CLASH: New Multiple-Images Constraining the Inner Mass Profile of MACS J1206.2-0847

We present a strong-lensing analysis of the galaxy cluster MACS J1206.2-0847 ($z$=0.44) using UV, Optical, and IR, HST/ACS/WFC3 data taken as part of the CLASH multi-cycle treasury program, with VLT/VIMOS spectroscopy for some of the multiply-lensed arcs. The CLASH observations, combined with our mass-model, allow us to identify 47 new multiply-lensed images of 12 distant sources. These images, along with the previously known arc, span the redshift range 1\la z\la5.5, and thus enable us to derive a detailed mass distribution and to accurately constrain, for the first time, the inner mass-profile of this cluster. We find an inner profile slope of $d\log \Sigma/d\log \theta\simeq -0.55\pm 0.1$ (in the range [1\arcsec, 53\arcsec], or 5\la r \la300 kpc), as commonly found for relaxed and well-concentrated clusters. Using the many systems uncovered here we derive credible critical curves and Einstein radii for different source redshifts. For a source at $z_{s}\simeq2.5$, the critical curve encloses a large area with an effective Einstein radius of \theta_{E}=28\pm3\arcsec, and a projected mass of $1.34\pm0.15\times10^{14} M_{\odot}$. From the current understanding of structure formation in concordance cosmology, these values are relatively high for clusters at $z\sim0.5$, so that detailed studies of the inner mass distribution of clusters such as MACS J1206.2-0847 can provide stringent tests of the $\Lambda$CDM paradigm.Comment: 7 pages, 1 table, 4 figures; submitted to ApJ Letters; V3: minor correction

The Cluster Lensing and Supernova Survey with Hubble (CLASH): Strong Lensing Analysis of Abell 383 from 16-Band HST WFC3/ACS Imaging

We examine the inner mass distribution of the relaxed galaxy cluster Abell 383 in deep 16-band HST/ACS+WFC3 imaging taken as part of the CLASH multi-cycle treasury program. Our program is designed to study the dark matter distribution in 25 massive clusters, and balances depth with a wide wavelength coverage to better identify lensed systems and generate precise photometric redshifts. This information together with the predictive strength of our strong-lensing analysis method identifies 13 new multiply-lensed images and candidates, so that a total of 27 multiple-images of 9 systems are used to tightly constrain the inner mass profile, $d\log \Sigma/d\log r\simeq -0.6\pm 0.1$ (r<160 kpc). We find consistency with the standard distance-redshift relation for the full range spanned by the lensed images, 1.01<z<6.03, with the higher redshift sources deflected through larger angles as expected. The inner mass profile derived here is consistent with the results of our independent weak-lensing analysis of wide-field Subaru images, with good agreement in the region of overlap. The overall mass profile is well fitted by an NFW profile with M_{vir}=(5.37^{+0.70}_{-0.63}\pm 0.26) x 10^{14}M_{\odot}/h and a relatively high concentration, c_{vir}=8.77^{+0.44}_{-0.42}\pm 0.23, which lies above the standard c-M relation similar to other well-studied clusters. The critical radius of Abell 383 is modest by the standards of other lensing clusters, r_{E}\simeq16\pm2\arcsec (for z_s=2.55), so the relatively large number of lensed images uncovered here with precise photometric redshifts validates our imaging strategy for the CLASH survey. In total we aim to provide similarly high-quality lensing data for 25 clusters, 20 of which are X-ray selected relaxed clusters, enabling a precise determination of the representative mass profile free from lensing bias. (ABRIDGED)Comment: 15 pages, 14 figures, 2 tabels; V3 matches the submitted version later published in Ap

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

FUTURE PERSPECTIVES IN MELANOMA RESEARCH. Meeting report from the “Melanoma Research: a bridge from Naples to the World. Napoli, December 5th–6 th2011”

After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A preponderance of gastrointestinal cancer patients transition into cachexia syndrome

Abstract Background Cancer cachexia is frequently documented by self‐reported, single time‐point weight histories. This approach lacks the granularity needed to fully elucidate the progression of cachexia syndrome. This study aimed to longitudinally assess body weight changes pre‐ and post‐cancer diagnosis in gastrointestinal (GI) cancer patients. Methods Body weights and relevant clinical data recorded in the electronic health record 12 months pre‐ and post‐GI cancer (colorectal, gastroesophageal, hepatobiliary and pancreatic) diagnosis were extracted. Weight loss was categorized by the International Consensus Definition for cachexia. Results A total of 879 patients were included in the final cohort including patients diagnosed with colorectal (n = 317), hepatocellular (n = 185), biliary (n = 72), pancreatic (n = 186) or gastroesophageal (n = 119) cancer. Stage of disease was equally distributed. Patients without cachexia at diagnosis (n = 608) remained weight stable during the 12 months pre‐diagnosis (+0.5 ± 0.5% body weight; P = 0.99). Patients with cachexia at diagnosis (n = 271) remained weight stable 6 to 12 months prior to diagnosis (+0.4 ± 0.8%; P > 0.9999) and lost 8.7 ± 0.6% (P < 0.0001) within the 6 months pre‐diagnosis. Patients without cachexia at diagnosis lost more weight post‐diagnosis (6.3 ± 0.6%) than patients with cachexia at diagnosis (4.7 ± 1.0%; P = 0.01). Pre‐diagnosis weight trajectories did not differ between primary malignancies or stage of disease in patients without or with cachexia at diagnosis (all P ≥ 0.05). Post‐diagnosis weight trajectories did differ by primary malignancy (P ≤ 0.0002) and stage (P < 0.0001). In both patients without and with cachexia at diagnosis, colorectal patients lost the least amount of weight post‐diagnosis and gastroesophageal patients lost the most amount of weight post‐diagnosis. Stage 4 patients without or with cachexia at diagnosis lost the most weight post‐diagnosis (P ≤ 0.0003). Regardless of cachexia status at diagnosis, patients lost more weight when treated with systemic therapy (7.1 ± 0.7%; P < 0.0001; n = 419) or radiation therapy (8.4 ± 1.4%; P = 0.02; n = 116) compared to those who did not. Patients who did not have surgery lost more weight post‐diagnosis (7.6 ± 1.1%; P < 0.0001; n = 355) compared to those who did have surgery. By 12 months post‐diagnosis, 83% of the surviving GI cancer patients in this cohort had transitioned into cachexia syndrome. Conclusions Significant weight loss in patients with GI cancer cachexia at diagnosis initiates at least 6 months prior to diagnosis, and most patients will transition into cachexia syndrome post‐diagnosis, regardless of pre‐diagnosis weight change and stage of disease. These findings punctuate the importance of weight surveillance in cancer detection and earlier palliative interventions post‐diagnosis in the GI cancer patient population

NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes

Egress of lipoprotein-derived cholesterol from lysosomes requires two lysosomal proteins, polytopic membrane-bound Niemann–Pick C1 (NPC1) and soluble Niemann–Pick C2 (NPC2). The reason for this dual requirement is unknown. Previously, we showed that the soluble luminal N-terminal domain (NTD) of NPC1 (amino acids 25–264) binds cholesterol. This NTD is designated NPC1(NTD). We and others showed that soluble NPC2 also binds cholesterol. Here, we establish an in vitro assay to measure transfer of [3H]cholesterol between these two proteins and phosphatidylcholine liposomes. Whereas NPC2 rapidly donates or accepts cholesterol from liposomes, NPC1(NTD) acts much more slowly. Bidirectional transfer of cholesterol between NPC1(NTD) and liposomes is accelerated >100-fold by NPC2. A naturally occurring human mutant of NPC2 (Pro120Ser) fails to bind cholesterol and fails to stimulate cholesterol transfer from NPC1(NTD) to liposomes. NPC2 may be essential to deliver or remove cholesterol from NPC1, an interaction that links both proteins to the cholesterol egress process from lysosomes. These findings may explain how mutations in either protein can produce a similar clinical phenotype

Combination antiretroviral treatment for women previously treated only in pregnancy: week 24 results of AIDS clinical trials group protocol A5227

Submitted by Rodrigo Senorans ([email protected]) on 2015-06-17T18:27:52Z No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Approved for entry into archive by Anderson Silva ([email protected]) on 2015-06-18T14:16:09Z (GMT) No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Approved for entry into archive by Anderson Silva ([email protected]) on 2015-06-18T14:16:57Z (GMT) No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5)Made available in DSpace on 2015-06-22T15:46:02Z (GMT). No. of bitstreams: 1 Combination_Antiretroviral_Treatment_for_Women.6.pdf: 419495 bytes, checksum: 6d7dd215a54dec2466c97e5bffda80e2 (MD5) Previous issue date: 2014New York Presbyterian Hospital. Cornell University. Weill Cornell Medical College. New York, NY, USA.Harvard School of Public Health. Center for Biostatistics and AIDS Research. Boston, MA, USA.Albert Einstein College of Medicine. Department of Obstetrics and Gynecology. Bronx, NY, USA.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST e AIDS. Rio de Janeiro, RJ, Brasil.kAsociación Civil Impacta Salud y Educación. Lima, Perú.kAsociación Civil Impacta Salud y Educación. Lima, Perú.Social and Scientific Systems. Inc. Silver Spring, MD, USA.National Institute of Allergy and Infectious Disease. HIV Research Branch. Division of AIDS. Bethesda, MD, USA.University of Rochester. School of Medicine and Dentistry. Rochester, NY, USA.Birmingham Veterans Affairs Medical Center. Birmingham, AL, USA / University of Alabama at Birmingham. School of Medicine, Birmingham, AL, USA.Background: Women with HIV and prior exposure to combination antiretroviral therapy (cART) solely for prevention of Mother to Child Transmission (pMTCT) need to know whether they can later be treated successfully with a commonly used regimen of efavirenz (EFV) and co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) Methods: Non-pregnant women with plasma HIV-1 RNA of ≥ 500 copies/mL, previously cART- exposed for pMTCT only, were eligible if they were off ART for ≥ 24 weeks prior to entry, were without evidence of drug resistance on standard genotyping, and were ready to start EFV plus FTC/TDF. The primary endpoint was virologic response (defined as plasma HIV RNA <400 copies/mL) at 24 weeks. Results: 54 women were enrolled between 10/07 and 12/09; 52/54 completed 24 weeks of follow- up. Median baseline CD4+ T-cell count was 265/mm3 and baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. Median prior cART duration was 14 weeks, and median time elapsed from the last pMTCT dose to entry was 22 months. Virologic response at 24 weeks was observed in 42/52 women or 81% (exact 95% CI: 68%–90%). There were no differences in response by country, by number or class of prior pMTCT exposures. While confirmed virologic failure occurred in 8 women, no virologic failures were observed in women reporting perfect early adherence. Conclusions: In this first prospective clinical trial studying combination antiretroviral re- treatment in women with a history of pregnancy-limited cART, the observed virologic response to TDF/FTC and EFV at 24 weeks was 81%. Virologic failures occurred and correlated with self-reported non-adherence