tbuckley/cabot-search huggingface dataset:
On the true meaning of leaving no one behind
Authors: Oscar J Mujica, Luis Gabriel Cuervo, Julia Aymerich, Diego González, Jarbas Barbosa da Silva
Journal: The Lancet Global Health (2019)

We read with delight the Editorial in The Lancet Global Health on leaving no one behind,1 and the francophone call for global health research that is more inclusive.2 The call and the Editorial bring attention to a common problem affecting non-English speakers in different ways, and sometimes blind and deaf people, and that challenge, until now, has been met with solutions that are specific to the needs of the target populations, such as languages, dialects, and internet access. This problem is well known to the UN, which, since 1946, has adopted a multilingualism policy to enable communications, establishing Arabic, Chinese, English, French, Russian, and Spanish as official and working languages.
Equivalent Doses Matter, Rather Than Types
Authors: Norio Hanafusa, Ken Tsuchiya
Journal: Journal of the American Society of Nephrology (2019)

We read the article by Sakaguchi et al.1 with much interest, it raised important issues in clinical practice. However, we would like to point out a specific issue in the management of anemia in Japan that might be misleading to readers elsewhere. The maximum dose allowed by the package insert differs considerably across the four types of erythropoiesis-stimulating agents (ESAs) available in Japan. The maximum allowed dose of epoetin α/β/κ is 9000 IU/wk, whereas those of darbepoetin and epoetin β pegol are 180 µg/wk and 250 µg/2 wk, respectively. In Sakaguchi et al.'s study, the dosing of each ESA seems to follow these regulations; the ESA doses in the highest tertile were 7618±2071 IU/wk, 56.1±26.3 µg/wk, 181.6±65.4 µg/mo, and 7841±2144 IU/wk, for epoetin α/β, darbepoetin α, epoetin β pegol, and epoetin κ, respectively, as shown in their Supplemental Table 4. Conversion ratios from epoetin to ESAs with longer t1/2s have been debated because the ratios can vary according to the patient's condition or even the time course of ESA therapy. For example, the conversion ratio from epoetin to darbepoetin is reported to be 200–400 IU/µg in many studies.2,3 Even when adopting 200 IU/µg, which is an underestimation of darbepoetin activity, 56.1 µg of darbepoetin would have action equivalent to 11,220 IU of epoetin, which is a modest estimate. Yet, by adopting a higher conversion ratio, the equivalent dose would be much larger. A similar issue is also true for epoetin β pegol. We appreciate the authors' efforts to eliminate bias, which is inevitable in an observational study, but the fact that differences in mortality by ESA type increased in a dose-dependent manner clearly shows that it was the higher doses of ESA that were associated with worse survival and not ESA type per se. ESA hyporesponsiveness is well known to be associated with worse survival.4 The outcomes for the entire population might have been swayed by the presence of patients requiring higher equivalent doses of long-acting ESAs, which in Japan can be prescribed at higher doses than epoetin. We therefore consider that the title of the article is misleading, and that it was in fact a higher dose of long-acting ESAs that was associated with worse survival. Elucidating the true association between ESA type and mortality is reserved for future prospective studies with between-group adjustments for doses of ESA. Disclosures Dr. Hanafusa and Prof. Tsuchiya have received lecture fees from Kyowa Hakko Kirin, Chugai Pharmaceutical, and Kissei Pharmaceutical. Dr. Hanafusa is an academic consultant for the Dialysis Outcomes and Practice Pattern Study program and is receiving fees from Kyowa Hakko Kirin. However, these have no bearing or influence on the content of this article.
Anatomic factors as contributing risk factors in implant therapy
Authors: Ausra Ramanauskaite, Jürgen Becker, Robert Sader, Frank Schwarz
Journal: Periodontology 2000 (2019)

Abstract Damage to the critical anatomic structures during dental implant placement can lead to serious complications, including intra‐ or postoperative bleeding, hematoma formation, or varying degrees of neurosensory alteration. These complications usually occur when the anatomic features of the major blood vessels and their anastomoses, neurovascular bundles, and alveolar ridge contour are not properly investigated prior to the surgery. Therefore, having proper knowledge of specific anatomic factors is key to avoiding intra‐ and postsurgical complications. The aim of the current review is to summarize the anatomic structures and their variations in the mandible and maxilla as contributing risk factors in implant therapy.
Synthetic probes for in vitro purification and in vivo tracking of hepatocytes derived from human pluripotent stem cells
Authors: Ji Young Park, Jiyou Han, Hyo Sung Jung, Gyunggyu Lee, Hyo Jin Kim, Gun-Sik Cho, Han-Jin Park, Choongseong Han, Jong Seung Kim, Jong-Hoon Kim
Journal: Biomaterials (2019)
Whole-genome sequencing and analysis of the Chinese herbal plant Gelsemium elegans
Authors: Yisong Liu, Qi Tang, Pi Cheng, Mingfei Zhu, Hui Zhang, Jiazhe Liu, Mengting Zuo, Chongyin Huang, Changqiao Wu, Zhiliang Sun, Zhaoying Liu
Journal: Acta Pharmaceutica Sinica B (2019)

Gelsemium elegans (G. elegans) (2n = 2x = 16) is genus of flowering plants belonging to the Gelsemicaeae family.Here, a high-quality genome assembly using the Oxford Nanopore Technologies (ONT) platform and high-throughput chromosome conformation capture techniques (Hi-C) were used.A total of 56.11 Gb of raw GridION X5 platform ONT reads (6.23 Gb per cell) were generated. After filtering, 53.45 Gb of clean reads were obtained, giving 160 × coverage depth. The de novo genome assemblies 335.13 Mb, close to the 338 Mb estimated by k-mer analysis, was generated with contig N50 of 10.23 Mb. The vast majority (99.2%) of the G. elegans assembled sequence was anchored onto 8 pseudo-chromosomes. The genome completeness was then evaluated and 1338 of the 1440 conserved genes (92.9%) could be found in the assembly. Genome annotation revealed that 43.16% of the G. elegans genome is composed of repetitive elements and 23.9% is composed of long terminal repeat elements. We predicted 26,768 protein-coding genes, of which 84.56% were functionally annotated.The genomic sequences of G. elegans could be a valuable source for comparative genomic analysis in the Gelsemicaeae family and will be useful for understanding the phylogenetic relationships of the indole alkaloid metabolism.
Targeting the Chromosomal Passenger Complex Subunit INCENP Induces Polyploidization, Apoptosis, and Senescence in Neuroblastoma
Authors: Ming Sun, Veronica Veschi, Sukriti Bagchi, Man Xu, Arnulfo Mendoza, Zhihui Liu, Carol J. Thiele
Journal: Cancer Research (2019)

Chromosomal passenger complex (CPC) has been demonstrated to be a potential target of cancer therapy by inhibiting Aurora B or survivin in different types of cancer including neuroblastoma. However, chemical inhibition of either Aurora B or survivin does not target CPC specifically due to off-target effects or CPC-independent activities of these two components. In a previous chromatin-focused siRNA screen, we found that neuroblastoma cells were particularly vulnerable to loss of INCENP, a gene encoding a key scaffolding component of the CPC. In this study, INCENP was highly expressed by neuroblastoma cells, and its expression decreased following retinoic acid-induced neuroblastoma differentiation. Elevated levels of INCENP were significantly associated with poor prognosis in primary tumors of neuroblastoma patients with high-risk disease. Genetic silencing of INCENP reduced the growth of both MYCN-wild-type and MYCN-amplified neuroblastoma cell lines in vitro and decreased the growth of neuroblastoma xenografts in vivo, with significant increases in murine survival. Mechanistically, INCENP depletion suppressed neuroblastoma cell growth by inducing polyploidization, apoptosis, and senescence. In most neuroblastoma cell lines tested in vitro, apoptosis was the primary cell fate after INCENP silencing due to induction of DNA damage response and activation of the p53-p21 axis. These results confirm that CPC is a therapeutic target in neuroblastoma, and targeting INCENP is a novel way to disrupt the activity of CPC and inhibit tumor progression in neuroblastoma. SIGNIFICANCE: Dysregulation of INCENP contributes to neuroblastoma tumorigenesis and targeting INCENP presents a novel strategy to disrupt the activity of chromosomal passenger complex and inhibit neuroblastoma progression.
Drug resistance of stem-like cells of BRCA1/p53 associated breast cancer in conditional knockout mice
Authors: Norazizah Shafee, Yoon Kim, Eva Lee, Eric Stanbridge
Journal: Cancer Research (2007)

5722  Cancer stem cells have been postulated to be involved in cancer recurrence and chemoresistance. We have observed that mammary gland tumors, in a mouse model that carries a tissue specific disruption of p53 and BRCA1, recurred after complete regression following cisplatin (CDDP) treatment. We sought to examine the possible involvement of CDDP-resistant cancer stem cells in this phenomenon, and to characterize these cells. We isolated potential cancer stem cells using FACS sorting based on CD24 and CD44 cell surface marker expression. We assayed for their ability to self-renew in culture and to initiate tumor growth in vivo. Our investigation revealed that these cells were able to grow in serum-free media as loose clusters of suspension cells. They were not able to form mammospheres, an observation that has recently been reported with human samples. Colony forming assays performed on irradiated NIH3T3 feeder layers showed that the CD24-positive cells resulted in ten-fold more colonies compared to CD44-positive cells. This observation suggested that CD24-positive cells were more likely to be the stem cells. Transplantation of the CD24-positive cells into cleared fat pads of immunodeficient mice resulted in tumor regeneration. CDDP treatment of the tumors resulted in partial regression, suggesting an increase in CDDP resistant cells in the regenerated tumor. This response appeared to be dependent on the number of cells injected, since a five-fold increase in cell number resulted in almost complete resistance to CDDP. FACS analysis of the regenerated tumors revealed a phenotypically diverse population of cells expressing a wide range of CD24 levels. These data are suggestive of the CD24-positive cells’ stemness, which reflects their ability to generate cells of diverse phenotypes. A large proportion of the CD24-positive cells was found to express high levels of CD29, another putative stem cell marker. A secondary transplantation, using 5000 of these CD24-positive cells, also resulted in tumor regeneration. Tumor growth increased tremendously in a short time period following the secondary cell injection. CDDP treatment had no effect on these tumors. FACS analysis of cells harvested from the tumors also showed regeneration of cells with a wide range of CD-24 expression levels. Most of the CD24-positive cells in this population were also CD29-positive. Our study demonstrates that CDDP resistance observed in this mouse model may involve drug-resistance cancer stem cells expressing high levels of CD24 and CD29. These data may provide useful information towards improved therapies targeting a small subpopulation of drug-resistant cancer stem cells.
Increasing access to tobacco cessation support for cancer patients: Results of an institution-wide screening and referral program in an NCI-designated comprehensive cancer center.
Authors: Mary E. Reid, Katharine Dobson Amato, Michael Zevon, Robert Reed, Pat Hysert, Robert Hysert, Stephanie Segal, Martin Mahoney, Chukwumere E. Nwogu, Andrew Hyland, James Roger Marshall, K. Michael Cummings, Graham Walter Warren
Journal: Journal of Clinical Oncology (2013)

1566 Background: Guidelines from ASCO and other national organizations recommend assessment of tobacco use and structured tobacco cessation support for cancer patients. However, most oncology providers fail to provide cessation assistance to cancer patients who use tobacco. Reported are results of a systematic approach to assessing tobacco use and delivering cessation support for cancer patients in a comprehensive cancer center. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an automated electronic medical record based system delivered by nursing at initial consult and follow-up. Patients eligible for tobacco cessation support (i.e. patients self-reporting tobacco use within 30 days) were automatically referred to a dedicated tobacco cessation service providing primarily phone based cessation support. Results: Of approximately 11,900 patients screened over 26 months, 2,978 patients were automatically triaged for cessation support. Contact priority was given to newly diagnosed patients in tobacco related disease sites. Using 1.25 full time cessation specialists, 1,531 received only a standard tobacco cessation mailing and no further contacts were attempted by the cessation service. In 1447 patients with attempted phone contact by the cessation service, 1189 (82.2%) were reached within 5 contact attempts. In 1,189 patients contacted, 52 (4.4%) were inappropriate referrals, 245 (20.6%) were in an active quitting phase, 465 (39.1%) were willing to prepare, and only 24 (2.0%) refused any intervention at initial contact. At the most recent follow-up, 44 patients (3.7%) requested no further contact and 90 additional patients (7.6%) were lost to follow-up. In the 1,045 remaining patients, 338 (32.3%) reported quitting tobacco use. Notably, in the 1,531 patients with no phone contact by the cessation service, only 14 proactively contacted the cessation service for assistance. Conclusions: An institution wide program to automate the delivery of tobacco cessation services was feasible with high patient contact rates, low patient refusal, and moderately high tobacco cessation rates.
Risk factors in bone augmentation procedures
Authors: Peter K. Moy, Tara Aghaloo
Journal: Periodontology 2000 (2019)

Abstract Bone augmentation is an extremely common procedure in implant dentistry today because of significant advancements with reactive biomaterials, a better understanding of the mechanism of action that is found with growth factors contained in platelets, and improvements in surgical techniques. The expectation is for the surgeon to place the dental implant in the position that best serves the requirements of the prosthetic restorations. With the increasing demands that patients have for ideal prosthetic results, surgeons are expected to predictably augment both hard and soft tissues to provide the anticipated esthetic and functional outcomes. Bone grafting can be performed before, during, and after the implant placement; however, these augmentation procedures come with increased cost, the risk of complications such as infection or failure, and lengthening of the total treatment time. In addition, a plethora of grafting materials are available commercially, where they are often inadequately studied, or there is minimal information regarding their predictability or long‐term success, or ability to support dental implants. It is clear that although the surgical field has seen major progress since early implant surgical techniques in the 1980s, major challenges still exist with hard tissue augmentation procedures. This review will discuss these challenges that are increased and often specific to bone graft healing, and which are becoming more common as implant site development often requires bone augmentation to improve volume or contour deficiencies. The risk factors that patients may present with that will affect outcomes with bone augmentation procedures are identified, and recommendations for the prevention of complications or managing complications once they have occurred are provided.
Drug company Aspen may pay NHS £8m after investigation alleges illegal deal to hike drug price
Authors: Elisabeth Mahase
Journal: BMJ (2019)

The drug company Aspen may have to pay the NHS £8m (€8.7m; $9.7m) after an investigation by the Competition and Markets Authority (CMA) into an arrangement it made with two rival companies, which left it as the sole supplier of a drug and therefore able to set prices without competition.1

The CMA suspected that the 2016 arrangement had broken competition law, as Aspen was believed to have paid competitors to stay out of the market. The drug in question—fludrocortisone acetate (100 microgram tablets)—is mainly used to treat Addison’s disease.

As a result of the ongoing investigation Aspen approached the CMA and …
Argininosuccinate synthetase gene expression in cancer patients in Taiwan: A potential marker for use of arginine deprivation therapy
Authors: Hui Chen, Shiou Yeh, Pei Chen
Journal: Cancer Research (2008)

2829  Introduction:  Arginine auxotrophy is a result of an incapability of tumors such as melanoma and hepatocellular carcinoma (HCC) to express argininosuccinate synthetase (ASS) and results in failure to utilize citrulline for arginine synthesis. Thus, depletion of environmental arginine can result in cancer cell death. Proof of principle of arginine deprivation therapy with pegylated arginine deiminase (ADI) has resulted in medical benefits in patients with melanoma or HCC, cancers with low levels of ASS. Thus, detection of ASS in primary cancer tissues may help to identify other cancers which are more susceptible to arginine depletion therapy, and enlarge the patient population who may benefit from this therapy. We endeavored to: (1) determine ASS deficiency in 13 common human cancers by both immunohistochemical staining and real-time PCR, and (2) establish a real-time ASS quantification assay from human liver tissues which have ASS pseudogenes.  Methods:  280 human cancer tissue specimens, from 13 different cancers, were studied. Changes of ASS mRNA expression in tumor tissue from 7 HCC patients were validated by quantitative real-time PCR. The specific primer pairs were selected from the 3’ end of the ASS gene transcript for real-time PCR.  Results:  The incidence of ASS deficiency in the 13 human cancers is listed in the table. Real time-PCR showed that, in 6 out of 7 HCCs, the RNA of ASS gene has been significantly down-regulated (4 to 100-fold lower).   Conclusion:  Immunohistochemical detection of ASS may prove an effective means for screening ASS deficiency in various human cancers. Moreover, we have successfully established a platform for real time quantification of ASS mRNA. These results will be helpful to define patients most likely to respond to arginine deprivation therapy in further clinical trials with pegylated ADI.
VEGF induces desmoplastic response, tamoxifen resistance, and metastasis in breast cancer
Authors: Zhican Qu, Andra R. Frost, Cynthia S. Moore, Yulia Maxuitenko, Jaideep V. Thottassery, Rongbao Li, Francis G. Kern
Journal: Cancer Research (2004)

5195  Vascular endothelial growth factor (VEGF) is a key angiogenesis factor. We report here that VEGF also plays a critical role in tamoxifen resistance and metastasis of breast cancer and in the desmoplastic host response. In vivo studies with a nude mouse xenograft model using an improved, doxycycline regulatable gene expression system have demonstrated that VEGF overexpression is sufficient to promote ER-positive, tamoxifen-responsive and non-metastatic breast tumors to become tamoxifen resistant and metastatic. MCF-7 breast cancer xenografts in nude mice became static and regressed when the mice were treated with tamoxifen, whereas, the tumors continued to grow when they expressed high levels of VEGF in the tamoxifen-treated mice. Experimental metastasis assays with tail vein injection showed that MCF-7 breast cancer cells colonized in lung and developed into macroscopic metastatic lesion when VEGF overexpression was induced. In the pulmonary metastatic sites, the MCF-7 cell colonies expressing a high level of VEGF were surrounded by an abundance of stromal cells, mostly fibroblasts, which resembled the desmoplastic response commonly observed in human breast and other types of cancers. In contrast, MCF-7 cells that expressed only the basal level of VEGF failed to survive and colonize in the lung. This suggests that tumor-released VEGF is a key factor for the tumor induced desmoplastic response and for tumor microenvironment remodeling. A desmoplastic response is rarely observed in other animal cancer models and is absent in most human tumor xenografts in athymic nude mice. Microscopic blood vessels were observed within the desmoplastic zone of microscopic metastasis, suggesting that neoangiogenesis occurs with desmoplasia. When the VEGF overexpression was reduced to the basal level, tumor growth became static and the metastasis incidence was decreased significantly, suggesting that inhibition of VEGF signaling may prolong tamoxifen sensitivity. These experimental results suggest a mechanism by which VEGF mediates, through its paracrine effect, the interaction of tumor and stromal cells in the microenvironment, enhances the survival and colonization of disseminated tumor cells in distant organs, and thereby confers tamoxifen-resistant tumor growth and metastasis. Combination of an antiestrogen and an anti-VEGF signaling agent may be an effective treatment for advanced breast cancer or for preventing metastasis development.
Cardiopulmonary Responses and Prognosis in Hypertrophic Cardiomyopathy
Authors: Gherardo Finocchiaro, Francois Haddad, Joshua W. Knowles, Colleen Caleshu, Aleksandra Pavlovic, Julian Homburger, Yael Shmargad, Gianfranco Sinagra, Emma Magavern, Myo Wong, Marco Perez, Ingela Schnittger, Jonathan Myers, Victor Froelicher, Euan A. Ashley
Journal: JACC Heart Failure (2015)
Shark single domain antibody to identify MHC/peptide complexes
Authors: Xochitl Cortez-Gonzalez, Michelle Quezada, Alexei Licea-Navarro, Maurizio Zanetti
Journal: Cancer Research (2007)

2749  Telomerase is the first universal cancer antigen and is currently be used as target of therapeutic vaccines. While much implication has been surmised on the immune response of normal individuals and cancer patients against selected HLA-restricted telomerase peptides, little is known on processing and presentation of this self antigen. One possible method to assess presentation is to identify telomerase peptides at the surface of tumor cells in conjunction with the HLA molecule. This can be realized using TCR-like antibodies. A systematic approach to this issue would require generating pools of TCR-like antibodies to probe tumor cells for a variety of peptides in combination with different HLA alleles. We explored the possibility to use phage expression libraries single domain antibodies produced in shark termed VNAR. These have structured characteristics that render them particularly suitable for the recognition of HLA/peptide complexes, such as its small molecular size (12 KDa) and compact V domain conformation in which the CDR2 is either very short or non-existing, and a long CDR3 loop which is chiefly responsible for the interaction with antigen. Therefore, VNAR are ideal mini-binding sites to recognize otherwise cryptic antigens sites which may be the case of HLA/peptide complexes at the cell surface. Here, we report on the identification of a VNAR from a phage library generated from a naive shark (Heterodontus francisci). M1 antibody was selected for binding to HLA-B7 complexed with telomerase peptide p1123, a dominant peptide in the human immune response against telomerase. By FACS, M1 bound T2-B7 human lymphoma cells pulsed with p1123, but not pulsed with HLA-B7 restricted telomerase peptide (p277). By fluorescence microscopy, M1 also stained T2-B7 cells pulsed with peptide with a diffuse puntiform pattern. Finally, M1 inhibited TCR recognition of target cells by murine CTL generated in HLA-B7 transgenic mice. These preliminary results suggest that shark VNAR are useful tools to study the expression of HLA/peptide complexes on tumor cells and should be pursued to generate libraries of mini-binding sites to probe cancer cells in patients.