bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA08: Immune checkpoint blockade in cancer therapy: New insights, opportunities, and prospects for cures
Authors: Allison James P. 
Published: March 2017

Abstract
The existence of multiple non-redundant inhibitory pathways that limit T cell responses offers novel strategies for mobilizing the immune system to attack cancer cells. The best characterized of these immune checkpoints is CTLA-4, which inhibits T cell proliferation by interfering with the interaction of the costimulatory molecule CD28 with its ligands B7-1 and B7-2 on the surface of antigen presenting cells. Antibodies to CTLA-4 have proven effective against multiple tumor types in both pre-clinical and clinical studies. Ipilimumab, an antibody to human CTLA-4, showed long term (&gt;4 years) survival benefit in about 20% of patients in a randomized, placebo-controlled trial in late stage melanoma. In 2011 it was approved by the FDA for treatment of late stage melanoma and is now a standard of care for that disease.
The mechanism(s) of action of anti-CTLA-4 are still being elucidated. We and others have shown that CLTA-4 limits T cell proliferation by a cell intrinsic mechanism. However, there is also evidence that anti-CTLA-4 has to engage the target on both effector (Teff) and regulatory (Treg) T cells. Thus anti-CTLA-4 exerts its anti-tumor effects by multiple mechanisms.
PD-1, another checkpoint, recruits a phosphatase and seems to interfere with T cell antigen receptor mediated signaling. It has two ligands, PD-L1 and PD-L2, which are both expressed on dendritic cells. However, many tumor cells also express PD-L1. Antibodies to PD-1 and PD-L1 have both shown objective responses against several tumor types in clinical trials with response rates of about 25%. A recent phase II trial of a combination of anti-PD-1 and anti-CTLA-4 in melanoma showed objective responses in about 50% of late stage melanoma patients.
Emerging data suggest that T cell responses are largely directed toward neoantigens arising as a result of mutational events associated with the carcinogenesis. While all tumors with antigens recognizable by the immune system should be targets for checkpoint blockade, it is becoming clear that certain types of tumors with lower burdens of mutations (e.g. prostate, breast, and kidney cancer) present special challenges for immune therapy. Strategies for effective treatment of such tumors will be discussed.
Citation Format: James P. Allison. Immune checkpoint blockade in cancer therapy: New insights, opportunities, and prospects for cures. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA08.
Abstract IA17: Technologies for personalizing cancer immunotherapies
Authors: Peng Songming , Zaretsky Jesse , Bethune Michael , Hsu Alice , Heath John E. , Noh Won Jun , Esswein Shannon , Ribas Antoni , Baltimore David , Heath James R. 
Published: March 2017

Abstract
At the heart of most cancer immunotherapies are the specific interactions between tumor-infiltrating T cells, and the antigens that attract those T cells into the tumor. It has become increasingly apparent that (mutation containing) neoantigens likely play an important role in this regard. Putative neoantigens are identified by tumor exome analysis, but finding which of those candidates actually promote T cell tumor infiltration is challenging, as is pairing such antigens with the cognate T cell receptor (TCR) genes. Technologies that can address this challenge can help pave the way for personalized immunotherapies. For example, the active neoantigens can be engineered into personalized cell-based cancer vaccines, while the cognate TCRs represent engineered T cell therapy opportunities. I will discuss a nanotech/microchip tool that we have recently developed to address this challenge. The platform allows for the non-destructive enumeration of neoantigen specific T cell populations from either tumor infiltrating lymphocytes (TILs) or unexpanded peripheral blood mononuclear cells (PBMCs), beginning with as few as 10,000 CD8+ cells. I will discuss the application of the platform for kinetic studies of patient responses to checkpoint inhibitor therapy (via blood analysis), as well as applications for matching neoantigen-specificity with T cell receptor genes. I will also discuss how the resultant data can be used to guide the refinement of neoantigen prediction algorithms.
Citation Format: Songming Peng, Jesse Zaretsky, Michael Bethune, Alice Hsu, John E. Heath, Won Jun Noh, Shannon Esswein, Antoni Ribas, David Baltimore, James R. Heath. Technologies for personalizing cancer immunotherapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA17.
Abstract IA27: T-cell transfer therapy targeting somatic mutations in human gastrointestinal cancers
Authors: Tran Eric 
Published: March 2017

Abstract
Accumulating correlative evidence suggests that the clinical responses observed in some patients with cancer after treatment with checkpoint inhibitors or adoptive T-cell therapy are mediated by T cells that target cancer mutations. More direct evidence that mutation-reactive T cells can mediate antitumor activity in humans was recently demonstrated in a patient with metastatic cholangiocarcinoma who experienced tumor regression after receiving a highly enriched population CD4+ T cells targeting a mutation in the ERBB2IP protein uniquely expressed by her cancer. Thus, strategies to identify and harness the mutation-reactive T-cell response may provide clinical benefit to some patients with cancer. To this end, we used a next-generation sequencing approach combined with high-throughput immunologic screening and found that tumor-infiltrating lymphocytes (TIL) from 29/32 patients with metastatic gastrointestinal (GI) cancers contained CD4+ and/or CD8+ T cells that recognized at least one neoepitope derived from somatic mutations expressed by the patient's own tumor. Most of the immunogenic mutations were unique and patient specific, however we also identified HLA-C*08:02-restricted CD8+ T cells from two patients with colorectal cancer that targeted the KRASG12D hotspot driver mutation found in many human cancers. Treatment of one of these patients with ~1.1 x 1011 KRASG12D-reactive T cells led to the regression of all metastatic lesions, but one lesion progressed 9 months after therapy. This lesion was resected and found to have loss of the chromosome 6 haplotype that encoded the HLA-C*08:02 allele thereby providing the tumor with a direct mechanism of immune escape from the transferred HLA-C*08:02-restricted KRASG12D-reactive T cells. The treatment of ten additional patients with variable frequencies of TIL targeting predominantly one patient-specific mutation has been largely ineffective. Thus, TIL therapy targeting somatic mutations can mediate tumor regression in some patients with metastatic GI cancers but most patients have not responded. We are currently investigating strategies to enhance the efficacy of T-cell transfer therapy against cancer mutations.
Citation Format: Eric Tran. T-cell transfer therapy targeting somatic mutations in human gastrointestinal cancers. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr IA27.
Abstract PR02: Antigen delivery targeting tumor-infiltrating macrophages leads to eradication of tumor highly resistant to immune checkpoint inhibitors
Authors: Muraoka Daisuke , Harada Naozumi , Seo Naohiro , Hayashi Tae , Fujii Keisuke , Yamaguchi Rui , Imoto Seiya , Miyano Satoru , Yagita Hideo , Akiyoshi Kazunari , Shiku Hiroshi 
Published: March 2017

Abstract
Recently, immune checkpoint inhibitors using anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies has been emerging as novel, effective modality for the treatment of cancer. However, immune checkpoint inhibitors have been proven to be effective only for a partial group of patients who have lymphocyte infiltration or inflammation in the tumor microenvironment prior to the treatment. Although the relationship between efficacy of checkpoint inhibitors and anti-tumor cellular immune response has been revealed, these studies paid attention only for the induction of immune responses in lymph node and do not pay attention to the mechanisms regulating the anti-tumor cellular immune responses in tumor site. In this study, by using checkpoint inhibitors-sensitive or resistant murine in vivo tumors, we explored a mechanism underlying the resistance focusing on immune cells at the tumor site. We newly identified CD11b+/F4/80+ tumor-associated macrophages as a key factor highly correlated to the resistance. In the resistant tumor, tumor-associated macrophages remained immature and did not exert antigen-presenting activity. A nanogel-based antigen delivery system enabled to selectively and efficiently deliver a long peptide antigen to tumor-associated macrophages. Co-administration of the nanogel:long peptide antigen and TLR agonist activated tumor-associated macrophages and induced antigen presentation by these cells. This change in the tumor microenvironment turned the resistant tumor to treatment-sensitive, in particular, adoptive transfer of TCR-engineered T cells after the treatment with nanogel:long peptide antigen and TLR agonist resulted in the cure of resistant tumor. These results indicate that the status and function of tumor-associated macrophages have a great impact on treatment sensitivity, and that these cells might be a promising target to improve the efficacy of immunotherapy including checkpoint inhibitors and adoptive cell therapies.
This abstract is also being presented as Poster B68.
Citation Format: Daisuke Muraoka, Naozumi Harada, Naohiro Seo, Tae Hayashi, Keisuke Fujii, Rui Yamaguchi, Seiya Imoto, Satoru Miyano, Hideo Yagita, Kazunari Akiyoshi, Hiroshi Shiku. Antigen delivery targeting tumor-infiltrating macrophages leads to eradication of tumor highly resistant to immune checkpoint inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr PR02.
Rac1 Pharmacological Inhibition Rescues Human Endothelial Dysfunction
Authors: Carrizzo Albino , Vecchione Carmine , Damato Antonio , di Nonno Flavio , Ambrosio Mariateresa , Pompeo Franco , Cappello Enrico , Capocci Luca , Peruzzi Mariangela , Valenti Valentina , Biondi‐Zoccai Giuseppe , Marullo Antonino G. M. , Palmerio Silvia , Carnevale Roberto , Spinelli Chiara C. , Puca Annibale A. , Rubattu Speranza , Volpe Massimo , Sadoshima Junichi , Frati Giacomo , Sciarretta Sebastiano 
Published: March 2017

Background

Endothelial dysfunction contributes significantly to the development of vascular diseases. However, a therapy able to reduce this derangement still needs to be identified. We evaluated the effects of pharmacological inhibition of Rac1, a small
GTP
ase protein promoting oxidative stress, in human endothelial dysfunction.

Methods and Results

We performed vascular reactivity studies to test the effects of
NSC
23766, a Rac1 inhibitor, on endothelium‐dependent vasorelaxation of saphenous vein segments collected from 85 subjects who had undergone surgery for venous insufficiency and from 11 patients who had undergone peripheral vascular surgery. The endothelium‐dependent vasorelaxation of the varicose segments of saphenous veins collected from patients with venous insufficiency was markedly impaired and was also significantly lower than that observed in control nonvaricose vein tracts from the same veins. Rac1 activity, reactive oxygen species levels, and reduced nicotine adenine dinucleotide phosphate (
NADPH
) oxidase activity were significantly increased in varicose veins, and
NSC
23766 was able to significantly improve endothelium‐dependent vasorelaxation of dysfunctional saphenous vein portions in a nitric oxide–dependent manner. These effects were paralleled by a significant reduction of
NADPH
oxidase activity and activation of endothelial nitric oxide synthase. Finally, we further corroborated this data by demonstrating that Rac1 inhibition significantly improves venous endothelial function and reduces
NADPH
oxidase activity in saphenous vein grafts harvested from patients with vascular diseases undergoing peripheral bypass surgery.

Conclusions
Rac1 pharmacological inhibition rescues endothelial function and reduces oxidative stress in dysfunctional veins. Rac1 inhibition may represent a potential therapeutic intervention to reduce human endothelial dysfunction and subsequently vascular diseases in various clinical settings.
Renal Denervation in the Acute Phase of Ischemic Stroke Provides Brain Protection in Hypertensive Rats
Authors: Hasegawa Yu , Nakagawa Takashi , Matsui Kunihiko , Kim-Mitsuyama Shokei 
Published: March 2017

Background and Purpose—
Renal denervation (RD) may protect against cardiovascular diseases regardless of blood pressure (BP)–lowering effect. We hypothesized that RD can improve the outcome of acute ischemic stroke (AIS) in hypertensive rats.

Methods—
An AIS model of spontaneously hypertensive stroke-prone rats (SHRSPs) was prepared by 90-minute middle cerebral artery occlusion followed by reperfusion. At 30 minutes poststroke, the SHRSPs were subjected to (1) sham operation or (2) RD to determine the beneficial effects of RD posttreatment. In addition, we evaluated the neuroprotective effects of RD posttreatment in Wistar Kyoto rats and RD pretreatment in SHRSPs with AIS.

Results—

RD significantly ameliorated neurological deficit and infarct volume at 1 and 7 days after middle cerebral artery occlusion. RD immediately and continuously normalized elevated BP during 24 hours. This normalization of BP by RD was associated with the reduction of cerebral blood flow during both middle cerebral artery occlusion and reperfusion periods. Thus, RD-induced BP normalization seems to ameliorate cerebrovascular overperfusion in SHRSPs with AIS. On the contrary, RD did not affect cerebral vascular resistance or cerebral vasoreactivity and did not increase Akt and endothelial NO synthase phosphorylation, thereby indicating no apparent change of cerebrovascular function. RD significantly attenuated cerebral oxidative stress as estimated by dihydroethidium staining and gp91
phox
expression. The beneficial effects were not seen in Wistar Kyoto rats, whereas RD pretreatment improved neurological function in SHRSPs.

Conclusions—
RD posttreatment improved outcome in the hypertensive AIS rat model. Therefore, we suggest that BP normalization by RD may be a promising therapeutic strategy for AIS.
A Case Study of Cloud Radar Observations and Large-Eddy Simulations of a Shallow Stratiform Orographic Cloud, and the Impact of Glaciogenic Seeding
Authors: Chu Xia , Geerts Bart , Xue Lulin , Pokharel Binod 
Published: March 2017

AbstractThe impact of glaciogenic seeding on precipitation remains uncertain, mainly because of the noisy nature of precipitation. Operational seeding programs often target cold-season orographic clouds because of their abundance of supercooled liquid water. Such clouds are complicated because of common natural seeding from above (seeder–feeder effect) or from below (blowing snow). Here, observations, mainly from a profiling airborne Doppler radar, and numerical simulations are used to examine the impact of glaciogenic seeding on a very shallow (<1 km), largely blocked cloud that is not naturally seeded from aloft or from below. This cloud has limited but persistent supercooled liquid water, a cloud-base (top) temperature of −12°C (−16°C), and produces only very light snowfall naturally. A Weather Research and Forecasting Model large-eddy simulation at 100-m resolution captures the observed upstream stability and wind profiles and reproduces the essential characteristics of the orographic flow, cloud, and precipitation. Both observations and simulations indicate that seeding locally increases radar (or computed) reflectivity in the target area, even after removal of the natural trend between these two periods in a nearby control region. A model sensitivity run suggests that seeding effectively glaciates the mostly liquid cloud and substantially increases snowfall within the seeding plume. This is due to a dramatic increase in the number of ice particles and not to their size. The increased ice particle concentration facilitates snow growth by vapor deposition in a cloud the temperature range of which is conducive to the Bergeron process.
Comments on “On the Choice of Average Solar Zenith Angle”
Authors: Li Jiangnan 
Published: March 2017

Abstract
The daytime-mean solar zenith angle (SZA) and the solar insolation–weighted-mean SZA are discussed from a global scale and from a latitude-dependent local-scale perspective. It is found that the choosing of daytime-mean SZA or insolation-weighted-mean SZA depends on whether the averaging process is zero-moment or single-moment weighted. It is a misleading to state that the solar insolation–weighted-mean SZA is more accurate than the daytime-mean SZA when averaging a radiation variable, as claimed by Cronin.
The Equivalent Barotropic Structure of Waves in the Tropical Atmosphere in the Western Hemisphere
Authors: Yang Gui-Ying , Hoskins Brian J. 
Published: March 2017

Abstract
Tropical waves are generally considered to have a baroclinic structure. However, analysis of ERA-Interim and NOAA OLR data for the period 1979–2010 shows that in the equatorial and Northern Hemisphere near-equatorial regions in the tropical Western Hemisphere (WH), westward- and eastward-moving transients, with zonal wavenumbers 2–10 and periods of 2–30 days, have little tilt in the vertical and can be said to be equivalent barotropic. The westward-moving transients in the equatorial region have large projections onto the westward mixed Rossby–gravity (WMRG) wave and those in the near-equatorial region project onto the gravest Rossby wave and also the WMRG. The eastward-moving transients have large projections onto the Doppler-shifted eastward-moving versions of these waves.
To examine how such equivalent barotropic structures are possible in the tropics, terms in the vorticity equation are analyzed. It is deduced that waves must have westward intrinsic phase speeds and can exist in the WH with its large westerly vertical shear. Throughout the depth, the advection of vorticity by the zonal flow and the β term are large and nearly cancel. In the upper troposphere the zonal advection by the strong westerly flow wins and the residual is partially balanced by vortex shrinking associated with divergence above a region of ascent. Below the region of ascent the β term wins and is partially balanced by vortex stretching associated with the convergence. An equivalent barotropic structure is therefore maintained in a similar manner to higher latitudes. The regions of ascent are usually associated with deep convection and, consistently, WH waves directly connected to tropical convection are also found to be equivalent barotropic.
Examination of Mixed-Phase Precipitation Forecasts from the High-Resolution Rapid Refresh Model Using Surface Observations and Sounding Data
Authors: Ikeda Kyoko , Steiner Matthias , Thompson Gregory 
Published: March 2017

Abstract
Accurate prediction of mixed-phase precipitation remains challenging for numerical weather prediction models even at high resolution and with a sophisticated explicit microphysics scheme and diagnostic algorithm to designate the surface precipitation type. Since mixed-phase winter weather precipitation can damage infrastructure and produce significant disruptions to air and road travel, incorrect surface precipitation phase forecasts can have major consequences for local and statewide decision-makers as well as the general public. Building upon earlier work, this study examines the High-Resolution Rapid Refresh (HRRR) model’s ability to forecast the surface precipitation phase, with a particular focus on model-predicted vertical temperature profiles associated with mixed-phase precipitation, using upper-air sounding observations as well as the Automated Surface Observing Systems (ASOS) and Meteorological Phenomena Identification Near the Ground (mPING) observations. The analyses concentrate on regions of mixed-phase precipitation from two winter season events. The results show that when both the observational and model data indicated mixed-phase precipitation at the surface, the model represents the observed temperature profile well. Overall, cases where the model predicted rain but the observations indicated mixed-phase precipitation generally show a model surface temperature bias of &lt;2°C and a vertical temperature profile similar to the sounding observations. However, the surface temperature bias was ~4°C in weather systems involving cold-air damming in the eastern United States, resulting in an incorrect surface precipitation phase or the duration (areal coverage) of freezing rain being much shorter (smaller) than the observation. Cases with predicted snow in regions of observed mixed-phase precipitation present subtle difference in the elevated layer with temperatures near 0°C and the near-surface layer.
Tropical Cyclone Gale Wind Radii Estimates for the Western North Pacific
Authors: Sampson Charles R. , Fukada Edward M. , Knaff John A. , Strahl Brian R. , Brennan Michael J. , Marchok Timothy 
Published: March 2017

Abstract
The Joint Typhoon Warning Center’s (JTWC) forecast improvement goals include reducing 34-kt (1 kt = 0.514 m s−1) wind radii forecast errors, so accurate real-time estimates and postseason analysis of the 34-kt wind radii are critical to reaching this goal. Accurate real-time 34-kt wind radii estimates are also critical for decisions regarding base preparedness and asset protection, but still represent a significant operational challenge at JTWC for several reasons. These reasons include a paucity of observations, the timeliness and availability of guidance, a lack of analysis tools, and a perceived shortage of personnel to perform the analysis; however, the number of available objective wind radii estimates is expanding, and the topic of estimating 34-kt wind radii warrants revisiting. In this work an equally weighted mean of real-time 34-kt wind radii objective estimates that provides real-time, routine operational guidance is described. This objective method is also used to retrospectively produce a 2-yr (2014–15) 34-kt wind radii objective analysis, the results of which compare favorably to the postseason National Hurricane Center data (i.e., the best tracks), and a newly created best-track dataset for the western North Pacific seasons. This equally weighted mean, when compared with the individual 34-kt wind radii estimate methods, is shown to have among the lowest mean absolute errors and smallest biases. In an ancillary finding, the western North Pacific basin average 34-kt wind radii calculated from the 2014–15 seasons are estimated to be 134 n mi (1 n mi = 1.852 km), which is larger than the estimates for storms in either the Atlantic (95 n mi) or eastern North Pacific (82 n mi) basins for the same years.