bluuebunny/crossref_metadata_2025 huggingface dataset:
Sordid Ironies and the Short-Fingered Vulgarian: Alison Jackson’s Mental Images
Authors: Perucci Tony
Published: February 2018

Alison Jackson’s pre-election photographs of Donald Trump’s “private moments” utilize a look-alike to envision Trump in a number of compromising positions. In ways that exceed the artist’s intention, the photographs’ play of the recognition of misrecognition fosters “ugly feelings” of ressentiment that might enable resistance not only to Trump but also to reactionary Republicans and neoliberal Democrats.
“Acatholic” Foundations: The Emergence of Charitable Endowments in the Greek Orthodox and Protestant Communities of Vienna (18th Century)
Authors: Saracino Stefano
Published: February 2018

This article aims at comparing the endowments founded during the 18th century by wealthy members of the Greek Orthodox and Protestant (Lutheran, Calvinist) communities in Vienna. Charitable endowments in fact offer a paramount example of the entanglement of economic, confessional and migration issues, which played an important role in the non-Catholic communities in the Habsburg capital before and after the Proclamation of Toleration in 1781. The analysis of relevant sources gives the impression that these endowments had a massive (material as well as symbolic) importance for these communities and shaped their relationship to a political regime that, even while performing enlightened reforms in the fields of culture and confession, was strengthening its control over the sector of charity.
Amomum nimkeyense (Zingiberaceae), a new species from Arunachal Pradesh, northeastern India
Authors: SABU MAMIYIL , HAREESH VADAKKOOT SANKARAN , MIBANG TATUM , DAS ARUP KUMAR
Published: February 2018

Amomum nimkeyense, a new species is described from Arunachal Pradesh, northeastern India. A detailed description of the plant, distribution and ecology along with colour photographs are provided for ease of identification.
Oribatid mites (Acari: Oribatida) recorded from Ireland: Catalogue, historical records, species habitats and geographical distribution, combinations, variations and synonyms
Authors: ARROYO JULIO , CONNELL TAGDH O , BOLGER THOMAS
Published: February 2018

We provide a catalogue of the oribatid species (Arachnida, Acari, Oribatida) recorded from Ireland between the first records at the beginning of the 20th century and 2015. The catalogue, which contains 246 named species includes information on the habitats and locations where the species were found in Ireland as well as the references (if the data were published) where these were recorded. In addition, we include information on the species authorship, together with comprehensive nomenclatural data on synonyms and combination/variations of the named species.        This catalogue increases the number of oribatids species known in Ireland by 50% since the most recent catalogue published in 1998 by Malcom Luxton.
Miscellanea Herpetologica Sanctithomae, with a provisional checklist of the terrestrial herpetofauna of São Tomé, Príncipe and Annobon islands
Authors: CERÍACO LUIS M. P. , MARQUES MARIANA P. , BAUER AARON M.
Published: February 2018

Five problematic cases regarding the presence of reptile taxa on the island of São Tomé (Gulf of Guinea) are reviewed. These cases deal with 1) the past presence of crocodilians in the island, 2) the putative type locality of Dipsas pulverulenta Fischer, 1856, 3) the dubious presence of a mamba (genus Dendroaspis) on the island, 4) an erroneous reference to the presence of Gastropyxis smaragdina, and 5) two specimens (Psammophis lineatus and Psammophis elegans) from Carl Weiss collection, currently deposited in the Zoological Museum of Hamburg and wrongly labelled as being from São Tomé island. A provisional checklist to the terrestrial herpetofauna of the three oceanic islands of the Gulf of Guinea—São Tomé, Príncipe and Annobon—is presented in order to clarify the current numbers of the endemics of each island, as well as to review and present current research.
Causes and Probability of Occurrence of Extreme Precipitation Events like Chennai 2015
Authors: Krishnamurthy Lakshmi , Vecchi Gabriel A. , Yang Xiaosong , van der Wiel Karin , Balaji V. , Kapnick Sarah B. , Jia Liwei , Zeng Fanrong , Paffendorf Karen , Underwood Seth
Published: February 2018

Unprecedented high-intensity flooding induced by extreme precipitation was reported over Chennai in India during November–December of 2015, which led to extensive damage to human life and property. It is of utmost importance to determine the odds of occurrence of such extreme floods in the future, and the related climate phenomena, for planning and mitigation purposes. Here, a suite of simulations from GFDL high-resolution coupled climate models are used to investigate the odds of occurrence of extreme floods induced by extreme precipitation over Chennai and the role of radiative forcing and/or large-scale SST forcing in enhancing the probability of such events in the future. The climate of twentieth-century experiments with large ensembles suggest that the radiative forcing may not enhance the probability of extreme floods over Chennai. Doubling of CO2 experiments also fails to show evidence for an increase of such events in a global warming scenario. Further, this study explores the role of SST forcing from the Indian and Pacific Oceans on the odds of occurrence of Chennai-like floods. Neither El Niño nor La Niña enhances the probability of extreme floods over Chennai. However, a warm Bay of Bengal tends to increase the odds of occurrence of extreme Chennai-like floods. In order to trigger a Chennai like-flood, a conducive weather event, such as a tropical depression over the Bay of Bengal with strong transport of moisture from a moist atmosphere over the warm Bay, is necessary for the intense precipitation.
American Policy in Gifted Education
Authors: VanTassel-Baska Joyce
Published: February 2018

This article explores the history of gifted education policy and practice in the United States over the last five decades, documenting the lack of sustained progress in obtaining sustained federal support. It also highlights two case examples, one at the state level and a second at the national level of where a policy in a specific aspect of gifted program development has been successfully advanced. Implications of the article suggest that gifted education policy is not coherent across the country, is controlled by state legislatures, and subject to annual scrutiny for continued and new funding.
Kinematic reliability and sensitivity analysis of the modified Delta parallel mechanism
Authors: Xu Dongtao
Published: February 2018

In order to improve the kinematic reliability, it is crucial to find out the influence of each error source on the kinematic reliability of the mechanism. Reliability sensitivity analysis is used to find the changing rate in the probability of reliability in relation to the changes in distribution parameters. Based on the structural response surface function method, the functional relation between the kinematic reliability of a modified Delta parallel mechanism and the original input-error vectors is described using the quadratic function with cross terms. Moreover, the partial derivatives of the functional relation with respect to the means and variances of the original input errors are derived, which can efficiently evaluate kinematic reliability sensitivity of the mechanism. The advantages of this method are as follows: First, the response surface function, which can be easily set up by the position-error model of the mechanism, is convenient for calculating the variance, partial derivative, and reliability sensitivity. Second, in this case (unlike in the traditional error-mapping model), although the input-error values are unknown, pseudorandom variables used as random input-error sources can be generated by MATLAB software. Furthermore, the kinematic reliability of the mechanism can be assessed using the Monte Carlo method.
Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy?
Authors: Loisel Fanny , Provost Bastien , Haddad François , Guihaire Julien , Amsallem Myriam , Vrtovec Bojan , Fadel Elie , Uzan Georges , Mercier Olaf
Published: February 2018

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.
The clinical characteristics and long‐term prognosis of pulmonary arterial hypertension associated with hereditary hemorrhagic telangiectasia
Authors: Li Wen , Xiong Chang‐ming , Gu Qing , Wang Xiao‐tong , Cheng Xiao‐ling , Huang Li , Yang Tao , Luo Qin , Zhao Zhi‐hui , Ni Xin‐hai , Liu Zhi‐hong , He Jian‐guo
Published: February 2018

Pulmonary arterial hypertension (PAH) is a severe complication of hereditary hemorrhagic telangiectasia (HHT); however, little is known about its clinical characteristics and prognosis. Nine newly diagnosed HHT‐PAH patients were prospectively recruited between October 2007 and January 2016 and were followed up every half‐year. Eighteen idiopathic pulmonary arterial hypertension (IPAH) patients, matched with HHT‐PAH patients on mean pulmonary arterial pressure, pulmonary capillary wedge pressure, pulmonary vascular resistance, cardiac index, and World Health Organization (WHO) functional class (FC), were recruited. The clinical characteristics of HHT‐PAH patients were described and the prognosis of these two cohorts were compared. Of HHT‐PAH patients, 55.56% were WHO FC III. Kaplan–Meier survival analysis showed one‐ and three‐year survival rates of HHT‐PAH patients were 77.8% and 53.3% respectively, which were worse than matched IPAH patients (log rank: P = 0.047). HHT‐PAH patients had higher red cell distribution width (14.88 ± 2.93% versus 13.19 ± 0.83%, P = 0.031), larger right ventricular anteroposterior diameter (34.67 ± 6.67 mm versus 28.56 ± 6.35 mm, P = 0.029), and lower mean corpuscular hemoglobin concentration (317.38 ± 17.71 g/L versus 335.72 ± 14.68 g/L, P = 0.011) than matched IPAH patients. Multivariate Cox proportional hazards regression analyses showed baseline total bilirubin independently predicted the mortality of HHT‐PAH after adjusting by age, cardiac index, mixed venous oxygen saturation, or serum uric acid. HHT‐PAH patients may have a worse prognosis than matched IPAH patients. Baseline total bilirubin may be a promising predictor for the long‐term prognosis in HHT‐PAH patients.
Student as a Producer: Overcoming Language and Contextual Issues of Using Online Videos
Authors: Adikaram Arosha S.
Published: February 2018

This article discusses how to overcome the language and cultural issues of using existing online videos in classroom discussions with nonnative English-speaking groups of students, through student-produced videos given as an authentic educational assignment. Implementation of the assignment and the use of student-produced videos in classroom discussions in a Master of Business Administration (MBA) program in an Asian context are described. Use of peer-instructor evaluation to enhance the meaningfulness of the assignment is also explained. Overall, the assignment led to more active and deeper learning for students, while providing a collection of videos to be used in future teaching for nonnative English-speaking students. Furthermore, recommendations for making the assignment more effective are provided.
Ferritin nanoparticles for improved self-renewal and differentiation of human neural stem cells
Authors: Lee Jung Seung , Yang Kisuk , Cho Ann-Na , Cho Seung-Woo
Published: February 2018

Background

Biomaterials that promote the self-renewal ability and differentiation capacity of neural stem cells (NSCs) are desirable for improving stem cell therapy to treat neurodegenerative diseases. Incorporation of micro- and nanoparticles into stem cell culture has gained great attention for the control of stem cell behaviors, including proliferation and differentiation.

Method

In this study, ferritin, an iron-containing natural protein nanoparticle, was applied as a biomaterial to improve the self-renewal and differentiation of NSCs and neural progenitor cells (NPCs). Ferritin nanoparticles were added to NSC or NPC culture during cell growth, allowing for incorporation of ferritin nanoparticles during neurosphere formation.

Results

Compared to neurospheres without ferritin treatment, neurospheres with ferritin nanoparticles showed significantly promoted self-renewal and cell-cell interactions. When spontaneous differentiation of neurospheres was induced during culture without mitogenic factors, neuronal differentiation was enhanced in the ferritin-treated neurospheres.

Conclusions

In conclusion, we found that natural nanoparticles can be used to improve the self-renewal ability and differentiation potential of NSCs and NPCs, which can be applied in neural tissue engineering and cell therapy for neurodegenerative diseases.
Single-cell protein analysis in support of biomarker evaluation for breast cancer immunotherapeutics.
Authors: Plaks Vicki
Published: February 2018

10

Background: Triple-negative breast cancer (TNBC) is being tested for PD-1/PD-L1 checkpoint inhibitors combination therapy. The relationship between tumor expression of PD-L1 and patient outcomes has been established using immunohistochemistry (IHC) biomarker assays across various malignancies. PD-L1 is expressed in tumor and immune cells within the tumors in TNBC, but only immune-cell PD-L1 is associated with response to anti-PD-L1 (atezolizumab) so differentiating tumor vs. immune PD-L1 expression is essential. The currently available IHC biomarker assays that relay on tissue biopsies struggle to provide clinically meaningful identification of responders vs. non-responders. Poor sensitivity and specificity is partially attributed to tumor heterogeneity that is not well-represented in these biopsies. In addition, PD-L1 expression may vary over time due to disease progression or treatment. Since tissue biopsy collection is often an invasive procedure, it is restricted. Needle biopsies can mitigate some of these issues as a minimally invasive method to probe multiple regions within several cancer lesions across several time points. MILO, a new single cell Western Blot (WB) technology allows quantitative measurements of multiple protein biomarkers within one cell in small samples. Methods: To evaluate the capability of MILO to differentiate between PD-L1 in immune and tumor cell populations, we interrogated BC cell lines as well as peripheral blood mononuclear cells (PBMCs) mixed in known ratios. We used MDA-MB-231 that shows high PD-L1 and low HER2 expression and BT-474, which shows the inverse expression profile for these biomarkers along with PBMCs as PD-L1+ immune cells. Primary breast tumor tissues are currently interrogated to establish utility in needle biopsies. Results: MILO demonstrated heterogeneity at the single-cell level of HER2 and PD-L1 expression in BC tumor cells and enabled differentiation between PD-L1 expression in immune vs. tumor cells using cell-specific markers and low cell numbers. Conclusions: MILO can improve patient selection and prediction of response to immune checkpoint inhibition by promoting the utility of needle biopsies to complement IHC of core biopsies.
Immunotherapy use, outcomes, and toxicities in gastrointestinal malignancies.
Authors: David Rachel Julie , Baran Andrea , Maggiore Ronald John
Published: February 2018

100

Background: Use of checkpoint inhibitors has expanded over recent years, and the gastrointestinal (GI) oncologic indications for immunotherapy (IO) continue to evolve. IO use in GI malignancies is still in its infancy, and we sought to describe our clinical experience thus far. Methods: We retrospectively identified all patients (pts) with GI malignancies treated with IO at the Wilmot Cancer Institute from December, 2015 through July, 2017. We examined patient and tumor-related clinicopathologic features. Our main outcomes of interest were best response on IO, and frequency/severity of IO toxicity. Fisher’s exact test was used to compare categorical factors between groups of interest. Results: 21 pts received IO for a GI malignancy, all of whom had metastases (mets). 76% of pts were male, and the median age was 62 years (range, 25 – 87). Common diagnoses were colorectal (CRC) (n = 10), gastroesophageal (GE) (n = 5), and hepatocellular cancers (HCC) (n = 4). 76% of pts received pembrolizumab, and 24% of pts received nivolumab. 67% received IO as ≥ 3rd-line therapy. The median time from diagnosis of metastatic disease to initiation of IO was 17.8 mos (range, 3 – 140). The median time on therapy was 2.62 months (95% CI 1.48, 6.52 mos) (range, 0.5 – 11 mos), with 3 pts still responding at the time of the analysis. Pts with HCC had the longest time on IO (8.95 mos), compared to 2.62 mos for GE, 2.39 mos for CRC, and 1.26 mos for all other (p = 0.10). Pts who received IO as 3rd or greater line of therapy had a significantly increased likelihood of non-response or progressive disease/death compared to pts who received IO as 2nd-line (p = 0.02). There was a trend towards non-response to IO in pts with liver mets vs. extrahepatic mets (p = 0.09). 57% experienced grade 3/4 toxicities: the most common were anemia (24%), hyponatremia (14%), and fatigue (14%). No IO-specific grade 3/4 immune-related toxicities were observed. Conclusions: The majority of our pts received IO as 3rd line therapy or beyond, and were significantly less likely to respond to treatment compared to those who received IO earlier on. The presence of liver mets is potentially associated with non-response to IO, and needs further exploration. No unexpected or severe IO-related toxicities were observed.
Expression of endogenous retroviruses and response to immune checkpoint therapy in renal cell cancer.
Authors: Panda Anshuman , De Cubas Aguirre , Beckermann Katy , Riedlinger Gregory , Stein Mark N. , Mayer Tina M. , Mehnert Janice M. , Rathmell Kimryn , Bhanot Gyan , Ganesan Shridar
Published: February 2018

104

Background: In certain cancers, including renal cell carcinoma (RCC), no clear correlation exists between mutation burden and response to immune checkpoint therapy. To look for other markers of immune activation, we investigated the correlation between expression of endogenous retroviruses (ERV) and evidence of immune checkpoint activation in multiple cancer types. Methods: RNA-seq data of 4,910 tumors of 21 cancers from TCGA was analyzed to identify cancers in which there was correlation between ERV expression and evidence of immune checkpoint activation as shown by increased expression of immune checkpoint genes and evidence of CD8+ T-cell infiltration. Expression of candidate ERVs was measured by quantitative RT-PCR in a set of 20 RCC specimens. Results: In the TCGA clear-cell renal cancer, ER+HER2- breast cancer, and colon cancer datasets showed correlation between expression of a subset of ERVs and markers of local immune checkpoint activation. Using hierarchical clustering, tumors could be classified into 3 groups (high/intermediate/low) based on expression of these ERVs. In all these cancer types, the high ERV expressing group showed evidence of immune activation (robust immune infiltration with high CD8+ T cell fraction) and checkpoint (PD-1, CTLA-4) pathway over-expression. Expression of gene pathways associated with histone modification was significantly correlated with overall ERV expression, suggesting underlying dysregulation of chromatin silencing. Of ERVs analyzed ERV3.2 and ERVK-2 were most consistently associated with markers of immune checkpoint activation in multiple cancer types. For validation, expression of ERVs were measured in tumor sepcimens 20 clear cell renal cancer patients treated with immune checkpoint blockade. Expression of ERV3-2 and ERVK-2, was significantly increased in patients with clinical response to immune checkpoint therapy in this cohort. Conclusions: These data suggest that expression of ERV may be associated with activation of immune checkpoint pathways in renal cell cancer and may predict response to immune checkpoint therapy. Similar associations may also exist in some other solid tumors.
Targeting autophagy and immunotherapy with hydroxychloroquine and interleukin 2 in patients with metastatic renal cell carcinoma (mRCC): A Cytokine Working Group study.
Authors: Appleman Leonard Joseph , Logan Theodore F. , Normolle Daniel Paul , Ernstoff Marc S. , Parikh Rahul Atul , McDermott David F. , Monk Paul , Olencki Thomas , Friedland David , Maranchie Jodi Kathleen , Butterfield Lisa Helene , Liang Xiaoyan , Lotze Michael T.
Published: February 2018

106

Background: We performed a Phase II study of the combination of the autophagy inhibitor, hydroxychloroquine (HCQ), along with high dose IL-2 in patients with advanced renal cancer. 31 patients were entered on this Cytokine Working Group Study conducted at six member institutions;NCT01550367. This combination in murine models was associated with diminished toxicity and increased efficacy, and, in preliminary studies, diminished high mobility group box 1 (HMGB1) protein, consistent with its established role in serving as a Damage Associated Molecular Pattern (DAMP) molecule and inducer of autophagy. Methods: The Study Design involved initiating oral Hydroxychloroquine 300 mg P.O bid. Aldesleukin (600,000 IU/kg) was administered q8hrs in courses consisting of two cycles separated by 7-14 days and constituting a single course. For patients with stable or responsive disease, additional courses were administered every approximately 85-90 days. Serum, plasma, Paxgene tubes, and peripheral blood mononuclear cells were obtained sequentially prior to therapy initiation and sequentially on D1 and D2 of each cycle following initiation of therapy. Results: 31 patients (9F, 22M) have been registered and 3 confirmed complete responses observed; the current median overall survival has not been reached in the 29pts. The Baseline Karnofsky Score of 100 (17pts), 90 (13pts), and 80(1 pt). The mean age was 57.5 years, range = (45.2, 68.8). 26 patients had a mean of 12.5 doses +/-4.7 (3, 23) with 13 pts receiving a second course and 4, a third. Platelet nadir was diminished from baseline by 26%. Of the 27 patients in the data set, 18 had at least one Grade 4 toxicity at least possibly related to treatment, and 9 patients had at least one Grade 3 adverse event at least possibly related to treatment but no Grade 4 events.Serologic and cellular data and complete clinical data will be submitted with the completed abstract. Conclusions: The combination of high dose aldesleukin and daily oral HCQ was well tolerated. We have concluded this trial and will report mature survival data, toxicity data, and biomarkers/autophagy measures with the final submission. Clinical trial information: NCT01550367.
Clonotypic T-cell responses in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with standard sipuleucel-T (sip-T) compared with patients receiving a booster treatment.
Authors: Zhang Li , Kandadi Harini , Paciorek Alan T , He Tao , Sheikh Nadeem Anwar , Fong Lawrence
Published: February 2018

107

Background: Sip-T is an FDA-approved autologous cellular immunotherapy for asymptomatic or minimally symptomatic mCRPC. Neoadjuvant sip-T induced activated T-cell infiltration to the prostate tissue (Fong 2014) and broadened the T cell receptor (TCR) repertoire vs control (Sheikh 2016). To test if sip-T induces memory T-cell responses, we compared treatment-induced changes in TCR repertoire of treatment-naïve pts (STRIDE) with those retreated with sip-T (P10-1). Methods: In STRIDE (N=52), pts received sip-T with concurrent or sequential enzalutamide (Petrylak 2015). In P10-1 (N=8), pts previously treated with sip-T in an androgen-dependent setting were retreated with a booster course after a median of 8.6 years (Beer 2013). PBMCs were collected at baseline and during/post–sip-T. Deep sequencing was performed using the ImmunoSEQ assay (Adaptive Biotechnologies). TCR diversity was assessed by Shannon diversity index and clonality. TCR dynamics was evaluated by Morisita’s distance (Zhang 2017). Results: Baseline TCR diversity was similar between the two trials (p=0.590, Shannon diversity index; p=0.700, clonality). Significant decreases in clonality were observed from baseline to wk 4 (p<0.001) and wk 6 (p=0.030) in STRIDE, but not in P10-1, indicating more expansion of T cell clones in STRIDE. Morisita’s distance was significantly higher at wk 2 (p=0.040) and 26 (p=0.013) in STRIDE vs P10-1, indicating a more consistent TCR repertoire in STRIDE across timepoints. The proportion of the clones enriched after sip-T treatment was significantly higher in P10-1 vs STRIDE (wk 6: p=0.007, wk 26: p=0.015, wk 52: p=0.026). The extent of change within the top 100 most abundant TCR sequences (clonal shuffling) was greater and initiated earlier in P10-1 vs STRIDE. Conclusions: Initial sip-T treatment of naïve mCRPC pts programs the TCR repertoire, which is maintained over time. Consistent with immunologic memory, retreatment with sip-T rapidly expands the number of enriched T-cell clones persisting up to 1 year after retreatment, which is characteristic of immunological boosting following successful treatment.
Long-amplicon TCRβ repertoire sequencing to reveal human T-cell receptor variable gene polymorphism: Implications for the prediction and interpretation of immunotherapy outcome.
Authors: Looney Timothy , Glavin Alexander , Pabla Sarabjot , Glenn Sean T. , Miller Lauren , Topacio-Hall Denise , Linch Elizabeth , Pankov Aleksandr , Zheng Jianping , Conroy Jeffrey M. , Morrison Carl , Lowman Geoffrey , Andersen Mark , Hyland Fiona
Published: February 2018

129

Background: Human T cell antigen receptors play a critical role in protective immune responses but are also implicated in autoimmune disease and immune-mediated adverse events during immunotherapy. The antigen specificity of the T cell receptor is determined in part by the sequence of the CDR and Framework regions encoded by the TCRB variable gene. Previous studies of population sequencing data indicate that current antigen receptor allele databases, such as IMGT, fail to capture a significant portion of human variation. Here we use long-amplicon multiplex sequencing of rearranged TCRB receptors to validate putative novel human variable gene alleles previously recovered from 1000 genomes data. Methods: TCRB rearrangements were amplified from cDNA from 85 Caucasians undergoing treatment for melanoma using AmpliSeq-based multiplex Framework 1 and Constant gene primers to produce ~330bp amplicons. Samples were sequenced using the Ion Torrent S5 530 chip to produce ~1.5M raw reads per sample. Ion Reporter was used for clonotyping and identification of variable gene sequences absent from the IMGT database. Putatively novel sequences were compared to those reported in the Lym1k database of alleles recovered from 1000 genomes data. Results: We identified 15 novel variable gene alleles that are absent from the IMGT database and result in amino acid changes to the CDR or Framework regions of the TCR. Typically, a single individual was found to be heterozygous for a novel variant, though we note two instances where multiple individuals possessed a novel variant. We also identified novel variable gene alleles that are absent from the Lym1k database, potentially due to challenges in inferring receptor alleles from short-read population sequencing studies. Conclusions: We find evidence for significant human diversity in TCRB variable gene alleles beyond what is currently represented in the IMGT database. TCRB sequencing using multiplex Framework 1 and Constant gene targeting primers is ideally suited for studying the role of TCRB polymorphism in autoimmune disease and immune-mediated adverse events during immunotherapy.
Effect of PDL1 signaling blockade on NK cell cytolytic activity towards ovarian cancer.
Authors: Oyer Jeremiah , Gitto Sarah B. , Altomare Deborah , Igarashi Robert , Copik Alicja
Published: February 2018

13

Background: The PD-1/PDL-1 axis is an immuno-oncology target for abrogating immune suppression. Anti-PD1 targeted mAb therapy has had success in several indications by alleviating suppression of cytolytic T cells. In addition to T cells, NK cells hold promise for adoptive applications for oncology. We developed a nanoparticle based stimulation method for producing large quantities (> 1,000 fold expansion within two weeks) of highly activated NK cells with high anti-tumor cytotoxicity and enhanced cytokine delivery. These NK cells (PM21-NK) release high amounts of IFNγ in response to tumors that stimulates the expression of PDL1 on tumor, which in turn enhances Treg development. Methods: The ability of PM21-NK cells to induce expression of PDL-1 on tumors was tested in vitro and in vivo. Furthermore, the in vivo efficacy of combination treatment of PM21-NK cells and anti-PDL1 was tested in NSG mice models for ovarian cancer. Results: The IFNγ production by PM21-NK cells increased from 1.4% to 9.9% (p < 0.001) upon exposure to SKOV-3 cells. SKOV-3 cells normally do not express PDL1 but PDL1 expression increased with 48 hours exposure to 20 ng/mL IFNγ (0.7% vs 65.1%). In and in vivo experiment, NSG mice intraperitoneally implanted with 1 x 106 SKOV-3 cells were treated with 107 T-cell depleted PM21-NK cells i.p. on days 8 and 13 and 25,000 U IL2 i.p. thrice weekly. Upon euthanization 21 days after tumor seeding, tumors in PM21-NK treated mice had increased PDL1+ tumors vs the untreated group (29.7% vs 14.5%, n = 6, p < 0.0001). Despite T-cell depletion, T-cells made up ~22% of hCD45+ events in perfused tumors, 83% of which were Tregs. In a follow-up survival experiment, combination treatment of anti-PDL1 and NK cells were tested in SKOV-3 implanted NSG mice (as above). Groups of mice were given 107 T-cell depleted PM-NK or vehicle i.p. days 4 and 7 and 25,000 U IL2 3x’s weekly and groups were given 10 mg/kg anti-PDL1 (Atezolizumab) or vehicle ctrl. on day 4 and later 5 mg/kg twice weekly. Untreated and Atezo alone survival were 24 and 23.5 days, respectively. Median survival for PM-NK + Atezo was 48 days compared to 40.5 for PM-NK alone (p = 0.042; n = 8). Conclusions: These data support the use of anti-PDL1 in NK cell therapy regardless of initial tumor PDL1 status.
Use of immune checkpoint inhibitors in a community practice within a vertically integrated health care system.
Authors: Cooper Robert Michael , Yamamoto Christopher , Truong Thach-Giao , Niu Fang , Moon Helen , Spence Michele M. , Chan Jim , Chiu Timothy , Hui Rita L.
Published: February 2018

130

Background: Four immune checkpoint inhibitors have been FDA approved from 2011 to 2016. Immune checkpoint inhibitors function differently from chemotherapy and have different benchmarks for response as well as different side effect profiles. This report examines how oncologists in two large medical groups have introduced these new treatments into their practices. Kaiser Permanente is a large HMO which insures 8.5 million members in the state of California and has an exclusive contract with 2 large medical groups to care for its members. There are over 200 medical oncologists caring for KP members practice at over 35 medical centers. The care of the KP members has been documented in an EPIC based medical record systems since 2006. Methods: The Pharmacy Research Outcomes Group has conducted a retrospective cohort study looking at patients who initiated Checkpoint inhibitors between March 2011 and September 2016 for this review and followed the patients till December 2016. Electronically available data collected for this review includes patient characteristics such as but not exclusive to: cancer diagnosis, previous therapies, current therapies, age, sex, ethnicity, immune related adverse events (IRAEs) proxy by diagnosis code, duration of immunotherapy, use of systemic steroids, Charlson Co-morbity Index and survival. Results: We reviewed a total of 1760 users of Checkpoint Inhibitors. We show the uptake of this class of medications aligns with approved checkpoint inhibitors and the new indications of these agents. We were able to electronically pull medical information and define IRAEs. Our data closely matches the expected incidence of IRAEs as reported in clinical trials. We were also able to monitor the use of steroids in response to these events. Conclusions: The ability to collect and track this information has allowed the group to better understand patient selection practices as well as management practices in the community practice setting.
Two distinct clinical trajectories of inflammatory thyroiditis evoked by checkpoint blockade in malignant melanoma.
Authors: Olsson-Brown Anna Claire , Lord Rosemary , Sacco Joseph J , Coles Mark Christopher , Wagg Jonathan , Pirmohamed Munir
Published: February 2018

131

Background: Oncological immune checkpoint inhibitors (CPI) commonly cause immune related adverse events (irAEs). Thyroid irAEs have a significant clinical impact requiring therapeutic intervention and clinical coordination whilst often causing treatment delays. Methods: Retrospective review of all patients treated with CPIs (pembrolizumab, nivolumab +/- ipilimumab) for metastatic melanoma at the Clatterbridge Cancer Centre, UK identified patients experiencing thyroid irAEs. Clinical/biochemical course (T4 and thyroid stimulating hormone (TSH) levels) and autoantibody titers were evaluated to identify characterisable trajectories. Results: From February 2016 to May 2017, 103 patients received anti-PD1 therapy; 90 receiving monotherapy and 13 combination. Thyroid irAEs were seen in 13(14.4%) and 3(23%) patients respectively. Two distinct trajectories were identified: a hyperthyroid phase with subsequent hypothyroidism (HH) and de novo hypothyroidism (DN). There were no outliers. HH was the predominant pattern (75%) and the sole manifestation in combination therapy. In the HH cohort 69% of patients were female. The peak T4 was 39.3pmol/L occurring, on average, 7.5 weeks after CPI initiation. T4 levels declined within 6-21 days and hypothyroidism occurred within 8 weeks. The DN cohort was exclusively female. Thyroid irAE occurred 12 weeks after CPI initiation. Baseline TSH in HH (2.49mU/l) was significantly lower than DN (5.77mU/l); p = 0.0092. Positive thyroid autoantibodies were detected in 5 patients across both groups. One patient (HH) had symptomatic thyroid dysfunction. Corticosteroids conveyed no benefit. All patients had permanent dysfunction requiring long term levothyroxine replacement. All continued with immunotherapy treatment; however notable irAE-related treatment hiatuses occurred. Conclusions: Retrospective review revealed two distinct thyroid irAE trajectories, HH and DN. The trajectories may have biochemical predictors, are rarely associated with symptoms and appear unrelated to thyroid autoantibodies. Trajectory identification will optimise patient outcomes, reduce ineffective steroid use and promote early hormone replacement.
Intestinal microbiota to predict risk for immune-related diarrhea in patients with lung cancer patients.
Authors: Liu Tian , Hu Yi
Published: February 2018

132

Background: Anti-programmed cell death 1 (PD-1) inhibitors, which enhance cellular immunity via blockade of PD-1, represent an effective option for the treatment of lung cancer and have shown some impressive efficacy. However, the inhibitors can also result in immune-related adverse events, such as immune-related diarrhea. Researches have shown that intestinal microbiota plays a vital role in gastrointestinal dysregulation. Whereas, the relationship between PD-1 inhibitors and immune-related diarrhea is still elusive. In our study, we aim to identify the correlation of intestinal microbiota and immune-related diarrhea, and hope to find specific bacteria as potential biomarkers of immune-related diarrhea. Methods: Twenty-six lung cancer patients who were treated with PD-1 inhibitors from 301 hospital were enrolled for retrospective analysis. And the fecal samples were obtained from patients before the first dose of PD-1 inhibitor. Based on whether they develop diarrhea or not, the patients were subgroup into progressed to diarrhea(PtD) group and diarrhea-free(D-F) group. Immune-related diarrhea was graded according to the National Cancer Institute Common Toxicity Criteria (CTC, version 4.0). And 16S rRNA sequencing was used to profile fecal bacterial composition. Results: There was no significant difference in baseline characteristics, such as microbial richness between PtD group and D-F group (P > 0.05). However, At the phylum level, Bacteroidetes were richer in D-F group, while Firmicutes were poorer, than that in PtD group. At the genus level, two families of the Bacteroidetes phylum ( Bacteroides and Parabacteroides) and a family of the Firmicutes phylum (Phascolarctobacterium) were more abundant in D-F group. Veillonella from Proteobacteria phylum was lower in D-F group than that in PtD group (all P < 0.05). Conclusions: Our study indicates that microbiota variation probably participates in the onset of immune-related diarrhea. Identifying these biomarkers may help us to diagnose the side effect earlier, and provides a novel treatment for immune-related diarrhea due to PD-1 inhibitors.
Characterization of progressive multifocal leukoencephalopathy (PML) in patients treated with rituximab, brentuximab and ibrutinib: A report from the Southern Oncology Network on Adverse Reactions (SONAR).
Authors: Kommalapati Anuhya , Tella Sri Harsha , Bennett Charles L.
Published: February 2018

133

Background: Since the advent of Rituximab (R) in 1997, cancer immunotherapy is increasingly used for management of lymphoproliferative disorders. Unexpected cases of PML have been reported in HIV-negative patients in 2005 receiving Rituximab ( R) and subsequently in 2012 and 2014, who received brentuximab vedotin ( B) or ibrutinib ( I), respectively. We sought to compare and contrast clinical characteristics and outcomes of PML in HIV-negative patients who were treated with R, B or I therapy. Methods: Retrospective analysis of the FDA adverse event reporting system (FAERS) and previously published data by our group with confirmed cases of PML associated with R (1997-2008), B and I therapy (2009-2015). Results: PML develops early during the therapy with B and I, compared to that of R group. Confirmation of the diagnosis of PML by MRI in conjunction with JC virus identification in the cerebrospinal fluid or brain biopsy using objective criteria was found only in 40-60% of the cases. Among confirmed cases of R, I, or B-associated PML, mortality was > 90%, usually occurring within weeks to months following diagnostic confirmation. Rare cases of survival were associated with return of immunologic function, including in one case development of an immune reconstitution syndrome. Conclusions: This is the first study that compared the clinical characteristics of PML in R, B and I. PML cases can occur early during the therapy using B and I, while usually occurs late with R. Additional research is needed to quantify the risk factors of PML and to know if this association is causal or incidental. Meanwhile, physicians and patients should be vigilant in detecting and reporting this rare AE to minimize future fatalities [Table: see text]
Immune-related adverse events requiring inpatient management: Spectrum of toxicity, treatment, and outcomes.
Authors: Balaji Aanika , Zhang Jiajia , Marrone Kristen , Elmariah Hany , Yarchoan Mark , Holdhoff Matthias , Zimmerman Jacquelyn W. , Hajjir Khalid , Armstrong Deborah Kay , Laheru Daniel A. , Mehra Ranee , Ho Won Jin , Reuss Joshua E. , Heng Joseph , Vellanki Paz , Naidoo Jarushka
Published: February 2018

138

Background: Immune checkpoint inhibitors (ICIs) are anti-cancer agents now in routine clinical practice, and may cause immune-related adverse events (irAEs). The proportion of inpatient admissions for irAEs, spectrum of toxicities, management and outcomes are not well described. Methods: Patients with solid tumors admitted to the inpatient oncology service at a tertiary academic center over 3 months, were identified. Patient demographics, treatment details, irAE event and management data, were collected for those who received ICIs, in an IRB-approved database. The diagnosis of irAEs was confirmed by the treating physician and oncologist. Associations between clinical details and irAEs were evaluated using Fisher's exact test. Results: We identified 240 inpatient oncology patients: 53 (22.1%) had received ICIs, and 25% (13/53) were admitted for irAEs. The majority of irAEs requiring admission were high grade (CTCAE grade 1-2: 6/13, 46%; grade 3+: 7/13, 54%), and included: colitis (31%), pneumonitis (23%), skin rash (8%), fever (8%), pancreatitis (8%), fatigue (8%), and renal transplant rejection (8%). Treatment for irAEs included: ICI withhold (2/13, 15%), oral/IV corticosteroids (10/13, 76%), and infliximab (1/13, 8%); with 85% of patients requiring subspecialty consultations. Those with irAEs had a shorter median length of stay vs. other inpatients (5 vs. 6 days). Most irAEs resolved/improved (11/13, 85%), while 15% worsened (1/13) or resulted in patient death (1/13). There was a numerically higher risk of any/grade3+ irAEs for those: treated with combination vs monotherapy (33% vs 23%; 100% vs 40%), age > 65 vs < 65 (33% vs 15%; 56% vs 50%), and former/current vs. never smokers (31% vs 19%; 63% vs 40%), however differences were not statistically significant. Conclusions: Patients with irAEs constitute a notable proportion of inpatient oncology admissions, with a higher incidence than in reported clinical trials. Initial data suggest that patients treated with combination ICIs, aged > 65, and former/current smokers may be more likely to be admitted for irAEs. The majority of irAE admissions require subspecialty consultations, signifying a growing need for multidisciplinary irAE management.
Consideration of the concordance rate of 22C3 and 28-8 antibody in NSCLC and its relation to the effect of nivolumab.
Authors: Kibata Kayoko , Kurata Takayasu , Takeyasu Yuki , Niki Maiko , Satsutani Naoko Murakami , Ogata Makoto , Yoshioka Hiroshige , Saito Tomohito , Murakawa Tomohiro , Tsuta Koji , Nomura Shosaku
Published: February 2018

143

Background: Anti-PD-1 antibodies (Abs) have improved survival significantly in patients (pts) with advanced non-small cell lung cancer (NSCLC). Depending on the extent of PD-L1 expression, these drugs have become the standard care of initial treatment and 2nd line therapy. However, PD-L1 expression has not yet been recognized as a robust biomarker. Currently, two Anti-PD-1 Abs (Nivolumab, Pembrolizumab) are commercially available in Japan, but have each diagnostic immunohistochemical (IHC) assays (22C3 and 28-8Ab), respectively. The concordance rate of these assays is not yet well understood and the effect of these agents in concordance and inconsistency cases are also unknown. Based on these background, we explored the concordance rate of 22C3 and 28-8 Ab and its relation with the effect of Nivolumab (Nivo). Methods: We investigated the concordance rate of 22C3 and 28-8 as well as treatment effect and response of 24 advanced NSCLC pts treated in Kansai Medical University Hospital from December 2015 and May 2017. All pts had been tumor biopsy for pathologically immunostained and received Nivo at least once. We compared the PD-L1 expression levels of two IHC assays with 22C3 and 28-8Ab measured in different laboratories independently. Results: Pts’ characteristics included adenocarcinoma in 12 pts, squamous cell carcinoma in 11, and others in 1 pts, respectively. In IHC reaction with 22C3Ab, 58.3% and 29.2% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells and with 28-8Ab, 37.5% and 16.7% of pts expressed PD-L1 on ≥1% and ≥50% of tumor cells, respectively. Of 24 cases, 1 case experienced CR, 5 cases PR. In CR case, expression level was dissociated at 50% with 22C3 and 5% with 28-8. In PR cases, 2 cases had high expression in both, and 2 cases had moderate expression in both assays. However, the remaining one was dissociated as moderate in 22C3 Ab and negative in 28-8. All PD pts expressed 0% with both of the two Abs. Conclusions: Although the number of cases is small, the concordance rate of the two Abs in advanced NSCLC cases is not necessarily high, but the agreement rate in response cases was likely to be high. As both 0% cases were ineffective, measuring with two Abs may be useful for forecasting invalid cases.
Targeting CD38 to improve anti-PD-1/CTLA-4 combination therapy in lung cancer.
Authors: Chen Limo , Li Yanli , Yi Xiaohui , Gibbons Don Lynn
Published: February 2018

144

Background: The combination of anti-PD-1 and anti-CTLA-4 is a promising strategy that is being clinically explored to treat a variety of cancer types. Some patients display primary resistance to this combination treatment, while others relapse after treatment. Although some cancer patients have long-term durable responses to the combination therapy of anti-PD-1 and anti-CTLA-4, physicians have been looking for biomarkers that predict response. Methods: Using multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the mechanisms of resistance to anti-PD-1/CTLA-4 combination therapy by evaluating the molecular and cellular immune profiles of the tumor microenvironment. Antibody-mediated cell depletion assays were also conducted to validate the mechanisms. Lastly, to determine the applicability to patients, we analyzed 791 lung cancer patients’ specimens with immunohistochemistry staining and mined many immune markers in multiple large independent patient databases (~1900 tumors). Results: We observed that tumor bearing mice treated with combined PD-1 and CTLA-4 blocking antibodies developed resistance through the up-regulation of CD38, and that targeting CD38 abolished the resistance in a manner dependent on B7-costimulation. Additionally, combined PD-1 and CTLA-4 blockade eradicates CD38-deficient tumors in mice. Further study revealed that control of tumors by triple blockade of CD38, PD-1, and CTLA-4 depended on improved functionality of CD4+/CD8+ TILs, which were reactivated by enriched CD103+ dendritic cells in the tumor microenvironment. Pathologic analysis revealed positive immunohistochemical staining for CD38 on tumor cells in 15-23% of cases and bioinformatic analyses revealed a strong correlation between CD38 expression and an immune inflammatory signature. Conclusions: Targeting CD38 improves the efficacy of anti-PD-1/CTLA-4 combination therapy in lung cancer. CD38 on tumor cells could potentially serve as a novel biomarker of resistance for immune checkpoint inhibition.