tbuckley/cabot-search huggingface dataset:
LTX-315, an oncolytic peptide, to convert immunogenically ‘cold' tumors to ‘hot' in patients with advanced or metastatic tumours: Results from an ongoing phase I study.
Authors: James F. Spicer, Jean-Francois Baurain, Ahmad Awada, Rebecca Sophie Kristeleit, Dag Erik Jossang, Aurelien Marabelle, Delphine Loirat, Hedda Wold, Berit Nicolaisen, Oystein Rekdal, Wenche Marie Olsen, Andrew Saunders, Paal Brunsvig
Journal: Journal of Clinical Oncology (2017)

3085 Background: Intratumoral LTX-315 disintegrates cytoplasmic organelles with release of tumor antigens in preclinical models accompanied by increase in tumor-infiltrating lymphocytes (TILs). LTX-315 induced complete regression in several rodent models, with systemic immune responses. LTX-315 is strongly synergistic preclinically with immune checkpoint inhibitors (ICI). We are conducting a phase 1 trial to evaluate LTX-315 in combination therapy. Methods: Patients with advanced metastatic solid tumours received injections of LTX-315 into a single accessible tumour over 6 weeks. Additional injections could be administered thereafter every 2 weeks. Biopsies of injected lesions were taken at baseline, and on treatment. Results: 28 have been enrolled to date, median age is 58 (range 32-80) and median prior treatments 2 (range 1-14). LTX-315 monotherapy was administered at doses of 2-7mg to a median of 1.8 tumour lesions (range 1-6) for a median of 9 weeks (range 1-33). In 24 patients all LTX-315-related adverse events were CTC grade 1 or 2, most commonly local erythema, flushing, pruritis and hypotension, most resolving within minutes of injection. Related grade 3 (3 patients) or 4 (1) allergic/anaphylaxis adverse event occurred and resolved without sequelae. Best response in 44 injected lesions in 20 evaluable patients included 2 complete responses, &gt; 50% reduction in 5 tumours, and 20 stable (injected ). Significant increases in TILs occurred in 67% (14 of 21) patients with biopsies of injected tumours available. Regression of distant non-injected tumour has been observed clinically on biopsy (abscopal effect). No irRC response in non-injected tumours has been observed in 16 evaluable patients. Stable disease (median duration 14 weeks) occurred in 50% of patients as best response (melanoma (4), sarcoma (3), breast (1)). Conclusions: This phase 1 study demonstrates that intratumoural LTX-315 has a manageable safety profile and induces increases in TILs in pre-treated patients. Partial and complete regression was seen in some injected tumours. Evaluation of LTX-315 in combination with ICIs in breast and melanoma is ongoing. Clinical trial information: NCT01986426.
Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study
Authors: Outi Varpuluoma, Anna-Kaisa Försti, Jari Jokelainen, Miia Turpeinen, Markku Timonen, Kaisa Tasanen, Laura Huilaja
Journal: Journal of the American Academy of Dermatology (2018)
The objectivity of moral norms is a top-down cultural construct
Authors: Burton Voorhees, Dwight Read, Liane Gabora
Journal: Behavioral and Brain Sciences (2018)

Abstract Encultured individuals see the behavioral rules of cultural systems of moral norms as objective. In addition to prescriptive regulation of behavior, moral norms provide templates, scripts, and scenarios regulating the expression of feelings and triggered emotions arising from perceptions of norm violation. These allow regulated defensive responses that may arise as moral idea systems co-opt emotionally associated biological survival instincts.
Childhood leukaemia may be preventable by exposure to infections in early life
Authors: Nigel Hawkes
Journal: BMJ (2018)

The more common form of childhood leukaemia is caused by a two stage process of genetic mutation and may be preventable, a leading expert in the disease has said.1

Acute lymphoblastic leukaemia (ALL) is the commonest childhood cancer in developed countries, affecting one in 2000 children up to the age of 15 and growing in incidence at 1% a year. More usually seen in richer countries and in firstborn children, there has been a suspicion that infection—or rather an abnormal response to infection—plays a role in its causation.

Mel Greaves of the Institute of Cancer Research in London, who has spent four decades studying the disease, says that two genetic changes are almost certainly responsible.

The first change occurs in the womb. Greaves told a briefing at the Science Media Centre in London that this genetic change is found in 5% of newborns, but only one in a 100 of them go on to develop ALL. No …
<i>In Vitro</i> Priming of Adoptively Transferred T Cells with a RORγ Agonist Confers Durable Memory and Stemness <i>In Vivo</i>
Authors: Xiao Hu, Kinga Majchrzak, Xikui Liu, Megan M. Wyatt, Chauncey J. Spooner, Jacques Moisan, Weiping Zou, Laura L. Carter, Chrystal M. Paulos
Journal: Cancer Research (2018)

Adoptive T-cell transfer therapy is an FDA- approved treatment for leukemia that relies on the ex vivo expansion and reinfusion of a patient's immune cells, which can be engineered with a chimeric antigen receptor (CAR) for more efficient tumor recognition. Type 17 T cells, controlled transcriptionally by RORγ, have been reported to mediate potent antitumor effects superior to those observed with conventionally expanded T cells. Here, we demonstrate that addition of a synthetic, small-molecule RORγ agonist during ex vivo expansion potentiates the antitumor activity of human Th17 and Tc17 cells redirected with a CAR. Likewise, ex vivo use of this agonist bolstered the antitumor properties of murine tumor-specific CD4+ and CD8+ T cells. Expansion in the presence of the RORγ agonist enhanced IL17A production without compromising IFNγ secretion in vitroIn vivo, cytokine neutralization studies revealed that IFNγ and IL17A were required to regress murine melanoma tumors. The enhanced antitumor effect of RORγ agonist treatment was associated with recovery of more donor T cells in the tumor and spleen; these cells produced elevated levels of cytokines months after infusion and expressed markers of long-lived stem and central memory cells such as Tcf7 and CD62L. Conversely, untreated cells mainly exhibited effector phenotypes in the tumor. Cured mice previously treated with agonist-primed T cells were protected from tumor rechallenge. Collectively, our work reveals that in vitro treatment with a RORγ agonist generates potent antitumor Type 17 effector cells that persist as long-lived memory cells in vivoSignificance: RORγ agonists can be used in vitro during T-cell expansion to enhance the efficacy of adoptive cell therapy (e.g., CAR-T) and to provide long-term protection against tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3888/F1.large.jpg Cancer Res; 78(14); 3888-98. ©2018 AACR.
Mycobacterium chimaera infection following cardiac surgery in the United Kingdom: clinical features and outcome of the first 30 cases
Authors: J.E. Scriven, A. Scobie, N.Q. Verlander, A. Houston, T. Collyns, V. Cajic, O.M. Kon, T. Mitchell, O. Rahama, A. Robinson, S. Withama, P. Wilson, D. Maxwell, D. Agranoff, E. Davies, M. Llewelyn, S.-S. Soo, A. Sahota, M.A. Cooper, M. Hunter, J. Tomlins, S. Tiberi, S. Kendall, M. Dedicoat, E. Alexander, T. Fenech, M. Zambon, T. Lamagni, E.G. Smith, M. Chand
Journal: Clinical Microbiology and Infection (2018)
Delivery of the improved BMP-2-Advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair
Authors: Rosanne M. Raftery, Irene Mencía-Castaño, Simon Sperger, Gang Chen, Brenton Cavanagh, Georg A. Feichtinger, Heinz Redl, Ara Hacobian, Fergal J. O'Brien
Journal: Journal of Controlled Release (2018)
Robotic versus conventional laparoscopic gastrectomy for gastric cancer: A retrospective cohort study
Authors: Hong-Bin Liu, Wen-Jie Wang, Hong-Tao Li, Xiao-Peng Han, Lin Su, Deng-Wen Wei, Ting-Bao Cao, Jian-Ping Yu, Zuo-Yi Jiao
Journal: International Journal of Surgery (2018)
Erratum: “Hydroxylated Polybrominated Biphenyl Ethers Exert Estrogenic Effects via Nongenomic G Protein–Coupled Estrogen Receptor Mediated Pathways”
Authors: Lin-Ying Cao, Xiao-Min Ren, Yu Yang, Bin Wan, Liang-Hong Guo, De Chen, Yong Fan
Journal: Environmental Health Perspectives (2018)

[This corrects the article DOI: https://doi.org/10.1289/EHP2387.].
Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy
Authors: R. Jeffrey Karnes, Vidit Sharma, Voleak Choeurng, Hussam Al-Deen Ashab, Nicholas Erho, Mohammed Alshalalfa, Bruce Trock, Ashley Ross, Kasra Yousefi, Harrison Tsai, Shuang G. Zhao, Jeffrey J. Tosoian, Zaid Haddad, Mandeep Takhar, S. Laura Chang, Daniel E. Spratt, Firas Abdollah, Robert B. Jenkins, Eric A. Klein, Paul L. Nguyen, Adam P. Dicker, Robert B. Den, Elai Davicioni, Felix Y. Feng, Tamara L. Lotan, Edward M. Schaeffer
Journal: Clinical Cancer Research (2018)

Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.
Micro and Nanofabrication methods to control cell-substrate interactions and cell behavior: A review from the tissue engineering perspective
Authors: Menekse Ermis, Ezgi Antmen, Vasif Hasirci
Journal: Bioactive Materials (2018)

Cell-substrate interactions play a crucial role in the design of better biomaterials and integration of implants with the tissues. Adhesion is the binding process of the cells to the substrate through interactions between the surface molecules of the cell membrane and the substrate. There are several factors that affect cell adhesion including substrate surface chemistry, topography, and stiffness. These factors physically and chemically guide and influence the adhesion strength, spreading, shape and fate of the cell. Recently, technological advances enabled us to precisely engineer the geometry and chemistry of substrate surfaces enabling the control of the interaction cells with the substrate. Some of the most commonly used surface engineering methods for eliciting the desired cellular responses on biomaterials are photolithography, electron beam lithography, microcontact printing, and microfluidics. These methods allow production of nano- and micron level substrate features that can control cell adhesion, migration, differentiation, shape of the cells and the nuclei as well as measurement of the forces involved in such activities. This review aims to summarize the current techniques and associate these techniques with cellular responses in order to emphasize the effect of chemistry, dimensions, density and design of surface patterns on cell-substrate interactions. We conclude with future projections in the field of cell-substrate interactions in the hope of providing an outlook for the future studies.
Tyrosine kinase inhibitor–induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors
Authors: Silvia Maifrede, Margaret Nieborowska-Skorska, Katherine Sullivan-Reed, Yashodhara Dasgupta, Paulina Podszywalow-Bartnicka, Bac Viet Le, Martyna Solecka, Zhaorui Lian, Elizaveta A. Belyaeva, Alina Nersesyan, Marcin M. Machnicki, Monika Toma, Nicolas Chatain, Malgorzata Rydzanicz, Huaqing Zhao, Jaroslav Jelinek, Katarzyna Piwocka, Tomasz Sliwinski, Tomasz Stoklosa, Rafal Ploski, Thomas Fischer, Stephen M. Sykes, Steffen Koschmieder, Lars Bullinger, Peter Valent, Mariusz A. Wasik, Jian Huang, Tomasz Skorski
Journal: Blood (2018)
Association of State Laws Permitting Denial of Services to Same-Sex Couples With Mental Distress in Sexual Minority Adults
Authors: Julia Raifman, Ellen Moscoe, S. Bryn Austin, Mark L. Hatzenbuehler, Sandro Galea
Journal: JAMA Psychiatry (2018)

Recent evidence suggests that state policies affecting sexual minorities are associated with health disparities. Twelve states have laws permitting the denial of services to same-sex couples, and the US Supreme Court is considering whether states can prohibit the denial of services to same-sex couples.We investigated whether state laws permitting individuals to refuse services to sexual minorities were associated with changes in the proportion of sexual minority adults reporting mental distress.This difference-in-difference-in-differences linear regression analysis with state fixed effects used Behavioral Risk Factor Surveillance System (BRFSS) data from 2014 through 2016 from adults aged 18 to 64 years in 3 states that implemented laws permitting the denial of services to same-sex couples (Utah, Michigan, and North Carolina) and 6 nearby control states (Idaho and Nevada, Ohio and Indiana, and Virginia and Delaware, respectively). Sexual minority adults were defined as those who identified as gay, lesbian, bisexual, or not sure of their sexual orientation under a module on sexual orientation that BRFSS implemented in 2014 and each state could opt to include. Analysis controlled for year and individual-level sex, race, ethnicity, age group, educational attainment, income, employment, and marital status. A permutation test was conducted to precisely estimate statistical significance.An interaction term indicating whether individuals identified as a sexual minority and lived in a state with a law permitting denial of services to same-sex couples in 2015.Mental distress, defined as poor mental health on 14 or more of the past 30 days.Of 109 089 participants, 4656 (4.8%; all percentages incorporate survey weights) identified as sexual minorities, 86141 (72.1%) were non-Hispanic white, and ages were uniformly distributed between 18 and 64 years. In 2014, 2038 of 16637 heterosexual adults (12.6%) and 156 of 815 sexual minority adults (21.9%) in the 3 same-sex denial states reported mental distress. The proportion of sexual minority adults reporting mental distress increased by 10.1 percentage points (95% CI, 1.8 to 18.5 percentage points, permutation-adjusted P value = .046) between 2014 and 2016 in states that passed laws permitting denial of services to same-sex couples compared with control states, a 46% relative increase in sexual minority adults experiencing mental distress. Laws permitting denial of services to same-sex couples were not associated with significant changes in heterosexual adults experiencing mental distress (-0.36 percentage points, 95% CI, -1.73 to 1.01 percentage points).Laws permitting denial of services to same-sex couples, which exist in 12 states and are under consideration by the US Supreme Court, are associated with a 46% increase in sexual minority adults experiencing mental distress.
Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells
Authors: Han Shao, Tingting Li, Rong Zhu, Xiaoting Xu, Jiandong Yu, Shengfeng Chen, Li Song, Seeram Ramakrishna, Zhigang Lei, Yiwen Ruan, Liumin He
Journal: Biomaterials (2018)
Abstract A48: Ube2v1 promotes EMT and metastasis by suppression of autophagy
Authors: Tong Shen, Lingdong Cai, Yuhong Liu, Jianming Li
Journal: Cancer Research (2018)

Abstract Ubiquitination is one of the basic post-translational modifications for cellular homeostasis. The conjugating enzyme (E2) family plays as a bridge linking the first step mediated by E1 with the final step mediated by E3 in the ubiquitin-proteasome system. However, the role of Ube2v1, one of ubiquitin-conjugating E2 enzyme variant proteins (Ube2v), in colorectal cancer (CRC) and autophagy is unclear. Here, we found that Ube2v1 is elevated in tumor samples of CRC patients and correlated with poorer survival of CRC patients. Furthermore, Ube2v1 promotes migration and invasion of CRC cells in vitro and boosts tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1 suppresses autophagy program and promotes EMT and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, rapamycin attenuates the enhanced in vitro migration and invasion and in vivo lung metastasis of Ube2v1 overexpression by inducing the autophagy pathway. Mechanistically, Ube2v1 increases histone H4 lysine 16 acetylation by downregulating expression of Sirt1 and epigenetically suppresses gene expression of autophagy genes in colorectal cancer. In conclusion, Ube2v1 functions as a global regulator for autophagy by epigenetically transcriptional suppression of autophagy, and consequently promotes EMT and metastasis of CRC. Our study functionally links Ube2v1, one member of E2 family in the ubiquitin-proteasome system to autophagy program in CRC progression and metastasis. Citation Format: Tong Shen, Lingdong Cai, Yuhong Liu, Jianming Li. Ube2v1 promotes EMT and metastasis by suppression of autophagy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A48.
What's in a name? That which we call IPF, by any other name would act the same
Authors: Athol U. Wells, Kevin K. Brown, Kevin R. Flaherty, Martin Kolb, Victor J. Thannickal
Journal: European Respiratory Journal (2018)

Idiopathic pulmonary fibrosis (IPF) remains a truly idiopathic fibrotic disease, with a modest genetic predilection and candidate triggers but no overall explanation for the development of disease in non-familial cases. Agreement on terminology has contributed to major clinical and translational advances since the millennium. It is likely that the entity currently captured by the term "IPF" will be radically reclassified over the next decade, either through "splitting" (into IPF subgroups responding selectively to individual disease-modifying agents) or through "lumping" of IPF with other forms of progressive fibrotic lung disease (with shared pathogenetic mechanisms and IPF-like disease behaviour). In this perspective, we summarise the clinical and pathogenetic justification for a focus on "the progressive fibrotic phenotype" in future clinical and translational research. By this means, we can hope to address the needs of non-IPF patients with inexorably progressive fibrotic disease, currently disenfranchised by lack of access to agents that are efficacious in IPF. In this regard, ongoing trials of anti-fibrotic therapies in non-IPF patients with progressive fibrosis may be highly influential. Future revision of IPF nomenclature may be warranted if there are major conceptual changes but without compelling justification, the benefits of renaming IPF are likely to be outweighed by the resulting confusion.
Efficacy of oral chemotherapy with capecitabine and temozolomide (CapTem) in metastatic neuroendocrine tumors (NETs): A single-institution experience.
Authors: Valeria Smiroldo, Carlo Carnaghi, Lorenza Rimassa, Nicola Personeni, Tiziana Pressiani, Silvia Bozzarelli
Journal: Journal of Clinical Oncology (2018)

487 Background: CapTem chemotherapy regimen represents one of the standard of treatment for NETs, an interesting option of care due to its feasibility and efficacy although not enough prospective data support this evidence. Methods: This retrospective analysis included all patients (pts) with metastatic NETs treated with CapTem regimen at our institution from April 2013 to April 2017. This oral chemotherapy included capecitabine 600 mg/m2/BID (capped at 1,000 mg BID total dose) on days 1–14 and temozolomide 75 mg/m2/BID on days 10–14 every 28 days according to the schedule published by Fine RL et al. (Cancer Chemother Pharmacol, 2013). Overall survival (OS), progression free survival (PFS), overall response rate (ORR) and toxicities were retrospectively evaluated. Results: Twenty-seven pts (15 males) were included. Median age was 61 yrs (range 46-85). Primary tumor included pancreas in 8 pts (29.6%), midgut 8 pts (29.6%), lung 8 pts (29.6%), other NETs 3 pts (11.1%). Most of pts had well-differentiated tumors (88.8%) and Ki67 was less than &lt;20% in 59% of pts. Median number of cycles was 6 (range 2-25). Ten pts (37.0%) received CapTem as 1st line treatment, 7 pts (25.9%) as 2nd line and 10 (37.0%) pts as &gt; 3rd line. ORR was 33.3%; 31.2% for Ki67 &lt; 20% group and 40.0% in Ki67 &gt;20%. DCR (partial response + stable disease) for the entire cohort was 59.2%. Median PFS was 4 mos, without any differences between pancreatic, midgut and lung groups, but mPFS was 8.0 mos for pts who received CapTem as 1st line treatment. At present mOS was not reached. In term of toxicity CapTem regimen was very well tolerated and only 1 pt reported a G3 reversible toxicity (neutropenia). No G3/4 toxicity were observed. Conclusions: Our experience confirms that CapTem regimen is effective and well tolerated. Efficacy does not seem to be related to the primary tumor or Ki67. DCR and ORR are superior to the response produced by tyrosine kinase inhibitors, suggesting a strategy when tumour shrinkage and symptom control are needed.
LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody–Drug Conjugates
Authors: James W. Purcell, Sonia G. Tanlimco, Jonathan Hickson, Melvin Fox, Mien Sho, Lisa Durkin, Tamar Uziel, Rick Powers, Kelly Foster, Thomas McGonigal, Subashri Kumar, Josue Samayoa, Dong Zhang, Joann P. Palma, Sasmita Mishra, Diane Hollenbaugh, Kurt Gish, Susan E. Morgan-Lappe, Eric D. Hsi, Debra T. Chao
Journal: Cancer Research (2018)

Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFβ on activated fibroblasts (αSMA+) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer-positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80+ macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.Significance: These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. Cancer Res; 78(14); 4059-72. ©2018 AACR.
A “top-down” approach to actuate poly(amine-co-ester) terpolymers for potent and safe mRNA delivery
Authors: Yuhang Jiang, Alice Gaudin, Junwei Zhang, Tushar Agarwal, Eric Song, Amy C. Kauffman, Gregory T. Tietjen, Yongheng Wang, Zhaozhong Jiang, Christopher J. Cheng, W. Mark Saltzman
Journal: Biomaterials (2018)