles and pyrazolo[4,3‐e]pyrrolo[1,2‐a]pyrazines II
Authors: Farghaly Abdel‐Rahman , El‐Kashef Hussein
Published: March 2011

Synthesis of the title compounds was achieved using the anils 2a, 2b, 2c, 2d, 2e and 5a, 5b, 5c derived from the 4‐aminopyrazole 1 as starting materials. These compounds were allowed to react with mercaptoacetic acid in boiling dry benzene to afford the corresponding thiazolidinones and spiro‐thiazolidinones 3a, 3b, 3c, 3d, 3e and 6a, 6b, 6c, respectively. Pictet—Spengler reaction of the 4‐aminopyrazole hydrochloride 7 with aromatic aldehydes and cyclic ketones resulted in the formation of new pyrazolo[4,3‐e]pyrrolo[1,2‐a]pyrazines 8a, 8b, 8c, 8d, 8e and 9a, 9b, respectively. Other derivatives of pyrazolo pyrrolopyrazines 10 and 11 were obtained via the reaction of the amino derivative 1 with 1,1′‐carbonyldiimidazol and CS2, respectively. J. Heterocyclic Chem., (2011).