Nitric oxide (NO) is an important regulatory molecule for the host defense that plays a fundamental role in the cardiovascular, immune, and nervous systems. NO is synthesized through the conversion of L-arginine to L-citrulline by the enzyme NO synthase (NOS), which is found in three isoforms classified as neuronal (nNOS), inducible (iNOS), and endothelial (eNOS). Recent evidence supports the theory that this bioactive molecule has an influential role in the disruption of normal brain and vascular homeostasis, a condition known to elucidate chronic hypoperfusion which ultimately causes the development of brain lesions and the pathology that typify Alzheimer disease (AD). In addition, vascular NO activity appears to be a major contributor to this pathology before any overexpression of NOS isoforms is observed in the neuron, glia, and microglia of the brain tree, where the overexpression the NOS isoforms causes the formation of a large amount of NO. We hypothesize that since an imbalance between the NOS isoforms and endothelin-1 (ET-1), a human gene that encodes for blood vessel constriction, can cause antioxidant system insufficiency; by using pharmacological intervention with NO donors and/or NO suppressors, the brain lesions and the downstream progression of brain pathology and dementia in AD should be delayed or minimized.

No abstract

We read with interest the recent article in Nature Medicine describing the influence of variation in CCL3L1 copy number and CCR5 genotype on immune recovery during highly active antiretroviral therapy (HAART) in HIV-1-infected individuals 1 . The chemotactic cytokine CCL3L1 (encoding the macrophage inflammatory protein-1αP (MIP-1αP) protein) is a potent ligand for the HIV-1 co-receptor CCR5, which is essential for viral entry into human host cells 2 . The recent study is part of a series that began in 2005 with a paper reporting effects of CCL3L1 copy number variation on HIV-1 acquisition, viral load and disease progression 3 , followed by several publications investigating clinically correlated phenotypes in a largely overlapping set of HIV-positive individuals 1,4,5 .Although these studies seem to generate considerable independent support for a role of CCL3L1 in viral control, many of the traits considered are at least partially correlated, and the studies include largely overlapping samples and presumably CCL3L1 assay data. For these reasons, we sought to reevaluate a core set of associations related to the effect of CCL3L1 copy number on viral control in a large group of HIV-infected individuals with known date of seroconversion enrolled in one of the nine cohorts of the Euro-CHAVI Consortium 6 (n = 1,042), in an African-American cohort from the TACC (n = 277) or in the MACS (n = 451 HIV-positive, n = 195 high-risk seronegative (HRSN)). We assayed for CCL3L1 copy number using a previously described method 3 (Supplementary Methods). A total of 1,855 subjects were successfully genotyped. Distributions of CCL3L1 copy numbers in individuals of European or African ancestry were similar to those reported elsewhere, with a median copy number of 2 or 4 in individuals of primarily European (range 0-9) or African (range 1-11) descent, respectively (Fig. 1a,b and Supplementary Figs. 1-4) 1,3,4,7 .We then tested for association of CCL3L1 copy number with HIV viral load at set point by linear regression after stratifying according to ethnicity and correcting for known covariates (gender, age at seroconversion and ancestry as determined by a principal components method described previously 8 ), and found no evidence of association (European, P = 0.14; African, P = 0.27) (Fig. 1c,d). Dividing the sample into the previously described "high-risk" (CCL3L1 low ) and "low-risk" (CCL3L1 high ) genotype groups (where high risk versus low risk is defined as having copy number below versus equal to or above the population median, respectively) 3 , we again found no evidence of association, either within each population (European, P = 0.10; African, P = 0.41) or in the combined sample (P = 0.35) (Table 1). Furthermore, a model including known functional polymorphisms in the CCR5 receptor (CCR5∆32, CCR5*HHE) in a subset of n = 820 individuals of European descent for which CCR5 effects had been tested previously (J.F., D. Ge, K.V.S., S.C., B. Ledergerber et al., unpublished data) showed that although the CCR5 polymorphisms were stro...

No abstract

Background Extranodal NK/T cell lymphoma (ENKTL) is an aggressive form of Epstein-Barr virus (EBV)-associated non-Hodgkin’s lymphoma which historically has a poor prognosis. When relapse occurs, particularly in the cerebral nervous system (CNS), survival is rare. The immune checkpoint pathway family of proteins is highly expressed in many human tumors, especially in EBV-related malignancies. To the best of our knowledge, there are no reports of immune checkpoint inhibitors used either alone or in combination for the treatment of ENTKL CNS relapse, yet there are promising results in metastatic CNS involvement of other malignancies. Case presentation This is the case of a 29-year-old Hispanic male with ENKTL who was treated at first relapse with 24 doses of the programmed death-ligand 1 (PD-L1) immune checkpoint inhibitor, atezolizumab, over a 17-month period. He remained in remission for 18 months until he experienced an isolated CNS relapse and on-going evidence of chronic EBV infection. Salvage therapy was provided as a combination of triple intrathecal (TIT) chemotherapy, radiation, and atezolizumab. He continues on maintenance atezolizumab and remains alive 1-year post CNS relapse. Conclusions The results from this case suggest that atezolizumab should be considered as part of the treatment regimen for relapsed ENKTL. They also demonstrate the benefit of using atezolizumab in combination with TIT chemotherapy and radiation as a viable treatment option for ENKTL CNS relapse and indicate that atezolizumab is an option for long-term maintenance therapy for patients with ENKTL.