Extensive characterization of EGFR and of its downstream pathways may help integrating the use of EGFR-targeted therapies in patients. WITH SQUAMOUS CELL ANAL CANCER

Squamous cell anal cancer (SCAC) is a rare disease. Patients are managed with chemoradiation therapy. When non-response occur, abdominoperitoneal resection is recommended. New therapeutic options are wondered to overcome the severe effects of this procedure. It has been demonstrated that the majority of SCAC are characterized by EGFR deregulation. Recently, the anti-EGFR monoclonal antibody cetuximab has been FDA and EMA approved for the treatment of colorectal cancer (CRC). Only sporadic studies investigated its use in SCAC. In SCAC little is known about EGFR and EGFR-downstream members alterations which are predictive markers of anti-EGFR therapies efficacy or impairment in patients affected by CRC. The aim of this study was to characterize EGFR, KRAS, BRAF and PIK3CA alterations in a series of patients with SCAC. We investigated 93 patients. EGFR gene copy number was evaluated by FISH. Mutations in KRAS, BRAF and PIK3CA genes were investigated by sequencing. EGFR gene copy number gain (FISH+) was found in 33/90 (37%) patients. KRAS mutations were found in 4/91 (4%) patients. BRAF was always wild-type (wt). PIK3CA mutations were found in 13/89 (15%) cases (10 in ex.9 and 3 in ex.20). Among 33 FISH+ cases, 3 (10%) patients showed a mutation in KRAS and 3 (10%) in PIK3CA ex.9. Considering studies on CRC demonstrating that a EGFR FISH+/ KRAS wt/PIK3CA wt or ex.9 mutated status is associated with clinical benefit from cetuximab, it can be hypothesized that a subgroup of SCAC (approximately 33%) might have a proficient molecular profile with respect to anti-EGFR treatments. Our results, therefore, suggest a possible integration of EGFRtargeted therapies in SCAC and emphasize the need of molecular analyses for a better patients\u2019 selection

Extensive characterization of EGFR and of its downstream pathways may help integrating the use of EGFR-targeted therapies in patients. WITH SQUAMOUS CELL ANAL CANCER

Squamous cell anal cancer (SCAC) is a rare disease. Patients are managed with chemoradiation therapy. When non-response occur, abdominoperitoneal resection is recommended. New therapeutic options are wondered to overcome the severe effects of this procedure. It has been demonstrated that the majority of SCAC are characterized by EGFR deregulation. Recently, the anti-EGFR monoclonal antibody cetuximab has been FDA and EMA approved for the treatment of colorectal cancer (CRC). Only sporadic studies investigated its use in SCAC. In SCAC little is known about EGFR and EGFR-downstream members alterations which are predictive markers of anti-EGFR therapies efficacy or impairment in patients affected by CRC. The aim of this study was to characterize EGFR, KRAS, BRAF and PIK3CA alterations in a series of patients with SCAC. We investigated 93 patients. EGFR gene copy number was evaluated by FISH. Mutations in KRAS, BRAF and PIK3CA genes were investigated by sequencing. EGFR gene copy number gain (FISH+) was found in 33/90 (37%) patients. KRAS mutations were found in 4/91 (4%) patients. BRAF was always wild-type (wt). PIK3CA mutations were found in 13/89 (15%) cases (10 in ex.9 and 3 in ex.20). Among 33 FISH+ cases, 3 (10%) patients showed a mutation in KRAS and 3 (10%) in PIK3CA ex.9. Considering studies on CRC demonstrating that a EGFR FISH+/ KRAS wt/PIK3CA wt or ex.9 mutated status is associated with clinical benefit from cetuximab, it can be hypothesized that a subgroup of SCAC (approximately 33%) might have a proficient molecular profile with respect to anti-EGFR treatments. Our results, therefore, suggest a possible integration of EGFRtargeted therapies in SCAC and emphasize the need of molecular analyses for a better patients’ selection

Macrophages produce and functionally respond to interleukin-34 in colon cancer

In colorectal cancer (CRC), macrophages represent a major component of the tumor mass and exert mostly functions promoting tumor cell survival, proliferation, and dissemination. Interleukin-34 (IL-34) is a cytokine overproduced by colon cancer (CRC) cells and supposed to make a valid contribution to the growth and diffusion of CRC cells. The biological functions of IL-34 are mediated by the macrophage colony-stimulating factor receptor (M-CSFR-1), which controls monocyte/macrophage differentiation, growth, and survival. We here investigated whether, in CRC, tumor-associated macrophages (TAMs) express M-CSFR-1 and functionally respond to IL-34. By flow-cytometry analysis of tumor-infiltrating cells (TICs) and lamina propria mononuclear cells (LPMCs) isolated from normal, adjacent mucosa of CRC patients, we showed that CD68/HLA-DRII-expressing TICs and LPMCs expressed M-CSFR-1. Both these cell types produced IL-34 even though the expression of the cytokine was more pronounced in TICs as compared to normal LPMCs. Moreover, in CRC samples, there was a positive correlation between IL-34-producing cells and CD68-positive cells. Stimulation of LPMCs and TICs with IL-34 resulted in enhanced expression of CD163 and CD206, two markers of type II-polarized macrophages, and this was evident at both RNA and protein level. In the same cell cultures, IL-34 stimulated expression and production of IL-6, a cytokine known to promote CRC cell growth and diffusion. Finally, knockdown of IL-34 in TICs with specific antisense oligonucleotides with: a specific antisesne oligonucleotide decreased IL-6 production and the number of TAMs producing this cytokine. This is the first to show a positive role of IL-34 in the control of TAMs in CRC, further supporting the notion that IL-34 sustains colon tumorigenesis

Community-Based Values for 2009 Pandemic Influenza A H1N1 Illnesses and Vaccination-Related Adverse Events

OBJECTIVE: To evaluate community-based values for avoiding pandemic influenza (A) H1N1 (pH1N1) illness and vaccination-related adverse events in adults and children. METHODS: Adult community members were randomly selected from a nationally representative research panel to complete an internet survey (response rate = 65%; n = 718). Respondents answered a series of time trade-off questions to value four hypothetical health state scenarios for varying ages (1, 8, 35, or 70 years): uncomplicated pH1N1 illness, pH1N1 illness-related hospitalization, severe allergic reaction to the pH1N1 vaccine, and Guillain-Barré syndrome. We calculated descriptive statistics for time trade-off amounts and derived quality adjusted life year losses for these events. Multivariate regression analyses evaluated the effect of scenario age, as well as respondent socio-demographic and health characteristics on time trade-off amounts. RESULTS: Respondents were willing to trade more time to avoid the more severe outcomes, hospitalization and Guillain-Barré syndrome. In our adjusted and unadjusted analyses, age of the patient in the scenario was significantly associated with time trade-off amounts (p-value<0.05), with respondents willing to trade more time to prevent outcomes in children versus adults. Persons who had received the pH1N1 vaccination were willing to trade significantly more time to avoid hospitalization, severe allergic reaction, and Guillain-Barré syndrome, controlling for other variables in adjusted analyses.(p-value<0.05) CONCLUSIONS: Community members placed the highest value on preventing outcomes in children, compared with adults, and the time trade-off values reported were consistent with the severity of the outcomes presented. Considering these public values along with other decision-making factors may help policy makers improve the allocation of pandemic vaccine resources

The role of youth mental health services in the treatment of young people with serious mental illness: two-year outcomes and economic implications

Aim: To evaluate the outcomes and economic case for a UK innovative youth-specific mental health service for 16 to 25 year olds. Methods: A pre-, during- and post-treatment comparative design for twenty young people at high risk of developing psychosis who received two years’ treatment with the service, using outcomes that concurred with the service aims: changes in mental health, employment rates and service use. Results: 45% of those at risk and with symptoms of serious mental illness commencing treatment were not receiving mental health services at baseline.. Compared to service use prior to treatment at the youth-specific service, hospital admissions, A&E and criminal justice system use appear to decrease over the two years of treatment and the year after treatment, with potential cost differences of £473,000. Mental health improved or stayed the same, compared to baseline. Employment rates improved, although the sample size for this is very small. Potential cost differences associated with service users moving into employment over the two years are £148,000. The estimated cost over two years of providing the youth-specific mental health service to these young people was £106,000. Conclusions: Given the extensive long-term negative consequences and high costs of untreated mental illness in the 16 to 25 age group and the documented problems young people have in receiving appropriate services, this youth-specific, age-appropriate service model appears to be successful, with improved outcomes and cost differences in the short-term, and with encouraging implications for the longer term

Search for polyoma-, herpes-, and bornaviruses in squirrels of the family Sciuridae

Background Squirrels (family Sciuridae) are globally distributed members of the order Rodentia with wildlife occurrence in indigenous and non-indigenous regions (as invasive species) and frequent presence in zoological gardens and other holdings. Multiple species introductions, strong inter-species competition as well as the recent discovery of a novel zoonotic bornavirus resulted in increased research interest on squirrel pathogens. Therefore we aimed to test a variety of squirrel species for representatives of three virus families. Methods Several species of the squirrel subfamilies Sciurinae, Callosciurinae and Xerinae were tested for the presence of polyomaviruses (PyVs; family Polyomaviridae) and herpesviruses (HVs; family Herpesviridae), using generic nested polymerase chain reaction (PCR) with specificity for the PyV VP1 gene and the HV DNA polymerase (DPOL) gene, respectively. Selected animals were tested for the presence of bornaviruses (family Bornaviridae), using both a broad-range orthobornavirus- and a variegated squirrel bornavirus 1 (VSBV-1)-specific reverse transcription-quantitative PCR (RT-qPCR). Results In addition to previously detected bornavirus RNA-positive squirrels no more animals tested positive in this study, but four novel PyVs, four novel betaherpesviruses (BHVs) and six novel gammaherpesviruses (GHVs) were identified. For three PyVs, complete genomes could be amplified with long-distance PCR (LD-PCR). Splice sites of the PyV genomes were predicted in silico for large T antigen, small T antigen, and VP2 coding sequences, and experimentally confirmed in Vero and NIH/3T3 cells. Attempts to extend the HV DPOL sequences in upstream direction resulted in contiguous sequences of around 3.3 kilobase pairs for one BHV and two GHVs. Phylogenetic analysis allocated the novel squirrel PyVs to the genera Alpha- and Betapolyomavirus, the BHVs to the genus Muromegalovirus, and the GHVs to the genera Rhadinovirus and Macavirus. Conclusions This is the first report on molecular identification and sequence characterization of PyVs and HVs and the detection of bornavirus coinfections with PyVs or HVs in two squirrel species. Multiple detection of PyVs and HVs in certain squirrel species exclusively indicate their potential host association to a single squirrel species. The novel PyVs and HVs might serve for a better understanding of virus evolution in invading host species in the future

First constraints of dense molecular gas at z~7.5 from the quasar P\=oniu\=a'ena

We report the detection of CO(6-5) and CO(7-6) and their underlying continua from the host galaxy of quasar J100758.264+211529.207 (P\=oniu\=a'ena) at z=7.5419, obtained with the NOrthern Extended Millimeter Array (NOEMA). P\=oniu\=a'ena belongs to the HYPerluminous quasars at the Epoch of ReionizatION (HYPERION) sample of 17 $z>6$ quasars selected to be powered by supermassive black holes (SMBH) which experienced the fastest mass growth in the first Gyr of the Universe. The one reported here is the highest-redshift measurement of the cold and dense molecular gas to date. The host galaxy is unresolved and the line luminosity implies a molecular reservoir of $\rm M(H_2)=(2.2\pm0.2)\times 10^{10}$ $\rm M_\odot$, assuming a CO spectral line energy distribution typical of high-redshift quasars and a conversion factor $\alpha=0.8$ $\rm M_{\odot} (K\,km \, s^{-1} \,pc^{2})^{-1}$. We model the cold dust spectral energy distribution (SED) to derive a dust mass of M$_{\rm dust} =(2.1\pm 0.7)\times 10^8$ $\rm M_\odot$, and thus a gas to dust ratio $\sim100$. Both the gas and dust mass are not dissimilar from the reservoir found for luminous quasars at $z\sim6$. We use the CO detection to derive an estimate of the cosmic mass density of $\rm H_2$, $\Omega_{H_2} \simeq 1.31 \times 10^{-5}$. This value is in line with the general trend suggested by literature estimates at $z < 7$ and agrees fairly well with the latest theoretical expectations of non-equilibrium molecular-chemistry cosmological simulations of cold gas at early times.Comment: Submitted to ApJ Letter

Prognostic and predictive role of EGFR pathway alterations in biliary cancer patients treated with chemotherapy and anti-EGFR

The association of anti-EGFR to gemcitabine and oxaliplatin (GEMOX) chemotherapy did not improve survival in biliary tract carcinoma (BTC) patients. Multiple mechanisms might be involved in the resistance to anti-EGFR. Here, we explored the mutation profile of EGFR extracellular domain (ECD), of tyrosine kinase domain (TKD), and its amplification status. EGFR mutational status of exons 12, 18-21 was analyzed in 57 tumors by Sanger sequencing. EGFR amplification was evaluated in 37 tumors by Fluorescent In Situ Hybridization (FISH). Kaplan-Meier curves were calculated using the log-rank test. Six patients had mutations in exon 12 of EGFR ECD and 7 in EGFR TKD. Neither EGFR ECD nor TKD mutations affected progression free survival (PFS) or overall survival (OS) in the entire population. In the panitumumab plus GEMOX (P-GEMOX) arm, ECD mutated patients had a worse OS, while EGFR TKD mutated patients had a trend towards shorter PFS and OS. Overall, the presence of mutations in EGFR or in its transducers did not affect PFS or OS, while the extrahepatic cholangiocarcinoma (ECC) mutated patients had a worse prognosis compared to WT. Nineteen out of 37 tumors were EGFR amplified, but the amplification did not correlate with survival. ECC EGFR amplified patients had improved OS, whereas the amplification significantly correlated with poor PFS (p = 0.03) in gallbladder carcinoma patients. The high molecular heterogeneity is a predominant feature of BTC: the alterations found in this work seem to have a prognostic impact rather than a predictive role towards anti-EGFR therapy

Automation of one-loop QCD corrections

We present the complete automation of the computation of one-loop QCD corrections, including UV renormalization, to an arbitrary scattering process in the Standard Model. This is achieved by embedding the OPP integrand reduction technique, as implemented in CutTools, into the MadGraph framework. By interfacing the tool so constructed, which we dub MadLoop, with MadFKS, the fully automatic computation of any infrared-safe observable at the next-to-leading order in QCD is attained. We demonstrate the flexibility and the reach of our method by calculating the production rates for a variety of processes at the 7 TeV LHC.Comment: 64 pages, 12 figures. Corrected the value of m_Z in table 1. In table 2, corrected the values of cross sections in a.4 and a.5 (previously computed with mu=mtop/2 rather than mu=mtop/4). In table 2, corrected the values of NLO cross sections in b.3, b.6, c.3, and e.7 (the symmetry factor for a few virtual channels was incorrect). In sect. A.4.3, the labeling of the four-momenta was incorrec