Reciprocal t(9;22) ABL/BCR fusion proteins: leukemogenic potential and effects on B cell commitment

Background: t(9;22) is a balanced translocation, and the chromosome 22 breakpoints (Philadelphia chromosome – Ph+) determine formation of different fusion genes that are associated with either Ph+ acute lymphatic leukemia (Ph+ ALL) or chronic myeloid leukemia (CML). The "minor" breakpoint in Ph+ ALL encodes p185BCR/ABL from der22 and p96ABL/BCR from der9. The "major" breakpoint in CML encodes p210BCR/ABL and p40ABL/BCR. Herein, we investigated the leukemogenic potential of the der9-associated p96ABL/BCR and p40ABL/BCR fusion proteins and their roles in the lineage commitment of hematopoietic stem cells in comparison to BCR/ABL. Methodology: All t(9;22) derived proteins were retrovirally expressed in murine hematopoietic stem cells (SL cells) and human umbilical cord blood cells (UCBC). Stem cell potential was determined by replating efficiency, colony forming - spleen and competitive repopulating assays. The leukemic potential of the ABL/BCR fusion proteins was assessed by in a transduction/transplantation model. Effects on the lineage commitment and differentiation were investigated by culturing the cells under conditions driving either myeloid or lymphoid commitment. Expression of key factors of the B-cell differentiation and components of the preB-cell receptor were determined by qRT-PCR. Principal Findings: Both p96ABL/BCR and p40ABL/BCR increased proliferation of early progenitors and the short term stem cell capacity of SL-cells and exhibited own leukemogenic potential. Interestingly, BCR/ABL gave origin exclusively to a myeloid phenotype independently from the culture conditions whereas p96ABL/BCR and to a minor extent p40ABL/BCR forced the B-cell commitment of SL-cells and UCBC. Conclusions/Significance: Our here presented data establish the reciprocal ABL/BCR fusion proteins as second oncogenes encoded by the t(9;22) in addition to BCR/ABL and suggest that ABL/BCR contribute to the determination of the leukemic phenotype through their influence on the lineage commitment

DEFECTS IN HEMATOPOIETIC DIFFERENTIATION IN NZB AND NZC MICE

Hematopoietic stem cell activity in inbred NZB and NZC mice has been determined by transplantation and endogenous spleen colony assays. Whereas NZB mice show normal colony-forming unit (CFU) activity in the transplantation assay, they show markedly elevated endogenous CFU. NZC mice also show this markedly elevated endogenous CFU activity, but in the transplantation assay show only about 5–10% of normal CFU counts. When NZC stem cells are tested for CFU activity in irradiated recipients of the H-2d type, almost normal colony numbers occur. NZB stem cells however also cannot form colonies in NZC mice. These results suggest that NZC mice have a defect in the micro-environment of the spleen which renders them incapable of allowing transplanted CFU to form colonies. Genetic analysis of both the NZC defect as a CFU recipient, and the elevated endogenous count in NZB and NZC, shows that both are controlled by single recessive genes which are not linked to either coat color, agouti, H-2 or Ig loci. Of even more relevance is the finding that these hematopoietic abnormalities are not linked to the genes involved in controlling autoantibody formation to red cells in the NZB mice. These mice therefore appear to show two distinct hematopoietic abnormalities, the analysis of which may be of considerable value in understanding the detailed events of hematopoietic stem cell differentiation

Helicobacter pylori infection appears essential for stomach carcinogenesis: Observations in Semarang, Indonesia

The gastric cancer incidence in Semarang, Indonesia, is exceedingly low: only approximately 1/100th of the level in Japan. To elucidate the reason, we carried out an ecological study recruiting 69 male and 102 female participants from the general populace in January 2005. Positive urea breath tests were 0% for both men and women, and Helicobacter pylori (H. pylori) IgG antibodies were found in 2% (0–5, 95% confidence interval) of men and 2% (0–4) of women, significantly lower than the 62% (58–65) and 57% (53–60), respectively, in Japan. Furthermore, there were no positive findings with the pepsinogen tests in Semarang, again significant in comparison with the 23% (22–25) and 22% (20–23) in Japan. Variation in smoking levels and consumption of NaCl, vegetables and fruit were found, but not to an extent that would allow explanation of the major differences in gastric cancer incidence. We may conclude that the very low prevalence of H. pylori infection and thus chronic atrophic gastritis account for the rarity of stomach cancer in Semarang, Indonesia. (Cancer Sci 2005; 96: 873–875

CNN Architectures for Large-Scale Audio Classification

Convolutional Neural Networks (CNNs) have proven very effective in image classification and show promise for audio. We use various CNN architectures to classify the soundtracks of a dataset of 70M training videos (5.24 million hours) with 30,871 video-level labels. We examine fully connected Deep Neural Networks (DNNs), AlexNet [1], VGG [2], Inception [3], and ResNet [4]. We investigate varying the size of both training set and label vocabulary, finding that analogs of the CNNs used in image classification do well on our audio classification task, and larger training and label sets help up to a point. A model using embeddings from these classifiers does much better than raw features on the Audio Set [5] Acoustic Event Detection (AED) classification task.Comment: Accepted for publication at ICASSP 2017 Changes: Added definitions of mAP, AUC, and d-prime. Updated mAP/AUC/d-prime numbers for Audio Set based on changes of latest Audio Set revision. Changed wording to fit 4 page limit with new addition

Overview of Players and Information in the Cancer Epidemiology and Control World in Asia

Cancer and related lifestyle diseases are on the increase across Asia and already account for over half the disease-associated mortality in the vast majority of the included countries. An understanding of the epidemiology is therefore of paramount importance. In addition, given the immensity of the problem, cooperation among all the interested parties is of the essence. The present series of reviews were complied with the aim of promoting better comprehension and interaction, focusing on cancer prevalence and the underlying risk and preventive factors in Asia. Data from Cancer Incidence in Five Continents and Globocan 2002, published by the International Agency for Research on Cancer, as well as various other cancer registry sources, were thus married with research information in the public domain, accessible through PubMed. It is hoped that the comprehensive approach adopted for the different regions will help bring together all of the Asian community of individuals involved in cancer epidemiology and control and contribute to establishment of Asian networks for collaborative research. The major players and the overall picture for cancer control are covered in the present overview. Further details are then provided in seven separate regional reviews: for North-Western and Central Asia; South-West Asia; South Asia; Mainland South-East Asia; Peninsular and Island South-East Asia, the Pacific; and North-East Asia. The final section covers possible organ-based strategies for cancer control and, lastly, an Appendix has been included listing research institutes and staff in Asia to facilitate contacts between interested individuals.MOORE MA, 2010, ASIAN PACIFIC J CA S, V11, P147SHIN HR, 2010, ASIAN PACIFIC J CA S, V11, P147Tanaka H, 2009, ASIAN PAC J CANCER P, V10, P1191Yoo KY, 2008, JPN J CLIN ONCOL, V38, P327, DOI 10.1093/jjco/hyn026Sobue T, 2008, INT J CLIN ONCOL, V13, P97, DOI 10.1007/s10147-008-0761-7Okamoto N, 2008, INT J CLIN ONCOL, V13, P90, DOI 10.1007/s10147-008-0759-1Park S, 2008, ASIAN PAC J CANCER P, V9, P371Moore MA, 2008, ASIAN PAC J CANCER P, V9, P815Akhtar F, 2007, ASIAN PAC J CANCER P, V8, P452Kawahara N, 2007, ASIAN PAC J CANCER P, V8, P464CURADO MP, 2007, IARC SCI PUBLICATION, V160WIANGNON S, 2007, ASIAN PAC J CANCER P, V8, P457AHN YO, 2007, J PREV MED PUB HLTH, V40, P265Deerasamee S, 2007, ASIAN PAC J CANCER P, V8, P547Tamakoshi A, 2007, ASIAN PAC J CANCER P, V8, P1Kawahara N, 2007, ASIAN PAC J CANCER P, V8, P146CHENG C, 2006, ASIAN PAC J CANCER P, V7, P350YOO KY, 2005, ASIAN PAC J CANCER P, V6, P238FERLAY J, 2004, GLOBOCAN 2002 CANC IBHURGRI Y, 2004, ASIAN PAC J CANCER P, V5, P77Coleman MP, 2003, CLIN MED, V3, P219Lim GCC, 2002, JPN J CLIN ONCOL, V32, pS37PARKIN DM, 2002, IARC SCI PUBLICATION, V155Tjindarbumi D, 2002, JPN J CLIN ONCOL, V32, pS17Hock LC, 2002, JPN J CLIN ONCOL, V32, pS62Vatanasapt V, 2002, JPN J CLIN ONCOL, V32, pS82Ngelangel CA, 2002, JPN J CLIN ONCOL, V32, pS52Anh PTH, 2002, JPN J CLIN ONCOL, V32, pS92YOO KY, 2002, ASIAN PAC J CANCER P, V3, P85Desai PB, 2002, JPN J CLIN ONCOL, V32, pS13ANH PHT, 2002, JPN J CLIN ONCOL, V32, pS82AHN YO, 2002, JPN J CLIN ONCOL S, V32, pS37YAMAGUCHI K, 2002, JPN J CLIN ONCOL S, V32, pS37TAJIMA K, 2002, ASIAN PAC J CANCER P, V3, P263ROSEMAWATI A, 2001, ASIAN PACIFIC J CA S, V2, P43Wang HE, 2001, ANN EMERG MED, V37, P38MOSAVIJARRAHI A, 2001, ASIAN PAC J CANCER P, V2, P25OSHIMA A, 2001, ASIAN PACIFIC J CA S, V2, P31PARKIN DM, 2001, ASIAN PAC J CANCER P, V2, pS1GAJALAKSHMI V, 2001, ASIAN PACIFIC J CA S, V2, P13SARJADI PT, 2001, ASIAN PACIFIC J CA S, V2, P21ESTEBAN DB, 2001, ASIAN PACIFIC J CA S, V2, P25QASEM BM, 2001, ASIAN PACIFIC J CA S, V2, P25AHN YO, 2001, ASIAN PACIFIC J CA S, V2, P39MUNKHTAIVAN A, 2001, ASIAN PACIFIC J CA S, V2, P47BHURGRI Y, 2001, ASIAN PACIFIC J CA S, V2, P51ALHAMDAN N, 2001, ASIAN PACIFIC J CA S, V2, P61ALLAWATI JA, 2001, ASIAN PACIFIC J CA S, V2, P71YOU SL, 2001, ASIAN PACIFIC J CA S, V2, P75DEERASAMEE S, 2001, ASIAN PACIFIC J CA S, V2, P79ANH PH, 2001, ASIAN PACIFIC J CA S, V2, P85FOO W, 2001, ASIAN PACIFIC J CA S, V2, P9PARKIN DM, 1997, IARC SCI PUBLICATION, V143PARKIN DM, 1992, IARC SCI PUBLICATION, V120MUIR CS, 1987, IARC SCI PUBLICATION, V88WATERHOUSE JAH, 1982, IARC SCI PUBLICATION, V42

Exome-wide association study of pancreatic cancer risk

We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P=3.27x10(-6); exome-wide statistical significance threshold P<2.5x10(-6)). Cases had more rare inactivating variants in DNA repair genes than controls, even after excluding 13 genes known to predispose to pancreatic cancer (adjusted odds ratio, 1.35, P=.045). At the suggestive threshold (P<.001), 6 genes were enriched for rare damaging variants (UHMK1, AP1G2, DNTA, CHST6, FGFR3, and EPHA1) and 7 genes had associations with pancreatic cancer risk, based on the sequence-kernel association test. We confirmed variants in BRCA2 as the most common high-penetrant genetic factor associated with pancreatic cancer and we also identified candidate pancreatic cancer genes. Large collaborations and novel approaches are needed to overcome the genetic heterogeneity of pancreatic cancer predisposition

Molecular genetic analysis of the 3p — syndrome

Molecular genetic analysis of five cases of 3p-syndrome (del(3)(qter-p25:)) was performed to investigate the relationship between the molecular pathology and clinical phenotype. Fluorescence in situ hybridization studies and analysis of polymorphic DNA markers from chromosome 3p25-p26 demonstrated that all four informative cases had distal deletions. However, the extent of the deletion was variable: in two patients with the most extensive deletions the deletion breakpoint mapped between RAF1 and D3S1250, in one patient the deletion breakpoint was between D3S1250 and D3S601, and in two patients the deletion commenced telomeric to D3S601 (and telomeric to D3S1317 in one of these). All five patients displayed the classical features of 3p- syndrome (mental retardation, growth retardation, microcephaly, ptosis and micrognathia) demonstrating that loss of sequences centromeric to D3S1317 is not required for expression of the characteristic 3p- syndrome phenotype. The three patients with the most extensive deletions had cardiac septal defects suggesting that a gene involved in normal cardiac development is contained in the interval D3S1250 and D3S18. The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects. At least three patients were deleted for the von Hippel - Lindau (VHL) disease gene although none had yet developed evidence of VHL disease. We conclude that molecular analysis of 3p- syndrome patients enhances the management of affected patients by identifying those at risk for VHL disease, and can be used to elucidate the critical regions for the 3p- syndrome phenotyp

A comparison of trends in population size and life history features of Atlantic salmon (Salmo salar) and anadromous and non-anadromous Brown trout (Salmo trutta) in a single catchment over 116 years

We use a long time series of catch abundance from a recreational fishery over 116 years to look for population trends in Atlantic salmon, and anadromous (sea trout) and non-anadromous (brown) trout for a single catchment, Loch Lomond, west central Scotland. Year strongly predicted variation in catches but catch effort did not meaningfully increase explained variation. Salmon showed periods of increasing and decreasing trends, for sea trout and brown trout there was an overall declining trend. Since 1952, Lomond salmon population trends differed from both wider Scotland and southern Europe, indicating that the Lomond population is partially buffered from drivers of change in salmon populations more widely. In contrast Lomond sea trout showed a similar declining trend to that of populations from the wider west of Scotland over this period. The Lomond populations showed some evidence of shorter-term cycling patterns; the drivers for which are unknown. Body size in salmon and sea trout declined but increased in brown trout; salmon returned to freshwater later, and the relative proportion of all caught trout that were anadromous increased across the time series. This study shows a long and protracted period of fundamental change to populations of these two species over 116 years

Long-term data for endemic frog genera reveal potential conservation crisis in the Bale Mountains, Ethiopia

Populations of many frogs have declined alarmingly in recent years, placing nearly one third of the >6,000 species under threat of extinction. Declines have been attributed largely to habitat loss, environmental degradation and/or infectious diseases such as chytridiomycosis. Many frogs undergo dramatic natural population fluctuations such that long-term data are required to determine population trends without undue influence of stochastic factors. We present long-term quantitative data (individuals encountered per person hour of searching) for four monotypic frog genera endemic to an Afromontane region of exceptional importance but growing conservation concern: one endemic to the Ethiopian highlands (Spinophrynoides osgoodi) and three endemic to the Bale Mountains (Altiphrynoides malcolmi, Balebreviceps hillmani, Ericabatrachus baleensis), collected during 15 field trips to the Bale Mountains between 1971 and 2009. Only a single confirmed sighting of S. osgoodi has been made since 1995. The other three species have also declined, at least locally. E. baleensis appears to have been extirpated at its type locality and at the same site B. hillmani has declined. These declines are in association with substantial habitat degradation caused by a growing human population. Chytrid fungus has been found on several frog species in Bale, although no dead or moribund frogs have been encountered. These results expose an urgent need for more amphibian surveys in the Bale Mountains. Additionally, we argue that detrimental human exploitation must be halted immediately in at least some parts of the Harenna Forest if a conservation crisis is to be averte