Search

Background: Cytotoxic anticancer agents are designed to kill tumor cells by interfering with cell division mechanisms. In contrast, non-cytotoxic anticancer agents intend to inhibit cancer growth by targeting specific proteins or signaling pathways or by activating the immune system.We investigated whether these different modes of action are reflected in study designs, objectives and results of Phase I studies. Materials and methods:We conducted a PubMed search for full length English articles published in 2012 and 2013 describing completed single-agent Phase I studies in adult patients with solid tumors. Parameters were extracted, entered into a database and used to compile summarizing tables. Results:We retrieved 191 single-agent Phase I reports. Non-cytotoxic agents were investigated in almost twice as many studies compared to cytotoxic agents (127 vs 64). In the majority of studies a 3 + 3 dose escalation design was used for both cytotoxic (64%) as well as non-cytotoxic agents (50%). The percentage of studies investigating a single tumor indication was larger with non-cytotoxic agents (29% vs 11%). On average, studies investigating non-cytotoxic agents had a slightly increased sample size (39.4 vs 31.9 patients), study duration (38.2 vs 33.0 months) and enrollment time (26.8 vs 24.5 months). The main routes of administration are intravenous (IV) and oral (PO) for both cytotoxic (78% and 17%) and non-cytotoxic agents (24% and 48%). The primary objectives in both groups were mainly safety and tolerability. The main difference in secondary objectives was the increased usage of pharmacodynamic (PD) endpoints with non-cytotoxic agents (63% vs 23%). The maximum tolerated dose (MTD) was more often reached in studies with cytotoxic agents (69% vs 33%). Small but not significant differences were seen in objective response rate (4.5% vs 6.1%) and stable disease (30.0% vs 33.5%) for cytotoxic vs non-cytotoxic agents. Conclusions: There are differences in study designs, objectives and results for studies with cytotoxic compared to non-cytotoxic agents. The main difference between the two groups is the use of a single indication (11% vs 29%), the route of administration (IV vs PO), the use of PD endpoints (23% vs 63%) and the establishment of the MTD (69% vs 33%). [ABSTRACT FROM AUTHOR]

A novel, palatable butyric acid-rich triglyceride oil has been developed and is available as a food supplement for adults in the United States and Canada. A program of safety studies was conducted with butyric acid-rich triglyceride oil for the pediatric population. The oil was tested in a microbial reverse mutation assay Ames Test OECD471 (Organisation for Economic Co-operation and Development) in which all bacterial strains showed negative responses over the complete dose range in two independently repeated experiments. All values were within the laboratory historical control data ranges. Further, data from the human lymphocyte micronucleus assay (OECD487) in the presence or absence of a metabolic activator (S9-mix), the oil did not induce a biologically relevant increase in the number of binucleated cells with micronuclei; therefore, the oil is considered not to be clastogenic or aneugenic. In a 90-day rat repeat dose toxicity study (OECD408), there were no unscheduled deaths, no treatment-related clinical signs, or effects on body weight and body weight gain, food consumption, ophthalmology, FOB parameters (including motor activity), clinical chemistry including thyroid hormones, and sperm parameters. There were no related organ weight changes, macroscopic or microscopic findings. In an extended one-generation reproductive toxicology study (EOGRTS) OECD443, there were no biologically important changes in body weight or body weight gain observed in the P generation male rats during the dosing period. At the end of the dosing period, the mean body weights in the male rats were 98% and 98% of the control group value in the 3720 and 4650 mg/kg/day dose groups, respectively. No biologically important changes in maternal body weights or body weight gains were observed during the premating, gestation, or lactation periods at dose levels up to and including 4650 mg/kg/day. Clinical signs observed in the P generation males and females were within the historical data ranges and not test substance related. There were no test substance-related changes in any other tested outcomes analyzed in the P generation males and females at doses up to and including 4650 mg/kg/day. In the F1 Generation, preweaning clinical signs observed in the males and females were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the preweaning period at maternal dose levels up to and including 4650 mg/kg/day. In the postweaning period, there were also no clinical signs observed in males and females; all were within the historical data ranges and not test article related. There were no statistically significant or biologically relevant abnormalities in any of the parameters analyzed throughout the postweaning period at maternal dose levels up to and including 4650 mg/kg/day including body weights. Taken together, data from these toxicity studies show that butyric acid-rich triglyceride oil is extremely safe with a "no observed adverse effect level" (NOAEL) considered to be 4650 mg/kg/day, the highest dose tested., (© 2024 John Wiley & Sons Ltd.)

Lacto-N-tetraose (LNT) is a human milk oligosaccharide with average concentrations ranging from 0.74 to 1.07 g/L in breastmilk, depending on the lactation stage. In this study, the preclinical safety of LNT produced by the Escherichia coli K-12 E2083 production strain was assessed. LNT was negative in both the bacterial reverse mutation assay and the in vitro micronucleus assay, demonstrating the absence of genotoxic potential for this substance. In the OECD 408 guideline compliant 90-day oral toxicity study rat, LNT did not induce any adverse effects in any treatment group up to and including the highest dose tested, and no LOAEL could be determined. Therefore, the no-observed-adverse effect level (NOAEL) is set at the highest dose level tested, i.e. a dietary level of 5 % (w/w), corresponding to ≥2856 mg/kg bw/day and ≥3253 mg/kg bw/day for males and females, respectively. This might be an underestimation of the NOAEL, caused by the range of dose levels tested. The results obtained in the current study are in good agreement with available data generated using other biotechnologically produced LNT batches and therefore support its safe use as a food ingredient., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dianne J. Delsing reports a relationship with FrieslandCampina that includes: employment. Hester van der Woude reports a relationship with FrieslandCampina that includes: consulting or advisory. Sylvia M.J.G. Pelgrom reports a relationship with FrieslandCampina that includes: consulting or advisory. Carin Buskens reports a relationship with FrieslandCampina that includes: consulting or advisory. Roy Hoffmans reports a relationship with FrieslandCampina that includes: consulting or advisory. Nora Krajcs reports a relationship with FrieslandCampina that includes: consulting or advisory., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Various case reports have described sudden sensorineural hearing loss (SSNHL) in patients with the 2019 novel coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our aim was to determine the incidence of COVID-19 in patients with SSNHL., Methods: All consecutive patients with audiometric confirmed SSNHL between November 2020 and March 2021 in a Dutch large inner city teaching hospital were included. All patients were tested for COVID-19 by polymerase-chain-reaction (PCR) and awaited the results in quarantine., Results: Out of 25 patients, zero (0%) tested positive for COVID-19. Two patients had previously tested positive for COVID-19: at three and eight months prior to the onset of hearing loss., Conclusions: This is the largest series to date investigating COVID-19 in SSNHL patients. In this series there is no apparent relationship between SSNHL and COVID-19., Competing Interests: The author disclose no conflicts of interest and source of funding., (Copyright © 2021, Otology & Neurotology, Inc.)

Background: This study was conducted to assess the effect of comorbidity, ethnicity, occupation, smoking and place of residence on allergic rhinitis (AR), acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS)., Methods: A GA2LEN (The Global Allergy and Asthma European Network) screening questionnaire was sent to a random sample of the Dutch population (n = 16700) in three different areas of the Netherlands., Results: Fifty percent (8347) of the questionnaires sent were returned. A total of 29% respondents (27-31% in different areas) met the criteria for AR, 18% (17-21%) for ARS and 16% (13-18%) for CRS. Risk factors for AR were itchy rash, eczema, adverse response after taking a painkiller, asthma, CRS and ARS. Moreover, the risk of AR was twice as low for full-time housewives/househusbands than for people with jobs. The risk of ARS or CRS was significantly higher in respondents with a doctor's diagnosis of CRS, AR, itchy rash or smoking. The risk of CRS was also significantly higher in respondents with an adverse response after taking painkillers, active smoking or asthma. Caucasians are generally less likely to have AR or CRS than Latin-Americans, Hindustani and African-Creoles, and more likely to have ARS than Asian, Hindustani, Mediterranean and African-Creoles., Conclusions: This study found shared and distinct risk factors for AR, ARS and CRS and therefore provides support for the belief that they have shared symptoms but are different diseases with different aetiologies.

Background: There is only limited accurate data on the epidemiology of rhinosinusitis in primary care. This study was conducted to assess the incidence of acute and chronic rhinosinusitis by analysing data from two Dutch general practice registration projects. Several patient characteristics and diseases are related to the diagnosis rhinosinusitis., Methods: The Continuous Morbidity Registration (CMR) and the Transitionproject (TP) are used to analyse the data on rhinosinusitis in primary practice. Both registries use codes to register diagnoses., Results: In the CMR 3244 patients are registered with rhinosinusitis and in the TP 5424 CMR: The absolute incidence of (acute) rhinosinusitis is 5191 (18.8 per 1000 patient years). Regarding an odds ratio of 5.58, having nasal polyps is strongest related to rhinosinusitis compared to the other evaluated comorbidities. A separate code for chronic rhinosinusitis exists, but is not in use. TP: Acute and chronic rhinosinusitis are coded as one diagnosis. The incidence of rhinosinusitis is 5574 or 28.7 per 1000 patient years. Patients who visit their general practitioner with "symptoms/complaints of sinus", allergic rhinitis and "other diseases of the respiratory system" have the highest chances to be diagnosed with rhinosinusitis. Medication is prescribed in 90.6 % of the cases., Conclusions: Rhinosinusitis is a common diagnosis in primary practice. In the used registries no difference could be made between acute and chronic rhinosinusitis, but they give insight in comorbidity and interventions taken by the GP in case of rhinosinusitis.

The fate of neural progenitor cells (NPCs) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-Catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain., (© 2014 AlphaMed Press.)

β-Catenin, apart from playing a cell-adhesive role, is a key nuclear effector of Wnt signaling. Based on activity assays in Drosophila, we generated mouse strains where the endogenous β-catenin protein is replaced by mutant forms, which retain the cell adhesion function but lack either or both of the N- and the C-terminal transcriptional outputs. The C-terminal activity is essential for mesoderm formation and proper gastrulation, whereas N-terminal outputs are required later during embryonic development. By combining the double-mutant β-catenin with a conditional null allele and a Wnt1-Cre driver, we probed the role of Wnt/β-catenin signaling in dorsal neural tube development. While loss of β-catenin protein in the neural tube results in severe cell adhesion defects, the morphology of cells and tissues expressing the double-mutant form is normal. Surprisingly, Wnt/β-catenin signaling activity only moderately regulates cell proliferation, but is crucial for maintaining neural progenitor identity and for neuronal differentiation in the dorsal spinal cord. Our model animals thus allow dissecting signaling and structural functions of β-catenin in vivo and provide the first genetic tool to generate cells and tissues that entirely and exclusively lack canonical Wnt pathway activity., (© 2011 by Cold Spring Harbor Laboratory Press)

Aims: To determine whether general practitioners (GPs) distinguish between the management of acute rhinosinusitis (ARS) and chronic rhinosinusitis (CRS), especially with regard to prescription of antibiotics and nasal steroids., Methods: A questionnaire on the management of rhinosinusitis was sent to 1000 GPs in The Netherlands., Results: Ninety-six percent discriminated between ARS and CRS. However, the definition of ARS and CRS varied. The percentage of GPs prescribing antibiotics rose as rhinosinusitis severity increased. The prescription rate of nasal corticosteroids was highest for CRS (88.6%). Prescribing nasal corticosteroids in ARS was not very common., Conclusions: Most GPs discriminate between ARS and CRS and 54% accepted (the EP3OS-defined) 12 weeks as the division between ARS and CRS. Antibiotics and nasal steroids are commonly used agents, but the management of rhinosinusitis is not always consistent with guidelines.

Evasion of DNA damage-induced cell death, via mutation of the p53 tumor suppressor or overexpression of prosurvival Bcl-2 family proteins, is a key step toward malignant transformation and therapeutic resistance. We report that depletion or acute inhibition of checkpoint kinase 1 (Chk1) is sufficient to restore gamma-radiation-induced apoptosis in p53 mutant zebrafish embryos. Surprisingly, caspase-3 is not activated prior to DNA fragmentation, in contrast to classical intrinsic or extrinsic apoptosis. Rather, an alternative apoptotic program is engaged that cell autonomously requires atm (ataxia telangiectasia mutated), atr (ATM and Rad3-related) and caspase-2, and is not affected by p53 loss or overexpression of bcl-2/xl. Similarly, Chk1 inhibitor-treated human tumor cells hyperactivate ATM, ATR, and caspase-2 after gamma-radiation and trigger a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The evolutionarily conserved "Chk1-suppressed" pathway defines a novel apoptotic process, whose responsiveness to Chk1 inhibitors and insensitivity to p53 and BCL2 alterations have important implications for cancer therapy.

The Wingless (Wg)/Wnt signal transduction pathway controls fundamental processes during animal development. Deregulation of the Wg/Wnt pathway has been causally linked to several forms of cancer, most notably to colorectal cancer. In response to Wg/Wnt signaling, Armadillo/beta-catenin associates in the nucleus with DNA bound TCF and several co-factors, among them Legless/BCL9, which provides a link to Pygopus. Recently, the second vertebrate homologue of Legless, BCL9-2 (or B9L), was characterized and proposed to mediate Wnt signaling in a Pygopus-independent manner, by binding to a Tyrosine-142-phosphorylated form of beta-catenin. Here we examine the role of Tyrosine-142 phosphorylation in several assays and find that it is neither important for the recruitment of BCL9-2, nor for the transcriptional activity of beta-catenin in cultured mammalian cells, nor in Drosophila for Wg signaling activity in vivo. Furthermore, we demonstrate that BCL9-2 can functionally replace Lgs both in cultured cells as well as in vivo and that this rescue activity depends on the ability of BCL9-2 to bind Pygo. Our results do not show a significant functional difference between BCL9-2 and BCL9 but rather suggest that the two proteins represent evolutionary duplicates of Legless, which have acquired distinct expression patterns while acting in a largely redundant manner.

The Wingless/Wnt pathway controls cell fates during animal development and regulates tissue homeostasis as well as stem cell number and differentiation in epithelia. Deregulation of Wnt signaling has been associated with cancer in humans. In the nucleus, the Wingless/Wnt signal is transmitted via the key effector protein Armadillo/beta-catenin. The recent identification and functional analysis of novel Armadillo/beta-catenin interaction partners provide new and exciting insights into the highly complex mechanism of Wingless/Wnt target gene activation.

Wnt signaling controls important aspects of animal development, and its deregulation has been causally linked to cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA binding proteins and the subsequent activation of target genes. The transcriptional activity of Armadillo (Arm, the Drosophila beta-catenin homolog) largely depends on two recently discovered components, Legless (Lgs) and Pygopus (Pygo). Lgs functions as an adaptor between Arm/beta-catenin and Pygo, but different mechanisms have been proposed as to how Arm/beta-catenin is controlled by Lgs and Pygo. Although Lgs and Pygo were originally thought to serve as nuclear cofactors for Arm/beta-catenin to enhance its transactivation capacity, a recent analysis argued that they function instead to target Arm/beta-catenin to the nucleus. Here, we used genetic assays in cultured cells and in vivo to discriminate between the two paradigms. Regardless of the measures taken to maintain the nuclear presence of Arm/beta-catenin, a transcriptional-activation function of Pygo could not be bypassed. Our findings therefore indicate that Arm/beta-catenin depends on Lgs and Pygo primarily for its transcriptional output rather than for its nuclear import.

The Wnt signalling system controls many fundamental processes during animal development and its deregulation has been causally linked to colorectal cancer. Transduction of Wnt signals entails the association of beta-catenin with nuclear TCF DNA-binding factors and the subsequent activation of target genes. Using genetic assays in Drosophila, we have recently identified a presumptive adaptor protein, Legless (Lgs), that binds to beta-catenin and mediates signalling activity by recruiting the transcriptional activator Pygopus (Pygo). Here, we characterize the beta-catenin/Lgs interaction and show: (1) that it is critically dependent on two acidic amino acid residues in the first Armadillo repeat of beta-catenin; (2) that it is spatially and functionally separable from the binding sites for TCF factors, APC and E-cadherin; (3) that it is required in endogenous as well as constitutively active forms of beta-catenin for Wingless signalling output in Drosophila; and (4) that in its absence animals develop with the same phenotypic consequences as animals lacking Lgs altogether. Based on these findings, and because Lgs and Pygo have human homologues that can substitute for their Drosophila counterparts, we infer that the beta-catenin/Lgs binding site may thus serve as an attractive drug target for therapeutic intervention in beta-catenin-dependent cancer progression.