Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers.

We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age ≥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3× normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.

Outcomes of Burkitt lymphoma with central nervous system involvement: evidence from a large multicenter cohort study.

Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.

Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy.

BACKGROUND: Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS: Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS: Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION: In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE: Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

Impact of Treatment Beyond Progression with Immune Checkpoint Blockade in Hodgkin Lymphoma.

Atypical response patterns following immune checkpoint blockade (ICB) in Hodgkin lymphoma (HL) led to the concept of continuation of treatment beyond progression (TBP); however, the longitudinal benefit of this approach is unclear. We therefore performed a retrospective analysis of 64 patients treated with ICB; 20 who received TBP (TBP cohort) and 44 who stopped ICB at initial progression (non-TBP cohort). The TBP cohort received ICB for a median of 4.7 months after initial progression and delayed subsequent treatment by a median of 6.6 months. Despite receiving more prior lines of therapy, the TBP cohort achieved longer progression-free survival with post-ICB treatment (median, 17.5 months vs. 6.1 months, p = .035) and longer time-to-subsequent treatment failure, defined as time from initial ICB progression to failure of subsequent treatment (median, 34.6 months vs. 9.9 months, p = .003). With the limitations of a retrospective study, these results support the clinical benefit of TBP with ICB for selected patients.

Diagnostic Utility of CT and Fluoroscopic Esophagography for Suspected Esophageal Perforation in the Emergency Department.

OBJECTIVE. We evaluated the diagnostic utility of CT in emergency department (ED) patients with suspected esophageal perforation and assessed whether subsequent fluoroscopic esophagography is necessary. MATERIALS AND METHODS. This retrospective study included consecutive adult patients presenting to an urban academic tertiary care ED from January 1, 2000, to August 31, 2017, who underwent CT and fluoroscopic esophagography within 1 calendar day (< 27 hours) of each other for suspected esophageal perforation. The use of oral or IV contrast material and the CT findings (i.e., pneumomediastinum, pleural effusion, pneumothorax, unexplained mediastinal fluid or stranding, esophageal wall air or frank esophageal wall disruption, or extraluminal oral contrast material) were documented. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Surgical or procedural intervention results or clinical follow-up results were the reference standard. RESULTS. One hundred three patients met the inclusion criteria. Sensitivity, specificity, PPV, and NPV for diagnosing esophageal perforation were 100.0%, 79.8%, 32.1%, and 100.0%, respectively, with CT and 77.8%, 98.9%, 87.5%, and 97.9% with fluoroscopic esophagography. Combining CT and fluoroscopic esophagography did not improve sensitivity, specificity, PPV, or NPV relative to using CT alone. The true-positive esophageal perforation rate was 8.7% for CT and 6.8% for fluoroscopic esophagography. When CT showed only pneumomediastinum (n = 51) or no pneumomediastinum (n = 14), the NPV of CT was 100.0%. CT with oral contrast material had a PPV of 38.5%, whereas CT without oral contrast material had a PPV of 26.7%. CONCLUSION. CT has a high NPV similar to that of fluoroscopic esophagography and has greater sensitivity than fluoroscopic esophagography for diagnosing suspected esophageal perforation. Fluoroscopic esophagrams do not provide additional information that changes clinical management beyond the information that CT provides. In ED patients with suspected esophageal perforation, CT with oral contrast material should be considered the initial imaging examination and can obviate fluoroscopic esophagography.

Adnexal mass staging CT with a disease-specific structured report compared to simple structured report.

OBJECTIVES: To assess a disease-specific structured report (dsSR) for CT staging of ovarian malignancy compared to a simple structured report (sSR). METHODS: This is a HIPAA-compliant, IRB-approved study with waiver of informed consent. An adnexal mass-specific structured reporting CT template was developed in collaboration between gynecologic oncologists and diagnostic radiologists. The study population included 24 consecutive women who had a staging CT prior to undergoing debulking surgery for a primary ovarian malignancy. Objective evaluation by radiologists for the presence of 19 key features and subjective evaluation by gynecologic oncologists were performed to assess the clarity and usefulness for procedural planning of dsSR and sSR. Accuracy, sensitivity, and specificity were assessed using operating room notes and pathology reports as the reference standard. RESULTS: Fewer key features were missing from dsSR than sSR: 0.2 ± 0.8 (range 0-2) vs.10.2 ± 1.7 (range 7-14), respectively (p < 0.0001). Compared to sSR, gynecologic oncologists deemed dsSR more helpful (4.3 ± 0.7 vs. 3.7 ± 0.8, p < 0.0001) and easier to understand (4.3 ± 0.6 vs. 3.9 ± 0.7, p = 0.0057) (on a scale 0-5, 0 not helpful/very difficult to understand; 5 extremely helpful/very clear to understand). Gynecologic oncologists reported a higher rate of potential to modify their surgical approach based on dsSR (33-42%) compared to sSR (13-17%), p = 0.004. CONCLUSIONS: Disease-specific structured reports were more reliable than simple structured reports in describing key features essential for procedural planning. dsSR was described as more helpful and easier to understand and more likely to lead to modification of the surgical approach by gynecologic oncologists compared to sSR. KEY POINTS: • Disease-specific structured report is easier to understand and more helpful for planning gynecological surgery as compared with simple structured report. • Disease-specific structured report for pre-operative evaluation of ovarian cancer provides better documentation of essential features required for surgical planning as compared with simple structured report. • Disease-specific structured report has the potential to modify the surgical approach as assessed by gynecologic oncologists.

An age dependent response to hydroxyurea in pediatric sickle cell anemia patients with alpha thalassemia trait.

Hydroxyurea (HU) is a key drug therapy for individuals with sickle cell anemia (SCA), yet its clinical and hematologic responses can be variable. Various studies have reported the role of α-thalassemia as one of the most prevalent heritable traits that may modify HU response. We provide data from 62 pediatric and adolescent patients with SCA, 26 with co-inherited α-thalassemia trait. Our data suggest that altered hematologic and clinical responses to HU therapy are noted in adolescent SCA individuals with co-inherited α-thalassemia trait. Adolescent patients who co-inherited α-thalassemia trait had a greater reduction in vaso-occlusive episodes compared to those without α-thalassemia, despite a less robust fetal hemoglobin induction as well as a lower maximum HU dose. This clinical improvement was associated with a lower MCH and higher RBC count. Responses to HU in younger SCA children (ages 5-11years) with co-inherited α-thalassemia trait, compared to those without α-thalassemia trait, did not show any difference in number vaso-occlusive episodes, fetal hemoglobin induction and change in MCH and RBC count.

Lactobacillus rhamnosus GG probiotic enteric regimen does not appreciably alter the gut microbiome or provide protection against GVHD after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GVHD) is a major adverse effect associated with allogeneic stem cell transplant. Previous studies in mice indicated that administration of the probiotic Lactobacillus rhamnosus GG can reduce the incidence of GVHD after hematopoietic stem cell transplant. Here we report results from the first randomized probiotic enteric regimen trial in which allogenic hematopoietic stem cell patients were supplemented with Lactobacillus rhamnosus GG. Gut microbiome analysis confirmed a previously reported gut microbiome association with GVHD. However, the clinical trial was terminated when interim analysis did not detect an appreciable probiotic-related change in the gut microbiome or incidence of GVHD. Additional studies are necessary to determine whether probiotics can alter the incidence of GVHD after allogeneic stem cell transplant.

BOLD v4: A Centralized Bioinformatics Platform for DNA-Based Biodiversity Data.

BOLD, the Barcode of Life Data System, supports the acquisition, storage, validation, analysis, and publication of DNA barcodes, activities requiring the integration of molecular, morphological, and distributional data. Its pivotal role in curating the reference library of DNA barcodes, coupled with its data management and analysis capabilities, makes it a central resource for biodiversity science. It enables rapid, accurate identification of specimens and also reveals patterns of genetic diversity and evolutionary relationships among taxa.Launched in 2005, BOLD has become an increasingly powerful tool for advancing the understanding of planetary biodiversity. It currently hosts 17 million specimen records and 14 million barcodes that provide coverage for more than a million species from every continent and ocean. The platform has the long-term goal of providing a consistent, accurate system for identifying all species of eukaryotes.BOLD's integrated analytical tools, full data lifecycle support, and secure collaboration framework distinguish it from other biodiversity platforms. BOLD v4 brought enhanced data management and analysis capabilities as well as novel functionality for data dissemination and publication. Its next version will include features to strengthen its utility to the research community, governments, industry, and society-at-large.

Management of Mammographic Architectural Distortion Based on Contrast-enhanced MRI and US Correlation.

OBJECTIVE: The objective was to evaluate outcomes of mammographic architectural distortion (AD) with and without MRI and US correlates. METHODS: A retrospective review of unexplained mammographic AD with subsequent MRI from January 1, 2007 to September 30, 2017 was performed using a reader-based study design. Mammographic, MRI, and US features and outcomes were documented. Truth was based on biopsy results or minimum two-year imaging follow-up. Measures of diagnostic accuracy were calculated. RESULTS: Fifty-six cases of AD were included: 29 (51.8%) detected on 2D mammogram and 27 (48.2%) detected on digital breast tomosynthesis. Of 35.7% (20/56) with MRI correlate, 40.0% (8/20) were enhancing masses, 55.0% (11/20) were non-mass enhancement (NME), and 5.0% (1/20) were nonenhancing AD. Of eight enhancing masses, 75.0% (6/8) were invasive cancers, and 25.0% (2/8) were high-risk lesions. Of 11 NME, 18.2% (2/11) were ductal carcinoma in situ, 36.4% (4/11) were high-risk lesions, and 45.4% (5/11) were benign. Of 64.3% (36/56) without MRI correlate, 94.4% (34/36) were benign by pathology or follow-up, one (2.8%, 1/36) was a 4-mm focus of invasive cancer with US correlate, and one (1/36, 2.8%) was a high-risk lesion. Of cases without MRI and US correlates, one (3.0%, 1/33) was a high-risk lesion and 97.0% (32/33) were benign. The negative predictive value of mammographic AD without MRI correlate was 97.2% (35/36) and without both MRI and US correlates was 100.0% (33/33). CONCLUSION: Mammographic AD without MRI or US correlate was not cancer in our small cohort and follow-up could be considered, reducing interventions.

Normal and abnormal functions of adenosine receptors in the central nervous system revealed by genetic knockout studies.

Endogenous adenosine is a widely distributed upstream regulator of a broad spectrum of neurotransmitters, receptors, and signaling pathways that converge to contribute to the expression of an array of important brain functions. Over the past decade, the generation and characterization of genetic knockout models for all four G-protein coupled adenosine receptors, the A1 and A2A receptors in particular, has confirmed and extended the neuromodulatory and integrated role of adenosine receptors in the control of a broad spectrum of normal and abnormal brain functions. After a brief introduction of the available adenosine receptor knockout models, this review focuses on findings from the genetic knockout approach, placing particular emphasis on the most recent findings. This review is organized into two sections to separately address (i) the role of adenosine receptors in normal brain processes including neuroplasticity, sleep-wake cycle, motor function, cognition, and emotion-related behaviors; and (ii) their role in the response to various pathologic insults to brain such as ischemic stroke, neurodegeneration, or brain dysfunction/disorders. We largely limit our overview to the prominent adenosine receptor subtypes in brain-the A1 and A2A receptors-for which numerous genetic knockout studies on brain function are available. A1 and A2A receptor knockouts have provided significant new insights into adenosine's control of complex physiologic (e.g., cognition) and pathologic (e.g., neuroinflammation) phenomena. These findings extend and strengthen the support for A1 and A2A receptors in brain as therapeutic targets in several neurologic and psychiatric diseases. However, they also emphasize the importance of considering the disease context-dependent effect when developing adenosine receptor-based therapeutic strategies.

Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning.

The adenosine A(2A) receptor (A(2A)R) is highly enriched in the striatum where it is uniquely positioned to integrate dopaminergic, glutamatergic, and other signals to modulate cognition. Although previous studies support the hypothesis that A(2A)R inactivation can be pro-cognitive, analyses of A(2A)R's effects on cognitive functions have been restricted to a small subset of cognitive domains. Furthermore, the relative contribution of A(2A)Rs in distinct brain regions remains largely unknown. Here, we studied the regulation of multiple memory processes by brain region-specific populations of A(2A)Rs. Specifically, we evaluated the cognitive impacts of conditional A(2A)R deletion restricted to either the entire forebrain (i.e., cerebral cortex, hippocampus, and striatum, fb-A(2A)R KO) or to striatum alone (st-A(2A)R KO) in recognition memory, working memory, reference memory, and reversal learning. This comprehensive, comparative analysis showed for the first time that depletion of A(2A)R-dependent signaling in either the entire forebrain or striatum alone is associated with two specific phenotypes indicative of cognitive flexibility-enhanced working memory and enhanced reversal learning. These selective pro-cognitive phenotypes seemed largely attributed to inactivation of striatal A(2A)Rs as they were captured by A(2A)R deletion restricted to striatal neurons. Neither spatial reference memory acquisition nor spatial recognition memory were grossly affected, and no evidence for compensatory changes in striatal or cortical D(1), D(2), or A(1) receptor expression was found. This study provides the first direct demonstration that targeting striatal A(2A)Rs may be an effective, novel strategy to facilitate cognitive flexibility under normal and pathologic conditions.

HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis.

Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.

The spectrum of kidney disease in patients with AIDS in the era of antiretroviral therapy.

With prolonged survival and aging of the HIV-infected population in the era of antiretroviral therapy, biopsy series have found a broad spectrum of HIV-related and co-morbid kidney disease in these patients. Our study describes the variety of renal pathology found in a prospective cohort of antiretroviral-experienced patients (the Manhattan HIV Brain Bank) who had consented to postmortem organ donation. Nearly one-third of 89 kidney tissue donors had chronic kidney disease, and evidence of some renal pathology was found in 75. The most common diagnoses were arterionephrosclerosis, HIV-associated nephropathy and glomerulonephritis. Other diagnoses included pyelonephritis, interstitial nephritis, diabetic nephropathy, fungal infection and amyloidosis. Excluding 2 instances of acute tubular necrosis, slightly over one-third of the cases would have been predicted using current diagnostic criteria for chronic kidney disease. Based on semi-quantitative analysis of stored specimens, pre-mortem microalbuminuria testing could have identified an additional 12 cases. Future studies are needed to evaluate the cost-effectiveness of more sensitive methods for defining chronic kidney disease, in order to identify HIV-infected patients with early kidney disease who may benefit from antiretroviral therapy and other interventions known to delay disease progression and prevent complications.

Prenatal exposure to lead, delta-aminolevulinic acid, and schizophrenia: further evidence.

BACKGROUND: A previously conducted study of prenatal lead exposure and schizophrenia using delta-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959-1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life. OBJECTIVES: In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959-1966). Using similar methods, in this study we found results that suggest a comparable association in this cohort. METHODS: We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education. RESULTS: The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 microg/dL of blood Pb was 1.92 (95% confidence interval, 1.05-3.87; p = 0.03). CONCLUSION: Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.

Adenosine A2A receptors in bone marrow-derived cells but not in forebrain neurons are important contributors to 3-nitropropionic acid-induced striatal damage as revealed by cell-type-selective inactivation.

Endogenous adenosine acting at the adenosine A2A receptor (A2AR) can modify brain injury in a variety of neurological disorder models. However, both A2AR activation and inactivation have been shown to be neuroprotective in different situations, raising the intriguing possibility that A2ARs in distinct cellular elements may have different and even opposing effects. In this study, we developed three novel transgenic models to dissect out cell-type-specific actions of A2ARs on striatal damage by the mitochondrial toxin 3-nitropropionic acid (3-NP). Whereas global inactivation of A2ARs exacerbated 3-NP-induced neurological deficit behaviors and striatal damage, selective inactivation of A2ARs in forebrain neurons (using the Cre/loxP strategy) did not affect neurological deficit or striatal damage after the acute systemic treatment of 3-NP and intrastriatal injection of malonate. However, selective inactivation of A2ARs in bone marrow-derived cells (BMDCs) by transplanting bone marrow cells from global A2AR knock-out (KO) mice into wild-type C57BL/6 mice produced a similar phenotype of global A2AR KO mice, i.e., exacerbation of 3-NP-induced striatal damage. Thus, cell-type-selective inactivation of A2ARs reveals that A2ARs in BMDCs but not in forebrain neurons are an important contributor to striatal damage induced by mitochondrial dysfunction.

Dopamine D(2) receptor activation modulates perceived odor intensity.

Dopaminergic modulation affects odor detection thresholds and olfactory discrimination capabilities in rats. The authors show that dopamine D(2) receptor modulation affects odor discrimination capabilities in a manner similar to the modulation of stimulus intensity. Performance in a simultaneous odor discrimination task was systematically altered by manipulations of both odorant concentration and D(2) receptor activation (agonist quinpirole, 0.025-0.5 mg/kg; antagonist spiperone, 0.5 mg/kg). Rats' discrimination performance systematically improved at higher odor concentrations. Blockade of D(2) receptors improved performance equivalent to increasing odor concentration by 2 log units, whereas activation of D(2) receptors reduced odor discrimination performance in a dose-dependent manner. Bulbar dopamine release may serve a gain control function in the olfactory system, optimizing its sensitivity to changes in the chemosensory environment.

Deletion of adenosine A2A receptors from astrocytes disrupts glutamate homeostasis leading to psychomotor and cognitive impairment: relevance to schizophrenia.

BACKGROUND: Adenosine A2A receptors (A2AR) modulate dopamine and glutamate signaling and thereby may influence some of the psychomotor and cognitive processes associated with schizophrenia. Because astroglial A2AR regulate the availability of glutamate, we hypothesized that they might play an unprecedented role in some of the processes leading to the development of schizophrenia, which we investigated using a mouse line with a selective deletion of A2AR in astrocytes (Gfa2-A2AR knockout [KO] mice]. METHODS: We examined Gfa2-A2AR KO mice for behaviors thought to recapitulate some features of schizophrenia, namely enhanced MK-801 psychomotor response (positive symptoms) and decreased working memory (cognitive symptoms). In addition, we probed for neurochemical alterations in the glutamatergic circuitry, evaluating glutamate uptake and release and the levels of key proteins defining glutamatergic signaling (glutamate transporter-I [GLT-I], N-methyl-D-aspartate receptors [NMDA-R] and α-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPA-R]) to provide a mechanistic understanding of the phenotype encountered. RESULTS: We show that Gfa2-A2AR KO mice exhibited enhanced MK-801 psychomotor response and decreased working memory; this was accompanied by a disruption of glutamate homeostasis characterized by aberrant GLT-I activity, increased presynaptic glutamate release, NMDA-R 2B subunit upregulation, and increased internalization of AMPA-R. Accordingly, selective GLT-I inhibition or blockade of GluR1/2 endocytosis prevented the psychomotor and cognitive phenotypes in Gfa2-A2AR KO mice, namely in the nucleus accumbens. CONCLUSIONS: These results show that the dysfunction of astrocytic A2AR, by controlling GLT-I activity, triggers an astrocyte-to-neuron wave of communication resulting in disrupted glutamate homeostasis, thought to underlie several endophenotypes relevant to schizophrenia.

Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.

BACKGROUND: Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. METHODS: We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice. RESULTS: Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. CONCLUSIONS: This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.

Deletion of striatal adenosine A(2A) receptor spares latent inhibition and prepulse inhibition but impairs active avoidance learning.

Following early clinical leads, the adenosine A(2A)R receptor (A(2A)R) has continued to attract attention as a potential novel target for treating schizophrenia, especially against the negative and cognitive symptoms of the disease because of A(2A)R's unique modulatory action over glutamatergic in addition to dopaminergic signaling. Through (i) the antagonistic interaction with the dopamine D(2) receptor, and (ii) the regulation of glutamate release and N-methyl-d-aspartate receptor function, striatal A(2A)R is ideally positioned to fine-tune the dopamine-glutamate balance, the disturbance of which is implicated in the pathophysiology of schizophrenia. However, the precise function of striatal A(2A)Rs in the regulation of schizophrenia-relevant behavior is poorly understood. Here, we tested the impact of conditional striatum-specific A(2A)R knockout (st-A(2A)R-KO) on latent inhibition (LI) and prepulse inhibition (PPI) - behavior that is tightly regulated by striatal dopamine and glutamate. These are two common cross-species translational tests for the assessment of selective attention and sensorimotor gating deficits reported in schizophrenia patients; and enhanced performance in these tests is associated with antipsychotic drug action. We found that neither LI nor PPI was significantly affected in st-A(2A)R-KO mice, although a deficit in active avoidance learning was identified in these animals. The latter phenotype, however, was not replicated in another form of aversive conditioning - namely, conditioned taste aversion. Hence, the present study shows that neither learned inattention (as measured by LI) nor sensory gating (as indexed by PPI) requires the integrity of striatal A(2A)Rs - a finding that may undermine the hypothesized importance of A(2A)R in the genesis and/or treatment of schizophrenia.