tbuckley/cabot-search huggingface dataset:
Screening for Dyslipidemia in Younger Adults: A Systematic Review for the U.S. Preventive Services Task Force
Authors: Roger Chou, Tracy Dana, Ian Blazina, Monica Daeges, Christina Bougatsos, Thomas L. Jeanne
Journal: Annals of Internal Medicine (2016)

Background: Dyslipidemia may occur in younger adults (defined as persons aged 21 to 39 years) and is an important risk factor for cardiovascular disease. Screening might identify younger adults with asymptomatic dyslipidemia who may benefit from lipid-lowering therapies. Purpose: To update the 2008 U.S. Preventive Services Task Force review on dyslipidemia screening in younger adults. Data Sources: The Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and MEDLINE through May 2016, and reference lists. Study Selection: Randomized, controlled trials; cohort studies; and case–control studies on screening for or treatment of asymptomatic dyslipidemia in adults aged 21 to 39 years. Data Extraction: The plan was for 1 investigator to abstract data and a second to check their accuracy, and for 2 investigators to independently assess study quality; however, no studies met the inclusion criteria. Data Synthesis: No study evaluated the effects of lipid screening versus no screening, treatment versus no treatment, or delayed versus earlier treatment on clinical outcomes in younger adults. In addition, no study evaluated the diagnostic yield of alternative screening strategies (such as targeted screening of persons with a family history of hyperlipidemia vs. general screening) in younger adults. Limitation: No direct relevant evidence. Conclusion: Direct evidence on the benefits and harms of screening for or treatment of dyslipidemia in younger adults remains unavailable. Estimating the potential effects of screening for dyslipidemia in this population requires extrapolation from studies performed in older adults. Primary Funding Source: Agency for Healthcare Research and Quality.
Commentary on “KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer”
Authors: Laura E. Benjamin
Journal: Cancer Research (2016)

See related article by Lievre et al., [Cancer Res 2006;66:3992–5][1] .

Ten years ago, Cancer Research published a translational science report by researchers in France describing the relationship between genetics and outcome for patients with metastatic colorectal cancer treated with the newest
Serum tumor marker (STM) decline rates during high-dose chemotherapy (HDCT) to predict outcome for germ cell tumor (GCT) patients (pts).
Authors: Darren Richard Feldman, Martin Henner Voss, Xiaoyu Jia, Lindsay Joy Van Alstine, Sujata Patil, Patricia Fischer, Joel Sheinfeld, George J. Bosl, Robert John Motzer
Journal: Journal of Clinical Oncology (2012)

4532 Background: STM decline rates predict outcome for GCT pts during 1 st -line conventional-dose chemotherapy. We investigated the importance of STM decline rates during salvage HDCT. Methods: HDCT included an initial low dose (LD) portion (1-2 cycles of paclitaxel plus ifosfamide [TI] + G-CSF) for stem cell collection followed by a high-dose (HD) portion (3 cycles of carboplatin + etoposide or TI + carboplatin). Eligible pts had elevated STM (AFP &gt;15 and/or HCG &gt;2.2) at the start of LD and completed ≥1 HD cycle. Slope and t 1/2 were calculated for HCG and AFP for cycles 1-2 of LD and HD starting with the peak value during days (d) 1-6 of LD and HD to avoid interference from lysis. T 1/2 for AFP ≤7d and HCG ≤3.5d were categorized as satisfactory (SAT); normalization within 7d was also considered SAT, regardless of t 1/2 . Pts with elevated AFP and HCG had to have adequate decline in both to be considered SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs. unsatisfactory (UNSAT) pts using the log-rank test. Results: Of 117 pts (115 male, 105 nonseminoma), the most common primary sites were testis (81) and mediastinum (26). 93, 19, and 5 pts completed 3, 2, and 1 HD cycles, respectively. Overall, 19/117 had SAT decline during LD (19/77 for HCG; 7/57 for AFP). For LD, there was no significant difference in PFS or OS for SAT vs. UNSAT decline. For HD, 17/96 had SAT decline (11/59 for HCG; 9/47 for AFP). SAT overall decline (HCG and AFP) during HD predicted superior PFS (p=0.0025) and OS (p=0.0046) with 2-year (yr) PFS 0.88 (0.59, 0.97) vs. 0.37 (0.26, 0.47) and 3yr OS 0.82 (0.55, 0.94) vs. 0.37 (0.26, 0.48). SAT HCG decline alone also predicted superior PFS (p=0.0018) and OS (p=0.004) with 2yr PFS 0.91 (0.51, 0.99) vs. 0.32 (0.19, 0.46) and 3yr OS 0.91 (0.51, 0.99) vs. 0.35 (0.22, 0.50) whereas only a non-significant trend for improved PFS (p=0.14) and OS (p=0.16) was seen for AFP alone. Conclusions: STM decline rates during the HD portion of salvage HDCT predicts favorable PFS and OS, mostly driven by HCG. However, UNSAT STM decline does not exclude long-term PFS/OS. STM decline rates during the initial LD portion of HDCT programs do not predict outcome; thus, UNSAT LD decline should not prohibit subsequent HDCT.
Abstract LB-123: STAT3 mediates APC-driven chemoresistance in breast cancer
Authors: Monica K. VanKlompenberg, Emily A. Leyden, Jian-Ting Zhang, Jenifer R. Prosperi
Journal: Cancer Research (2016)

Abstract Breast tumors frequently develop resistance to treatment with a variety of standard (i.e. cisplatin or doxorubicin) or targeted chemotherapeutic agents, resulting in tumor recurrence and increased patient mortality. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost by hypermethylation or mutation in up to 70% of sporadic breast cancers; however, the downstream effects of APC loss have not been well explored in breast cancer. Heterozygous Apc mutation using the ApcMin/+ mouse model enhanced tumorigenesis in the mouse mammary tumor virus - Polyoma Middle T transgenic model (MMTV-PyMT). Cells isolated from MMTV-PyMT;ApcMin/+ mice are resistant to chemotherapy, express higher levels of multidrug resistance protein 1 (MDR1), and have a greater population of tumor initiating cells (TICs) compared to controls. Here we demonstrate that APC loss-of-function cells have increased activation of signal transducer and activator of transcription 3 (STAT3) and the anti-apoptotic protein Mcl-1. STAT3 over-expression is common in breast cancer, leads to poor prognosis, and up-regulates MDR1 expression leading to chemotherapeutic resistance. To explore the functional role of STAT3 in mediating therapeutic resistance in APC loss-of-function models, we examined the impact of STAT3 inhibition on MDR1 and the TIC population to cause therapeutic resistance in the MMTV-PyMT;ApcMin/+ vs MMTV-PyMT;Apc+/+ murine breast cancer cells. We have made the novel observation that chemotherapy treatment has a time-dependent effect on the activation of STAT3 and expression of Mcl-1 specific to Apc-mutant cells. Finally, we have assessed the use of STAT3 inhibitors in combination with standard chemotherapy to alleviate APC-mediated resistance. Combined these data suggest that loss of APC activates STAT3-driven pathways resulting in the development of chemotherapeutic resistance. Citation Format: Monica K. VanKlompenberg, Emily A. Leyden, Jian-Ting Zhang, Jenifer R. Prosperi. STAT3 mediates APC-driven chemoresistance in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-123.
Abstract 2469: The role of L1 in proliferation and chemoresistance of retinoblastoma
Authors: Dong Hyun Jo, Kyungmin Lee, Jin Hyoung Kim, Hyoung Oh Jun, Young Hoon Kim, Young-Lai Cho, Young Suk Yu, Jeong-Ki Min, Jeong Hun Kim
Journal: Cancer Research (2016)

Abstract Retinoblastoma is the most common intraocular malignant tumor in children, affecting approximately 1 in 20,000 live births. In this study, we investigated the role of L1, a transmembrane protein, in proliferation and chemoresistance of retinoblastoma to figure out the potential for the novel therapeutic target. Retinoblastoma tissues demonstrated varying degrees of L1 positivity in 86.6% (26/30) of samples. In particular, the degree of L1 positivity was inversely related with that of Flexner-Wintersteiner rosette formation. Further in vitro studies using stable cell lines which showed up- or down-regulation of L1 demonstrated that L1 was associated with cell-cell adhesion and proliferation of retinoblastoma cells. Retinoblastoma cells with low expression of L1 showed decreased tumor formation in vivo. In addition, L1 expression was related with resistance to carboplatin, one of the most-widely utilized chemotherapeutic agents against retinoblastoma. In line with these results, retinoblastoma cells with higher expression of L1 demonstrated increased resistance to carboplatin in vivo. We also observed diffuse and dense expression of L1 in retinoblastoma tissues from 4 patients who underwent enucleation despite intensive chemotherapy based on carboplatin. Taken together, L1 was related with proliferation and chemoresistance of retinoblastoma and might be a potential therapeutic target of retinoblastoma. Citation Format: Dong Hyun Jo, Kyungmin Lee, Jin Hyoung Kim, Hyoung Oh Jun, Young Hoon Kim, Young-Lai Cho, Young Suk Yu, Jeong-Ki Min, Jeong Hun Kim. The role of L1 in proliferation and chemoresistance of retinoblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2469.
Maternal mortality rates rise in US, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Maternal mortality rates in 48 US states and the District of Columbia increased by nearly 27% from the year 2000 to 2014, up from 18.8 per 100 000 live births to 23.8, an analysis of state death certificates has found, placing the United States far behind other industrialized nations.1 Only one state, California, saw a decline.

The researchers said the findings indicated that the US had not met the United Nations millennium development goal of reducing maternal mortality rates by 75% by 2015.

They wrote, “Clearly at a time when the World Health Organization reports that 157 of 183 countries studied had decreases in maternal mortality between 2000 and …
Esophageal post-inflammatory polyposis in extensive and severe Crohn’s disease treated with anti-tumor necrosis factor alpha
Authors: Paola Soriani, Gian Tontini, Helmut Neumann, Sauid Ishaq, Maria Annunziata, Luca Pastorelli, Maurizio Vecchi
Journal: Endoscopy (2016)

Post-inflammatory polyposis (PIP) of the large bowel is a common endoscopic finding in patients with inflammatory bowel disease as it results from reparative processes following severe inflammation. To date, extra-intestinal localization of PIP is exceptional and poorly understood [1] [2] [3].
Pim Inhibition Suppresses Osteoclastogenesis and Tumor Growth in Myeloma
Authors: Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Derek Hanson, Keiichiro Watanabe, Shiro Fujii, Kumiko Kagawa, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Shuji Ozaki, Toshio Matsumoto, Masahiro Abe
Journal: Blood (2015)
Abstract 2716: Lipid mediated “nutrients sensing” checkpoint in G1 phase of the cell cycle
Authors: Deven Patel, David Foster
Journal: Cancer Research (2016)

Abstract One of the hallmarks of cancers is dysregulation of G1 phase cell cycle progression- where cells decide their fate whether they should divide, arrest or undergo apoptosis. There is a growth factor-dependent Restriction point (R), where cells commit to replicate its genome or to enter a state of quiescence. Unicellular organisms only respond to the nutrients, a point known as START. In mammalian system, we have shown equivalent to START, “Cell Growth” checkpoints, where it senses Essential Amino Acids (EAAs), a “Conditionally” EAA glutamine (Q), and at last a checkpoint regulated by mTOR, which we think it senses nutrients and is the final arbitrator of the G1-S phase progression. mTOR- mammalian/mechanistic target of rapamycin integrates the growth factor signaling with nutrient sensing signaling and known to be involved in protein translation and proliferation. Another key nutrient needed for cell growth is lipids which is required as building blocks for plasma membrane synthesis and signaling molecules. Phosphatidic acid has been shown to be required for the activity of mTORC1 and mTORC2. In this study, we investigated the involvement of lipids in the cell cycle progression and how the signals are integrated. Upon lipid deprivation, normal fibroblasts cells arrest in G1-phase of the cell cycle. There is a distinct and distinguishable lipid sensing checkpoint from EAAs and Q. Temporally it is different from other nutrient sensing checkpoints in the late G1-phase of the cell cycle. In summary, there is a series of “nutrient sensing” checkpoints late in the G1-phase followed by mTOR “Growth” checkpoint. Dysregulation of these checkpoints in cancer cells may present better opportunity to target them with different therapeutic approach. Citation Format: Deven Patel, David Foster. Lipid mediated “nutrients sensing” checkpoint in G1 phase of the cell cycle. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2716.
Organ preservation in patients with rectal cancer with clinical complete response after neoadjuvant therapy.
Authors: Jesse Joshua Smith, Oliver S Chow, Anne Eaton, Maria Widmar, Garrett Michael Nash, Larissa K. F. Temple, Jose G. Guillem, Martin R. Weiser, Karyn A. Goodman, Andrea Cercek, Leonard Saltz, Marc J. Gollub, Mithat Gonen, Julio Garcia-Aguilar, Philip Paty
Journal: Journal of Clinical Oncology (2015)

509 Background: Nonoperative management (NOM) of rectal cancer following a clinical complete response (cCR) to neoadjuvant therapy is a non-standard approach. We review our experience with NOM to evaluate safety and efficacy. Methods: A retrospective review of prospectively collected data between 2006 and 2014 was conducted. We compared patients completing neoadjuvant therapy for stage I to III rectal cancers who: a) achieved cCR and were treated with NOM, or b) underwent standard total mesorectal excision (TME) and achieved a pathologic complete response (pCR). Kaplan-Meier estimates and the log-rank test were used. Results: Seventy-three patients underwent NOM after cCR. From 369 rectal resections performed, 72 (20%) achieved pCR and form the comparison group. Median follow-up across both groups was 3.3 years. Rectal preservation was achieved in 56 (77%) of the patients treated with NOM. Of the 19 NOM patients with local regrowth, 18 were salvaged successfully with standard TME (n=16) or local excision (n=2), with one patient pending a salvage operation (n=1). No significant differences were noted in the number of distant recurrences between the NOM and pCR groups. Four-year disease-specific survival and overall survival between the two groups were not significantly different. Conclusions: In this highly selected group of patients with cCR to neoadjuvant treatment, NOM with surgical salvage of local tumor regrowth achieved local control in all patients. The oncologic outcome for NOM patients at 4 years was comparable to patients with pCR after rectal resection. These data continue to suggest that NOM does not compromise oncologic outcome, and that preservation of the rectum is achieved in a majority of patients. [Table: see text]
Abstract 4154: Neuropilin-1 expressing macrophages promote neuropilin-1 expression on lymphocytes by direct interaction and exert antitumor activity in HER2 positive breast cancer
Authors: Kosuke Kawaguchi, Eiji SUzuki, Masashi Inoue, Isao Kii, Tatsuki R. Karaoke, Masahiro Hiram, Keiko Iwaisako, Pu Fengling, Mariko Niche, Ayane Yamaguchi, Hironori Haga, Masatoshi Hagiwara, Masakazu Toi
Journal: Cancer Research (2016)

Abstract Tumor-infiltrating immune cells (TIIs) in HER2+ breast cancer (BC) play an important role in treatment with anti-HER2 therapy. However, the precise mechanisms of how TIIs exert anti-tumor activity remain unclear. Neuropilin-1 (NRP-1) on macrophages regulates immune functions in various cancers and thus we explored the role of NRP-1 expressing macrophages in anti-tumor activity in HER2+ BC. We show that NRP-1 on macrophages regulated the migration of and chemokine secretion from macrophages in vitro. Furthermore, in vivo studies using a humanized mouse model showed that NRP-1 knockdown of macrophages in adoptively transferring peripheral blood mononuclear cells (PBMCs) suppressed anti-tumor activity and infiltration of CD45+ immune cells into tumors. Interestingly, NRP-1 expressing TIIs were mainly CD4+ T cells, despite little expression of NRP-1 on CD4+ T cells in PBMCs. We found that NRP-1 expression on CD4+ T cells was induced by NRP-1 transfer from macrophages to T cells. In HER2+ BC patients, NRP-1 expressing TIIs correlated with better clinical outcomes. These results demonstrate that NRP-1 expressing macrophages are key subsets of immune cells in trastuzumab-mediated anti-tumor activity and may predict better outcomes for HER2+ BC patients. In conclusion, NRP-1 expression is required for differentiation and activation of macrophages. NRP-1 expressing macrophages promote NRP-1 expression on CD4+ T cells by direct interaction and contribute to anti-tumor immune responses in HER2+ BC. Citation Format: Kosuke Kawaguchi, Eiji SUzuki, Masashi Inoue, Isao Kii, Tatsuki R. Karaoke, Masahiro Hiram, Keiko Iwaisako, Pu Fengling, Mariko Niche, Ayane Yamaguchi, Hironori Haga, Masatoshi Hagiwara, Masakazu Toi. Neuropilin-1 expressing macrophages promote neuropilin-1 expression on lymphocytes by direct interaction and exert antitumor activity in HER2 positive breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4154.
P0935 : Non-alcoholic steatohepatitis (NASH): 2 complementary dietary mouse models
Authors: M.V. Machado, G.A. Michelotti, G. Xie, J. Boursier, T. Pereira de Almeida, L. Kruger, G. Karaca, C. Guy, A.M. Diehl
Journal: Journal of Hepatology (2015)
Abstract 1006: Novel adjuvants in triple negative breast cancer chemotherapy
Authors: Antonio Rampoldi, Adriana Harbuzariu, Tia L. Harmon, Ruben R. Gonzalez-Perez
Journal: Cancer Research (2016)

Abstract Background: Obese patients develop more frequently triple negative breast cancer (TNBC) that has not target therapy and are commonly treated with chemotherapeutics. Leptin, whose levels are elevated in obesity, can induce TNBC proliferation, angiogenesis and resistance to chemotherapeutics. An antagonist for leptin receptor OB-R, leptin peptide receptor antagonist 2 (LPrA2), has been shown to block leptin signaling and decrease tumor progression. LPrA2 also countervails leptin induced resistance to chemotherapeutic agents. We used pegylation or iron oxide nanoparticle (IONPs) as adjuvants to increase LPrA2 solubility, stability and effectiveness. Hypothesis: Conjugated LPrA2 will decrease TNBC cells proliferation, expression of leptin target molecules and tumorigenesis. Methods: Human TNBC and murine breast adenocarcinoma derived cell line E0771 (progesterone and HER2 receptor negative) were used. The E0771 cell line was generated from an estrogen receptor positive (ER+) mammary adenocarcinoma isolated from a C57BL/6J mouse. E0771 was made insensitive to estrogen by treatment with drug Tamoxifen (TAM) mimicking TNBC. To specifically assess the role of RBP-Jk (CBS/CSL, an essential transcription factor for Notch signaling) the CRISPR/Cas9 system was used to disrupt RBP-JK gene expression in both wild-type and TAM treated E0771 cells. Cells were treated with chemotherapeutics (Paclitaxel, Doxorubicine, Ciclophosphamide) in presence of leptin and LPrA2-conjugates. The expression of leptin-targeted molecules, Breast Cancer Stem Cells (BCSC) and EMT markers were analyzed after cell treatment. Results: Chemotherapeutics effects on proliferation, survival and molecular markers were modified by the addition of LPrA2-conjugates. Notch molecules (receptors and ligands) were downregulated by LPrA2 treatment. Conclusion: The current data indicate that Leptin inhibition could be used as an adjuvant for chemotherapeutic treatments in TNBC patients. LPrA2-conjugates could increase the efficacy of chemotherapy. Acknowledgements: This work was partially supported by the National Institute of Health and National Cancer Institute Grant U54 CA118638, NIH/SBIR 1R41CA183399-01A1, and DOD Idea Award BC W81XWH-13-1-0382 to RRGP; and facilities, and support services at Morehouse School of Medicine (NIH RR03034 and 1C06 RR18386) and NIH/NCRR grant 1G12RR026250-03. Citation Format: Antonio Rampoldi, Adriana Harbuzariu, Tia L. Harmon, Ruben R. Gonzalez-Perez. Novel adjuvants in triple negative breast cancer chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1006.
Abstract 4584: Apoptosis-mediated AXL activation: Contribution to metastatic cancers
Authors: Annelien Zweemer, Aaron Meyer, Douglas Lauffenburger
Journal: Cancer Research (2016)

Abstract AXL is a receptor tyrosine kinase that is widely expressed in a variety of cancers and is predictive of poor patient outcome. This receptor is an essential epithelial-to-mesenchymal transition-induced regulator of cancer metastasis and is related to the occurrence of treatment resistance. AXL activation requires both the lipid moiety phosphatidylserine (PtdSer) and the bridging protein ligand Gas6. PtdSer is only available to mediate AXL activation when it is externalized on cell membranes, an event that occurs specifically during apoptosis. For that reason, we aimed to identify if apoptotic cell debris is capable of activating AXL on cancer cells and how this would affect the metastatic capacity of these cells. In a non-AXL expressing tumor cell line (HCC827) apoptosis was induced by means of UV-irradiation. We detected AXL activation of AXL-expressing MDA-MB-231 cells that were treated with HCC827 cell debris, suggesting that apoptotic debris of dying tumor cells is capable of activating AXL in surviving surrounding tumor cells. Next we determined the contribution of PtdSer-mediated AXL activation to the migration of MDA-MB-231 cells in a wound scratch assay. The addition of warfarin, which prevents autocrine Gas6 binding to PtdSer, decreased migration to a similar extent as the AXL inhibitor R428. This study revealed that PtdSer-mediated AXL activation contributes to the migration properties of MDA-MB-231 cells. As we detected AXL activation upon addition of PtdSer-containing apoptotic cells debris, this suggests that the induction of apoptosis by cancer therapeutics might enhance the metastatic capacities of neighboring surviving tumor cells. This finding may broadly impact the oncology field given AXL's widespread expression among different types of cancers, and provides a rationale for the design of novel combination therapies for decreasing tumor metastasis. Citation Format: Annelien Zweemer, Aaron Meyer, Douglas Lauffenburger. Apoptosis-mediated AXL activation: Contribution to metastatic cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4584.