CAR T Cell Therapy in Hematological Malignancies: Implications of the Tumor Microenvironment and Biomarkers on Efficacy and Toxicity

Chimeric antigen receptor (CAR) T cell therapy has ushered in a new era in cancer treatment. Remarkable outcomes have been demonstrated in patients with previously untreatable relapsed/refractory hematological malignancies. However, optimizing efficacy and reducing the risk of toxicities have posed major challenges, limiting the success of this therapy. The tumor microenvironment (TME) plays an important role in CAR T cell therapy’s effectiveness and the risk of toxicities. Increasing research studies have also identified various biomarkers that can predict its effectiveness and risk of toxicities. In this review, we discuss the various aspects of the TME and biomarkers that have been implicated thus far and discuss the role of creating scoring systems that can aid in further refining clinical applications of CAR T cell therapy and establishing a safe and efficacious personalised medicine for individuals.     

An Iron Refractory Phenotype in Obese Adipose Tissue Macrophages Leads to Adipocyte Iron Overload

Adipocyte iron overload is a maladaptation associated with obesity and insulin resistance. The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance.     

Optimization of nuclear magnetic resonance and gas chromatography-mass spectrometry-based fingerprinting methods to characterize goat milk powder

This study is the first to provide a comprehensive characterization of the liquid and volatile fractions of whole goat milk powder (GMP). Robust nuclear magnetic resonance (NMR)- and gas chromatography-mass spectrometry (GC-MS)-based chemical fingerprinting methods were optimized and implemented. The untargeted ¹H-NMR analysis resolved 44 metabolites in the liquid fractions of GMP. The NMR fingerprinting technique effectively identified metabolites coming from the aliphatic, sugar, and aromatic regions that can be important in defining the technological properties and quality of the GMP. The untargeted headspace gas chromatography-mass spectrometry fingerprinting was able to detect a total of 50 volatiles including alkanes, ketones, alcohols, aromatics, alkenes, aldehydes, esters, acid, and sulfur compounds. The GMP was dominated by volatiles in the alkane group, while only a few esters were detected. Goat milk is a premium product and vulnerable to fraudulent activities such as adulteration or counterfeit. Therefore, proper characterization and identification is a crucial first step to verify its authenticity and quality.     

Transfer of value from fit.

People experience regulatory fit when they pursue a goal in a manner that sustains their regulatory orientation (E. T. Higgins, 2000). Five studies tested whether the value experienced from regulatory fit can transfer to a subsequent evaluation of an object. In Studies 1 and 2, participants gave the same coffee mug a higher price if they had chosen it with a strategy that fit their orientation (eager strategy/promotion; vigilant strategy/prevention) than a strategy that did not fit. Studies 3-5 investigated possible mechanisms underlying this effect. Value transfer was independent of positive mood, perceived effectiveness (instrumentality), and perceived efficiency (ease), and occurred for an object that was independent of the fit process itself. The findings supported a value confusion account of transfer. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Assessment of test user qualifications: A research-based measurement procedure.

The qualifications of test purchasers have been a concern of the American Psychological Association since 1950, when ethical standards for test distribution, on the basis of a 3-level classification of tests, were developed. The standards relied on professional credentials and on occupational titles to screen test purchasers. In response to widespread recognition that credentials and titles were inadequate to screen test purchasers, the Test User Qualifications Working Group used 2 job analysis methods to determine test user competencies. This article describes the results of that research that can be applied to improving testing practices, including (a) 86 test user competencies and 7 factors accounting for much test misuse, (b) a test classification system based on critical incidents of test misuse, and (c) empirically based test purchaser qualification forms. These products are designed to help achieve responsible test use. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The intersection of race and gender: Examining the politics of identity in women's studies.

Although race and gender are often treated as discrete dimensions of social identity, their conceptualization as intersecting categories has become central in some feminist critiques of existing theory. This study examined women's awareness of the intersection of race and gender in relation to attitudes regarding 2 issues manifesting identity politics in women's studies: (a) the marginalization of women of color and (b) proposals for separate women of color studies programs. Identity and attitude measures were completed by 110 female students enrolled in a women's studies program. The results of a structural equation model lend support to the hypotheses that attitudes toward a separate women of color studies program would be determined by an awareness of the race/gender intersection, and by a perception that women of color are marginalized in existing programs. Responses to issues regarding race and gender in women's studies are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Distribution of Mercury,Trace Organics,and Other Heavy Metals in Detroit River Sediments

In 1980 the Ontario Ministry of the Environment carried out a surficial bottom sediment survey of the Detroit River. The survey was designed to update changes in sediment mercury levels from a 1970 study, and to determine the spatial distribution of trace organics and other heavy metals as a baseline for future investigations. The contamination of sediments along the Ontario shoreline of the river was localized near known inputs such as Little River, the West Windsor sewage treatment plant, Turkey Creek, and Riviere aux Canards. Almost the entire U.S. shoreline sediments exhibited elevated levels (above provincial dredging guidelines) of contaminants such as heavy metals and PCBs. Levels of one order of magnitude higher than those on the Canadian shore were prevalent along the U.S. shore. Mercury levels exhibited a substantial decline during the period 1970–1980. Increases in chromium, copper, lead, and zinc in the vicinity of the mouth of the Rouge River along the U.S. shoreline during the same period suggest both recent and continuing inputs from industrial and municipal sources.     

Detection of intermodal proprioceptive–visual contingency as a potential basis of self-perception in infancy.

Four studies investigated 29 3-mo-old (Exp IV) and 60 5-mo-old (Exps I–III) infants' capacity to detect proprioceptive–visual relations uniting self-motion with a visual display of that motion. Previous research has shown that 5-mo-old infants can detect the invariant relationship between their own leg motion and a video display of that motion. The 1st 3 experiments showed that the 5-mo-olds discriminated between a perfectly contingent live display of their own leg motion and a noncontingent display of self or a peer. They showed this discrimination by preferential fixation of the noncontingent display. This effect was evident even when an S's direct view of his/her own body was occluded, eliminating video image discrimination on the basis of an intramodal visual comparison between the sight of self-motion and the video display of that motion. These results suggest that the contingency provided by a live display of one's body motion is perceived by detecting the invariant intermodal relationship between proprioceptive information for motion and the visual display of that motion. The detection of these relations may be fundamental to the development of self-perception in infancy. Although 3-mo-olds did not show significant discrimination of the contingent and noncontingent displays in Exp IV, they did show significantly more extreme looking proportions to the 2 displays than did the 5-mo-olds. This may reflect the infant's progression from a self- to a social orientation. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A critique of Alloy and Tabachnik's theoretical framework for understanding covariation assessment.

Alloy and Tabachnik (1984) recently proposed a theoretical framework for integrating animals' and people's covariation assessment. The framework assumes that animals and humans form cognitive representations of event contingencies that interact with prior expectations to influence covariation assessment. We point out misrepresentations in Alloy and Tabachnik's evaluation of the animal and human covariation assessment literature and some incorrect predictions that their model makes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Health effects of vibration in agriculture - Pilot for an epidemiological study

A pilot study has been conducted to prepare for an epidemiological study into the effects of vibration on tractor drivers. The reason for the study is that, despite a large volume of existing data on health and vibration (over 43,000 exposed workers having been studied) there is still no good basis for estimating dose-response relationships between vibration and health. There have been three main difficulties:

• - Many studies have not measured vibration, or have not measured it thoroughly enough.

• - Confounding variables such as posture have not been entirely controlled for, because well-matched control groups do not exist.

• - Health data have tended to be binary incidence data rather than continuous scale data, reducing the sensitivity of the studies.

The pilot study has produced procedures to overcome these difficulties.