Publications by authors named "Rintaro Ono"

17 Publications

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Clonal evidence for the development of neuroblastoma with extensive copy-neutral loss of heterozygosity arising in a mature teratoma.

Cancer Sci 2021 Jul 6;112(7):2921-2927. Epub 2021 May 6.

Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
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http://dx.doi.org/10.1111/cas.14931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253283PMC
July 2021

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

EBioMedicine 2021 Feb 10;64:103235. Epub 2021 Feb 10.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Electronic address:

Background: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL.

Methods: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia.

Findings: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo.

Interpretation: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL.

Funding: This study was supported by RIKEN (RIKEN President's Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
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http://dx.doi.org/10.1016/j.ebiom.2021.103235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878180PMC
February 2021

Prevalence and characteristics of Kawasaki disease before and during the COVID-19 pandemic.

World J Pediatr 2021 04 6;17(2):215-217. Epub 2021 Feb 6.

Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-8560, Japan.

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http://dx.doi.org/10.1007/s12519-021-00412-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866965PMC
April 2021

Ruxolitinib for hematopoietic cell transplantation-associated hemophagocytic lymphohistiocytosis.

Int J Hematol 2021 Feb 26;113(2):297-301. Epub 2020 Sep 26.

Department of Pediatrics, St. Luke's International Hospital, 9-1 Akashicho, Chuo-ku, Tokyo, 104-0044, Japan.

Hemophagocytic lymphohistiocytosis (HLH) is a severe complication after allogeneic hematopoietic cell transplantation (HCT) and can cause graft failure or multi-organ failure. Here, we report two children with refractory HCT-associated HLH treated with ruxolitinib. In the first patient, ruxolitinib resolved fever, cytopenia and hyperferritinemia. In another patient, although severe hepatic failure, which developed and worsened before the administration of ruxolitinib, was irreversible, rapid improvement in fever, leukopenia and hyperferritinemia was observed. Of note, multiplex cytokine profiling showed amelioration of cytokine storm in both patients. Ruxolitinib may be an encouraging option for HCT-associated HLH.
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http://dx.doi.org/10.1007/s12185-020-02999-3DOI Listing
February 2021

Effect of Asian dust on respiratory symptoms among children with and without asthma, and their sensitivity.

Sci Total Environ 2021 Jan 18;753:141585. Epub 2020 Aug 18.

Department of Pediatrics, National Hospital Organization Fukuoka National Hospital, 4-39-1 Yakatabaru, Minami-ku, Fukuoka 811-1394, Japan. Electronic address:

There has been little study on the effect of Asian dust exposure on respiratory symptoms among children who are vulnerable to environmental factors. In this panel study, we investigated the effect of Asian dust on respiratory symptoms among children with and without asthma, and their sensitivity. Children attending two elementary schools (137 total), and 23 children with asthma from cooperating medical institutions in Fukuoka prefecture were recruited. Subjects measured peak expiratory flow rate (PEF), and recorded asthma-like symptoms, cough, nasal symptoms and use of medication in a diary from April 1, 2013 to June 30, 2013. To assess exposure to Asian dust, we used Light Detection and Ranging (LIDAR) data. For the analysis of the association between Asian dust and respiratory symptoms, the case-crossover design and generalized estimating equation (GEE) models were used. Taking individual sensitivity to respiratory aggravation into consideration, the subjects were classified into three groups: children without asthma, children with asthma who do not use long-term preventive medication (CA) and children with asthma who use long-term preventive medication (CA-LTM). For CA, Asian dust exposure was significantly associated with asthma-like symptoms, with a hazard ratio of 5.17 (95%CI: 1.02=26.12) at Lag0, and the change in %maxPEF, -1.65% (95%CI:-2.82, -0.48) at Lag0. For children without asthma, a statistically significant association was found between Asian dust exposure and the change in %maxPEF, -0.56% (95%CI: -1.31, -0.08) at Lag1. However, no adverse effects were observed in CA-LTM. Temperature had significant effects on %maxPEF for three groups. Asian dust, photochemical oxidant and pollen caused simultaneously additive adverse effects on nasal symptoms for children without asthma. This study suggests the possibility that long-term preventive medication to manage asthma may suppress aggravation of respiratory symptoms due to Asian dust and may be an effective prevention.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141585DOI Listing
January 2021

Kawasaki disease shock syndrome: Case report and cytokine profiling.

Pediatr Int 2019 Jun 19;61(6):620-622. Epub 2019 Jun 19.

Department of Pediatrics, St Luke's International hospital, Tokyo, Japan.

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http://dx.doi.org/10.1111/ped.13864DOI Listing
June 2019

Human NK cell development in hIL-7 and hIL-15 knockin NOD/SCID/IL2rgKO mice.

Life Sci Alliance 2019 04 1;2(2). Epub 2019 Apr 1.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.
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http://dx.doi.org/10.26508/lsa.201800195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445396PMC
April 2019

Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.

EBioMedicine 2019 Mar 13;41:584-596. Epub 2019 Feb 13.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. Electronic address:

Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence.

Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34CD38CD45RA haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34 cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice.

Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation.

Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.
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http://dx.doi.org/10.1016/j.ebiom.2019.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441951PMC
March 2019

Deregulated Mucosal Immune Surveillance through Gut-Associated Regulatory T Cells and PD-1 T Cells in Human Colorectal Cancer.

J Immunol 2018 05 26;200(9):3291-3303. Epub 2018 Mar 26.

Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan;

Disturbed balance between immune surveillance and tolerance may lead to poor clinical outcomes in some malignancies. In paired analyses of adenocarcinoma and normal mucosa from 142 patients, we found a significant increase of the CD4/CD8 ratio and accumulation of regulatory T cells (Tregs) within the adenocarcinoma. The increased frequency of Tregs correlated with the local infiltration and extension of the tumor. There was concurrent maturation arrest, upregulation of programmed death-1 expression, and functional impairment in CD8 T cells (CTLs) isolated from the adenocarcinoma. Adenocarcinoma-associated Tregs directly inhibit the function of normal human CTLs in vitro. With histopathological analysis, Foxp3 Tregs were preferentially located in stroma. Concurrent transcriptome analysis of epithelial cells, stromal cells, and T cell subsets obtained from carcinomatous and normal intestinal samples from patients revealed a distinct gene expression signature in colorectal adenocarcinoma-associated Tregs, with overexpression of , , and , whereas their ligands and were found upregulated in cancerous epithelium. Overexpression of and , associated with carcinogenesis and metastasis, in cancer-associated stromal cells suggests that both cancer cells and stromal cells play important roles in the development and progression of colorectal cancer through the formation of a tumor microenvironment. The identification of CTL anergy by Tregs and the unique gene expression signature of human Tregs and stromal cells in colorectal cancer patients may facilitate the development of new therapeutics against malignancies.
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http://dx.doi.org/10.4049/jimmunol.1701222DOI Listing
May 2018

Association between daily ambient air pollution and respiratory symptoms in children with asthma and healthy children in western Japan.

J Asthma 2018 07 8;55(7):712-719. Epub 2018 Jan 8.

d National Hospital Organization Fukuoka Hospital , Fukuoka , Japan.

Objective: In recent years, air pollutant concentrations in Japan have decreased slightly; however, there are growing concerns about the influences of transnational air pollution on respiratory illness. We aimed to clarify the short-term association between the ambient air pollution and respiratory symptoms among children without asthma, children with asthma not using long-term medications (CA-nonLTM), and those using them (CA-LTM).

Methods: A total of 138 children attending 2 primary schools and 71 children with asthma regularly visiting cooperating medical institutions were recruited. Study participants measured peak expiratory flow (PEF) twice a day and recorded coughing, nasal symptoms, and medication use in a diary. Predicted associations between daily air pollutant concentrations and respiratory symptoms, and PEF were evaluated using case-crossover and generalized estimate equation models.

Results: Changes in %maxPEF per 10 ppb oxidant (Ox) increase in children without asthma, CA-nonLTM, and CA-LTM were -0.26% (95% CI: -0.49, -0.03), -0.51% (95% CI: -0.89, -0.12), and -0.20% (95% CI: -0.42, 0.01), respectively. The odds ratios for coughing per 10 ppb Ox increase in the Lag0 model were 1.34 (95% CI: 1.11, 1.60), 1.52 (95% CI: 1.12, 2.07), and 1.06 (95% CI: 0.93, 1.20), respectively. These suggested that the Ox concentration has graded effects on %maxPEF and coughing, in the following descending order, CA-nonLTM, children without asthma, and CA-LTM. The Ox concentration was also positively associated with nasal symptoms in children without asthma and CA-LTM.

Conclusion: Our results suggest that using long-term medications to manage asthma may play an important role in preventing exacerbation of respiratory symptoms due to air pollution.
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http://dx.doi.org/10.1080/02770903.2017.1369988DOI Listing
July 2018

Haploidentical hematopoietic cell transplantation for disseminated Ewing sarcoma.

Pediatr Int 2017 Feb 27;59(2):223-226. Epub 2016 Dec 27.

Department of Pediatrics, St Luke's International Hospital, Tokyo, Japan.

We describe the case of a 13-year-old girl with multifocal disseminated Ewing sarcoma family of tumor (ESFT) who received a 5/8 human leukocyte antigen-matched haploidentical hematopoietic cell transplantation to generate a graft-versus-tumor effect. The patient had grade 2 acute graft-versus-host disease (GVHD) of the skin and chronic GVHD nausea and abdominal pain that required prednisolone for 17 months, but has been free from ESFT for 3 years 10 months after therapy. The present case suggests a beneficial effect of haploidentical hematopoietic cell transplantation in disseminated ESFT.
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http://dx.doi.org/10.1111/ped.13195DOI Listing
February 2017

Impact of omalizumab on medical cost of childhood asthma in Japan.

Pediatr Int 2016 May;58(5):425-8

Department of Pediatrics, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan.

Omalizumab is effective in children with severe asthma, but its impact on medical cost in Japan is not clear. We evaluated the impact of omalizumab on medical cost by comparing the pre- vs post-omalizumab-initiation medical costs of 12 children with severe asthma who received omalizumab for 2 years, and calculating incremental cost-effectiveness ratio for omalizumab therapy. Health outcome was measured as hospital-free days (HFD). The median total medical costs and medication fee per patient increased significantly after omalizumab initiation because of the high cost of omalizumab. The median hospitalization fee per patient, however, decreased significantly after omalizumab initiation due to reduction in hospitalization. Omalizumab led to an estimated increase of 40.8 HFD per omalizumab responder patient per 2 years. The cost was JPY 20 868 per additional HFD. Omalizumab can therefore reduce hospitalization cost in children with severe asthma in Japan.
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http://dx.doi.org/10.1111/ped.12936DOI Listing
May 2016

Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice.

Blood 2016 Feb 23;127(6):722-34. Epub 2015 Dec 23.

Laboratory for Human Disease Models and.

Induction of specific immune response against therapy-resistant tumor cells can potentially improve clinical outcomes in malignancies. To optimize immunotherapy in the clinic, we aimed to create an in vivo model enabling us to analyze human cytotoxic T-lymphocyte (CTL) responses against human malignancies. To this end, we developed NOD/SCID/IL2rgKO (NSG) mice expressing the HLA class I molecules HLA-A*0201 and A*2402. In the bone marrow (BM) and spleen of HLA class I transgenic (Tg) NSG mice transplanted with cord blood hematopoietic stem cells (HSCs), we found human memory CD8(+) T cells and antigen-presenting cells. To evaluate antigen-specific human CTL responses, we immunized HLA class I Tg NSG mice using polyinosinic:polycytidylic acid mixed Wilms tumor 1 (WT1) peptides, with or without WT1 peptide-loaded autologous dendritic cells. After immunization, the frequencies of HLA-restricted WT1-specific CTLs increased significantly in the spleen. Next, we transplanted the WT1-specific T-cell receptor (WT1-TCR) gene-transduced human HSCs into HLA class I Tg NSG newborn mice. WT1 tetramer-positive CD8(+) T cells differentiated from WT1-TCR-transduced HSCs in the recipients' BM, spleen, and thymus. Upon stimulation with WT1 peptide in vitro, these CTLs produced interferon-γ and showed lytic activity against leukemia cells in an antigen-specific, HLA-restricted manner. HLA class I Tg NSG xenografts may serve as a preclinical model to develop effective immunotherapy against human malignancies.
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http://dx.doi.org/10.1182/blood-2014-10-604777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751022PMC
February 2016

[A case of food-dependent exercise-induced anaphylaxis caused by ingestion of orange].

Arerugi 2015 Feb;64(2):149-55

Division of Pediatrics, National Fukuoka Hospital.

The patient was a 10-year-old girl who presented with a history of anaphylactic episodes on three occasions, that developed in association with exercise after she ate citrus fruit. She underwent tolerance tests, as food-dependent exercise-induced anaphylaxis (FDEIA) induced by citrus fruit was suspected. The result of the test for the combination of intake of oranges and exercise was negative. The patient presented with swollen eyelid and wheezing following combined intake of orange and aspirin, based on which she was diagnosed as having FDEIA. Many patients developing an allergic reaction to fruit are diagnosed as having oral allergy syndrome (OAS), and only few cases of FDEIA are reported. Immunoblot tests revealed antigens of 9 kDa, 39 kDa and 53 kDa in this patient, and an inhibition study with oranges revealed that the 39 kDa and 53 kDa antigens were probably antigen-specific allergens. Although the studied patient showed a strongly positive result for IgE antibodies specifically directed at cedar pollen, no common antigenicity with cedar pollen could be recognized. The final diagnosis was a type of FDEIA caused by 39 kDa and 53 kDa proteins, which are different from antigens previously identified in patients with citrus fruits allergy. It should be the first report of such a case.
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February 2015

Identification of CD34+ and CD34- leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia.

Blood 2015 Feb 23;125(6):967-80. Epub 2014 Dec 23.

Laboratory for Human Disease Models RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34(+)CD38(+)CD19(+) and CD34(-)CD19(+) cells initiated leukemia, and in MLL-AF9 patients, CD34(-)CD19(+) cells were LICs. In MLL-ENL patients, either CD34(+) or CD34(-) cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34(+)CD38(-)CD19(-)CD33(-) cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34(+)CD38(-)CD19(-)CD33(-) cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4(+) single positive (SP), CD8(+) SP, and CD4(+)CD8(+) double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34(+)CD38(+) and CD34(-) LICs but not in CD34(+)CD38(-)CD19(-)CD33(-) HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia.
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http://dx.doi.org/10.1182/blood-2014-03-563304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4319237PMC
February 2015

Acute megakaryoblastic leukemia with acquired trisomy 21 and GATA1 mutations in phenotypically normal children.

Eur J Pediatr 2015 Apr 30;174(4):525-31. Epub 2014 Sep 30.

Department of Pediatrics, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan,

Unlabelled: GATA1 mutations are found almost exclusively in children with myeloid proliferations related to Down syndrome (DS). Here, we report two phenotypically and cytogenetically normal children with acute megakaryoblastic leukemia (AMKL) whose blasts had both acquired trisomy 21 and GATA1 mutation. Patient 1 was diagnosed with transient abnormal myelopoiesis in the neonatal period. Following spontaneous improvement of the disease, leukemic blasts increased 7 months later. He received less intensive chemotherapy, and he is now 6 years old in complete remission. Patient 2 was diagnosed with AMKL at the age of 18 months. Although he received intensive chemotherapy and a cord blood transplantation, he died without gaining remission. In both cases, trisomy 21 and GATA1 mutation were detected only in leukemic blasts, but not in germline samples. Based on a literature review, we identified reports describing 14 non-DS AMKL with GATA1 mutation and acquired trisomy 21. Of those, 12 cases were diagnosed during the neonatal period, whereas the remaining 2 cases were diagnosed at the age of 22 and 31 months, respectively.

Conclusion: These cases suggest that GATA1 mutation may cooperate with the additional chromosome 21 in developing myeloid proliferations even in non-DS patients.
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http://dx.doi.org/10.1007/s00431-014-2430-3DOI Listing
April 2015

Pelagic fishing at 42,000 years before the present and the maritime skills of modern humans.

Science 2011 Nov;334(6059):1117-21

Department of Archaeology and Natural History, College of Asia and the Pacific, Australian National University, Canberra, Australian Capital Territory 0200, Australia.

By 50,000 years ago, it is clear that modern humans were capable of long-distance sea travel as they colonized Australia. However, evidence for advanced maritime skills, and for fishing in particular, is rare before the terminal Pleistocene/early Holocene. Here we report remains of a variety of pelagic and other fish species dating to 42,000 years before the present from Jerimalai shelter in East Timor, as well as the earliest definite evidence for fishhook manufacture in the world. Capturing pelagic fish such as tuna requires high levels of planning and complex maritime technology. The evidence implies that the inhabitants were fishing in the deep sea.
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http://dx.doi.org/10.1126/science.1207703DOI Listing
November 2011
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