tbuckley/cabot-search huggingface dataset:
Intrahepatic T‐Cell Receptor β Immune Repertoire Is Essential for Liver Regeneration
Authors: Qing Liang, Zeyuan Liu, Chao Zhu, Bin Wang, Xiaoke Liu, Yanan Yang, Xue Lv, Haiyu Mu, Kejia Wang
Journal: Hepatology (2018)

T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T‐cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High‐throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRβ immune repertoire in liver regeneration (LR). We investigated hepatic regeneration in TCRβ chain‐deficient ( tcrb –/– ) mice by two‐thirds partial hepatectomy (PHx) method. Our results demonstrated that tcrb –/– mice revealed a reduced capacity for LR, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signaling activation and inflammatory factors was observed in regenerated tcrb –/– livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRβ immune repertoire during LR, indicating that PHx resulted in remarkably lower TCRβ diversity in intrahepatic T lymphocytes. Conclusion: Taken together, our data suggest that TCRβ deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs LR, and the TCRβ reconstitution is required for hepatic immunocyte recruitment and activation during LR.
Dual target gene therapy to EML4-ALK NSCLC by a gold nanoshell-based system
Authors: Siwen Li, Yuxi Liu, Yalan Rui, Liping Tang, Samuel Achilefu, Yueqing Gu
Journal: Theranostics (2018)

Although EML4-ALK transforming fusion gene is represented in only 8% of non-small cell lung cancer (NSCLC) cases, its expression is partly responsive for the failure of current NSCLC treatments. Preventing secondary mutation of the ALK protein through direct gene manipulation could overcome NSCLC drug resistance. Method: In this study, we developed a gold nanoshell (HAuNs) drug carrier for delivery and selective photo-thermal release of genes that target ALK and microRNA-301 in NSCLC. Additionally, the densely-coated nanoshell adsorbed high amounts of the positively-charged anticancer drug doxorubicin (DOX), generating an exciting multidimensional treatment strategy that includes gene-, thermal- and chemo- therapy. Results: The ALK mRNA and microRNA-301 genes as the double targets exhibited the combined effect. The drug carrier system significantly improved the drug accumulation in tumor tissues due to the enhanced vascular permeability by photothermal effect, dense spherical structure and RGD peptide modification. In vitro and in vivo results demonstrated the multiple therapeutic effects of the gold nanoshell-based system was better than the monotherapy. Conclusion: The above results indicated the gold nanoshell-based system would be a promising translational nano-formulation platform for effective treatment of EML4-ALK-positive NSCLC.
Uncoupling Diagnosis and Treatment of Incidentally Imaged Renal Masses
Authors: Joana B. Neves, Maxine G. B. Tran
Journal: JAMA Internal Medicine (2018)

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Predictive value of tumor growth rate during previous treatment for tumor response to regorafenib (REGO) and trifluridine/tipiracil (TFTD) in metastatic colorectal cancer (mCRC).
Authors: Takeshi Kawakami, Toshiki Masuishi, Yasuyuki Kawamoto, Katsuhiro Omae, Tetsuhito Muranaka, Hiroshi Nakatsumi, Satoshi Yuki, Yoshito Komatsu, Kentaro Yamazaki, Yusuke Onozawa, Hirofumi Yasui, Masahiro Tajika, Shigenori Kadowaki, Hiroya Taniguchi, Kei Muro
Journal: Journal of Clinical Oncology (2018)

766 Background: Although REGO and TFTD have been recognized as standard salvage treatments for patients (pts) with refractory mCRC, it is still unclear which drug should be used first. Tumor growth rate (TGR) during the pre-treatment period is associated with survival in lung and laryngeal cancer treated with chemoradiotherapy. However, little is known about the association between TGR during the pre-treatment period and tumor response to REGO and TFTD. Methods: We retrospectively analyzed the data of consecutive mCRC pts who were treated with REGO or TFTD at three institutions. We classified pts into slow-growing (SG) or rapid-growing (RG) groups according to TGR, and appearance of new lesions (NL+) or their absence (NL–) during the pre-treatment period. TGR was calculated as follows: TGR = (D 1 − D 0 )/100D 0 (CT 1 − CT 0 ), where CT 1 is the date of computed tomography (CT) at progressive disease, CT 0 is the date of CT before CT 1 , and D n is the sum of target lesion diameters at CT n (according to RECIST version 1.1). SG was defined as NL– with a low TGR ( &lt; 0.33), and RG was defined as NL− with a high TGR (≥0.33) or NL+, irrespective of TGR. Results: A total of 244 pts (RG/SG: 133/111, REGO/TFTD: 132/112) were eligible. The proportion of RG pts with a long duration from first-line chemotherapy and SG pts with elevated ALP was higher in the REGO group, while the proportion of SG pts with poor PS was higher in the TFTD group. The disease control rate (DCR) was similar in both groups (REGO 29% vs TFTD 23%, p = 0.556) among RG pts, while the DCR of TFTD was significantly better than REGO in SG pts In a multivariate analysis of predictive factors for DCR, drug selection was an independent factor for DCR in SG pts (odds ratio 3.51; 95% CI 1.33-9.27; p = 0.011). In RG group, DCRs of NL+ pts were worse than that of NL- pts (16% vs 36% in REGO group, p = 0.109; 9% vs. 31% in TFTD group, 0.108). Conclusions: TGR during the pre-treatment period would be helpful in selecting between REGO and TFTD, especially for pts with slow-growing tumors. Pts with appearance of new lesions may not benefit from either REGO or TFTD as salvage treatment.
Epithelial barrier dysfunction in desmoglein-1 deficiency
Authors: Laura Polivka, Smail Hadj-Rabia, Elodie Bal, Stéphanie Leclerc-Mercier, Marine Madrange, Yamina Hamel, Damien Bonnet, Stéphanie Mallet, Hubert Lepidi, Caroline Ovaert, Patrick Barbet, Christophe Dupont, Bénédicte Neven, Arnold Munnich, Lisa M. Godsel, Florence Campeotto, Robert Weil, Emmanuel Laplantine, Sylvie Marchetto, Jean-Paul Borg, William I. Weis, Jean-Laurent Casanova, Anne Puel, Kathleen J. Green, Christine Bodemer, Asma Smahi
Journal: Journal of Allergy and Clinical Immunology (2018)
Influence of liposomal irinotecan (nal-IRI) and non-liposomal irinotecan, alone and in combination, on tumor growth and angiogenesis in colorectal cancer (CRC) models.
Authors: Annette K Larsen, Cristiano Trindade, Anaïs Bouygues, Lila K Louadj, Sandrine K Thouroude, Stephan G Klinz, Ashish Kalra, João Henriques, Benoist Chibaudel, Aimery De Gramont, Alexandre E Escargueil, Paul Mesange
Journal: Journal of Clinical Oncology (2018)

711 Background: The long circulating liposomal irinotecan nal-IRI (MM-398/PEP02, Onivyde) is approved for treatment of metastatic pancreatic cancer after disease progression with gemcitabine-based therapy. Besides their direct cytotoxic activity, camptothecins are thought to inhibit tumor angiogenesis via downregulating hypoxia-inducible factor 1 leading to attenuation of VEGF expression. Due to different deposition kinetics, irinotecan HCl and nal-IRI are likely to show different activities in vivo suggesting that a combination of the two agents may optimize intratumoral exposure and improve treatment efficacy. Methods: The activities of nal-IRI, irinotecan and their combination were compared in three human CRC xenograft models with different sensitivity to SN-38, the active metabolite of irinotecan, in vitro. Nal-IRI was dosed at 5 mg/kg q7d, while irinotecan HCl was dosed at 25 mg/kg at days 1 and 2 q7d. The activity of different regimens on tumor cell viability, hypoxia markers and the microvascular density was determined by quantitative biomarker analysis. Results: The relative antitumor activity of nal-IRI was most pronounced in tumor models with natural or acquired irinotecan resistance. Combinations of nal-IRI with irinotecan HCl was significantly better than irinotecan HCl alone in all tumor models although nal-IRI only provided 10% additional irinotecan. The antitumor activity of nal-IRI and Irintecan HCl in combination was accompanied by up to two times more tumor cell death and a marked 3-7 fold reduction of the microvessel density. Despite the strong antiangiogenic effect resulting in tumor hypoxia, the increase in HIF1α and, to lesser degree, HIF2α, was relatively modest and VEGF signal intensity remained at 85-115% of control values. Conclusions: Our results suggest that both irinotecan HCl and nal-IRI can counteract the hypoxia-mediated increase of HIF1α in vivo as previously reported in vitro. Furthermore, the combination of the two formulations demonstrated significant efficacy benefits. A combination of irinotecan HCl and nal-IRI merits further clinical investigation.
Hemoglobin A1c Accurately Predicts Continuous Glucose Monitoring–Derived Average Glucose in Youth and Young Adults With Cystic Fibrosis
Authors: Christine L. Chan, Emma Hope, Jessica Thurston, Timothy Vigers, Laura Pyle, Philip S. Zeitler, Kristen J. Nadeau
Journal: Diabetes Care (2018)

In cystic fibrosis (CF), hemoglobin A1c (HbA1c) is thought to underestimate glycemia. However, few studies have directly assessed the relationship between HbA1c and average glucose in CF. We determined the relationships among glycemic markers-HbA1c, fructosamine (FA), glycated albumin (%GA), and 1,5-anhydroglucitol (1,5-AG)-and continuous glucose monitoring (CGM) in CF, hypothesizing that alternate markers would better predict average sensor glucose (ASG) than HbA1c.CF participants and a group of healthy control subjects (HCs), ages 6-25 years, wore CGM for up to 7 days. Pearson correlations assessed the relationships between CGM variables and HbA1c, FA, %GA, and 1,5-AG. The regression line between HbA1c and ASG was compared in CF versus HC. Linear regressions determined whether alternate markers predicted ASG after adjustment for HbA1c.CF (n = 93) and HC (n = 29) groups wore CGM for 5.2 ± 1 days. CF participants were 14 ± 3 years of age and 47% were male, with a BMI z score -0.1 ± 0.8 and no different from HCs in age, sex, or BMI. Mean HbA1c in CF was 5.7 ± 0.8% (39 ± 9 mmol/mol) vs. HC 5.1 ± 0.2% (32 ± 2 mmol/mol) (P < 0.0001). All glycemic markers correlated with ASG (P ≤ 0.01): HbA1c (r = 0.86), FA (r = 0.69), %GA (r = 0.83), and 1,5-AG (r = -0.26). The regression line between ASG and HbA1c did not differ in CF versus HC (P = 0.44). After adjustment for HbA1c, %GA continued to predict ASG (P = 0.0009) in CF.HbA1c does not underestimate ASG in CF as previously assumed. No alternate glycemic marker correlated more strongly with ASG than HbA1c. %GA shows strong correlation with ASG and added to the prediction of ASG beyond HbA1c. However, we are not advocating use of HbA1c for diabetes screening in CF based on these results. Further study will determine whether glycemic measures other than ASG differ among different types of diabetes for a given HbA1c.
Misdiagnosis of Li-Fraumeni Syndrome in a Patient With Clonal Hematopoiesis and a Somatic <i>TP53</i> Mutation
Authors: Rachel L. Mitchell, Cory Kosche, Kelly Burgess, Shreya Wadhwa, Lela Buckingham, Ritu Ghai, Jacob Rotmensch, Oleksandra Klapko, Lydia Usha
Journal: Journal of the National Comprehensive Cancer Network (2018)

Li-Fraumeni syndrome (LFS) is a rare genetic disorder that confers a high risk of developing certain malignancies at a young age. It is caused by germline mutations in the TP53 gene and is typically diagnosed by sequencing this gene in blood cells. The presence of a mutation in approximately half of the DNA reads (allelic fraction of 50%) is an indicator of a germline mutation, such as that in LFS. Clonal hematopoiesis (CH) is an expansion of a hematopoietic clone containing a somatic driver mutation with a low allelic fraction, usually not more than 10% to 20%. This report presents a patient with fallopian tube carcinoma who underwent multigene panel testing for cancer predisposition and was found to have a mutation in the TP53 gene, c.733G>T (p.Gly245Cys). Since the TP53 mutation had an allelic fraction of approximately 50%, it was interpreted as being germline, and the patient was diagnosed as having LFS. A year later, she developed acute myelogenous leukemia. Subsequent mutational analysis showed that the TP53 mutation was absent in her benign tissue sample but present in leukemic cells. Furthermore, sequencing of the fallopian tube tumor tissue revealed a different TP53 gene mutation, c.818G>T (p.Arg273Leu). These observations confirmed that the previously identified mutation in her blood was somatic rather than germline and that she had CH at the time of genetic testing. CH can occasionally lead to a misdiagnosis of a germline mutation and a cancer predisposition syndrome that has significant implications for patients and their families. Therefore, the abnormal result of genetic testing for hereditary cancer susceptibility should be carefully interpreted when the clinical presentation is atypical, when the patient is older, when the gene in question is known to have potential germline and somatic mutations such as the TP53 gene, and when the allelic fraction is approximately 50%.
Interferon-Stimulated Genes Are Involved in Cross-resistance to Radiotherapy in Tamoxifen-Resistant Breast Cancer
Authors: Annemarie E.M. Post, Marcel Smid, Anika Nagelkerke, John W.M. Martens, Johan Bussink, Fred C.G.J. Sweep, Paul N. Span
Journal: Clinical Cancer Research (2018)

Purpose: Treatment resistance is the main cause of adverse disease outcome in breast cancer patients. Here, we aimed to investigate common features in tamoxifen-resistant and radioresistant breast cancer, as tamoxifen-resistant breast cancer cells are cross-resistant to irradiation in vitroExperimental Design: RNA sequencing of tamoxifen-resistant and radioresistant breast cancer cells was performed and validated by quantitative PCR. Pathways were further investigated in vitro and in breast cancer patient cohorts to establish their relation with treatment resistance.Results: Both tamoxifen-resistant and radioresistant breast cancer cells had increased expression levels of genes involved in type I IFN signaling compared with nonresistant cells. IFN-stimulated genes (ISG) were induced in a dose-dependent and time-dependent manner after tamoxifen treatment and irradiation. Tamoxifen treatment also led to ssDNA presence in the cytoplasm, which is known to induce expression of ISGs, a phenomenon that has already been described for irradiation. Moreover, in a breast cancer patient cohort, high expression levels of ISGs were found in the primary tumor in around half of the patients. This was associated with a tumor-infiltrating lymphocyte (TIL) expression signature, although the ISGs were also expressed by the tumor cells themselves. Importantly, the expression of ISGs correlated with outcome in breast cancer patients treated with adjuvant tamoxifen or radiotherapy, but not in systemically untreated patients or chemotherapy-treated patients.Conclusions: Our data indicate that expression of ISGs by tumor cells is involved in acquired, treatment-induced resistance to tamoxifen and radiotherapy, and might play a role in intrinsic resistance via interaction with TILs. Clin Cancer Res; 24(14); 3397-408. ©2018 AACR.
Tenofovir Disoproxil Fumarate use during pregnancy and infant bone health and growth: the Tenofovir in pregnancy study
Authors: A. Kourtis, J. Wiener, L. Wang, B. Fan, J. Shepherd, L. Chen, W. Liu, C. Shepard, L. Wang, A. Wang, M. Bulterys
Journal: Journal of Hepatology (2018)
Increased risk of liver cancer in cirrhotic patients associated to direct acting antivirals
Authors: M. Reig, Z. Mariño, A. Darnell, S. Lens, V. Sapena, A. Díaz, E. Belmonte, C. Perelló, J.L.C. Panero, C.R. de Lope, S. Llerena, X. Torras, A.G. Moya, M. Sala, R. Morillas, B. Minguez, J. Llaneras, S. Coll, J.A. Carrión, M. Iñarrairaegui, B. Sangro, R. Vilana, M. Sole, C. Ayuso, J. Ríos, X. Forns, J. Bruix
Journal: Journal of Hepatology (2018)
Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice
Authors: Jie Huang, Hao Yin, Shan-Shan Rao, Ping-Li Xie, Xu Cao, Tai Rao, Shu-Ying Liu, Zhen-Xing Wang, Jia Cao, Yin Hu, Yan Zhang, Juan Luo, Yi-Juan Tan, Zheng-Zhao Liu, Ben Wu, Xiong-Ke Hu, Tuan-Hui Chen, Chun-Yuan Chen, Hui Xie
Journal: Theranostics (2018)

Recently, researchers identified a distinct vessel subtype called type H vessels that couple angiogenesis and osteogenesis.We previously found that type H vessels are reduced in ovariectomy (OVX)-induced osteoporotic mice, and preosteoclasts are able to secrete platelet-derived growth factor-BB (PDGF-BB) to stimulate type H vessel formation and thereby to promote osteogenesis.This study aimed to explore whether harmine, a β-carboline alkaloid, is capable of preventing bone loss in OVX mice by promoting preosteoclast PDGF-BB-induced type H vessel formation.Methods: The impact of harmine on osteoclastogenesis of RANKL-stimulated RAW264.7 cells was verified by gene expression analysis and tartrate-resistant acid phosphatase (TRAP) staining.Enzyme-linked immunosorbent assay (ELISA) was conducted to test PDGF-BB production by preosteoclasts.A series of angiogenesis-related assays in vitro were performed to assess the pro-angiogenic effects of the conditioned media from RANKL-stimulated RAW264.7 cells treated with or without harmine.Meanwhile, the role of PDGF-BB in this process was determined.In vivo, OVX mice were intragastrically administrated with harmine emulsion or an equal volume of vehicle. 2 months later, bone samples were collected for µCT, histological, immunohistochemical and immunofluorescent analyses to evaluate bone mass, osteogenic and osteoclastic activities, as well as the numbers of type H vessels. Bone marrow PDGF-BB concentrations were assessed by ELISA.Results: Exposure of RANKL-stimulated RAW264.7 cells to harmine enhanced the formation of preosteoclasts and the production of PDGF-BB.Harmine augmented the ability of RANKL-stimulated RAW264.7 cells to promote angiogenesis of endothelial cells, whereas the effect was blocked by PDGF-BB inhibition.In vivo, the oral administration of harmine emulsion to OVX mice resulted in enhanced trabecular bone mass and osteogenic responses, increased numbers of preosteoclasts, as well as reduced numbers of osteoclasts and fat cells.Moreover, OVX mice treated with harmine exhibited higher levels of bone marrow PDGF-BB and much more type H vessels in bone.Conclusion: Harmine may exert bone-sparing effects by suppression of osteoclast formation and promotion of preosteoclast PDGF-BB-induced angiogenesis.
The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time
Authors: Jan-Marino Ramirez, Nathan A. Baertsch
Journal: Annual Review of Neuroscience (2018)

Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time.
Oxybutynin for Hot Flashes Due to Androgen Deprivation in Men
Authors: Thomas J Smith, Charles L Loprinzi, Curtiland Deville
Journal: New England Journal of Medicine (2018)

Control of Androgen-Deprivation Hot Flashes A patient with prostate cancer and debilitating hot flashes and night sweats had nearly complete relief of symptoms with oxybutynin. Further studies are ...
The Neutral Theory in Light of Natural Selection
Authors: Andrew D Kern, Matthew W Hahn
Journal: Molecular Biology and Evolution (2018)

In this perspective, we evaluate the explanatory power of the neutral theory of molecular evolution, 50 years after its introduction by Kimura. We argue that the neutral theory was supported by unreliable theoretical and empirical evidence from the beginning, and that in light of modern, genome-scale data, we can firmly reject its universality. The ubiquity of adaptive variation both within and between species means that a more comprehensive theory of molecular evolution must be sought.