Regarding: ‘Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array'

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Tallimustine in advanced previously untreated colorectal cancer, a phase II study.

Tallimustine is a novel benzoyl mustard derivative from distamycin A with a unique mode of action. It is a DNA minor groove binder and produces highly sequence-specific alkylations. Previous studies have shown significant anti-tumour effects in animal models. We performed a phase II study in previously untreated patients with advanced colorectal cancer, using a schedule of i.v. bolus infusions of 900 microgram m-2 once every 4 weeks. Seventeen patients were enrolled, and no responses were documented in 14 evaluable patients. Toxicity mainly consisted a highly selective neutropenia, which warrants further investigation of this agent in combination with myeloid growth factors

UGT1A1*28 genotype and irinotecan dosage in patients with metastatic colorectal cancer: a Dutch Colorectal Cancer Group study

The aim of the study was to investigate the associations between UGT1A1*28 genotype and (1) response rates, (2) febrile neutropenia and (3) dose intensity in patients with metastatic colorectal cancer treated with irinotecan. UGT1A1*28 genotype was determined in 218 patients receiving irinotecan (either first-line therapy with capecitabine or second-line as monotherapy) for metastatic colorectal cancer. TA7 homozygotes receiving irinotecan combination therapy had a higher incidence of febrile neutropenia (18.2%) compared to the other genotypes (TA6/TA6 : 1.5%; TA6/TA7 : 6.5%, P=0.031). TA7 heterozygotes receiving irinotecan monotherapy also suffered more febrile neutropenia (19.4%) compared to TA6/TA6 genotype (2.2%; P=0.015). Response rates among genotypes were not different for both regimens: combination regimen, P=0.537; single-agent, P=0.595. TA7 homozygotes did not receive a lower median irinotecan dose, number of cycles (P-values ⩾0.25) or more frequent dose reductions compared to the other genotypes (P-values for trend; combination therapy: 0.62 and single-agent: 0.45). Reductions were mainly (>80%) owing to grade ⩾3 diarrhoea, not (febrile) neutropenia. TA7/TA7 patients have a higher incidence of febrile neutropenia upon irinotecan treatment, but were able to receive similar dose and number of cycles compared to other genotypes. Response rates were not significantly different

Phase I study of Carzelesin (U-80,244) given (4-weekly) by intravenous bolus schedule

Carzelesin is a cyclopropylpyrroloindole analogue which acts as a DNA-sequence-specific alkylating agent. In this phase I study, Carzelesin was given as a 4-weekly 10 min IV infusion to 51 patients with advanced solid tumours. Patients received a median of two courses (range 1–5) at one of nine dose levels: 24, 48, 96, 130, 150, 170, 210, 250 and 300 μg m−2. According to NCI-CTC criteria, non-haematological toxicities (grade 1/2) included fever, nausea and vomiting, mucositis and anorexia, none of which was clearly dose related. The dose-limiting toxicity was haematological and consisted mainly of neutropenia and to a lesser extent thrombocytopenia. From the dose level 150 μg m−2, the haematological toxicity (particularly thrombocytopenia) was delayed in onset, prolonged and cumulative in some patients. In several courses, double WBC nadirs occurred. The maximum tolerated dose for a single course was 300 μg m−2. From the dose level 170 μg m−2, the intended dose intensity could not be delivered to most patients receiving > 2 courses owing to cumulative haematological toxicity. The dose level with the best dose intensity for multiple courses was 150 μg m−2. The pharmacokinetics of Carzelesin and its metabolites (U-76,073; U-76,074) have been established in 31 patients during the first course of treatment using a HPLC method. Carzelesin exhibited linear pharmacokinetics. The concentration of U-76,074 (active metabolite) extended above the lower limit of quantitation (1 ng ml−1) for short periods of time and only at the higher dose levels. There was no relationship between neutropenia and the AUC of the prodrug Carzelesin, but the presence of detectable plasma levels of the active metabolite U-76,074 was usually associated with a substantial decrease in ANC values. © 1999 Cancer Research Campaig

Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer.

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin

Закономерности распределения аномальных концентраций гелия в палеозойских отложениях Донбасса

Підвищені концентрації гелію у вільних і розчинених газах у вугільно-породному масиві Донбасу приурочені до зон зчленування Донбасу з Приазовським і Воронезьким кристалічними масивами і Головної антикліналі. Диз'юнктивні тектонічні порушення глибокого закладення служили, ймовірно, шляхами транзиту гелію від кристалічних порід фундаменту в палеозойські відклади Донбасу, і підвищений вміст гелію може служити індикатором шляхів транзиту газів з глибоких горизонтів Донецького вугільного басейну.Elevated concentrations of helium in free and dissolved gases in coal-rock mass of the Donets Coal Basin are confined to the junction zones of the Donets Coal Basin with the Priazovie and Voronezh crystalline core-areas and Glavnaya (Principal) Anticline. Deep-laid disjunctive dislocations were probably the ways for transit of helium from crystalline basement rocks into Paleozoic deposits of the Basin. Elevated concentrations of helium can also serve as indicators of the ways for transit of gases from deep levels of the Donets Coal Basin

Aspergillus niger genome-wide analysis reveals a large number of novel alpha-glucan acting enzymes with unexpected expression profiles

The filamentous ascomycete Aspergillus niger is well known for its ability to produce a large variety of enzymes for the degradation of plant polysaccharide material. A major carbon and energy source for this soil fungus is starch, which can be degraded by the concerted action of α-amylase, glucoamylase and α-glucosidase enzymes, members of the glycoside hydrolase (GH) families 13, 15 and 31, respectively. In this study we have combined analysis of the genome sequence of A. niger CBS 513.88 with microarray experiments to identify novel enzymes from these families and to predict their physiological functions. We have identified 17 previously unknown family GH13, 15 and 31 enzymes in the A. niger genome, all of which have orthologues in other aspergilli. Only two of the newly identified enzymes, a putative α-glucosidase (AgdB) and an α-amylase (AmyC), were predicted to play a role in starch degradation. The expression of the majority of the genes identified was not induced by maltose as carbon source, and not dependent on the presence of AmyR, the transcriptional regulator for starch degrading enzymes. The possible physiological functions of the other predicted family GH13, GH15 and GH31 enzymes, including intracellular enzymes and cell wall associated proteins, in alternative α-glucan modifying processes are discussed

Considerations for management strategy evaluation for small pelagic fishes

Management strategy evaluation (MSE) is the state-of-the-art approach for testing and comparing management strategies in a way that accounts for multiple sources of uncertainty (e.g. monitoring, estimation, and implementation). Management strategy evaluation can help identify management strategies that are robust to uncertainty about the life history of the target species and its relationship to other species in the food web. Small pelagic fish (e.g. anchovy, herring and sardine) fulfil an important ecological role in marine food webs and present challenges to the use of MSE and other simulation-based evaluation approaches. This is due to considerable stochastic variation in their ecology and life history, which leads to substantial observation and process uncertainty. Here, we summarize the current state of MSE for small pelagic fishes worldwide. We leverage expert input from ecologists and modellers to draw attention to sources of process and observation uncertainty for small pelagic species, providing examples from geographical regions where these species are ecologically, economically and culturally important. Temporal variation in recruitment and other life-history rates, spatial structure and movement, and species interactions are key considerations for small pelagic fishes. We discuss tools for building these into the MSE process, with examples from existing fisheries. We argue that model complexity should be informed by management priorities and whether ecosystem information will be used to generate dynamics or to inform reference points. We recommend that our list of considerations be used in the initial phases of the MSE process for small pelagic fishes or to build complexity on existing single-species models.publishedVersio

Gastrointestinal ulceration as a possible side effect of bevacizumab which may herald perforation

Chemotherapy plus bevacizumab is currently considered as the standard 1st line treatment of advanced colorectal cancer (ACC). Whereas GI perforation is a known side effect of bevacizumab, the development of GI ulcers has not been reported. We identified 18 patients with ACC who participated in a phase III multicentre trial which included chemotherapy and bevacizumab, who developed a GI ulcer (n = 6), perforation (n = 8) or both (n = 4). The risk of developing a symptomatic GI ulcer or perforation was 1.3% and 1.6%, respectively. Central review of the histology specimens showed ulceration and/or granulation tissue with neovascularisation. The majority (89%) of events developed early during treatment. Given these observations, as well as the relationship between VEGF and mucosal injury healing, we suggest that GI ulcers may occur as a side effect of treatment with bevacizumab and may herald perforation