bluuebunny/crossref_metadata_2025 huggingface dataset:
MOZ is essential for maintenance of hematopoietic stem cells
Authors: Katsumoto Takuo , Aikawa Yukiko , Iwama Atsushi , Ueda Shinobu , Ichikawa Hitoshi , Ochiya Takahiro , Kitabayashi Issay
Published: May 2006

Monocytic leukemia zinc-finger protein (MOZ), a MYST family histone acetyltransferase, is involved in the chromosome translocations associated with acute myeloid leukemia. MOZ acts as a transcriptional coactivator for AML1, which is essential for establishment of definitive hematopoiesis. To investigate the roles of MOZ in normal hematopoiesis, we generated MOZ-null mice. MOZ−/− mice died around embryonic day 15 (E15). In MOZ−/− E14.5 embryos, hematopoietic stem cells, lineage-committed progenitors, and B lineage cells were severely reduced. On the other hand, arrest of erythroid maturation and elevated myeloid lineage populations were observed. MOZ-deficient fetal liver cells could not reconstitute hematopoiesis of recipients after transplantation. Analysis using microarray and flow cytometry revealed that expression of thrombopoietin receptor (c-Mpl), HoxA9, and c-Kit was down-regulated. These results show that MOZ is required for maintenance of hematopoietic stem cells, and that it plays a role in differentiation of erythroid and myeloid cells. Some aspects of the MOZ−/− phenotype are similar to that observed in PU.1-deficient mice. MOZ was able to interact with PU.1 and activate PU.1-dependent transcription, thus suggesting a physical and functional link between PU.1 and MOZ.
Loss of transforming growth factor-β type II receptor promotes metastatic head-and-neck squamous cell carcinoma
Authors: Lu Shi-Long , Herrington Heather , Reh Douglas , Weber Stephen , Bornstein Sophia , Wang Donna , Li Allen G. , Tang Chin-Fang , Siddiqui Yasmin , Nord Jo , Andersen Peter , Corless Christopher L. , Wang Xiao-Jing
Published: May 2006

The prognosis of head-and-neck squamous cell carcinoma (HNSCC) has not been improved in the past 20 years. Validation of HNSCC biomarkers for targeted therapy has been hindered by a lack of animal models mimicking human HNSCC at both the pathological and molecular levels. Here we report that overexpression of K-ras or H-ras and loss of transforming growth factor-β type II receptor (TGFβRII) are common events in human HNSCC. Activation of either K-ras or H-ras in combination with TGFβRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases. These tumors displayed pathology indistinguishable from human HNSCCs and exhibited multiple molecular alterations commonly found in human HNSCCs. Additionally, elevated endogenous TGFβ1 in these lesions contributed to inflammation and angiogenesis. Our data suggest that targeting common oncogenic pathways in tumor epithelia together with blocking the effect of TGFβ1 on tumor stroma may provide a novel therapeutic strategy for HNSCC.
Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1
Authors: Zhang Chun-Li , Zou Yuhua , Yu Ruth T. , Gage Fred H. , Evans Ronald M.
Published: May 2006

During mammalian embryogenesis, precise coordination of progenitor cell proliferation and differentiation is essential for proper organ size and function. The involvement of TLX (NR2E1), an orphan nuclear receptor, has been implicated in ocular development, as Tlx−/− mice exhibit visual impairment. Using genetic and biochemical approaches, we show that TLX modulates retinal progenitor cell proliferation and cell cycle re-entry by directly regulating the expression of Pten and its target cyclin D1. Additionally, TLX finely tunes the progenitor differentiation program by modulating the phospholipase C and mitogen-activated protein kinase (MAPK) pathways and the expression of an array of cell type-specific transcriptional regulators. Consequently, Tlx−/− mice have a dramatic reduction in retina thickness and enhanced generation of S-cones, and develop severe early onset retinal dystrophy. Furthermore, TLX interacts with atrophin1 (Atn1), a corepressor that is involved in human neurodegenerative dentatorubral-pallidoluysian atrophy (DRPLA) and that is essential for development of multiple tissues. Together, these results reveal a molecular strategy by which an orphan nuclear receptor can precisely orchestrate tissue-specific proliferation and differentiation programs to prevent retinal malformation and degeneration.
Genetics and biology of pancreatic ductal adenocarcinoma
Authors: Hezel Aram F. , Kimmelman Alec C. , Stanger Ben Z. , Bardeesy Nabeel , DePinho Ronald A.
Published: May 2006

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States with a median survival of <6 mo and a dismal 5-yr survival rate of 3%–5%. The cancer’s lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer’s cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment.
Elongation of theKcnq1ot1transcript is required for genomic imprinting of neighboring genes
Authors: Mancini-DiNardo Debora , Steele Scott J.S. , Levorse John M. , Ingram Robert S. , Tilghman Shirley M.
Published: May 2006

The imprinted gene cluster at the telomeric end of mouse chromosome 7 contains a differentially methylated CpG island, KvDMR, that is required for the imprinting of multiple genes, including the genes encoding the maternally expressed placental-specific transcription factor ASCL2, the cyclin-dependent kinase CDKN1C, and the potassium channel KCNQ1. The KvDMR, which maps within intron 10 ofKcnq1, contains the promoter for a paternally expressed, noncoding, antisense transcript,Kcnq1ot1.A 244-base-pair deletion of the promoter on the paternal allele leads to the derepression of all silent genes tested. To distinguish between the loss of silencing as the consequence of the absence of transcription or the transcript itself, we prematurely truncated theKcnq1ot1transcript by inserting a transcriptional stop signal downstream of the promoter. We show that the lack of a full-lengthKcnq1ot1transcript on the paternal chromosome leads to the expression of genes that are normally paternally repressed. Finally, we demonstrate that five highly conserved repeats residing at the 5′ end of theKcnq1ot1transcript are not required for imprinting at this locus.
Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes
Authors: Fleischer Tracey C. , Weaver Connie M. , McAfee K. Jill , Jennings Jennifer L. , Link Andrew J.
Published: May 2006

Translation regulation is a critical means by which cells control growth, division, and apoptosis. To gain further insight into translation and related processes, we performed multifaceted mass spectrometry-based proteomic screens of yeast ribosomal complexes and discovered an association of 77 uncharacterized yeast proteins with ribosomes. Immunoblotting revealed an EDTA-dependent cosedimentation with ribosomes in sucrose gradients for 11 candidate translation-machinery-associated (TMA) proteins. Tandem affinity purification linked one candidate, LSM12, to the RNA processing proteins PBP1 and PBP4. A second candidate, TMA46, interacted with RBG1, a GTPase that interacts with ribosomes. By adapting translation assays to high-throughput screening methods, we showed that null yeast strains harboring deletions for several of the TMA genes had alterations in protein synthesis rates (TMA7 and TMA19), susceptibility to drugs that inhibit translation (TMA7), translation fidelity (TMA20), and polyribosome profiles (TMA7, TMA19, and TMA20). TMA20 has significant sequence homology with the oncogene MCT-1. Expression of human MCT-1 in the Δtma20 yeast mutant complemented translation-related defects, strongly implying that MCT-1 functions in translation-related processes. Together these findings implicate the TMA proteins and, potentially, their human homologs, in translation related processes.
The chicken talpid3 gene encodesa novel protein essentialfor Hedgehog signaling
Authors: Davey Megan G. , Paton I. Robert , Yin Yili , Schmidt Maike , Bangs Fiona K. , Morrice David R. , Smith Terence Gordon , Buxton Paul , Stamataki Despina , Tanaka Mikiko , Münsterberg Andrea E. , Briscoe James , Tickle Cheryll , Burt Dave W.
Published: May 2006

Talpid3 is a classical chicken mutant with abnormal limb patterning and malformations in other regions of the embryo known to depend on Hedgehog signaling. We combined the ease of manipulating chicken embryos with emerging knowledge of the chicken genome to reveal directly the basis of defective Hedgehog signal transduction in talpid3 embryos and to identify the talpid3 gene. We show in several regions of the embryo that the talpid3 phenotype is completely ligand independent and demonstrate for the first time that talpid3 is absolutely required for the function of both Gli repressor and activator in the intracellular Hedgehog pathway. We map the talpid3 locus to chromosome 5 and find a frameshift mutation in a KIAA0586 ortholog (ENSGALG00000012025), a gene not previously attributed with any known function. We show a direct causal link between KIAA0586 and the mutant phenotype by rescue experiments. KIAA0586 encodes a novel protein, apparently specific to vertebrates, that localizes to the cytoplasm. We show that Gli3 processing is abnormal in talpid3 mutant cells but that Gli3 can still translocate to the nucleus. These results suggest that the talpid3 protein operates in the cytoplasm to regulate the activity of both Gli repressor and activator proteins.
DNA damage triggers nucleotide excision repair-dependent monoubiquitylation of histone H2A
Authors: Bergink Steven , Salomons Florian A. , Hoogstraten Deborah , Groothuis Tom A.M. , de Waard Harm , Wu Junxin , Yuan Li , Citterio Elisabetta , Houtsmuller Adriaan B. , Neefjes Jacques , Hoeijmakers Jan H.J. , Vermeulen Wim , Dantuma Nico P.
Published: May 2006

Chromatin changes within the context of DNA repair remain largely obscure. Here we show that DNA damage induces monoubiquitylation of histone H2A in the vicinity of DNA lesions. Ultraviolet (UV)-induced monoubiquitylation of H2A is dependent on functional nucleotide excision repair and occurs after incision of the damaged strand. The ubiquitin ligase Ring2 is required for the DNA damage-induced H2A ubiquitylation. UV-induced ubiquitylation of H2A is dependent on the DNA damage signaling kinase ATR (ATM- and Rad3-related) but not the related kinase ATM (ataxia telangiectasia-mutated). Although the response coincides with phosphorylation of variant histone H2AX, H2AX was not required for H2A ubiquitylation. Together our data show that monoubiquitylation of H2A forms part of the cellular response to UV damage and suggest a role of this modification in DNA repair-induced chromatin remodeling.
ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth
Authors: Vives Virginie , Su Jian , Zhong Shan , Ratnayaka Indrika , Slee Elizabeth , Goldin Robert , Lu Xin
Published: May 2006

ASPP2 stimulates the apoptotic function of the p53 family in vivo. We show here that ASPP2−/− pups died before weaning. This postnatal lethality was significantly enhanced in p53+/− background and both deletions are synthetic lethal. ASPP2+/− mice developed spontaneous tumors. The tumor onset was accelerated by γ-irradiation or in p53+/− background. Tumors derived from ASPP2+/− mice retained wild-type ASPP2 allele even though some of them lost p53. These provide the first genetic evidence that ASPP2 is a haploinsufficient tumor suppressor that shares overlapping function(s) with p53 in mouse development and tumor suppression.
Structure determination of A
2
M
3+TaO6 and A
2
M
3+NbO6 ordered perovskites: octahedral tilting and pseudosymmetry
Authors: Barnes Paris W. , Lufaso Michael W. , Woodward Patrick M.
Published: May 2006

The room-temperature crystal structures of six A
2
M
3+
M
5+O6 ordered perovskites have been determined from neutron and X-ray powder diffraction data. Ba2YNbO6 adopts the aristotype high-symmetry cubic structure (space group Fm\overline 3m, Z = 4). The symmetries of the remaining five compounds were lowered by octahedral tilting distortions. Out-of-phase rotations of the octahedra about the c axis were observed in Sr2CrTaO6 and Sr2GaTaO6, which lowers the symmetry to tetragonal (space group = I4/m, Z = 2, Glazer tilt system = a
0
a
0
c
−). Octahedral tilting analogous to that seen in GdFeO3 occurs in Sr2ScNbO6, Ca2AlNbO6 and Ca2CrTaO6, which lowers the symmetry to monoclinic (space group P21/n, Z = 2, Glazer tilt system = a
−
a
−
c
+). The Sr2
MTaO6 (M = Cr, Ga, Sc) compounds have unit-cell dimensions that are highly pseudo-cubic. Ca2AlNbO6 and Ca2CrTaO6 have unit-cell dimensions that are strongly pseudo-orthorhombic. This high degree of pseudosymmetry complicates the space-group assignment and structure determination. The space-group symmetries, unit-cell dimensions and cation ordering characteristics of an additional 13 compositions, as determined from X-ray powder diffraction data, are also reported. An analysis of the crystal structures of 32 A
2
MTaO6 and A
2
MNbO6 perovskites shows that in general the octahedral tilt system strongly correlates with the tolerance factor.
Na2Si3O7: an incommensurate structure with crenel-type modulation functions, refined from a twinned crystal
Authors: Krüger Hannes , Kahlenberg Volker , Friese Karen
Published: May 2006

The structure of metastable, incommensurately modulated Na2Si3O7 has been determined from single-crystal X-ray diffraction data. In contrast to previous investigations which stated that the compound crystallizes in an orthorhombic space group, this study shows that the compound is monoclinic with a pseudo-orthorhombic cell and is affected by twinning. The structure is described in the (3 + 1)-dimensional superspace. Crenel-type modulation functions are used to account for an aperiodic sequence of right- and left-handed zweier single chains of silicate tetrahedra. The modulation mainly affects one of the two symmetrically independent tetrahedral chains, which are connected to build up [Si3O7]2− layers. Sodium cations are coordinated by five oxygen ligands and provide linkage between adjacent tetrahedral sheets. Distortions of the silicate tetrahedra and crystal chemical relationships of the title compound to sodium and lithium di- and metasilicates are discussed in detail.
On the mechanism of some first-order enantiotropic solid-state phase transitions: from Simon through Ubbelohde to Mnyukh
Authors: Herbstein Frank H.
Published: May 2006

The first (so-called) lambda transition in solids was found in the specific heat measurements for NH4Cl at 242 K by F. Simon in 1922 [Simon (1922). Ann. Phys.
68, 241–280]. Analogous phenomena found in many other solids gave rise to doubts (expressed most clearly by A. R. Ubbelohde some 50 years ago) about the applicability of classical thermodynamics to some phase transitions [Ubbelohde (1956). Brit. J. Appl. Phys.
7, 313–321]. However, Y. Mnyukh's studies of enantiotropic phase transitions in eight organic crystals showed that all proceed by a nucleation-and-growth mechanism [summarized in Mnyukh (2001), Fundamentals of Solid State Phase Transitions, Ferromagnetism and Ferroelectricity. 1st Books]. Nucleation is localized at defects in the parent phase; growth can be epitaxic and oriented if parent and daughter phases have closely similar structures, or random (not oriented) if there are substantial structural differences. This conclusion is supported by a critical review of Mnyukh's eight examples and other results published in the interim. It seems that Ubbelohde's invocation of `hybrid crystals' and `smeared transitions' can mostly be accounted for by lack of equilibrium in the phase-transition studies cited by him. However, the intermediate phase in 4,4′-dichlorobenzophenone appears to have structural resemblances to Ubbelohde's' `hybrid crystal'.
`Ionic' size differences from bond-valence parameters and from ionic radii
Authors: Keller Egbert , Krämer Volker
Published: May 2006

Expectation values for size differences between pairs of `ions' (atoms in oxidation states ≠ 0) embedded into similar coordination environments are calculated from tables of bond-valence parameters and ionic radii.
Subungual glomus tumor diagnosis based on imaging
Authors: TAKEMURA Noriko , FUJII Norikazu , TANAKA Toshihiro
Published: May 2006

A 50‐year‐old woman had had tenderness of the nail bed of the right thumb for more than 20 years. For the previous 5 or 6 years, she had also had attacks of pain with exposure to cold, and deformity of the right thumb nail plate began to appear. There was red discoloration on the proximal aspect of the nail bed, and a longitudinal fissure on the distal aspect of the nail plate. Ultrasonography showed a well‐circumscribed hypoechoic area under the proximal aspect of the nail plate and the nail matrix. Color Doppler ultrasonography showed subtle flow signals within the hypoechoic area. Magnetic resonance imaging showed a well‐circumscribed mass in the same place that the ultrasonography indicated. It was isointense to the dermis of the nail bed on the T1‐weighted image and hyperintense on the T2‐weighted image. Radiography showed subtle dorsal bone erosion in the distal phalanx. Surgery was performed. Histologically, the diagnosis of a subungual glomus tumor was made. We diagnosed the exact location and size of the subungual glomus tumor by preoperative imaging and completely removed it easily and safely. Imaging is very useful for diagnosing tumors of the nail unit.
A case of perforating pilomatricoma
Authors: CIRALIK Harun , COBAN Yusuf Kenan , ARICAN Ozer
Published: May 2006

Pilomatricoma is a rare skin neoplasm, most commonly seen in the head and neck region, and occurring in the first two decades of life. It is usually solitary and varies from 0.5 to 2 cm in diameter. Its etiology is unknown. Perforating pilomatricoma is a rare clinical variant that presents as a draining, crusted nodule or ulcer, and is reported to arise faster than the classic pilomatricoma. Herein, we report a case of 35‐year‐old female, who had a 4‐month history of a growing mass on her leg. On physical examination, a 4‐cm diameter, asymptomatic, erythematous, ulcerated mass was noted on the left anterio‐lateral upper leg. The first histopathological analysis of a punch biopsy from the lesion was reported as basal cell carcinoma. Therefore, the lesion was totally excised. There were shadow cells, squamoid cells, and basaloid aggregations more prominently in the one area in the tumor. In addition, calcification, foreign body giant cells and inflammatory cells were present. Punch or excisional biopsies are preferred as a method of diagnosis for the majority of cutaneous neoplasms. If total excision is not the method of choice, multiple punch biopsies should be made from different areas in large skin tumors for correct diagnosis.
Angiolymphoid hyperplasia with eosinophilia affecting the nail bed and underlying bone
Authors: TSUBOI Hiromi , MASUZAWA Mikio , KATSUOKA Kensei
Published: May 2006

A 69‐year‐old Japanese woman had a dark red, 1‐cm nodule located in the nail bed of the middle toe of her right foot. An X‐ray examination revealed an osteolytic lesion of the distal phalanx of the right middle toe. Histopathology showed a proliferation of blood vessels surrounded by epithelioid cells and an infiltration of many eosinophils and some inflammatory cells. There has been no recurrence after surgical excision of the skin lesion and the distal phalanx of the right middle toe.
Circumscribed palmar or plantar hypokeratosis: Report of a Korean case and published work review
Authors: LEE Sang Eun , KIM You Chan , KIM Soo‐Chan
Published: May 2006

Circumscribed palmar or plantar hypokeratosis is a rare dermatosis characterized by a solitary, well‐circumscribed patch with scaly borders chiefly on the palm or sole; it usually occurs in middle‐aged or elderly women. We report the case of a 52‐year‐old Korean woman with two characteristic lesions of circumscribed palmar hypokeratosis on the left palm. Clinically, the lesions simulated porokeratosis of Mibelli, but histologically there was no cornoid lamellation in the serial sections and there were the characteristic histopathological features of circumscribed palmar or plantar hypokeratosis including a stair‐like configuration with an abrupt thinning of the stratum corneum and a decreased granular layer. We also review the 16 cases of circumscribed palmar or plantar hypokeratosis reported in the published work.
Chromosome and sister chromatid exchange studies in Behcet's patients
Authors: OZTAS Sitki , GULLULU Gulay , TATAR Abdulgani , ASTAM Neslihan , AKYOL Ilknur , KARAKUZU Ali , AKTAS Akin , ODABAS Ali Riza
Published: May 2006

Behcet's disease is a chronic multisystemic disease of unknown pathogenesis characterized by four major symptoms: oral aphthous ulcers, skin lesions, ocular symptoms and genital ulcerations. The disease is spread throughout the world, but it is most frequent in Turkey, Japan, Korea and China. Although HLA‐Bw51 has been found to predominate in Behcet's cases, the genetic etiology has not yet been clarified. In this study, we investigated the chromosomal abnormalities and sister chromatid exchange rates in patients with Behcet's diseases. Thirty‐eight patients with Behcet's disease (diagnosed for the first time) and 30 healthy subjects (as controls) were included in this study. Although numerical and structural chromosomal abnormalities were not detected in our patients, we found an increased rate of sister chromatid exchange in patients over the control groups (P < 0.01). On the basis of these results, we discuss the genetic etiology of Behcet's disease.
Melkersson–Rosenthal syndrome with diffuse facial swelling and multiple cranial nerve palsies
Authors: KHANDPUR Sujay , MALHOTRA Amit Kumar , KHANNA Neena
Published: May 2006

We report an unusual case of Melkersson–Rosenthal syndrome presenting as diffuse facial swelling with facial, glossopharyngeal and vagus nerve palsies. A skin biopsy revealed non‐caseating epithelioid cell granulomas throughout the dermis. The disease responded poorly to systemic steroids, antihistamines, antibiotics and potassium iodide.
A mutilating arthropathy, “rhupus hands” associated with multiple synovial cysts in a patient with Systemic Lupus Erythematosus
Authors: HITOMI Katsuhiro , YAMASAKI Osamu , ASAGOE Kenji , IWATSUKI Keiji
Published: May 2006

“Rhupus hands” is a phrase coined to describe one of the deforming arthropathies associated with systemic lupus erythematosus (SLE), because the clinical features are indistinguishable from those of rheumatoid arthritis. Herein, we report a case of rhupus hands with multiple synovial cysts arising in a 60‐year‐old woman with SLE.
A case of erythrokeratoderma variabilis: Loosened gap junctions in the acanthotic epidermis
Authors: TAMAKI Yukiko , TAMAKI Eiko , SAKAI Rie , TAKAHASHI Kenzo , HORIGUCHI Yuji
Published: May 2006

A 15‐year‐old Japanese female without contributory personal or family medical history had demonstrated irregular, keratotic plaques in the lower extremities since infancy that had been gradually enlarging. The keratotic plaques showed partial erythematous change, which altered shape over a relatively short period, leaving pigmentation. The biopsy specimen taken from the erythematous, keratotic plaque showed typical church‐spire‐like papillomatosis with acanthosis, and thickening of granular and horny layers. Gene analysis targeting connexin 30.3 and 31, based on the diagnosis of erythrokeratoderma variabilis, did not demonstrate any abnormality of these genes. However, ultrastructural observation disclosed an increased amount of gap junctions, some of which showed four layers on high‐powered electron microscopy, suggesting loosened connection of the plasma membrane of the keratinocytes through the gap junctions. This loosened gap junction structure was also observed in a case of lamellar ichthyosis, examined as a reference. The disturbed cell‐to‐cell interaction through latent damage to the gap junctions may be related to the keratotic changes of the epidermis in these skin diseases.
Food‐induced anaphylaxis caused by ingestion of royal jelly
Authors: TAKAHAMA Hideto , SHIMAZU Takekazu
Published: May 2006

We report a case of food‐induced anaphylaxis caused by ingestion of royal jelly. After taking royal jelly and several other medicinal products, a 33‐year‐old Japanese male developed severe facial pruritus and erythema, followed by vertigo, numbness in his fingers, generalized pruritus, wheals, dyspnea, wheezing and impaired consciousness. He was treated with corticosteroid and fluid therapy, and his symptoms subsided. Upon allergy testing, his only positive reaction was to royal jelly. Given the clinical symptoms and the positive prick test to royal jelly, a diagnosis of anaphylaxis due to the ingestion of royal jelly was made. In this paper, we describe this case and review the relevant published work.
Fibrous hamartoma of infancy manifesting as multiple nodules with hypertrichosis
Authors: YOON Tae Young , KIM June Woo
Published: May 2006

Fibrous hamartoma of infancy is a rare benign tumor, which usually occurs within the first year of life. Most cases present as a solitary, painless, skin‐colored subcutaneous nodule; multiple lesions are rarely reported. There have also been a few cases which have showed overlying skin changes, including hypertrichosis and alterations in pigmentation. We report a rare case of fibrous hamartoma of infancy in a 6‐month‐old female who presented as multiple nodules with overlying hypertrichosis on the left buttock. To the best of our knowledge, there have been only two reported cases in the dermatological published work that showed these unusual findings simultaneously.
Identification of p53–46F as a super p53 with an enhanced ability to induce p53‐dependent apoptosis
Authors: Nakamura Yasuyuki , Futamura Manabu , Kamino Hiroki , Yoshida Koji , Nakamura Yusuke , Arakawa Hirofumi
Published: May 2006

More than half of human cancers contain mutations in the tumor suppressor protein p53, most of which accumulate in the DNA binding domain of the protein. Here we report the identification of a mutant p53, designated p53–46F, in which Ser‐46 is replaced with phenylalanine. In vitro, adenovirus‐mediated transduction of the p53–46F gene induced apoptosis more efficiently than wild‐type p53 in a number of cancer cell lines, whereas Ser‐15 phosphorylation of p53–46F was enhanced in all cancer cell lines examined. Moreover, the expression level of the cell cycle inhibitor p21/WAF1 was decreased in cell lines infected with adenovirus p53–46F (Ad‐p53–46F). p53–46F caused a more enhanced level of transcriptional activation of several p53‐target genes, including Noxa, p53AIP1 and p53RFP, compared with wild‐type p53. In vivo, adenovirus‐mediated gene transfer of p53–46F enhanced apoptosis, thus suppressing tumor growth of a lung cancer cell line more effectively than wild‐type p53 or p53–121F, another p53 mutant. Collectively, our data suggest that p53–46F is an active version of p53 that demonstrates enhanced induction of p53‐dependent apoptosis. This is probably mediated by upregulated transactivation of genes downstream of p53, increased Ser‐15 phosphorylation and a decrease in p21/WAF1 levels. We propose p53–46F as an alternative candidate to wild‐type p53 for use in developing new therapeutic strategies for the treatment of cancer. (Cancer Sci 2006; 97: 633–641)
Synthetic small interfering RNA targeting heat shock protein 105 induces apoptosis of various cancer cells both in vitro and in vivo
Authors: Hosaka Seiji , Nakatsura Tetsuya , Tsukamoto Hirotake , Hatayama Takumi , Baba Hideo , Nishimura Yasuharu
Published: May 2006

We previously reported that heat shock protein 105 (HSP105), identified by serological analysis of a recombinant cDNA expression library (SEREX) using serum from a pancreatic cancer patient, was overexpressed in various human tumors and in the testis of adult men by immunohistochemical analysis. In the present study, to elucidate the biological function of the HSP105 protein in cancer cells, we first established NIH3T3 cells overexpressing murine HSP105 (NIH3T3‐HSP105). The NIH3T3‐HSP105 cells acquired resistance to apoptosis induced by heat shock or doxorubicin. The small interfering RNA (siRNA)‐mediated suppression of HSP105 protein expression induced apoptosis in human cancer cells but not in fibroblasts. By a combination of siRNA introduction and doxorubicin or heat shock treatment, apoptosis was induced synergistically in a human colon cancer cell line, HCT116. In vivo, siRNA inoculation into the human gastric cancer cell line KATO‐3 established in the flank of an NOD SCID mouse suppressed the tumor growth. This siRNA‐induced apoptosis was mediated through caspases, but not the p53 tumor suppressor protein, even though the HSP105 protein was bound to wild‐type p53 protein in HCT116 cells. These findings suggest that the constitutive overexpression of HSP105 in cancer cells is involved in malignant transformation by protecting tumor cells from apoptosis. HSP105 may thus be a novel target molecule for cancer therapy and a treatment regimen using synthetic siRNA to suppress the expression of HSP105 protein may provide a new strategy for cancer therapy. (Cancer Sci 2006; 97: 623–632)
Alterations in ATR in nasal NK/T‐cell lymphoma and chronic active Epstein–Barr virus infection
Authors: Liu Angen , Takakuwa Tetsuya , Luo Wen‐Juan , Fujita Shigeki , Aozasa Katsuyuki
Published: May 2006

Nasal natural killer (NK)/T‐cell lymphoma (NKTCL) and chronic active Epstein–Barr virus infection (CAEBV) are relatively frequent, especially in Asia, and are poor in prognosis. Both diseases are proliferative diseases of NK/T cells that show highly complicated karyotypes, suggesting the involvement of chromosomal instability. ATR is an important gene for DNA damage response and chromosomal stability. To evaluate the role of ATR gene alterations in the pathogenesis of NKTCL and CAEBV, the whole coding region of the ATR gene was examined in cell lines derived from NKTCL and CAEBV, as well as tumor samples from patients. ATR alterations were detected in two of eight NKTCL and in one of three CAEBV lines. Most aberrant transcripts observed were deletions resulting from aberrant splicing. ATR alterations were also detected in four of 10 NKTCL clinical samples. Both NKTCL and CAEBV cell lines with ATR alterations showed a delay or abrogation in repair of ionizing radiation‐induced DNA double‐strand breaks and ultraviolet‐induced DNA single‐strand breaks, and both exhibited a defect in p53 accumulation. These findings show that alterations in the ATR gene result in an abnormal response to DNA double‐strand break and single‐strand break repair, suggesting a role for ATR gene alterations in NKTCL lymphomagenesis. (Cancer Sci 2006; 97: 605–610)
Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer overexpressing the insulin‐like growth factor receptor type 1
Authors: Ueda Shigeto , Tsuda Hitoshi , Sato Kazuhiko , Takeuchi Hideki , Shigekawa Takashi , Matsubara Osamu , Hiraide Hoshio , Mochizuki Hidetaka
Published: May 2006

The insulin‐like growth factor receptor type 1 (IGF1R) is suggested to play important roles in cancer cell growth through cross‐talk with hormone receptors and growth factor receptors. However, its clinical significance in breast cancers in vivo is still unclear. We examined immunohistochemically the expression of IGF1R, phosphorylated‐AKT (pAKT) and phosphorylated‐ERK1/2 (pERK1/2) using tissue microarray slides containing 150 cases of primary breast carcinoma. Their mutual correlation and correlation with the status of hormone receptors epidermal growth factor receptor and human epidermal growth factor receptor type 2 were also investigated. IGF1R overexpression was detected in 71 cases (47%), and was correlated with lower nuclear grade (P = 0.03), positive estrogen receptor (ER) and/or progesterone receptor status (P = 0.002). pERK1/2 expression, detected in 53 cases (35%), was correlated with positive ER (P < 0.0001) and lower nuclear grade (P = 0.014). pAKT expression, detected in 88 cases (59%), was not correlated with nuclear grade, hormone receptors status or other clinical parameters. Of the 71 IGF1R‐overexpressing tumors, pERK1/2 expression was detected in 27 (56%) of 48 ER‐positive cases but in only four (17%) of 23 ER‐negative cases (P = 0.022). In contrast, pAKT expression was constantly (64% or higher) detected irrespective of hormone receptor status in IGF1R‐overexpressing breast cancers. Taken together, these findings suggest that IGF1R overexpression might activate pERK1/2 and pAKT in hormone receptor‐positive breast cancer, but activate only pAKT in hormone receptor‐negative breast cancer. (Cancer Sci 2006; 97: 597–604)
Review article: the clinical pharmacology of proton pump inhibitors
Authors: SACHS G. , SHIN J. M. , HOWDEN C.W.
Published: May 2006

Proton pump inhibitors inhibit the gastric H+/K+‐ATPase via covalent binding to cysteine residues of the proton pump. All proton pump inhibitors must undergo acid accumulation in the parietal cell through protonation, followed by activation mediated by a second protonation at the active secretory canaliculus of the parietal cell.

The relative ease with which these steps occur with different proton pump inhibitors underlies differences in their rates of activation, which in turn influence the location of covalent binding and the stability of inhibition. Slow activation is associated with binding to a cysteine residue involved in proton transport that is located deep in the membrane. However, this is inaccessible to the endogenous reducing agents responsible for restoring H+/K+‐ATPase activity, favouring a longer duration of gastric acid inhibition. Pantoprazole and tenatoprazole, a novel proton pump inhibitor which has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, are activated more slowly than other proton pump inhibitors but their inhibition is resistant to reversal. In addition, tenatoprazole has a greatly extended plasma half‐life in comparison with all other proton pump inhibitors.

The chemical and pharmacological characteristics of tenatoprazole give it theoretical advantages over benzimidazole‐based proton pump inhibitors that should translate into improved acid control, particularly during the night.
Review article: acid‐related disease – what are the unmet clinical needs?
Authors: KATZ P. O. , SCHEIMAN J. M. , BARKUN A. N.
Published: May 2006

Proton pump inhibitors have dramatically improved the management options available for patients with acid‐related disorders.

In patients with gastro‐oesophageal reflux disease, currently available proton pump inhibitors provide an excellent outcome for the majority; however, they do not provide optimal pH control in many. Proton pump inhibitors co‐therapy reduces, but does not eliminate, the risk of gastrointestinal ulcers and complications in patients taking non‐steroidal anti‐inflammatory drugs, while in patients with upper gastrointestinal bleeding, it may be difficult to reach and maintain the current therapeutic target of intragastric pH of 6–7.

This article reviews the effectiveness of current antisecretory therapy in these three acid‐related diseases and areas of unmet clinical need. The potential role of a proton pump inhibitor with an extended duration of action and enhanced acid control from a single daily dose, particularly improved control at night, is discussed. Finally, therapy that could be administered without regard to time of day and/or food intake would offer dosing flexibility and thus have a positive effect on patients’ compliance.
Review article: the opportunities and benefits of extended acid suppression
Authors: SCARPIGNATO C. , PELOSINI I.
Published: May 2006

Acid suppression therapy with proton pump inhibitors is associated with well‐established benefits in the management of gastro‐oesophageal reflux (GERD) and other acid‐related disorders. However, a number of issues still remain unsettled. Despite their clinical efficacy, when given once daily, currently available proton pump inhibitors may not adequately control intragastric acidity during the night in a significant proportion of both healthy subjects and GERD patients, in whom symptom relief remains suboptimal.

Although some novel proton pump inhibitors have been synthesized, only few reached clinical testing. Amongst them, tenatoprazole represents a true advance displaying a long half‐life (five to seven times longer than that of currently available drugs) and extended acid suppression covering both day and night. All the available clinical studies suggest both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. As this last compound provides – amongst the members of the class – the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing proton pump inhibitors.

Tenatoprazole appears to be a promising proton pump inhibitor for the treatment of acid‐related diseases, where it has the potential to address unmet clinical needs.
Prospective study on the behaviour of the metalloprotease ADAMTS13 and of von Willebrand factor after bone marrow transplantation
Authors: Peyvandi F. , Siboni S. M. , Lambertenghi Deliliers D. , Lavoretano S. , De Fazio N. , Moroni B. , Lambertenghi Deliliers G. , Mannuccio Mannucci P.
Published: May 2006

Thrombotic microangiopathies (TMAs) are rare but serious complications of bone marrow transplantation (BMT). Clinical manifestations are similar to those of thrombotic thrombocytopenic purpura (TTP), but prognosis is generally poorer despite plasma exchange. The enzymatic activity of the plasma metalloprotease ADAMTS13, which cleaves ultralarge thrombogenic multimers of von Willebrand factor (VWF) derived from activated endothelial cells, is very low or undetectable in patients with classic TTP, and protease deficiency is thought to play a mechanistic role in the formation of platelet thrombi in the microcirculation. This is the first prospective study to evaluate the incidence of TMA in 46 consecutively recruited patients undergoing autologous or allogeneic BMT and explore in parallel the behaviour of ADAMTS13, VWF antigen and VWF multimer size. The incidence of post‐BMT TMA was 6% (three of 46); all cases occurred after allogeneic BMT. Compared with baseline values plasma ADAMTS13 activity was significantly reduced in patients undergoing BMT, particularly after the conditioning regimen (mean values: 50 ± 22 vs. 77 ± 32%; P < 0·0001). In the three patients who developed TMA, ADAMTS13 decreased after conditioning, but was very low in one case only (8%). VWF antigen levels progressively increased after the conditioning regimen (228 ± 75 vs. 178 ± 76% at baseline, P = 0·002). The mean proportion of high‐molecular weight VWF multimers did not change in the various stages of BMT, even though ultralarge multimers were transiently found in same cases with and without TMA. Hence, the measurements evaluated in this study are not clinically useful to predict the occurrence of post‐BMT TMA.
Allogeneic haematopoietic cell transplantation from alternative donors with a conditioning regimen of low‐dose irradiation, fludarabine and cyclophosphamide in Fanconi anaemia
Authors: Yabe Hiromasa , Inoue Hiroyasu , Matsumoto Masae , Hamanoue Satoshi , Koike Takashi , Ishiguro Hiroyuki , Koike Hideki , Suzuki Kazuo , Kato Shunichi , Kojima Seiji , Tsuchida Masahiro , Mori Tetsuya , Adachi Souichi , Tsuji Koichiro , Koike Kenichi , Morimoto Akira , Sako Masahiro , Yabe Miharu
Published: May 2006

A pilot study was undertaken using a fludarabine‐based conditioning regimen to improve haematopoietic cell transplantation (HCT) from alternative donors in 27 Fanconi anaemia (FA) patients. Patients were conditioned with 150–180 mg/m2 of fludarabine, 40 mg/kg of cyclophosphamide, 5–10 mg/kg of antithymocyte globulin, and 300–450 cGy of thoracoabdominal/total body irradiation. One patient who received unrelated cord blood transplantation failed to engraft, another patient died of sepsis. The 1‐year overall survival was 96·3% (95% CI, 89–100). This conditioning regimen exerted an immunosuppressive effect that enabled durable engraftment in alternative donor HCT without severe toxicity.
Effects of HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo‐controlled trial
Authors: McKenzie Joyce , Fisher B Miles , Jaap Alan J. , Stanley Adrian , Paterson Kenneth , Sattar Naveed
Published: May 2006

Background  Increasingly strong links are being recognized between diabetes, insulin resistance and liver fat accumulation [e.g. nonalcoholic fatty liver disease (NAFLD)]. Recent data indicating that hormone replacement therapy (HRT) may lessen diabetes risk is intriguing but explanatory mechanisms are unclear.

Objective  Post hoc investigation of the possibility that HRT may favourably influence liver enzyme levels commonly elevated in patients with diabetes. We examined liver function test data from a 6‐month trial of a low‐dose continuous combined HRT (1 mg 17β oestradiol and 0·5 mg norethisterone acetate).

Design  Double‐blind, randomized placebo‐controlled.

Patients  Fifty women with type 2 diabetes.

Measurements  Liver enzyme levels (AST, ALT, gamma‐glutamylytransferase [GGT], and alkaline phosphatase [ALP]).

Results  Forty‐five women completed the study with 19/22 in the active group demonstrating compliance as measured by sex hormone changes. Relative to placebo recipients (n = 23), women randomized and compliant to HRT demonstrated significant reductions in ALT [−14 (−23 to −6) U/l, P = 0·002], AST [−9·2 (−14 to −5) U/l, P < 0·001] and ALP [−60·8 (−80 to −42) U/l, P < 0·001]. Circulating concentrations in GGT were also significantly reduced (P = 0·035). All changes were significant using an intention‐to‐treat analysis.

Conclusion  HRT containing low‐dose oestradiol and norethisterone reduces serum concentrations of liver function enzymes, potentially due to a lowering of liver fat accumulation. Better understanding of mechanisms by which this HRT improves liver function tests could help the design of new therapies to treat individuals with NAFLD.
Hypopituitarism and mortality in pituitary adenoma
Authors: Lindholm J. , Nielsen E. Husted , Bjerre P. , Christiansen J. Sandahl , Hagen C. , Juul S. , Jørgensen J. , Kruse A. , Laurberg P. , Stochholm K.
Published: May 2006

Background and objective  Previous studies on hypopituitarism and mortality have concluded that insufficient pituitary function is associated with decreased survival. For several reasons the results are difficult to compare – particularly because definitions and treatment of hypopituitarism have varied and various underlying disorders have been included. The purpose was to assess the relationship between mortality and pituitary function.

Patients and design  One hundred and sixty consecutive patients (99 men and 61 women) with functionless, suprasellar pituitary adenoma. All were operated on transsphenoidally during the period 1985–1996. Additional radiotherapy was given to 29 patients. Mortality was calculated 12·4 years (median, range 8·1–19·9) after operation. Postoperative hormonal deficits were treated in most, though GH substitution was given only to a minority of patients.

Results  Postoperatively 30% of the patients had normal pituitary function (normal adrenocortical, thyroid and gonadal function), 26% were panhypopituitary and 36% had partial pituitary insufficiency. Forty‐one patients had died (34·7 expected) yielding a standard mortality ratio (SMR) of 1·18 (95% confidence limits (CI) 0·87–1·60). SMR was significantly increased in women (1·97, CI 1·20–3·21) but not in men (0·83, CI 0·55–1·26). SMR in patients with normal pituitary function, panhypopituitarism and partial insufficiency were not different from that in the general population. SMR in hypopituitary women was substantially higher than in men with pituitary insufficiency. Treatment with growth hormone in GH‐deficient patients did not influence survival.

Conclusion  Pituitary surgery for nonfunctioning adenoma and subsequent pituitary insufficiency had no effect on mortality in men, but was associated with significantly increased mortality in women. Suboptimal hormonal substitution in women may play a role.
The analysis of volatiles from thermally oxidized virgin olive oil using dynamic sorption–thermal desorption and solid phase micro‐extraction techniques
Authors: Kanavouras Antonis , Hernandez Ruben J.
Published: May 2006

Virgin olive oil was thermally oxidized by heating in a conventional oven. Volatiles produced during this process were isolated either by dynamic headspace‐thermal desorption (DHS‐TD) with Tenax‐TA trapping material, or solid phase micro‐extraction (SPME) with nonpolar polydimethysiloxane (PDMS) and polydimethysiloxane‐divinylbenzene (PDMS/DVB) fibres. Volatiles collected in the former case were isolated by using gas chromatography (GC) and characterized by an ion trap mass spectrometer, while those extracted by SPME were isolated by GC and characterized by the use of a time‐of‐flight‐mass spectrometer (TOFMS). More compounds were isolated by DHS‐TD compared to SPME which is, however, a quick process that can be even faster when combined with the high speed chromatography equipment of TOFMS. Fifty‐eight compounds were isolated from olive oil samples using the PDMS/DVB bi‐polar fibres and 39 using the nonpolar PDMS. A quick descriptive analysis of oxidized olive oil is best obtained by using the SPME technique with a PDMS/DVB bi‐polar fibre.
Time course of the colour of young red wines from Vitis vinifera L. during ageing in bottle
Authors: Monagas María , Martín‐Álvarez Pedro J. , Gómez‐Cordovés Carmen , Bartolomé Begoña
Published: May 2006

The colour characteristics of red wines from Vitis vinifera L. cv Tempranillo, Graciano and Cabernet Sauvignon (vintage 2000) from Navarra (Spain), was studied during 26 months of ageing in bottle through the evaluation of the wine visible spectrum and of several colorimetric indices (colour intensity, %red, %yellow, %blue, %dA and tint) and CIELAB variables (L*, C*, h, a* and b*). During ageing in bottle, the spectrum of Tempranillo wine (pH 4.3) mainly changed in the absorbance range between 420 and 500 nm, whereas Graciano (pH 3.5) and Cabernet Sauvignon (pH 3.6) wines registered a decrease in absorbance in the interval between 500 and 560 nm. The time course of the different wine colour parameters was found to fit either a second‐order polynomium or a linear model, depending on the grape variety employed. CIELAB variables could be described in terms of their colorimetric index counterparts, showing b* and h relative greater errors. Although the wine total chromatic changes in CIELAB units registered after 26 months of ageing in bottle indicated changes perceivable by the human eye (ΔE* ≥ 2.7) for the three varieties studied, Graciano and Cabernet Sauvignon wines showed a more balanced colour evolution than Tempranillo wine.