bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY23-02: Host immune responses to HPV and HPV vaccines
Authors: Pinto Ligia 
Published: July 2017

Abstract
Human papillomavirus (HPV) infection is the cause of multiple cancers in both women and men. There are three different licensed HPV prophylactic vaccines. Currently licensed L1 virus-like particles (VLP)–based HPV vaccines target two to nine different HPV types and have demonstrated excellent efficacy against the targeted HPV types and associated disease. Host immune responses to HPV vaccines and infection will be presented and discussed. Briefly, HPV vaccines induce nearly 100% seroconversion to all HPV types included in the vaccine. High titers of high-affinity anti-L1 IgG antibodies, to the HPV types included in the vaccine, are generated after vaccination, and these persist for several years after vaccination at levels considerably higher than those observed in natural infection. Although correlates of vaccine protection have not been identified, neutralizing antibodies are believed to be the main effectors of protection against HPV infection. Vaccine-induced antibodies are detectable not only in serum but also at mucosal sites of infection, such as the cervix and oral cavity. Local HPV-specific antibody levels, although lower, correlate well with circulating levels. Immunogenicity data have shown noninferiority of antibody responses after two doses of HPV vaccine, and the recommended number of vaccine doses was recently reduced from three to two. There is some evidence suggesting that even one dose of the bivalent HPV vaccine may provide similar protection to the recommended dose regimens. Antibody levels following one dose of the bivalent vaccine, although lower, have been shown to be stable over 4 years of follow-up and vaccine recipients remained HPV16/18 seropositive, suggesting that a single dose of the bivalent vaccine may provide durable protection against infection. The robust immunogenicity of the HPV vaccines contrasts with the immune responses observed after natural infection, in which seroconversion has been shown in only a percentage of individuals with incident HPV infection. Furthermore, levels of antibodies induced by vaccination are much higher than the levels observed after infection and appear to be preserved over time. A better understanding of long-term protection of the vaccine as well as a more comprehensive evaluation of correlates of immune protection against HPV infection are still needed.
Citation Format: Ligia Pinto. Host immune responses to HPV and HPV vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY23-02. doi:10.1158/1538-7445.AM2017-SY23-02
Abstract SY25-03: From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy
Authors: Sharma Padmanee 
Published: July 2017

Abstract
Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted presurgical and tissue-based clinical trials, which permit access to tumor tissues for laboratory studies. To compare and contrast data, we chose one tumor type that responds well to immune checkpoint therapy and one that does not. The first presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. The second presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in patients with localized prostate cancer. In addition, we evaluated data from patients with melanoma who received immune checkpoint therapy. These data enabled us to identify the ICOS/ICOSL pathway as relevant for antitumor immune responses in the setting of anti-CTLA-4 therapy. We also identified resistance mechanisms, including expression of other immune inhibitory pathways such as VISTA and loss of the IFNγ signaling pathway in tumor cells. These data will be discussed in greater detail.
Citation Format: Padmanee Sharma. From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-03. doi:10.1158/1538-7445.AM2017-SY25-03
Abstract SY25-04: Tumor and host factors regulating immunotherapy responsiveness
Authors: Gajewski Thomas Frank 
Published: July 2017

Abstract
Checkpoint blockade immunotherapy is favored in patients having a T cell-inflamed tumor microenvironment at baseline. Therefore, absence of a T cell-inflamed phenotype represents a first approximation of immunotherapy resistance. Investigation of molecular features of tumor genomics, host genetics, and commensal microbiota that correlate with the degree of spontaneous T-cell infiltration has revealed multiple layers of pathways that impact on relative response versus resistance to immunotherapeutic interventions. The first tumor-intrinsic oncogene pathway demonstrated mechanistically to mediate T-cell exclusion from the tumor microenvironment and lack of checkpoint blockade efficacy is the Wnt/β-catenin pathway. Additional molecular aberrations correlated with deficient immune infiltration in various cancers include loss of function mutation or absence of PTEN, LKB1, or p53 and activation of FGFR3 or PPAR-γ. Mouse modeling has revealed that tumor cell-intrinsic β-catenin pathway activation also mediates downstream resistance to adoptive T-cell therapy, due to defective expression of key chemokines. In one patient case analyzed, transition from a β-catenin-negative to a β-catenin-positive phenotype has been associated with secondary resistance to immunotherapy. TCGA and other large genomic datasets have been an invaluable tool for identifying such molecular correlates, through availability of tumor RNAseq and exome sequencing data as well as germline SNP analysis. Host germline polymorphisms also have been identified that correlate with the degree of T-cell infiltration in the tumor, and mouse models are being utilized to investigate mechanisms. Specific commensal bacteria associated with the degree of T-cell infiltration also have been identified in animal models, and similar analyses are ongoing with human stool samples in patients undergoing checkpoint blockade therapy. A common feature of non-T cell-inflamed tumors is a relative lack of Batf3-dendritic cells and absence of a type I IFN gene signature. Thus, regulation at the level of innate immunity seems to be a key determining factor. Strategies aimed at boosting innate immune activation in the tumor microenvironment represent a major category of therapeutic intervention to convert non-T cell-inflamed tumors to T cell-inflamed, and STING agonists and probiotics are beginning to be investigated clinically.
Citation Format: Thomas Frank Gajewski. Tumor and host factors regulating immunotherapy responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-04. doi:10.1158/1538-7445.AM2017-SY25-04
Abstract SY28-01: Stromal contributions of adipocytes to cancer
Authors: Scherer Philipp E. 
Published: July 2017

Abstract
The past few years have provided substantial evidence for the vital role of the local tumor microenvironment in various aspects of tumorigenesis. With obesity and its pathophysiologic sequelae still on the rise, the adipocyte is increasingly moving to center stage in the context of tumor stroma-related studies. To date, we have limited insights into how systemic changes associated with obesity and altered adipokine secretion influence the incidence and progression of obesity-associated cancers. Adipocytes are the major constituents of adipose tissue and play a key role in whole body metabolism. They not only fulfill an important role as a buffer for excess triglycerides, but they also secrete many lipid and protein factors and are therefore considered major endocrine cells that influence metabolism of other tissues, including liver, muscle, brain, and pancreatic β-cells. With chronic excess of energy intake, adipocytes develop hypertrophy and face various physiologic insults, such as hypoxia, oxidative stress, and disruptions in the protein secretory pathway due to ER stress. As a result, adipocytes become dysfunctional and less efficient at fulfilling their primary function of storing and neutralizing potentially toxic free fatty acids. Adipocyte dysfunction has been widely appreciated as a major cause underlying obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, cardiovascular disease, chronic inflammation, and cancers due to inappropriate release of mitogenic and inflammatory factors. As a result, these dysfunctional adipocytes also support the growth of infiltrating transformed ductal epithelial cells in the mammary gland, at the level of secretion of critical growth factors, proinflammatory cytokines, increased ECM production, and support of tumor lesion growth through release of critical metabolites. Therefore, the adipocyte with its paracrine influence on the microenvironment as well as its endocrine functions is an important area of research for both primary and metastatic tumor growth.
Citation Format: Philipp E. Scherer. Stromal contributions of adipocytes to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2017-SY28-01
Abstract SY29-02: Novel mechanisms of PARP inhibitor resistance
Authors: D'Andrea Alan D. 
Published: July 2017

Abstract
Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes including FANCN/PALB2, FANCO/RAD51, FANCJ/BRIP, and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues, topoisomerase inhibitors, and PARP-inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer, where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations. PARP inhibitor resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism—namely, the restoration of RF stability—appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient tumors can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types.
Citation Format: Alan D. D'Andrea. Novel mechanisms of PARP inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY29-02. doi:10.1158/1538-7445.AM2017-SY29-02
Abstract SY32-01: The new genetics and treatment of CLL
Authors: Croce Carlo M. 
Published: July 2017

Abstract
Loss of miR-15/16 on chromosome 13q14 is the most common genetic alteration in CLL. Recently, we discovered that miR-15/16 target BCL2, an antiaptoptic gene we discovered and named in 1984. Thus, loss of miR-15/16 leads to overexpression of BCL2 (the driver) and causes sensitivity of CLL cells to the antiBcl2 drug venetoclax that is capable of inducing complete remission of CLL in patients and was approved by the FDA in April 2016. The discovery of the involvement of miR-15/16 in CLL also indicated that alterations in genes not encoding proteins can cause cancer. Before our publication of 2002, the dogma was that alterations in protein coding genes, oncogenes, and suppressor genes, cause cancer. We speculate that by looking at other targets of miR-15/16 we might discover other biomarkers that are overexpressed because of miR-15/16 loss, providing novel opportunities to discover targetable targets. Since it seems likely that among the billions of leukemic cells in patients, there are a few that do not respond to the drug—for example, because of mutations in the Bcl2 pocket binding the drug—it is important to develop other drugs capable of killing CLL cells because they have lost miR-15/16. We propose to define whether loss of miR-15/16 may lead to overexpression of specific surface markers that can be targeted by specific monoclonal antibodies. The availability of these antibodies will allow the killing of the same leukemic cells by using a combination of the antibodies and venetoclax minimizing the possibility of drug resistance. Finally, we will assess the role of a new family of short noncoding RNAs we have discovered, ts-RNAs, in the pathogenesis of CLL.
Citation Format: Carlo M. Croce. The new genetics and treatment of CLL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY32-01. doi:10.1158/1538-7445.AM2017-SY32-01
Abstract SY33-02: Fueling T cells and antitumor immunity
Authors: Rathmell Jeffrey C. 
Published: July 2017

Abstract
Lymphocyte activation leads to rapid proliferation and differentiation, and we have shown that T-cell subsets require distinct metabolic programs. The effector CD4 T-cell fates (Th1, Th2, Th17) activate a highly glycolytic program. Regulatory CD4 T cells (Treg), in contrast, utilize a more oxidative metabolism and utilize lipids as a major fuel. These metabolic distinctions may allow new understanding of T-cell function in tumors and approaches to manipulate immunity. We have now examined the metabolism of Treg in detail and found that FoxP3 itself can promote oxidative metabolism characteristic of Treg and that this is critical to maximize Treg suppressive capacity. Treg can be glycolytic and proliferative in vivo. We found, however, that glucose uptake and glycolysis impaired Treg stability. Thus, Treg regulate glycolytic and oxidative metabolism to balance proliferation and suppressive function. Conversely, the requirement of effector T cells for glucose uptake and glycolysis poses a barrier to inflammatory function in tumors. Understanding mechanisms that regulate T-cell metabolism may provide new tools to modulate immunity through the balance of T-cell effector and regulatory populations.
Citation Format: Jeffrey C. Rathmell. Fueling T cells and antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY33-02. doi:10.1158/1538-7445.AM2017-SY33-02
Tropical Atmospheric Madden–Julian Oscillation: A Strongly Nonlinear Free Solitary Rossby Wave?
Authors: Yano Jun-Ichi , Tribbia Joseph J. 
Published: July 2017

Abstract
The Madden–Julian oscillation (MJO), a planetary-scale eastward-propagating coherent structure with periods of 30–60 days, is a prominent manifestation of intraseasonal variability in the tropical atmosphere. It is widely presumed that small-scale moist cumulus convection is a critical part of its dynamics. However, the recent results from high-resolution modeling as well as data analysis suggest that the MJO may be understood by dry dynamics to a leading-order approximation. Simple, further theoretical considerations presented herein suggest that if it is to be understood by dry dynamics, the MJO is most likely a strongly nonlinear solitary Rossby wave. Under a global quasigeostrophic equivalent-barotropic formulation, modon theory provides such analytic solutions. Stability and the longevity of the modon solutions are investigated with a global shallow-water model. The preferred modon solutions with the greatest longevities compare well overall with the observed MJO in scale and phase velocity within the factors.
Therapeutic Effects of Doxycycline on the Quality of Repaired and Unrepaired Achilles Tendons
Authors: Nguyen Quynhhoa T. , Norelli Jolanta B. , Graver Adam , Ekstein Charles , Schwartz Johnathan , Chowdhury Farzana , Drakos Mark C. , Grande Daniel A. , Chahine Nadeen O. 
Published: July 2017

Background: Achilles tendon tears are devastating injuries, especially to athletes. Elevated matrix metalloproteinase (MMP) activity after a tendon injury has been associated with deterioration of the collagen network and can be inhibited with doxycycline (Doxy). Hypothesis: Daily oral administration of Doxy will enhance the histological, molecular, and biomechanical quality of transected Achilles tendons. Additionally, suture repair will further enhance the quality of repaired tendons. Study Design: Controlled laboratory study. Methods: Randomized unilateral Achilles tendon transection was performed in 288 adult male Sprague-Dawley rats. The injured tendons were either unrepaired (groups 1 and 2) or surgically repaired (groups 3 and 4). Animals from groups 2 and 4 received Doxy daily through oral gavage, and animals from groups 1 and 3 served as controls (no Doxy). Tendons were harvested at 1.5, 3, 6, and 9 weeks after the injury (n = 18 per group and time point). The quality of tendon repair was evaluated based on the histological grading score, collagen fiber orientation, gene expression, and biomechanical properties. Results: In surgically repaired samples, Doxy enhanced the quality of tendon repair compared with no Doxy ( P = .0014). Doxy had a significant effect on collagen fiber dispersion, but not principal fiber angle. There was a significant effect of time on the gene expression of MMP-3, MMP-9 and TIMP1, and Doxy significantly decreased MMP-3 expression at 9 weeks. Doxy treatment with surgical repair increased the dynamic modulus at 6 weeks but not at 9 weeks after the injury ( P < .001). Doxy also increased the equilibrium modulus and decreased creep strain irrespective of the repair group. Doxy did not have a significant effect on the histology or biomechanics of unrepaired tendons. Conclusion: The findings indicate that daily oral administration of Doxy accelerated matrix remodeling and the dynamic and equilibrium biomechanics of surgically repaired Achilles tendons, although such enhancements were most evident at the 3- to 6-week time points. Clinical Relevance: The inhibition of MMPs at the optimal stage of the repair process may accelerate Achilles tendon repair and improve biomechanical properties, especially when paired with surgical management.
Effect of First Tarsometatarsal Joint Derotational Arthrodesis on First Ray Dynamic Stability Compared to Distal Chevron Osteotomy
Authors: Klemola Tero , Leppilahti Juhana , Laine Vesa , Pentikäinen Ilkka , Ojala Risto , Ohtonen Pasi , Savola Olli 
Published: July 2017

Background: Hallux valgus alters gait, compromising first ray stability and function of the windlass mechanism at the late stance. Hallux valgus correction should restore the stability of the first metatarsal. Comparative studies reporting the impact of different hallux valgus correction methods on gait are rare. We report the results of a case-control study between distal chevron osteotomy and first tarsometatarsal joint derotational arthrodesis (FTJDA). Methods: Two previously studied hallux valgus cohorts were matched: distal chevron osteotomy and FTJDA. Seventy-seven feet that underwent distal chevron osteotomy (chevron group) and 76 feet that underwent FTJDA (FTJDA group) were available for follow-up, with a mean of 7.9 years (range, 5.8-9.4 years) and 5.1 years (range, 3.0-8.3 years), respectively. Matching criteria were the hallux valgus angle (HVA) and a follow-up time difference of a maximum 24 months. Two matches were made: according to the preoperative HVA and the HVA at late follow-up. Matching provided 30 and 31 pairs, respectively. Relative impulses (%) of the first toe (T1) and metatarsal heads 1 to 5 (MTH1-5), weightbearing radiographs, and American Orthopaedic Foot & Ankle Society (AOFAS) (hallux metatarsophalangeal-interphalangeal [MTP-IP]) scores were studied. Results: The relative impulse of MTH1 was higher in the FTJDA group, whereas a central dynamic loading pattern was seen in the chevron group. This result remained when relative impulses were analyzed according to the postoperative HVA. The mean difference in the HVA at follow-up was 6.2 degrees (95% confidence interval, 3.0-9.5; P = .001) in favor of the FTJDA group. Conclusion: The dynamic loading capacity of MTH1 was higher in the FTJDA group in comparison to the chevron group. The follow-up HVA remained better in the FTJDA group. Level of Evidence: Level III, case-control study.
Attribution of oral cancer in the Sudan to Toombak dipping
Authors: Hassanin Ahmed Abbas , Idris Ali Mohamed 
Published: July 2017

Background: Toombak dipping-a form of smokeless tobacco-is highly prevalent in the Sudan. Materials and methods: For a case–control study, we selected oral cancer cases ( n = 98) and controls ( n = 98) at the Khartoum Teaching Dental Hospital. They were directly interviewed using a validated and a reliable instrument. For descriptive statistics, χ2 test was used for determining the odds ratio (OR) measuring the association between exposed and non-exposed. The effects of the confounding factors were tested by multivariate logistic regression analyses. The attributable risk of this agent in oral carcinogenesis was evaluated. Results: Significant risks for Toombak dipping (OR 3.8, 95% CI 1.7–8.6) and cigarette smoking (OR 2.7, 95% CI: 1.2–6.2) were found. The site of Toombak dipping and the tumor location showed positive correlation. The attribute risk for exclusive dippers was found to be 93% and 67% in females and males, respectively, whereas the adjusted attributable risk was 70.1%. The remaining 20–30% risks were attributed to other risk factors. Conclusion: In the Sudan, Toombak dipping is a major risk factor for oral squamous cell carcinoma. We were able to demonstrate a high attributable risk to this agent in oral carcinogenesis.