bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B89: The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models
Authors: Kato Yukinari , Shiina Satoshi , Natsume Atsushi , Abe Shinji , Nishioka Yasuhiko , Ogasawara Satoshi , Kaneko Mika K.
Published: March 2017

Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, which is expressed in lymphatic endothelium. PDPN is also highly expressed in many cancers such as malignant pleural mesothelioma (MPM), lung cancer, and malignant brain tumors including glioblastoma (GBM). We previously developed a rat anti-PDPN monoclonal antibody NZ-1 (rat IgG2a, lambda), and a rat-human chimeric anti-PDPN antibody NZ-8 (human IgG1, kappa), which induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against PDPN-positive cancer cells. Firstly, we demonstrated the antitumor effect of not only NZ-1/NZ-8 but also NZ-12 (human IgG1, lambda), a novel rat-human chimeric anti-PDPN antibody derived from NZ-1, in an MPM orthotopic xenograft SCID mouse model. Treatment with NZ-1 and rat NK (CD161a+) cells inhibited the growth of tumors and the production of pleural effusion in NCI-H290/PDPN or NCI-H226 orthotopic xenograft mouse models. NZ-8 and human NK (CD56+) cells also inhibited tumor growth and pleural effusion in MPM orthotopic xenograft mice. Moreover, NZ-12 induced potent ADCC mediated by human MNC, compared with NZ-1/NZ-8. Antitumor effects were observed following treatment with NZ-12 and human NK (CD56+) cells in MPM orthotopic xenograft mice. Secondly, we constructed a lentiviral vector expressing chimeric antigen receptor (CAR) comprising NZ-1-based single chain variable fragment (scFv) with CD28, 4-1BB, and CD3zeta intracellular domains. CAR-transduced peripheral blood monocytes (PBMCs) were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. Taken together, PDPN-targeting antibody therapy or PDPN-targeting CAR T cell therapy might provide an efficacious therapeutic strategy for the treatment of MPM or GBM.

Citation Format: Yukinari Kato, Satoshi Shiina, Atsushi Natsume, Shinji Abe, Yasuhiko Nishioka, Satoshi Ogasawara, Mika K. Kaneko. The chimeric antibody NZ-12 or CAR T cells targeting human podoplanin possesses antitumor activity against orthotopic xenograft models. [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 B89.
Abstract IA03: Anti-tumor T cells: You are what you eat
Authors: Cui Guoliang , Ho Ping-Chih , Amezquita Robert , Kaech Susan M.
Published: March 2017

Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. In contrast, resting memory CD8 T cells depend less on high rates of glycolysis and more on fatty acid oxidation to persist, self-renew and respond to secondary infection. This talk will discuss the concept of metabolic checkpoints for immune cells in tumors, referring to the idea that the nutrients utilized by different types of T cells can affect both their energetic demands and their functionality. In particular, the metabolic state of exhausted T cells found in tumors is only recently starting to be studied. Our data in mouse models of cancer suggest that a glucose-poor, fatty acid-rich tumor microenvironment limits aerobic glycolysis, but promotes fatty acid uptake in tumor-infiltrating T cells, which suppresses tumoricidal effector functions and increases PD-1 expression. This talk will discuss recent analyses of the signaling pathways that respond to these nutrient alterations in T cells in tumors and how this may relate to new modalities of treatment in combination with checkpoint blockade.

Citation Format: Guoliang Cui, Ping-Chih Ho, Robert Amezquita, Susan M. Kaech. Anti-tumor T cells: You are what you eat. [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 IA03.
Abstract IA08: Immune checkpoint blockade in cancer therapy: New insights, opportunities, and prospects for cures
Authors: Allison James P.
Published: March 2017

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 (>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

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

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

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.
Crosstalk between Bile Acids and Gut Microbiota and Its Impact on Farnesoid X Receptor Signalling
Authors: Wahlström Annika , Kovatcheva-Datchary Petia , Ståhlman Marcus , Bäckhed Fredrik , Marschall Hanns-Ulrich
Published: March 2017

Background: The gut microbiota has a substantial impact on health and disease. The human gut microbiota influences the development and progression of metabolic diseases; however, the underlying mechanisms are not fully understood. The nuclear farnesoid X receptor (FXR), which regulates bile acid homeostasis and glucose and lipid metabolism, is activated by primary human and murine bile acids, chenodeoxycholic acid and cholic acid, while rodent specific primary bile acids tauromuricholic acids antagonise FXR activation. The gut microbiota deconjugates and subsequently metabolises primary bile acids into secondary bile acids in the gut and thereby changes FXR activation and signalling. Key Message: Mouse models have been used to study the crosstalk between bile acids and the gut microbiota, but the substantial differences in bile acid composition between humans and mice need to be considered when interpreting data from such studies and for the development of so-called humanised mouse models. Conclusion: It is of special importance to elucidate how a human gut microbiota influences bile acid composition and FXR signalling in colonised mice.
Dialysis Requirement and Long-Term Major Adverse Cardiovascular Events in Patients with Chronic Kidney Disease and Superimposed Acute Kidney Injury
Authors: Omotoso Bolanle A. , Turgut Faruk , Abdel-Rahman Emaad M. , Xin Wenjun , Ma Jennie Z. , Scully Kenneth W. , Arogundade Fatiu A. , Balogun Rasheed A.
Published: March 2017

Background: Chronic kidney disease (CKD) patients who experience superimposed acute kidney injury (AKI) have been shown to be at higher risk of long-term sequelae of AKI when compared to those who do not experience AKI. It remains unclear whether the need for temporary dialysis intervention following superimposed AKI in patients with CKD has any effect on the long-term major adverse cardiovascular events (MACE). This study examines the relationship between temporary dialysis therapy following AKI and long-term major cardiovascular events in patients with background CKD. Methods: The study population consists of adults who developed AKI while on admission at the University of Virginia Medical Center between January 1, 2002 and December 31, 2012, and who had preadmission estimated glomerular filtration rate (eGFR) between 20 and 60 mL/min/1.73 m2 and survived beyond 30 days of AKI. Demographic and baseline clinical variables were used to generate propensity score. Survivors who had temporary dialysis were matched to those managed conservatively according to the propensity score in a ratio of 1:3. Results: Overall, 6,634 (n = 381 and 6,253 in the temporary dialysis-requiring AKI and non-dialysis AKI groups respectively) met entry criteria for the full cohort. Of these, 381 (5.7%) received temporary dialysis. There were 3,147 (47.4% of all patients) MACE events during the study period. The crude incidence for MACE after 30 days of AKI was similar in both dialyzed and non-dialyzed patients. After the propensity score matching, the adjusted hazard ratio for MACE in dialyzed versus non dialyzed patients was 1.162 (95% CI 0.978-1.381). Conclusions: Treatment of AKI with temporary dialysis in hospitalized patients with baseline eGFR between 20 and 60 mL/min/1.73 m2 was not associated with an increased risk for subsequent admission for MACE. If confirmed by prospective studies, clinicians may not need to worry that the dialysis procedure may contribute to additional risk for long-term MACE in CKD patients with superimposed AKI.
Evidence of an in vitro Coupled Diffusion Mechanism of Lesion Formation within Microcosm Dental Plaque
Authors: Owens Gareth J. , Lynch Richard J.M. , Hope Christopher K. , Cooper Lee , Higham Susan M. , Valappil Sabeel P.
Published: March 2017

The purpose of this study was to determine whether or not the dual constant-depth film fermenter (dCDFF) is able to produce caries-like enamel lesions and to ascertain further information regarding the performance of this fully functional biological caries model. Conditions were defined by the continuation (CF) or cessation (FF) of a saliva-type growth medium supply during 50-mM sucrose exposures (8 times daily). Hydroxyapatite (n = 3) and bovine enamel (n = 3) substrata were included within each condition and samples extracted after 2, 4, 8, and 16 days. Community profiles were generated for fastidious anaerobes, Lactobacillus spp., Streptococcus spp., mutans streptococci (MS), and Veillonella spp. using selective culture techniques and enamel demineralisation assessed by transverse microradiography. Results demonstrated that the dCDFF model is able to produce caries-like enamel lesions with a high degree of sensitivity where reduced ionic strength within the FF condition increased surface layer mineral deposition. Between conditions, biofilm communities did not differ significantly, although MS in the biofilms extracted from the FF condition rose to a higher proportion (by 1.5 log10 units), and Veillonella spp. were initially greater within the CF condition (by 2.5 log10 units), indicating an enhanced ability for the clearance of low-pKa acids following exposures to sucrose. However, both conditions retained the ability for caries-like lesion formation.
Searching for a Lifeline: Transcriptome Profiling Studies of Influenza Susceptibility and Resistance
Authors: Kobzik Lester
Published: March 2017

Excess or dysregulated host inflammatory responses cause much of the morbidity and mortality caused by severe influenza. Given the limitations of vaccines and antiviral drugs, novel therapeutics to modulate host responses and improve outcomes in severe influenza are needed. One strategy is to learn from the direct comparison of high-survivor versus high-mortality animal models. This review surveys the results of lung transcriptome profiling studies in murine models that directly compare susceptible versus resistant hosts challenged with identical influenza infections. The potential contributions and limitations of these studies are discussed. To amplify their power, the studies are subjected to a meta-analysis, which helps identify frequently dysregulated pathways and potentially novel areas for investigation. Using connectivity map-based tools (LINCS), transcriptome signatures linked to susceptibility can identify candidate drugs that merit testing for in vivo efficacy.
Female Patient with Alport Syndrome and Concomitant Membranous Nephropathy: Susceptibility or Association of Two Diseases?
Authors: Veloso Mariana P. , Neves Precil D.M.M. , Jorge Lectícia B. , Dias Cristiane B. , Yu Luis , Pinheiro Rafaela B.B. , Testagrossa Leonardo A. , Malheiros Denise M. , Balbo Bruno E.P. , Lerário Antônio M. , Onuchic Luiz F. , Woronik Viktoria
Published: March 2017

Alport syndrome (AS) is a disorder of collagen IV, a component of glomerular basement membrane (GBM). The association of AS and immunocomplex nephropathies is uncommon. This is a case of a 37-year-old woman with family history of X-linked AS, including 4 affected sons. This patient developed full-blown nephrotic syndrome along a 3-month period, a presentation not consistent with AS progression. This scenario suggested an alternative diagnosis. A kidney biopsy was therefore performed, showing membranous nephropathy (MN) in addition to GBM structural alterations compatible with AS. Whole exome sequencing also confirmed the diagnosis of X-linked AS, revealing a heterozygous pathogenic mutation in COL4A5. While a negative serum anti-phospholipase A2 receptor did not rule out a primary form of MN, it was also uncertain whether positive serologic tests for syphilis could represent a secondary factor. It is currently unknown whether this unusual association represents AS susceptibility to immunocomplex-mediated diseases or simply an association of 2 disorders.
Standing Posture at Work Does Not Increase the Risk of Varicose Veins among Health Care Providers in Taiwan
Authors: Huang Hsin-Kai , Weng Shih-Feng , Su Shih-Bin , Wang Jhi-Joung , Guo How-Ran , Hsu Chien-Chin , Huang Chien-Cheng , Lin Hung-Jung
Published: March 2017

Objective: This study compared the risk of varicose veins (VV) among physicians, nonphysician health care providers (HCP), and the general population. Subjects and Methods: The Taiwan National Health Insurance Research Database was used to identify 28,844 physicians and 26,099 nonphysician HCP and an identical number of age- and sex-matched patients from the general population. Using logistic regression analyses, VV risks between physicians and the general population, nonphysician HCP and the general population, and physicians and nonphysician HCP, and among physician specialists were compared by tracing their medical histories between 2007 and 2011. Results: Physicians and nonphysician HCP had cumulative VV incidences of 0.12% (34/28,844) and 0.13% (33/26,099), respectively, during the 5-year period, compared to that of the general population within the same 5-year period. Physicians and nonphysician HCP did not have a higher VV risk than the general population after adjusting for deep vein thrombosis (DVT) history (adjusted odds ratio [AOR] 0.86; 95% confidence interval [CI] 0.53-1.40, and AOR 1.43; 95% CI 0.82-2.50, respectively). Physicians did not a have higher VV risk than nonphysician HCP (AOR 0.80; 95% CI 0.43-1.51) after adjusting for age, sex, and DVT history. Surgery had the highest incidence (0.22%) while pediatrics and emergency medicine had the lowest incidence (0%) of VV risk among physician specialists; however, the difference was not significant (all p values >0.05). Conclusion: In this study, VV risk did not differ among physicians, nonphysician HCP, and the general population.
Hypertrophic Pachymeningitis and the Syndrome of Inappropriate Antidiuretic Hormone Secretion: Coincidence or Cause
Authors: Harsch Igor Alexander , Schiffer Anne , Konturek Peter C.
Published: March 2017

Objective: To investigate a potential cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Clinical Presentation and Intervention: A 70-year-old female patient had nausea and collapsed. Although euvolemic, pathological laboratory findings showed hyponatremia and hypoosmolality, and cerebral magnetic resonance imaging showed hypertrophic pachymeningitis. Secondary hypertrophic pachymeningitis was excluded. Other nonneurological reasons for SIADH were also excluded. Moderate fluid restriction restored an almost normal serum osmolality and sodium. Conclusion: This case of SIADH was conservatively treated with moderate fluid restriction that almost restored normal serum osmolality and sodium levels.
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.
Aristotle and Musicologists on Three Functions of Music
Authors: Destrée Pierre
Published: March 2017

In Pol. 8, we find two rather different threefold divisions of the aims, or usages, of music. At the very beginning of his analysis, Aristotle first lists (1339a11-26): amusement and relaxation; moral education; leisure . Strikingly enough though, when it comes up again at the end of the treatise on musical education, this threefold division has undergone a few remarkable changes. Now, the division comes up between moral education, emotional purgation/purification, and “thirdly”, Aristotle says, “leisure, rest and relaxation of one’s tensions (τρίτον δὲ πρὸς διαγωγὴν πρὸς ἄνεσίν τε καὶ πρὸς τὴν τῆς συντονίας ἀνάπαυσιν)” (1341b36-41). The main difficulty that this new enumeration creates is notable: how to explain that now the third aim of music seems to consist in the ensemble of leisure, repose and relaxation, while leisure and relaxation were first introduced as two distinct aims? I argue that πρὸς διαγωγὴν should be best considered a gloss.
Typification of infrageneric names in Ulmus L. (Ulmaceae)
Authors: WHITTEMORE ALAN T.
Published: March 2017

The genus Ulmus Linnaeus (1753: 225) is a frequent forest tree in many parts of the northern hemisphere. Because of its great economic importance (Heybroek 2015), it has attracted the attention of many botanists. Although the genus is small (no more than 40 species; Sherman-Broyles 1997, Fu et al. 2004) and shows limited morphological variation, a surprising number of infrageneric taxa have been described. Recognition of infrageneric taxa began with the early work of Dumortier (1827) and continued with monographs by two authors in the mid-nineteenth century (Spach 1841a, 1841b, Planchon 1848), followed by several studies in the twentieth century (Moss 1914, Schneider 1916, Grudzinskaya 1974, Fu et al. 1979, Richens 1983). Most recently, Wiegrefe et al. (1994) have supported parts of the traditional classifications, but indicated the necessity of breaking up the traditional Ulmus subg. Microptelea (Spach) Planch., often defined to include all fall-flowering elms but clearly not natural in this sense.
Notes on species of the genus Chlaenius Bonelli, 1810 (Coleoptera: Carabidae, Chlaeniini) from four agro-climatic zones of Rajasthan, with description of two new species
Authors: CHANU N.YAIPHABI , SWAMINATHAN R.
Published: March 2017

Fourteen species of the genus Chlaenius from the semi-arid and sub-humid plain zones of Rajasthan (India) have been revised in this paper, including the description of two new species: Chlaenius (Lissauchenius) udaipurensis sp. nov. and Chlaenius (Chlaeniellus) pseudotristis sp. nov. A key to these species has been given with suitable line diagrams and photographs to illustrate key taxonomic characters including labrum, mentum, maxillary and labial palpi, pronotum, elytra and aedeagus.
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

The 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

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

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

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 <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

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.
A Member Saved Is a Member Earned? The Recruitment-Retention Trade-Off and Organizational Strategies for Membership Growth
Authors: Shi Yongren , Dokshin Fedor A. , Genkin Michael , Brashears Matthew E.
Published: March 2017

A long line of research documents the essential role of social networks in mediating the recruitment and retention of members in organizations. But organizations also comprise a primary context where people form social ties. We investigate how the network structure an organization creates among its members influences its ability to grow and reproduce. In particular, we propose that two dimensions of organizational strategy influence affiliation dynamics: (1) the extent to which an organization induces social interaction among its members (social encapsulation), and (2) the time and energy that an organization demands of its members (time and energy demand). We examine membership dynamics in an ecology where competitor organizations deploying varied strategies vie for the same pool of members. Results show a curvilinear relationship between membership growth and the rate of social encapsulation. Furthermore, we find that time and energy demand mediates the effect of social encapsulation by shaping its members’ opportunities for maintaining external affiliations. Different opportunity structures result in different levels of network turnover, thus either reinforcing or dissolving intra-organizational ties. For most types of organizations, attaining sustained growth requires a balance between open networks (for recruitment) and network closure (for retention).
The Influence of Hand Immersion Duration on Manual Performance
Authors: Ray Matthew , Sanli Elizabeth , Brown Robert , Ennis Kerri Ann , Carnahan Heather
Published: March 2017

Objective:

To investigate the effect of hand immersion duration on manipulative ability and tactile sensitivity.

Background:

Individuals in maritime settings often work with hands that have been immersed in water. Although research has shown that hand immersion duration differentially impacts skin adhesion and tactile sensitivity, the effect of hand immersion on manipulative ability has not been directly tested. Given how critical manipulative ability is for the safety and performance of those working at sea, the effect of hand immersion duration on manual performance was investigated.

Method:

Tests of manipulative ability (Purdue Pegboard, Grooved Pegboard, reef knot untying) and tactile sensitivity (Touch-Test) were completed following no-exposure, short-exposure, and long-exposure hand immersions in thermoneutral water.

Results:

Compared to the no immersion condition, the Purdue Pegboard performance was reduced in both immersion conditions (short exposure, –11%; long exposure, –8%). A performance decrement was only observed in the short exposure condition (+15% in time to complete task) for the reef knot untying task. There were no statistical differences in the Grooved Pegboard or Touch-Test scores between exposure conditions.

Conclusion:

Immersing the hands in water decreases manipulative ability except for when object properties reduce the slipperiness between the hand and object.

Application:

Manual performance in a wet environment may be conserved by designing tools and objects with edges and textures that can offset the slipperiness of wet hands. To maintain safety, the time requirements for working with wet hands needs to be considered.
The Spillover of Genomic Testing Results in Families: Same Variant, Different Logics
Authors: Timmermans Stefan , Stivers Tanya
Published: March 2017

Due to heritability, next-generation genetic tests have the potential to affect family members beyond the patient being tested. Geneticists and genetic counselors, in dialogue with patients and their relatives, will need to establish for whom and in what way genomic testing results matter during the communication of testing results, indicating the spillover of presumed pathological variants. On the basis of video-recorded consultations of the return of exome results in a genetics clinic, we distinguish three different logics deployed to explain the relevance of the findings for the patient, extended family members, and unborn relatives. While geneticists tend to be cautious in interpreting findings for the patient and living relatives, the findings become more deterministic in the context of reproductive decision making. The presentation of results then establishes the causal role of variants and reflects back on disability as a state to be prevented, in the process establishing genetic ties between kin.
Measurement of on-farm diversification in Vietnam
Authors: Tung Diep Thanh
Published: March 2017

This study aims to assess levels of on-farm diversification in Vietnam. The results reflect regional differences in terms of on-farm diversification and its determinants. Households in northern regions have adapted to the fragmented and small-sized parcels of land by diversifying their on-farm activities. In contrast, the Mekong Delta region in the south of Vietnam is characterized by larger agricultural parcels and a specialization in rice production. Land use fragmentation, as reflected by a large number of plots in a given area, is one of the most important reasons for the high levels of on-farm diversification, while the higher share of non-farm income in total income is the reason of lower levels of on-farm diversification. Households have reacted to natural and economic shocks by diversifying their on-farm activities. The non-stationary Markov chain model used here shows various diversification scenarios and trends. In most cases, the on-farm diversification is expected to reduce in coming years.
Assessing agricultural land suitability in the Fakkeh region, Iran
Authors: Albaji Mohammad , Alboshokeh Abrahim
Published: March 2017

Land suitability assessments can provide useful information to help optimize agricultural land use. Due to the current lack of appropriate land management practices in the Fakkeh region, southwest Iran, a land suitability evaluation study for key agricultural crops, including wheat, alfalfa, maize and barley, covering 43,700 ha was undertaken. Qualitative evaluation was carried out using two methods, the simple limitation and parametric methods (Storie and square root method), to compare land and climate characteristics with crop needs. The most important limiting factors in wheat, alfalfa and barley production included the physical properties of the soil, especially light soil texture. The major limiting factors in maize production were low relative humidity and high n/ N ratio during the plant growth period, light soil texture, soil salinity and alkalinity.
Rethinking India
Authors: Baxi Upendra
Published: March 2017

Bhikhu Parekh, Debating India: Essays on Indian Political Discourse, New Delhi, Oxford University Press, 2015, xix+224 pp., ₹895, ISBN-10: 0198060459/ ISBN-13:9780198060451.