Subtle, CXCR3-dependent, chemotaxis of cytotoxic cells within infected tissues allows efficient target localization

Toxicolog

Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30-50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3-4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90-100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.Immune checkpoint blockade has become standard care for patients with recurrent metastatic head and neck squamous cell carcinoma (HNSCC). Here the authors present the results of a non-randomized phase Ib/IIa trial, reporting safety and efficacy of neoadjuvant nivolumab monotherapy and nivolumab plus ipilimumab prior to standard-of-care surgery in patients with HNSCC. .Otorhinolaryngolog

Jet production in ep collisions at high Q(2) and determination of alpha(s)

The production of jets is studied in deep-inelastic e(+/-) p scattering at large negative four momentum transfer squared 150 LT Q(2) LT 15000 GeV2 using HERA data taken in 1999-2007, corresponding to an integrated luminosity of 395 pb(-1). Inclusive jet, 2-jet and 3-jet cross sections, normalised to the neutral current deep-inelastic scattering cross sections, are measured as functions of Q(2), jet transverse momentum and proton momentum fraction. The measurements are well described by perturbative QCD calculations at next-to-leading order corrected for hadronisation effects. The strong coupling as determined from these measurement

Tissue structure damage in late-stage knee osteoarthritis: medication, markers, and disease modification before replacement surgery

The aim of this thesis is to gain more insight in the characteristics of end-stage osteoarthritic patients who are about to undergo total knee replacement surgery. Their use of medication, potential markers of actual characteristics of joint damage and inflammation, and effects of potential disease modification by drugs were studied. For this purpose, a clinical trial was performed with patients with end-stage knee osteoarthritis. While on the waiting list for total knee replacement surgery, patients were randomized to receive pharmacological treatment for four to six weeks prior to joint replacement surgery. At the moment of surgery cartilage and synovial tissue were harvested for detailed macroscopic, microscopic, and biochemical evaluation. Clinical effects of medication before surgery and clinical effects of surgery itself were evaluated by use of questionnaires. It appeared that most patients on the waiting list for total knee replacement surgery experience significant levels of pain and limitations due to their disease. But surprisingly, the majority of the patients on the waiting list did not take adequate pain medication. When patients were asked one and a half year after total knee replacement surgery whether they would have undergone the treatment again with the present (post-treatment) knowledge, it was revealed that 13% of the treated patients would not have undergone the treatment if they knew the clinical outcome beforehand.Radiographs also appear to be good indicators for the actual severity of joint damage in contrast to clinical characteristics and should be taken into account when selecting patients for joint replacement surgery. Adipokine levels were all clearly higher compared to controls without any radiographic sign of cartilage damage, also after adjustment for gender, age, and BMI. In the OA population clear relations with age were found for adiponectin and resistin and with BMI for leptin and adiponectin. No associations were found between serum levels of adipokines and cartilage damage whereas a marginal positive association was found with synovial inflammation. Supporting an important role of adipokines in osteoarthritis, but the mechanism remains to be elucidated. In a pilot study the effects of celecoxib compared to a frequently used conventional NSAID indomethacin was investigated. The result of this pilot study was the basis for a larger prospective, randomized, observer blinded clinical trial. The promising effect of the earlier study could however not be confirmed by this randomized, observer blinded clinical trial. In conclusion, celecoxib appears to have less clear disease modifying osteoarthritic drug (DMOAD) properties as originally supposed. This thesis demonstrates that end-stage knee osteoarthritis patients are very different in their demographic, radiographic, and actual joint tissue characteristics. It also demonstrates that part of the patients undergoing total knee replacement surgery could have delayed their surgery if they had used adequate pharmacological therapy and proper selection based on radiographic damage. Celecoxib might be treatment of choice although DMOAD activity is not unambiguously proven

Elucidating fungal Rigidoporus species FMD21 lignin-modifying enzyme genes and 2,3,7,8-tetrachlorodibenzo-p-dioxin degradation by laccase isozymes

White-rot fungus Rigidoporus sp. FMD21 is a lignin-modifying enzyme producing fungus that can degrade dioxin. Extracellular enzymes from FMD21 include laccase and manganese peroxidase which are promising enzymes for myco-remediation because of their wide substrate specificity and mild catalysis conditions. The FMD21 genome was sequenced using Ion Torrent technology and consists of 38.98 Mbps with a GC content of 47.4 %. Gene prediction using Augustus with Basidiomycota reference setting resulted in 8245 genes. Functional gene annotations were carried out by using several programs and databases. We focused on laccase and ligninolytic peroxidase genes, which are most likely involved in the degradation of aromatic pollutants. The genome of FMD21 contains 12 predicted laccase genes (10 out of 12 predicted as full length) and 13 putative ligninolytic peroxidases which were annotated as MnP or versatile peroxidases. Four predicted laccases showed a higher than 65 % binding chance to 2,3,7,8-TCDD with the highest at 72 % in in silico docking analysis. Heterologous expressed laccases showed activity towards three tested substrates included ABTS, guaiacol and 2,6-DMP. ABTS displayed two-stage oxidation which differed from natural FMD21 laccases. 2,3,7,8-TCDD was degraded by 50 % after two weeks of enzymatic treatment by three out of five laccase isozymes which were natural laccases secreted by FMD21. In this study, we provide direct evidence for the 2,3,7,8-TCDD biodegradation capability of fungal laccases