Unsupervised Classification During Time-Series Model Building.

Researchers who collect multivariate time-series data across individuals must decide whether to model the dynamic processes at the individual level or at the group level. A recent innovation, group iterative multiple model estimation (GIMME), offers one solution to this dichotomy by identifying group-level time-series models in a data-driven manner while also reliably recovering individual-level patterns of dynamic effects. GIMME is unique in that it does not assume homogeneity in processes across individuals in terms of the patterns or weights of temporal effects. However, it can be difficult to make inferences from the nuances in varied individual-level patterns. The present article introduces an algorithm that arrives at subgroups of individuals that have similar dynamic models. Importantly, the researcher does not need to decide the number of subgroups. The final models contain reliable group-, subgroup-, and individual-level patterns that enable generalizable inferences, subgroups of individuals with shared model features, and individual-level patterns and estimates. We show that integrating community detection into the GIMME algorithm improves upon current standards in two important ways: (1) providing reliable classification and (2) increasing the reliability in the recovery of individual-level effects. We demonstrate this method on functional MRI from a sample of former American football players.

Defining engagement in adolescent substance abuse treatment.

Youth engagement in substance use treatment is an important construct for research and practice, but it has been thinly and inconsistently defined in the literature. Most research has measured engagement by initiation, attendance, and retention in treatment. Because youth generally enter substance use treatment as a result of compliance with external requirements, defining engagement in this way might be insufficient. This qualitative participatory research study describes five focus groups with 31 adults working with youth in substance use treatment. Focus groups were designed and conducted by youth researchers in collaboration with university-based partners. We categorized participants' descriptions of engagement into five domains, identified as "CARES": Conduct, Attitudes, Relationships, Empowerment, and Social Context. These domains represent a comprehensive and ecologically-based definition of engagement that situates engagement in the context and trajectory of youth development, has clear implications for assertive clinical practice, and provides a foundation for developing an operationalized measure.

The influence of autoregressive relation strength and search strategy on directionality recovery in group iterative multiple model estimation.

Unified structural equation modeling (uSEM) implemented in the group iterative multiple model estimation (GIMME) framework has recently been widely used for characterizing within-person network dynamics of behavioral and functional neuroimaging variables. Previous studies have established that GIMME accurately recovers the presence of relations between variables. However, recovery of relation directionality is less consistent, which is concerning given the importance of directionality estimates for many research questions. There is evidence that strong autoregressive relations may aid directionality recovery and indirect evidence that a novel version of GIMME allowing for multiple solutions could improve recovery when such relations are weak, but it remains unclear how these strategies perform under a range of study conditions. Using comprehensive simulations that varied the strength of autoregressive relations among other factors, this study evaluated the directionality recovery of two GIMME search strategies: (a) estimating autoregressive relations by default in the null model (GIMME-AR) and (b) generating multiple solution paths (GIMME-MS). Both strategies recovered directionality best-and were roughly equivalent in performance-when autoregressive relations were strong (e.g., ß = .60). When they were weak (ß ≤ .10), GIMME-MS displayed an advantage, although overall directionality recovery was modest. Analyses of empirical data in which autoregressive relations were characteristically strong (resting state functional MRI) versus weak (daily diary) mirrored simulation results and confirmed that these strategies can disagree on directionality when autoregressive relations are weak. Findings have important implications for psychological and neuroimaging applications of uSEM/GIMME and suggest specific scenarios in which researchers might or might not be confident in directionality results. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Unsupervised classification reveals consistency and degeneracy in neural network patterns of emotion.

In the present study, we used an unsupervised classification algorithm to reveal both consistency and degeneracy in neural network connectivity during anger and anxiety. Degeneracy refers to the ability of different biological pathways to produce the same outcomes. Previous research is suggestive of degeneracy in emotion, but little research has explicitly examined whether degenerate functional connectivity patterns exist for emotion categories such as anger and anxiety. Twenty-four subjects underwent functional magnetic resonance imaging (fMRI) while listening to unpleasant music and self-generating experiences of anger and anxiety. A data-driven model building algorithm with unsupervised classification (subgrouping Group Iterative Multiple Model Estimation) identified patterns of connectivity among 11 intrinsic networks that were associated with anger vs anxiety. As predicted, degenerate functional connectivity patterns existed within these overarching consistent patterns. Degenerate patterns were not attributable to differences in emotional experience or other individual-level factors. These findings are consistent with the constructionist account that emotions emerge from flexible functional neuronal assemblies and that emotion categories such as anger and anxiety each describe populations of highly variable instances.

Newly discovered antiterminator RNAs in bacteriophage.

Antiterminator RNA directly modifies the transcription elongation complex so that it terminates less efficiently at intrinsic and factor-dependent terminators. These unusual RNAs were first discovered in bacteriophage HK022, where the nascent transcripts of the phage put sites promote full expression of phage genes during lytic infection. The activity of antiterminator RNA depends on specific structural elements that form as the transcript exits RNA polymerase. To further our understanding of the critical sequence features that permit RNA to serve as a transcriptional antiterminator, we have identified eight antiterminator RNA sequences in bacteriophages or prophages. There is strong sequence conservation among most of the put sequences, but sequence divergence is tolerated if critical structural elements are preserved. The most diverged antiterminator RNA is found in bacteriophage HK639. The HK639 putL transcript is an efficient antiterminator, and it has a novel structural feature that is critical for its activity. HK639 also displays a unique pattern of sensitivity to amino acid substitutions in the ß' subunit zinc binding domain of RNA polymerase, adding to existing evidence that this domain interacts specifically with antiterminator RNA.

Do mitochondria play a role in remodelling lace plant leaves during programmed cell death?

BACKGROUND: Programmed cell death (PCD) is the regulated death of cells within an organism. The lace plant (Aponogeton madagascariensis) produces perforations in its leaves through PCD. The leaves of the plant consist of a latticework of longitudinal and transverse veins enclosing areoles. PCD occurs in the cells at the center of these areoles and progresses outwards, stopping approximately five cells from the vasculature. The role of mitochondria during PCD has been recognized in animals; however, it has been less studied during PCD in plants. RESULTS: The following paper elucidates the role of mitochondrial dynamics during developmentally regulated PCD in vivo in A. madagascariensis. A single areole within a window stage leaf (PCD is occurring) was divided into three areas based on the progression of PCD; cells that will not undergo PCD (NPCD), cells in early stages of PCD (EPCD), and cells in late stages of PCD (LPCD). Window stage leaves were stained with the mitochondrial dye MitoTracker Red CMXRos and examined. Mitochondrial dynamics were delineated into four categories (M1-M4) based on characteristics including distribution, motility, and membrane potential (ΔΨm). A TUNEL assay showed fragmented nDNA in a gradient over these mitochondrial stages. Chloroplasts and transvacuolar strands were also examined using live cell imaging. The possible importance of mitochondrial permeability transition pore (PTP) formation during PCD was indirectly examined via in vivo cyclosporine A (CsA) treatment. This treatment resulted in lace plant leaves with a significantly lower number of perforations compared to controls, and that displayed mitochondrial dynamics similar to that of non-PCD cells. CONCLUSIONS: Results depicted mitochondrial dynamics in vivo as PCD progresses within the lace plant, and highlight the correlation of this organelle with other organelles during developmental PCD. To the best of our knowledge, this is the first report of mitochondria and chloroplasts moving on transvacuolar strands to form a ring structure surrounding the nucleus during developmental PCD. Also, for the first time, we have shown the feasibility for the use of CsA in a whole plant system. Overall, our findings implicate the mitochondria as playing a critical and early role in developmentally regulated PCD in the lace plant.

Initial validation of the trust of automated systems test (TOAST).

Trust is a key determinant of whether people rely on automated systems in the military and the public. However, there is currently no standard for measuring trust in automated systems. In the present studies, we propose a scale to measure trust in automated systems that is grounded in current research and theory on trust formation, which we refer to as the Trust in Automated Systems Test (TOAST). We evaluated both the reliability of the scale structure and criterion validity using independent, military-affiliated and civilian samples. In both studies we found that the TOAST exhibited a two-factor structure, measuring system understanding and performance (respectively), and that factor scores significantly predicted scores on theoretically related constructs demonstrating clear criterion validity. We discuss the implications of our findings for advancing the empirical literature and in improving interface design.

In vitro and in vivo analysis of [(64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2)]: a site-directed radiopharmaceutical for positron-emission tomography imaging of T-47D human breast cancer tumors.

INTRODUCTION: Human breast cancer, from which the T-47D cell line was derived, is known to overexpress the gastrin-releasing peptide receptor (GRPR) in some cases. Bombesin (BBN), an agonist for the GRPR, has been appended with a radionuclide capable of positron-emission tomography (PET) imaging and therapy. (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) (NO2A=1,4,7-triazacyclononane-1,4-diacetate) has produced high-quality microPET images of GRPR-positive breast cancer xenografted tumors in mice. METHODS: The imaging probe was synthesized by solid-phase peptide synthesis followed by manual conjugation of the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) bifunctional chelator and radiolabeling in aqueous solution. The radiolabeled conjugate was subjected to in vitro and in vivo studies to determine its specificity for the GRPR and its pharmacokinetic profile. A T-47D tumor-bearing mouse was imaged with microPET/CT and microMRI imaging. RESULTS: The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) targeting vector was determined to specifically localize in GRPR-positive tissue. Accumulation was observed in the tumor in sufficient quantities to allow for identification of tumors in microPET imaging procedures. For example, uptake and retention in T-47D xenografts at 1, 4 and 24 h were determined to be 2.27+/-0.08, 1.35+/-0.14 and 0.28+/-0.07 % ID/g, respectively. CONCLUSIONS: The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) produced high-quality microPET images. The pharmacokinetic profile justifies investigation of this bioconjugate as a potentially useful diagnostic/therapeutic agent. Additionally, the bioconjugate would serve as a good starting point for modification and optimization of similar agents to maximize tumor uptake and minimize nontarget accumulation.

Focusing personality assessment on the person: Modeling general, shared, and person specific processes in personality and psychopathology.

Personality and psychopathology are composed of dynamic and interactive processes among diverse psychological systems, manifesting over time and in response to an individual's natural environment. Ambulatory assessment techniques promise to revolutionize assessment practices by allowing access to the dynamic data necessary to study these processes directly. Assessing manifestations of personality and psychopathology naturalistically in an individual's own ecology allows for dynamic modeling of key behavioral processes. However, advances in dynamic data collection have highlighted the challenges of both fully understanding an individual (via idiographic models) and how s/he compares with others (as seen in nomothetic models). Methods are needed that can simultaneously model idiographic (i.e., person-specific) processes and nomothetic (i.e., general) structure from intensive longitudinal personality assessments. Here we present a method, group iterative multiple model estimation (GIMME) for simultaneously studying general, shared (i.e., in subgroups), and person-specific processes in intensive longitudinal behavioral data. We first provide an introduction to the GIMME method, followed by a demonstration of its use in a sample of individuals diagnosed with personality disorder who completed daily diaries over 100 consecutive days. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Uncovering general, shared, and unique temporal patterns in ambulatory assessment data.

Intensive longitudinal data provide psychological researchers with the potential to better understand individual-level temporal processes. While the collection of such data has become increasingly common, there are a comparatively small number of methods well-suited for analyzing these data, and many methods assume homogeneity across individuals. A recent development rooted in structural equation and vector autoregressive modeling, Subgrouping Group Iterative Multiple Model Estimation (S-GIMME), provides one method for arriving at individual-level models composed of processes shared by the sample, a subset of the sample, and a given individual. As this algorithm was motivated and validated for use with neuroimaging data, its performance is less understood in the context of ambulatory assessment data. Here, we evaluate the performance of the S-GIMME algorithm across various conditions frequently encountered with daily diary (compared to neuroimaging) data; namely, a smaller number of variables, a lower number of time points, and smaller autoregressive effects. We demonstrate, for the first time, the importance of the autoregressive effects in recovering data-generating connections and directions, and the ability to use S-GIMME with lengths of data commonly seen in daily diary studies. We demonstrate the use of S-GIMME with an empirical example evaluating the general, shared, and unique temporal processes associated with a sample of individuals with borderline personality disorder (BPD). Finally, we underscore the need for methods such as S-GIMME moving forward given the increasing use of intensive longitudinal data in psychological research, and the potential for these data to provide novel insights into human behavior and mental health. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

99mTc(CO)3-DTMA bombesin conjugates having high affinity for the GRP receptor.

INTRODUCTION: Targeted diagnosis of specific human cancer types continues to be of significant interest in nuclear medicine. 99mTc is ideally suited as a diagnostic radiometal for in vivo tumor targeting due to its ideal physical characteristics and diverse labeling chemistries in numerous oxidation states. METHODS: In this study, we report a synthetic approach toward design of a new tridentate amine ligand for the organometallic aqua-ion [99mTc(H2O)3(CO)3]+. The new chelating ligand framework, 2-(N,N'-Bis(tert-butoxycarbonyl)diethylenetriamine) acetic acid (DTMA), was synthesized from a diethylenetriamine precursor and fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy (1H and 13C). DTMA was conjugated to H2N-(X)-BBN(7-14)NH2, where X=an amino acid or aliphatic pharmacokinetic modifier and BBN=bombesin peptide, by means of solid phase peptide synthesis. DTMA-(X)-BBN(7-14)NH2 conjugates were purified by reversed-phase high-performance chromatography and characterized by electrospray-ionization mass spectrometry. RESULTS: The new conjugates were radiolabeled with [99mTc(H2O)3(CO)3]+ produced via Isolink radiolabeling kits to produce [99mTc(CO)3-DTMA-(X)-BBN(7-14)NH2]. Radiolabeled conjugates were purified by reversed-phase high-performance chromatography. Effective receptor binding behavior was evaluated in vitro and in vivo. CONCLUSIONS: [99mTc(CO)3-DTMA-(X)-BBN(7-14)NH2] conjugates displayed very high affinity for the gastrin releasing peptide receptor in vitro and in vivo. Therefore, these conjugates hold some propensity to be investigated as molecular imaging agents that specifically target human cancers uniquely expressing the gastrin releasing peptide receptor subtypes.

The effects of linking substituents on the in vivo behavior of site-directed, peptide-based, diagnostic radiopharmaceuticals.

A number of human cancers are known to over-express the gastrin-releasing peptide receptor (GRPr) on cell surfaces. The high specificity and affinity of bombesin (BBN), an amphibian analogue of mammalian gastrin-releasing peptide, for the GRPr makes it an ideal candidate for delivery of diagnostic probes, such as 99mTc radiometal, to tumor sites. An optimized targeting agent possesses high tumor uptake with minimal uptake in normal tissues. In this study, 99mTc-targeting vectors of bombesin using various amino acid/aliphatic pharmacokinetic modifiers or linking groups were evaluated to determine the effect of the spacer on receptor binding affinity, internalization/externalization and biodistribution. Conjugates of the general type [DPR-X-BBN] (X = amino acid/aliphatic pharmacokinetic modifier) were synthesized by solid phase peptide synthesis (SPPS) and metallated with either low-valent, radioactive Tc-99m(I) or non-radioactive Re(I)-tricarbonyl precursors. All of the new non-metallated and metallated conjugates were characterized by electrospray ionization mass spectrometry (ESI-MS). Receptor binding affinity, internalization/externalization and biodistribution studies in normal (CF-1) and tumor (human prostate PC-3-bearing mice) are reported. The effectiveness of targeting xenografted PC-3 tumors in rodents for two of the new 99mTc-BBN conjugates is demonstrated herein using small animal single photon emission computed tomography (SPECT).

Parsing Heterogeneity in the Brain Connectivity of Depressed and Healthy Adults During Positive Mood.

BACKGROUND: There is well-known heterogeneity in affective mechanisms in depression that may extend to positive affect. We used data-driven parsing of neural connectivity to reveal subgroups present across depressed and healthy individuals during positive processing, informing targets for mechanistic intervention. METHODS: Ninety-two individuals (68 depressed patients, 24 never-depressed control subjects) completed a sustained positive mood induction during functional magnetic resonance imaging. Directed functional connectivity paths within a depression-relevant network were characterized using Group Iterative Multiple Model Estimation (GIMME), a method shown to accurately recover the direction and presence of connectivity paths in individual participants. During model selection, individuals were clustered using community detection on neural connectivity estimates. Subgroups were externally tested across multiple levels of analysis. RESULTS: Two connectivity-based subgroups emerged: subgroup A, characterized by weaker connectivity overall, and subgroup B, exhibiting hyperconnectivity (relative to subgroup A), particularly among ventral affective regions. Subgroup predicted diagnostic status (subgroup B contained 81% of patients; 50% of control subjects; χ2 = 8.6, p = .003) and default mode network connectivity during a separate resting-state task. Among patients, subgroup B members had higher self-reported symptoms, lower sustained positive mood during the induction, and higher negative bias on a reaction-time task. Symptom-based depression subgroups did not predict these external variables. CONCLUSIONS: Neural connectivity-based categorization travels with diagnostic category and is clinically predictive, but not clinically deterministic. Both patients and control subjects showed heterogeneous, and overlapping, profiles. The larger and more severely affected patient subgroup was characterized by ventrally driven hyperconnectivity during positive processing. Data-driven parsing suggests heterogeneous substrates of depression and possible resilience in control subjects in spite of biological overlap.

Development of local knowledge of environmental contamination in Sydney, Nova Scotia: environmental health practice from an environmental justice perspective.

In Sydney, Nova Scotia, from 1901 through 1988 a coke and steel factory operated with no pollution controls, depositing over a million tons of particulate matter and releasing several thousands of tons of coal tar into the estuary. Previously we documented the presence of lead, arsenic and PAHs, in soil above Canadian guidelines, and in house dust in the communities surrounding the site [Lambert, TW, Lane, S. Lead, arsenic, and polycyclic aromatic hydrocarbons in soil and house dust in the communities surrounding the Sydney, Nova Scotia, tar ponds. Environ Health Perspect 2004; 112:35-41.]. In this paper we further the research by documenting and developing community knowledge with a study of resident's observations and experiences of the industrial contamination. We conducted two surveys, a quantitative door-to-door survey and qualitative dust interview, designed to complement each other and bring together the observations and experiences in the different communities to develop the local knowledge. The combined methodology uses techniques from both social and physical science, and was developed with the cooperation of community members. The research supports the proposition that local knowledge adds contextual meaning that complements the physical measurement of environmental contaminants, in order to understand the complex environment in which people live, and the multiple exposure pathways through which they can be affected. Residents in all three communities provided vivid observations and detailed experiences of the industrial pollution in their community and homes. The local knowledge is consistent with our physical data and review of the historical scientific research in Sydney, and supports the inference that the community was adversely impacted by the coke and steel facility. From a justice perspective, the three communities should be equally considered for remediation as part of the 'tar pond remediation policy' rather than the current policy of including only a few streets and houses.

Lead, arsenic, and polycyclic aromatic hydrocarbons in soil and house dust in the communities surrounding the Sydney, Nova Scotia, tar ponds.

This study evaluated lead, arsenic, and polycyclic aromatic hydrocarbon (PAH) contamination in the residential communities adjacent to the Sydney, Nova Scotia, tar ponds, the area considered Canada's worst contaminated site. The tar pond remediation policy has been limited to the site and some residential properties. We compared background concentrations in 91 soil samples taken 5-20 km from the coke oven site with those in soil samples from the three communities surrounding the tar ponds: Whitney Pier, Ashby, and North End. These surrounding communities were statistically different from background regarding arsenic, lead, and PAHs. Twenty percent of the background soil samples and 95% of the tar pond soil samples were above the Canadian health-risk-based soil guidelines for arsenic (12 ppm), and 5% of the background samples and 80% of the tar pond soil samples were above the Canadian guidelines for lead (140 ppm). Regarding dust lead and arsenic loading, the results provide no evidence that Whitney Pier is significantly different than Ashby and North End. Children in these communities are predicted to have a 1-15% chance of blood lead > 10 microg/dL. The results suggest that lead and arsenic found in the homes originate outside. The lead content of paint in the homes was not evaluated, but consideration of painted wood at the doorway did not confound the results of the study. The results indicate that the residential environment has been adversely affected by PAHs, lead, and arsenic and should be considered for remediation.

The separation of between-person and within-person components of individual change over time: a latent curve model with structured residuals.

OBJECTIVE: Although recent statistical and computational developments allow for the empirical testing of psychological theories in ways not previously possible, one particularly vexing challenge remains: how to optimally model the prospective, reciprocal relations between 2 constructs as they developmentally unfold over time. Several analytic methods currently exist that attempt to model these types of relations, and each approach is successful to varying degrees. However, none provide the unambiguous separation over time of between-person and within-person components of stability and change, components that are often hypothesized to exist in the psychological sciences. Our goal in this article is to propose and demonstrate a novel extension of the multivariate latent curve model to allow for the disaggregation of these effects. METHOD: We begin with a review of the standard latent curve models and describe how these primarily capture between-person differences in change. We then extend this model to allow for regression structures among the time-specific residuals to capture within-person differences in change. RESULTS: We demonstrate this model using an artificial data set generated to mimic the developmental relation between alcohol use and depressive symptomatology spanning 5 repeated measures. CONCLUSIONS: We obtain a specificity of results from the proposed analytic strategy that is not available from other existing methodologies. We conclude with potential limitations of our approach and directions for future research.

Clarifying the nature of startle habituation using latent curve modeling.

Startle habituation is present in all startle studies, whether as a dependent variable, discarded habituation block, or ignored nuisance. However, there is still much that remains unknown about startle habituation, including the following: (1) what is the nature of the startle habituation curve?; (2) at what point does startle habituation approach an asymptote?; and (3) are there gender differences in startle habituation? The present study investigated these three questions in a sample of 94 undergraduates using both traditional means-based statistical methods and latent curve modeling. Results provided new information about the nature of the startle habituation curve, indicated that the optimal number of habituation trials with a 100dB startle stimulus is 13, and showed that females display greater startle reactivity but habituate toward the same level as males.

Re(V) and Re(III) complexes with sal2phen and triphenylphosphine: rearrangement, oxidation and reduction.

Reactions of Re(V), tetradentate Schiff base complexes with tertiary phosphines have previously yielded both rearranged Re(V) and reduced Re(III) complexes. To further understand this chemistry, the rigid diiminediphenol (N(2)O(2)) Schiff base ligand sal(2)phen (N,N'-o-phenylenebis(salicylaldimine)) was reacted with (n-Bu(4)N)[ReOCl(4)] to yield trans-[ReOCl(sal(2)phen)] (1). On reaction with triphenylphosphine (PPh(3)), a rearranged Re(V) product cis-[ReO(PPh(3))(sal(2)phen*)]PF(6) (2), in which one of the imines was reduced to an amine during the reaction, and the reduced Re(III) products trans-[ReCl(PPh(3))(sal(2)phen)] (4) and trans-[Re(PPh(3))(2)(sal(2)phen)](+) (5) were isolated. Reaction of sal(2)phen with [ReCl(3)(PPh(3))(2)(CH(3)CN)] resulted in the isolation of [ReCl(2)(PPh(3))(2)(salphen)] (3). The compounds were characterized using standard spectroscopic methods, elemental analyses and single crystal X-ray crystallography.

Radiolabeled regulatory peptides for imaging and therapy.

PURPOSE OF REVIEW: The purpose of the present review is to describe new, innovative strategies of diagnosing and treating specific human cancers using a cadre of radiolabeled regulatory peptides. RECENT FINDINGS: Peptide receptor-targeted radionuclide therapy is a method of site-directed radiotherapy that specifically targets human cancers expressing a cognate receptor-subtype in very high numbers. Ideally, the procedure targets only the primary or metastatic disease and is minimally invasive, with little radiation damage to normal, collateral tissues. For treatment strategies of this type to be effective, it is critical to evaluate the toxicity of the treatment protocol, the radiation dosimetry of the therapeutic regimen, and the biological profile of the radiopharmaceutical, including biodistribution and pharmacokinetics of the drug. Site-directed molecular imaging procedures via gamma-scintigraphy can address many of the critical issues associated with peptide receptor-targeted radionuclide therapy and it is, therefore, necessary to describe the effective balance between the clinical benefits and risks of this treatment strategy. SUMMARY: Continued development in the design or chemical structure of radiolabeled, biologically active peptides could do much to improve the targeting ability of these drugs, thereby creating new and innovative strategies for diagnosis or treatment of human cancers.