Efficacy and toxicity of adjuvant chemotherapy in elderly patients with colorectal cancer:the ACCORE study

BACKGROUND: Elderly patients with primary colorectal cancer (CRC) are less frequently treated with adjuvant chemotherapy than younger patients due to concerns regarding toxicity and efficiency. We investigated how age, performance status (PS) and comorbidity influence treatment outcomes. PATIENTS AND METHODS: A retrospective single-centre study of 529 patients with stages II–III CRC treated with adjuvant chemotherapy (5-fluorouracil/capecitabine+/÷oxaliplatin) from 2001 to 2011 at Herlev Hospital, Denmark. Baseline characteristics, chemotherapy and outcome were analysed with respect to age after adjusting for PS and comorbidity. RESULTS: Elderly patients (>70 years) had significantly more comorbidity (p<0.001) and poorer PS (p=0.001) than younger patients. Elderly were more frequently treated with single-agent therapy (p=0.001) and at lower initial dose (p<0.001). There was no age-dependent difference in 3-year disease-free survival (DFS; HR 1.09, 95% CI 0.80 to 1.47, p=0.59), in grade 3–5 toxicity (29% vs 28%, p=0.86) or in 10-year CRC mortality (28%, HR 1.07, p=0.71). In elderly patients, a reduction in chemotherapy dose intensity compared with full dose had no impact on DFS or CRC mortality. Elderly patients receiving <50% of planned cycles had shorter DFS (HR=1.78, p=0.020) and higher CRC mortality (HR=2.17, p=0.027) than elderly receiving all cycles. Poor PS in younger and elderly patients was related to shorter DFS (HR=1.95, p=0.002; HR=1.6, p=0.035, respectively) and overall survival (OS; HR=2.28, p<0.001; HR=2.03, p=0.002). Comorbidity in younger patients was significantly related to shorter DFS (HR 2.72, p<0.001), OS (HR 3.16, p<0.001) and higher CRC mortality (HR 2.70, p=0.001). CONCLUSIONS: Choice of regimen, primary dose reduction and given dose intensity in patients treated with adjuvant chemotherapy for CRC were highly dependent on age. However, age had no impact on DFS and CRC mortality. Comorbidity in younger patients and PS in all patients were associated with shorter DFS and higher CRC mortality

Antibody engineering & therapeutics, the annual meeting of the antibody society December 7-10, 2015, San Diego, CA, USA

The 26th Antibody Engineering & Therapeutics meeting, the annual meeting of The Antibody Society united over 800 participants from all over the world in San Diego from 6-10 December 2015. The latest innovations and advances in antibody research and development were discussed, covering a myriad of antibody-related topics by more than 100 speakers, who were carefully selected by The Antibody Society. As a prelude, attendees could join the pre-conference training course focusing, among others, on the engineering and enhancement of antibodies and antibody-like scaffolds, bispecific antibody engineering and adaptation to generate chimeric antigen receptor constructs. The main event covered 4 d of scientific sessions that included antibody effector functions, reproducibility of research and diagnostic antibodies, new developments in antibody-drug conjugates (ADCs), preclinical and clinical ADC data, new technologies and applications for bispecific antibodies, antibody therapeutics for non-cancer and orphan indications, antibodies to harness the cellular immune system, building comprehensive IgVH-gene repertoires through discovering, confirming and cataloging new germline IgVH genes, and overcoming resistance to clinical immunotherapy. The Antibody Society's special session focused on "Antibodies to watch" in 2016. Another special session put the spotlight on the limitations of the new definitions for the assignment of antibody international nonproprietary names introduced by the World Health Organization. The convention concluded with workshops on computational antibody design and on the promise and challenges of using next-generation sequencing for antibody discovery and engineering from synthetic and in vivo libraries

Development of Atlantic Salmon (Salmo salar L.) Under Hypoxic Conditions Induced Sustained Changes in Expression of Immune Genes and Reduced Resistance to Moritella viscosa

Atlantic salmon is characterized with high sensitivity to low dissolved oxygen (DO) levels. Hypoxia can affect diverse biological processes with consequences that can be manifested immediately or with delay. Effects of hypoxia on the immune system and the resistance to a bacterial pathogen were investigated. Two groups were reared at, respectively, normal (NO, 80–100%) and low (LO, 60%) levels of DO over 10 months after which both groups were reared at NO. Smoltification was initiated after 13 months by a winter signal for 6 weeks, followed by constant light for 6 weeks. Samples were collected at the start and end of the constant light period. Expression of 92 immune and stress genes was analyzed in the gill, head kidney, and spleen using a Biomark HD. Most of differentially expressed genes showed higher levels in LO fish compared to NO fish; many immune genes were downregulated during smoltification and these changes were stronger in NO fish. A notable exception was pro-inflammatory genes upregulated in gill of NO fish. Further, salmon were challenged with Moritella viscosa, the causative agent of winter ulcer. Mortality was registered from 5 days post infection (dpi) to the end of trial at 36 dpi. Survival was consistently higher in NO than LO fish, reaching a maximum difference of 18% at 21–23 dpi that reduced to 10% at the end. Analyses with a genome-wide microarray at 36 dpi showed strong responses to the pathogen in gill and spleen. Notable features were the stimulation of eicosanoid metabolism, suggesting an important role of lipid mediators of inflammation, and the downregulation of chemokines. Many immune effectors were activated, including multiple lectins and acute phase proteins, enzymes producing free radicals, and matrix metalloproteinases. The transcriptomic changes induced with a bacterial challenge were similar in NO and LO. After the challenge, interferons a and g and panel of genes of innate antiviral immunity showed higher expression in LO, especially in the gill. The results from the present study suggest that chronic hypoxia in early life stimulated immune genes and attenuated their downregulation associated with smoltification. However, these changes did not improve protection against a bacterial pathogen of major concern in salmon aquaculture

Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults

Importance: The prevalence and baseline risk factors of post-COVID-19 condition (PCC) remain unresolved among the large number of young people who experienced mild COVID-19. Objectives: To determine the point prevalence of PCC 6 months after the acute infection, to determine the risk of development of PCC adjusted for possible confounders, and to explore a broad range of potential risk factors. Design, Setting, and Participants: This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 and 25 years who underwent reverse transcription-polymerase chain reaction (RT-PCR) testing. At the early convalescent stage and at 6-month follow-up, participants underwent a clinical examination; pulmonary, cardiac, and cognitive functional testing; immunological and organ injury biomarker analyses; and completion of a questionnaire. Participants were classified according to the World Health Organization case definition of PCC at follow-up. Association analyses of 78 potential risk factors were performed. Exposures: SARS-CoV-2 infection. Main Outcomes and Measures: The point prevalence of PCC 6 months after RT-PCR testing in the SARS-CoV-2-positive and SARS-CoV-2-negative groups, and the risk difference with corresponding 95% CIs. Results: A total of 404 individuals testing positive for SARS-CoV-2 and 105 individuals testing negative were enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A total of 22 of the SARS-CoV-2-positive and 4 of the SARS-CoV-2-negative individuals were lost to follow-up, and 16 SARS-CoV-2-negative individuals were excluded due to SARS-CoV-2 infection in the observational period. Hence, 382 SARS-CoV-2-positive participants (mean [SD] age, 18.0 [3.7] years; 152 male [39.8%]) and 85 SARS-CoV-2-negative participants (mean [SD] age, 17.7 [3.2] years; 31 male [36.5%]) could be evaluated. The point prevalence of PCC at 6 months was 48.5% in the SARS-CoV-2-positive group and 47.1% in the control group (risk difference, 1.5%; 95% CI, -10.2% to 13.1%). SARS-CoV-2 positivity was not associated with the development of PCC (relative risk [RR], 1.06; 95% CI, 0.83 to 1.37; final multivariable model utilizing modified Poisson regression). The main risk factor for PCC was symptom severity at baseline (RR, 1.41; 95% CI, 1.27-1.56). Low physical activity (RR, 0.96; 95% CI, 0.92-1.00) and loneliness (RR, 1.01; 95% CI, 1.00-1.02) were also associated, while biological markers were not. Symptom severity correlated with personality traits. Conclusions and Relevance: The persistent symptoms and disability that characterize PCC are associated with factors other than SARS-CoV-2 infection, including psychosocial factors. This finding raises questions about the utility of the World Health Organization case definition and has implications for the planning of health care services as well as for further research on PCC

Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restriced glioblastoma

L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes

Rationale and Design of the First Double-Blind, Placebo-Controlled Trial with Allogeneic Adipose Tissue-Derived Stromal Cell Therapy in Patients with Ischemic Heart Failure:A Phase II Danish Multicentre Study

Background. Ischemic heart failure (IHF) has a poor prognosis in spite of optimal therapy. We have established a new allogeneic Cardiology Stem Cell Centre adipose-derived stromal cell (CSCC_ASC) product from healthy donors. It is produced without animal products, in closed bioreactor systems and cryopreserved as an off-the-shelf product ready to use. Study Design. A multicentre, double-blind, placebo-controlled phase II study with direct intramyocardial injections of allogeneic CSCC_ASC in patients with chronic IHF. A total of 81 patients will be randomised at 2 : 1 to CSCC_ASC or placebo. There is no HLA tissue type matching needed between the patients and the donors. Methods. The treatment will be delivered by direct injections into the myocardium. The primary endpoint is change in the left ventricle endsystolic volume at 6-month follow-up. Secondary endpoints are safety and changes in left ventricle ejection fraction, myocardial mass, stroke volume, and cardiac output. Other secondary endpoints are change in clinical symptoms, 6-minute walking test, and the quality of life after 6 and 12 months. Conclusion. The aim of the present study is to demonstrate safety and the regenerative efficacy of the allogeneic CSCC_ASC product from healthy donors in a double-blind, placebo-controlled, multicentre study in patients with IHF

Spatial-proteomics reveals phospho-signaling dynamics at subcellular resolution

Dynamic change in subcellular localization of signaling proteins is a general concept that eukaryotic cells evolved for eliciting a coordinated response to stimuli. Mass spectrometry-based proteomics in combination with subcellular fractionation can provide comprehensive maps of spatio-temporal regulation of protein networks in cells, but involves laborious workflows that does not cover the phospho-proteome level. Here we present a high-throughput workflow based on sequential cell fractionation to profile the global proteome and phospho-proteome dynamics across six distinct subcellular fractions. We benchmark the workflow by studying spatio-temporal EGFR phospho-signaling dynamics in vitro in HeLa cells and in vivo in mouse tissues. Finally, we investigate the spatio-temporal stress signaling, revealing cellular relocation of ribosomal proteins in response to hypertonicity and muscle contraction. Proteomics data generated in this study can be explored through https://SpatialProteoDynamics.github.io

Eradication of multi-resistant Salmonella typhimurium DT104 infections in 15 Danish swine herds

Multi-resistant Salmonella typhimurium DTI 04 (=DTI 04) was first isolated in United Kingdom in the 1980s. DT104 was isolated in Denmark for the first time in 1996 (1). Retrospective analysis of isolates detected DTI 04 in a Danish swine herd in 1991. The majority of the Danish isolates are characterized by being resistant to 5 frequently used antibiotics; ampicillin, chloramphenicol, streptomycin, sulphonamides and tetracycline (ACStSuT), but isolates being resistant to e.g. flouroquinolones as well have been detected. DTI 04 is now known as an important and emerging pathogen in many countries (2, 3, 4, 5). DTI 04 has spread rapidly between animals within the herd, between herds and to other species (6). Salmonella \u27JYphimurium DTl 04 remains the second most common Salmonella in humans in England and Wales in 1997,95 pet. of the isolates were resistant to four or more antibiotics with the most common resistance pattern is that of ACStSuT (7). The described combination of the ability to spread rapidly and the multiresistance towards antibiotics used frequently in animals and humans implies that DTI 04 can be a serious problem for both animals and humans. By June 1999 DTI04has been detected in 16 swine herds, 12 combined swine and cattle herds and 2 cattle herds in Denmark. HumaneDTI04 cases have slightly increased in Denmark from 1997 to 1998. DTI04 now accounts for 13 pet. of Salmonella typhimurium phage types compared to 7 pet. in 1997. This increase is explained by the first community outbreak of DTI 04 in Denmark

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson