tbuckley/cabot-search huggingface dataset:
IMMU-15. A UNIQUE SELF-STIMULATIVE PROPERTY OF CD70 CAR ADVANCES T CELL FUNCTION AND ANTI-TUMOR RESPONSE IN GLIOBLASTOMA
Authors: Linchun Jin, Alicia Hou, Haipeng Tao, Aida Karachi, Meng Na, Zhiguo Lin, Loic Deleyrolle, Elias Sayour, Duane Mitchell, Jianping Huang
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Glioblastoma (GBM) is a refractory brain tumor that desperately needs new therapeutic interventions. Our group identified CD70 as a novel target of CAR-T therapy for this malignancy. We demonstrate that CD70 is overexpressed by low-/high-grade gliomas and associated with poor survival for patients; CD70 promotes CD8 specific cell death and tumor-associated macrophage infiltration in gliomas. The CD70 CAR (using CD27, a natural costimulatory receptor of T cells as an antigen-binding region) T cells can efficiently eradicate CD70 positive tumors in syngeneic and xenograft mouse models. OBJECTIVE To evaluate the properties of CD70 CAR-transduced T cells in GBM treatment. METHODS CD70 CAR or IL13Rα2 CAR was linked with fluorescent reporter gene EGFP, and cloned into a retroviral vector (pMSGV8). In vitro T cell culture and flow cytometry were used to evaluate the self-enrichment property and susceptibility to TCR stimulation of the CAR T cells. KI67, Bcl-2, CD70 gene expression was tested by qPCR to measure the proliferation/apoptosis properties of the CAR T cells. Cytokine profile was analyzed by ELISA. The anti-tumor response was evaluated using Xenograft mouse models. RESULTS Compared with IL13Rα2 CAR T cells, the frequency of CD70 CAR T cells was significantly increased 3 weeks post transduction, and approximately 100 to 150-fold CD70 CAR T cell expansion without additional stimuli was achieved in vitro. The expanded CD70 CAR T cells were mostly (up to 85%) CD8+ T cells three weeks post CAR transduction. Enhanced proliferative capacity and production of IL-2, IFN-γ, and TNF-α of the CD70 CAR-transduced T cells upon anti-CD3/CD28 stimulation were also revealed. Results from animal models show that the CD70 CAR T cells present superior in vivo persistence and antitumor efficacy. CONCLUSION We show the auto-stimulative property, as well as superior T cell function and antitumor efficacy of CD70 CAR T cells in GBM models.
Discovery of DWP213388, a Potent ITK and BTK Selective Dual Inhibitor with Excellent Efficacy and Safety, for Treating Gvhd
Authors: Deokki Eom, Jae Hun Jung, Eun Kyung KIM, Wolyoung Kim, Qingri Li, Jaehyun Jung, Sohee Im, Yong Dae Shin, Hyaejung Hyun, Joon Seok Park
Journal: Blood (2019)
This Is a Title in Title Case: A Combination of Low-Dose Decitabine and Chidamide Resulted in Synergistic Effects on the Proliferation and Apoptosis of Human Myeloid Leukemia Cell Lines
Authors: Fangfang Xu, Honggang Guo, Mingyue Shi, Siwei Liu, Min Wei, Kai Sun, Yuqing Chen
Journal: Blood (2019)
Regulatory T Cell Adoptive Immunotherapy Promotes B Cell Immunity after Haploidentical Transplantation
Authors: Sara Piccinelli, Antonella Mancusi, Eni Hoxha, Loredana Ruggeri, Franca Falzetti, Alessandra Carotti, Adelmo Terenzi, Samanta Bonato, Matteo Paradiso, Tiziana Zei, Roberta Iacucci Ostini, Barbara Bigerna, Brunangelo Falini, Mauro Di Ianni, Massimo Fabrizio Martelli, Andrea Velardi, Antonio Pierini
Journal: Blood (2019)
TAMI-79. THERAPEUTIC REVERSAL OF PRENATAL PONTINE ID1 SIGNALING IN DIPG
Authors: Viveka Nand Yadav, Micah K Harris, Dana Messinger, Chase Thomas, Jessica R Cummings, Tao Yang, Rinette Woo, Robert Siddaway, Martin Burkert, Stefanie Stallard, Tingting Qin, Brendan Mullan, Ruby Siada, Ramya Ravindran, Michael Niculcea, Kevin F Ginn, Melissa A H Gener, Kathleen Dorris, Nicholas A Vitanza, Susanne V Schmidt, Jasper Spitzer, Jiang Li, Mariella G Filbin, Xuhong Cao, Maria G Castro, Pedro R Lowenstein, Rajen Mody, Arul Chinnaiyan, Pierre Desprez, Sean McAllister, Cynthia Hawkins, Sebastian M Waszak, Sriram Venneti, Carl Koschmann
Journal: Neuro-Oncology (2021)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with rare survival beyond two years. This poor prognosis is largely due to the tumor's highly infiltrative and invasive nature. Nearly 80% of DMGs harbor K27M mutation in the genes encoding histone H3.1 (H3F3A) or H3.3 (HISTIH3B), often with concurrent ACVR1 mutation. Inhibitor of DNA-binding (ID) proteins are key transcriptional regulators of genes involved in lineage commitment and are associated with invasiveness and poor clinical outcomes in multiple human cancers. Introduction of H3K27M and ACVR1 mutations increase ID1 expression in cultured astrocytes, but this has not been confirmed in human tumors or targeted therapeutically. We developed an in-utero electroporation (IUE) murine H3K27M-driven tumor model, which demonstrates increased ID1 expression in H3K27M- and ACVR1-mutated tumor cells. Exome and transcriptome sequencing analysis of multi-focal DMG tumors (n=52) and normal brain tissue revealed that increased ID1 expression is associated with H3K27M/ACVR1-mutation and brainstem location, and correlates with poor survival in patients. ChIP-sequencing for H3K27ac and H3K27me3 in multiple DMG tumors (n=5) revealed that the ID1 gene is epigenetically active, which matches the epigenetic state of murine prenatal hindbrain cells. Higher ID1-expressing astrocyte-like DIPG cells share a similar transcriptional program with ID1+/SPARCL1+ positive oligo/astrocyte-precursor (OAPC) cells from the developing human brain and demonstrate upregulation of gene sets involved in regulation of cell migration. Both genetic and pharmacologic [cannabidiol (CBD)] suppression of ID1 result in decreased DIPG cell invasion/migration in vitro and invasion/tumor growth in multiple in vivo models. Mechanistically, CBD reduces proliferation through production of reactive oxygen species. Further, DIPG patients treated off-trial with CBD (n=15) displayed reduced ID1 tumor expression and improved overall survival. In summary, ID1 is upregulated in DIPG through K27M-mediated epigenetic reactivation of a developmental OAPC-like transcriptional state, and ID1-driven invasiveness of DIPG is therapeutically targetable with CBD.
‘Are women grateful to be here or do women kick ass?’ #Sportskongres2020
Authors: Karen Kotila, Kristian Thorborg, Thomas Bandholm, Michael Skovdal Rathleff, Heidi Klakk, Carsten B Juhl
Journal: British Journal of Sports Medicine (2019)

#sportskongres2020 is a congress that is rated among the best sports medicine congresses in the world. A congress that in the past has failed to live up to Danish gender equality goals, but now recognises the value of gender equality and strives to take it one step further—pay attention to women and let them kick ass.

‘Are women grateful to be here or do women kick ass’ was the question Abby Wambach, former US soccer national team captain, posed in her graduation speech at the Barnard College in 2018. Wambach made the important point that women, herself included, are often brought up to be grateful, nice girls, staying on the career path and not mouthing off. Abby nails it; gender equality is a complex matter that draws attention to children’s upbringing and the perception of how women ought to behave. The quest for gender equality does not start nor end with equal opportunity. As pointed out by Bekker et al 1 in a recent editorial. ‘The question, then, is far from how we can merely get more women to participate, but rather ‘how can we make ourselves …
EPID-33. GENDER-SPECIFIC PROBABILISTIC ATLASES OF GLIOBLASTOMA REVEAL IMPACT OF TUMOR LOCATION ON PROGRESSION FREE SURVIVAL
Authors: Niha Beig, Marwa Ismail, Anas Saeed Bamashmos, Volodymyr Statsevych, Virginia Hill, Anant Madabhushi, Manmeet Ahluwalia, Pallavi Tiwari
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Recent epidemiological studies suggest that gender differences in Glioblastoma (GBM) influence the prognostic outcome of patients, and thus should be considered for patient management. In this feasibility study, we developed population atlases of pre-treatment MRI lesions to evaluate whether progression free survival (PFS) in gender-specific GBM patients have a spatial proclivity to hemispheric or lobe-specific locations. METHODS 203 pre-operative MRI sequences (1.5T/3T T1w, T2w, FLAIR scans, multi-center) of GBM (125 males [m] &amp; 78 females [f]) from TCIA (n=130), Ivy-GAP (n=32) and participating institution (n=41), along with PFS (median cut-off =189 days [m], 78 days [f]) were analysed. Frequency atlases (improved PFS [i-PFS] &amp; worse PFS [ω-PFS]) of tumor occurrence in T2/FLAIR hyperintense regions were developed for each gender, by averaging voxel intensities across all patients. To compute significant differences (p-value&lt; 0.05), voxel-based analysis of differential involvement (ADIFFI) based on two-tailed Fisher’s exact test was performed on (a) m: i-PFS (n= 61) vs m: ω-PFS (n= 62), and (b) f: i-PFS (n= 39) vs f: ω-PFS (n= 39) atlases. Prominent clusters were identified and mapped to LONI Probabilistic Brain Atlas (LPBA40) parcellations to provide anatomic localization for each gender’s PFS. RESULTS ADIFFI analysis revealed that m: i-PFS tumors were more often localized to the inferior frontal gyrus of left hemisphere with a frequency of 20% whereas m: ω-PFS were more often localized to the right insular cortex (p&lt; 0.005). f: i-PFS tumors were more often localized to the right hemisphere in the parietal and temporal lobe, while f: ω-PFS had 15.7% occurrence in the superior and middle frontal gyri of the right hemisphere (p&lt; 0.03). CONCLUSION Our analysis suggests spatial proclivity of gender-specific PFS to hemispheric and lobe-specific locations in the brain. Gender-specific prognostic models and nomograms may be more accurate than unisex models and nomograms for GBM patients.
Oligoclonal Expansion of Effector Memory CD8+CD57+ T Cells May Sustain Bone Marrow Destruction in Aplastic Anemia
Authors: Valentina Giudice, Xingmin Feng, Lin Zenghua, Maria del Pilar Fernandez Ibanez, Keyvan Keyvanfar, Carmine Selleri, Neal S. Young
Journal: Blood (2016)
Ibrutinib Treatment in CLL Patients Improves T Cell Function and Blinatumomab Redirected Cytotoxicity
Authors: Meixiao Long, Erich Williams, Clara Berard, Carolyn Cheney, Eileen Hu, Seema A. Bhat, Kerry A. Rogers, Jennifer Woyach, Natarajan Muthusamy, John C. Byrd
Journal: Blood (2019)
Clinical and Genomic Factors Are Predictive of Response and Prognostic of Progression-Free Survival in Patients with Waldenström Macroglobulinemia Treated with Ibrutinib
Authors: Jorge J. Castillo, Joshua Gustine, Maria Demos, Andrew Keezer, Kirsten Meid, Gloria G Chan, Jiaji G Chen, Maria Luisa Guerrera, Amanda Kofides, Manit Munshi, Nicholas Tsakmaklis, Xia Liu, Lian Xu, Guang Yang, Zachary R Hunter, Steven P Treon
Journal: Blood (2019)
Value of Digital Patient Reported Outcomes (PROs) - Long-Term Management of Treatment Fatigue in Relapsed or Refractory Multiple Myeloma
Authors: Noa Biran, Emre Yucel, Robin Anthony Kouyaté, Gillian McGovern, Antoinette Schoenthaler, Olivia Durling, Rashmi Unawane, Andrew Schutt, Sumeet Panjabi
Journal: Blood (2019)
Implication of Inherited Genetic Variants Associated with Follicular Lymphoma Susceptibility in the Prognosis of Patients Treated By Immunochemotherapy in PRIMA Study
Authors: Herve Ghesquieres, Youenn Drouet, Sarah Huet, Guillaume Cartron, Marie-Helene Delfau, Fritz Offner, Pauline Brice, Luc Xerri, Reda Bouabdallah, Gilles A. Salles
Journal: Blood (2019)
Clinical, Hematological, Genetic, and Pathological Significance in Newly Diagnosed High Grade B-Cell Lymphoma and Diffuse Large B-Cell Lymphoma
Authors: Qingyuan Qu, Lingyan Zhang, Chao Xue, Xueling Ge, Xiao Lv, Kang Lu, Xin Wang, Yujie Jiang
Journal: Blood (2019)
Response-Adapted Therapy with Infusional EPOCH Chemotherapy Plus Rituximab in HIV-Associated, B-Cell Non-Hodgkin's Lymphoma
Authors: Juan Carlos Ramos, Richard F. Ambinder, Joseph Sparano, Jeannette Y Lee, Lawrence D Kaplan, William Wachsman, David M. Aboulafia, Ariela Noy, Lee Ratner, David H. Henry, Amy Chadburn, Ethel Cesarman, Ronald T. Mitsuyasu
Journal: Blood (2019)
Somatic Bzip Mutations of CEBPA Are Associated with Favorable Outcome Regardless of Presence As Single Vs. Double Mutation
Authors: Katherine Tarlock, Todd A. Alonzo, Yi-Cheng Wang, Robert B. Gerbing, Rhonda E. Ries, Tiffany A. Hylkema, William G. Woods, Todd M Cooper, Alan S Gamis, Richard Aplenc, Soheil Meshinchi
Journal: Blood (2019)
The Critical Role of Kindlin-3 in Intiation of Physiological Thrombus Formation ~ Analysis of Kindlin-3 Deficient Patient
Authors: Hisashi Kato, Shigenori Honda, Hirokazu Kashiwagi, Nobuko Nishiura, Keigo Akuta, Koichi Kokame, Toshiyuki Miyata, Yoshiaki Tomiyama
Journal: Blood (2019)
GENE-07. INFLUENCE OF EPIGENETIC MODULATION OF THE T-CELL REGULATORS EXPRESSION ON GLIOBLASTOMAS BY HISTONE 3 LYSINE METHYLTRANSFERASE OR DEMETHYLASE ON THE PROGNOSIS OF THE GLIOBLASTOMA PATIENTS
Authors: Mee-Seon Kim, Young Sam Lee, Dae Choel Kim, Young Zoon Kim
Journal: Neuro-Oncology (2019)

Abstract PURPOSE The primary aim of this study is to investigate the expression of the T cell stimulators and inhibitors as well as histone modifying enzymes in the glioblastoma cells. Based on the expression of these proteins, authors estimate the prognostic role in glioblastoma patients and also validate the known prognostic factors. MATERIALS AND METHODS Using 84 FFPE samples of glioblastoma in the pathologic archives at our institute, immunohistochemical staining for T cell stimulators (CD 27, CD 28, CD 137, OX40, ICOS), inhibitors (CTLA-4, PD-1, PD-L1, TIM3, CD200R), histone 3 lysine methyltransferase (MLL4, RIZ, EZH1, NSD2), and histone 3 lysine demethylase (KDM5c, JMJD1a, UTX, JMJD5). RESULTS Median values of the immunohistochemical staining for T cell stimulators and inhibitors were 16.3% of CD27, 10.4% of CD28, 47.5% of CD137, 52.9% of ICOS, 32.2% of OX40, 31.4% of CTLA-4, 7.2% of PD-1, 55.5% of PD-L1, 62.2% of TIM3, and 42.8% of CD200R. In multivariate analysis, increased expression of CD28 (p=0.042), CD137 (p=0.009), EZH1 (p=0.040), and decreased expression of CTLA-4 (p=0.003), PDL-1 (p=0.020) in glioblastoma cells were independently associated with longer OS as well as known prognostic factors such as young age, high KPS, wide extent of resection, PRA class, and methylated MGMT promoter. Interestingly, 42 of 43 samples (97.7%) with decreased PDL1 expression had the increased EZH1 expression, 31 of 33 samples (93.9%) with decreased CTLA4 expression had the increased RIZ expression, 25 of 26 samples (96.2%) with increased CD137 expression had the increased UTX expression, and 36 of 39 samples (92.3%) with increased CD28 expression had the increased JMJD1a expression, respectively. CONCLUSION The result of presenting study suggest that the regulators of T cell can be considered as independent prognostic factors in glioblastoma patients and the expression of these regulators can be controlled by unique histone 3 lysine methylation enzymes.
PD2.01 PD-L1 and Other Potential Predictive Biomarkers Measured in Plasma by RT-PCR in cfRNA and cfDNA to Monitor Clinical Responses in Metastatic Lung Cancer Patients
Authors: L. Raez, J. Usher, D. Sumarriva, K. Danenberg, B. Hunis, Y. Jaimes, G. Domingo, P. Danenberg
Journal: Journal of Thoracic Oncology (2019)
TMIC-53. IMPACT OF HFE EXPRESSION AND SEX ON THE TUMOR IMMUNE MICROENVIRONMENT IN GLIOBLASTOMA
Authors: Darya Nesterova, Sang Lee, Brad Zacharia, Justin Lathia, Joshua Rubin, Michael Berens, Jill Barnholtz-Sloan, James Connor
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite aggressive treatment, the median survival for patients with GBM remains approximately 1 year. Recent evidence demonstrates GBM is a sexually dimorphic disease, and that females have greater overall survival. We previously showed expression levels of HFE, an iron-regulating gene, significantly impacts survival in GBM. Moreover, this effect is sex-specific: females with low HFE expressing tumors have significantly longer survival than males with similar HFE expression. Moreover, HFE expression and survival appeared to correlate with markers of immune activity within the tumors. To further explore the impact of HFE expression on the immune infiltration of GBM, we utilized available TCGA GBM data for analysis by EstimateMe and DeconvuluteMe. These platforms utilize expression data to estimate the magnitude and cellular composition of immune cell infiltrates in tumors, respectively. We sought to correlate these computational measures with HFE expression levels and survival. We confirmed that immune and stromal cell infiltration of tumors is negatively correlated to survival. Consistent with our findings that high HFE levels have a negative impact on survival, high HFE expressing tumors possessed higher levels of both immune and stromal cell infiltration. Additionally, sex of the patient, but not MGMT methylation status, was significantly correlated with immune and stromal infiltration, with males displaying higher levels of infiltration. High HFE tumors were composed of greater numbers of all immune cell types than low HFE tumors. In both HFE groups, monocytes and macrophages comprised the greatest fraction of cells. At low HFE and positive MGMT methylation (where we previously noted the greatest survival differences), we find females have lower monocyte and M2 macrophage markers compared to males with similar features. Collectively, these data suggest that an HFE-immune cell infiltrate axis contributes to sex differences in GBM survival.
Water and Salt Depletion
Authors: A. J. Galbraith
Journal: BMJ (1947)

Treated as Mannikin" Dr. HADFIELD spoke of the mental and emotional development of the child, reminding the conference that the child was a different person at different stages of life.The child, he said, was too often treated as a mannikin, but in fact the child of 2 was quite different from the child of 6, and he again from the child of 12.The child of from 4 to 7 was an independent, unsociable creature, filled with a first sense of achieve- ment; from 9 to 10, and again in adolescence, he-was a mem- ber of a "gang."At about 15 he entered upon a romantic phase, which was quite a different thing from the more sexual experience of 18.Dr. Hadfield accordingly warned parents not to regard as abnormal many manifestations in the development of their children which were perfectly normal to their age and only temporary.It was natural for a child of 2 to be self-willed and for a youth of 15 to fall romantically in love.If such phases were checked they would persist into the ensuing phase and trouble would be caused.He pleaded for freedom for the personality of the child and the inculcation of the only discipline which was worth while, namely, self-discipline.At least nine out of ten " don'ts " were quite unnecessary.The human infant had fewer fixed reflexes than any of the animals, and for that reason it was able to learn by experience.
COMP-05. A DRUG ASSOCIATION MAP OF GLIOBLASTOMA INFORMS PRECISION TARGETING OF p53-DEPENDENT METABOLIC STATES
Authors: Patrik Johansson, Elin Almstedt, Milena Doroszko, Soumi Kundu, Claire Vinel, David Lane, Marika Nestor, Silvia Marino, Cecilia Krona, Sven Nelander
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. Because GBMs are genetically and functionally diverse, there is little systematic understanding of how hundreds of approved drugs may be active against GBM subpopulations. To identify new pharmacological subgroups of GBM, we studied comprehensively the variation in drug response across 100 well-characterised patient-derived GBM cell cultures and used statistical models to explain patient specific cellular drug response in terms of molecular markers, pathway signatures and drug mechanism-of-action. We find that the response to proteasome inhibitors, currently under clinical development for GBM, shows extreme variation across cases, which is phenocopied \emph{in vivo} and predicted by p53 pathway activity. The resistance to proteasome inhibitor response is explained by a subset of p53 functional GBM cases, which exhibit more efficient scavenging of reactive oxygen species (ROS), thereby protecting against ROS-dependent apoptosis. By interference against this protective feedback loop using secondary inhibitors, synergistic killing of GBM cells is achieved. Our results define a sizable metabolic subclass of GBM cells, with implications for precision and combination targeting.
Platelet Function in Paroxysmal Nocturnal Haemoglobinuria
Authors: Fathima Mohiyaddin Ayyalil, Samantha J Montague, Sarah Hicks, Amandeep Kaur, Anila Jahangiri, Nalini Pati, Philip Crispin, Yujie Zheng, Xu Tienan, Lucy Coupland, Woei Ming Lee, James D'Rozario, Elizabeth E. Gardiner
Journal: Blood (2019)
Distinct effects of ruxolitinib and interferon-alpha on murine JAK2V617F myeloproliferative neoplasm hematopoietic stem cell populations
Authors: Rebecca J. Austin, Jasmin Straube, Claudia Bruedigam, Gabor Pali, Sebastien Jacquelin, Therese Vu, Joanne Green, Julius Gräsel, Lianne Lansink, Leanne Cooper, Shin-Jye Lee, Nien-Tsu Chen, Chung-Wei Lee, Ashraful Haque, Florian H. Heidel, Richard D’Andrea, Geoff R. Hill, Ann Mullally, Michael D. Milsom, Megan Bywater, Steven W. Lane
Journal: Leukemia (2019)
ACTR-58. BASELINE REQUIREMENTS FOR NOVEL AGENTS BEING CONSIDERED FOR BRAIN CANCER EFFICACY TRIALS: REPORT OF AN ABTC WORKSHOP
Authors: Stuart Grossman, Carlos Romo, Michelle Rudek-Renaut, Jeffrey Supko, Joy Fisher, Burt Nabors, Patrick Wen, David Peereboom, Benjamin Ellingson, Xiaobu Ye
Journal: Neuro-Oncology (2019)

Abstract Despite advances in the understanding of molecular pathways, the availability of NGS panels to identify potentially drugable mutations, the proliferation of targeted therapies, and the progress seen in other cancers, only one novel agent (temozolomide) has significantly improved the survival of patients with glioblastoma in the past three decades. A major factor distinguishing brain cancer from other malignancies is the presence of the blood-brain barrier that restricts entry into the central nervous system of over 95% of drugs currently approved by the FDA. Clinical investigators have historically justified glioblastoma efficacy trials with pharmacokinetic data documenting measurable brain concentrations in animals or in contrast enhancing brain tumor specimens from patients. However, the discovery of effective therapeutic agents (whose mechanism of action requires that the drug directly reaches the cancer) will likely require that therapeutic drug concentrations (rather than measurable levels or blood:brain ratios) be delivered to non-contrast enhancing regions of the brain. The importance of delivering therapeutic concentrations of drug to non-enhancing brain is highlighted by knowledge that a gross total resection of all enhancing portions of a glioblastoma provides no chance of cure and limited improvement in overall survival. Utilizing these more stringent emerging criteria to select novel agents for efficacy studies will encourage pre-clinical and phase I studies to define the CNS penetration of new drugs and determine a therapeutic concentration for each agent. This will aid in the rational prioritization of agents selected for phase II studies. A full report of the outcome of the ABTC workshop on this topic will be presented. This will include: 1) methods to determine “therapeutic” drug concentrations for glioblastoma, 2) methods to quantify drug concentrations in non-enhancing brain, 3) pharmacokinetic and pharmacodynamic considerations, and 4) potential shortcomings of this approach.