The proteasomal and apoptotic phenotype determine bortezomib sensitivity of non-small cell lung cancer cells

Bortezomib is a novel anti-cancer agent which has shown promising activity in non-small lung cancer (NSCLC) patients. However, only a subset of patients respond to this treatment. We show that NSCLC cell lines are differentially sensitive to bortezomib, IC50 values ranging from 5 to 83 nM. The apoptosis-inducing potential of bortezomib in NSCLC cells was found to be dependent not only on the apoptotic phenotype but also on the proteasomal phenotype of individual cell lines. Upon effective proteasome inhibition, H460 cells were more susceptible to apoptosis induction by bortezomib than SW1573 cells, indicating a different apoptotic phenotype. However, exposure to a low dose of bortezomib did only result in SW1573 cells, and not in H460 cells, in inhibition of proteasome activity and subsequent apoptosis. This suggests a different proteasomal phenotype as well. Additionally, overexpression of anti-apoptotic protein Bcl-2 in H460 cells did not affect the proteasomal phenotype of H460 cells but did result in decreased bortezomib-induced apoptosis. In conclusion, successful proteasome-inhibitor based treatment strategies in NSCLC face the challenge of having to overcome apoptosis resistance as well as proteasomal resistance of individual lung cancer cells. Further studies in NSCLC are warranted to elucidate underlying mechanisms

Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report

BACKGROUND: Bortezomib (Velcade(®)), a dipeptide boronate proteasome inhibitor, is a novel anti-cancer agent registered for multiple myeloma (MM). It has also shown promising clinical activity in non-small cell lung cancer (NSCLC). Clinical experience with bortezomib so far indicates that overall incidence of cardiac failure associated with bortezomib therapy remains incidental. Nevertheless, acute development or exacerbation of congestive cardiac failure has been associated with bortezomib treatment. CASE PRESENTATION: We present here a case of severe, but reversible, congestive cardiac failure in a lung cancer patient who had no prior cardiac history, after receiving an experimental treatment of bortezomib combined with chemotherapy. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), as retrospectively measured in archived serum samples, were suggestive of pre-existent (sub-clinical) left ventricular dysfunction. CONCLUSION: Based on literature, we hypothesize that baseline presence of sub clinical cardiomyopathy, characterized by a dysregulation of the ubiquitin-proteasome system, could have predisposed this patient for a cardiac side effect induced by systemic proteasome inhibition. Patients with heart disease or risk factors for it should be closely monitored when being submitted to treatment with proteasome inhibition therapy such as bortezomib. Caution is therefore warranted in lung cancer patients who often present with cardiac comorbidities

Comparison of Carboplatin With 5-Fluorouracil vs. Cisplatin as Concomitant Chemoradiotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma

Background: Chemoradiotherapy (CRT) including three cycles of cisplatin is considered the standard of care for locally advanced head and neck squamous cell carcinoma (LA-HNSCC). However, around one-third of the patients cannot complete cisplatin because of toxicity. Carboplatin plus 5-fluorouracil (carbo-5FU) is another accepted treatment option with a different toxicity profile. We compared tolerability and efficacy of concomitant carbo-5FU and cisplatin. Patients and Methods: We conducted a retrospective analysis of LA-HNSCC patients treated with CRT in two Dutch cancer centers between 2007 and 2016. All patients received intensity-modulated radiotherapy. One center routinely administered carboplatin 300–350 mg/m2 at day 1, 22, and 43 followed by 5FU 600 mg/m2/day for 96 h. The other center used cisplatin 100 mg/m2 at day 1, 22, and 43. The primary endpoint of this study was chemotherapy completion rate. Secondary endpoints included overall survival (OS), disease-free survival (DFS), locoregional control (LRC) and distant metastasis–free interval (DMFS), toxicity, and unplanned admissions. Results: In the carbo-5FU cohort (n = 211), 60.2% of the patients completed chemotherapy vs. 76.7% (p < 0.001) of the patients in the cisplatin cohort (n = 223). Univariate analysis showed a higher risk of death in the carbo-5FU cohort [hazard ratio (HR) 1.53, 95% CI, 1.09–2.14, p = 0.01] with a 3-year OS of 65.4 vs. 76.5% for cisplatin. OS was independently associated with T and N stage and p16 status, but not with chemotherapy regimen (HR 1.08, 95% CI, 0.76–1.55, p = 0.65). Three-year DFS was 70.0% for carbo-5FU vs. 78.6% for cisplatin (HR 1.37, 95% CI, 0.93–2.01, p = 0.05). A similar outcome was observed for both LRC (HR 1.27, 95% CI, 0.74–2.09, p = 0.4) and DMFS (HR 1.08, 95% CI 0.62–1.90, p = 0.77). The risk of discontinuation for chemotherapy-associated toxicity was higher in the carbo-5FU cohort than in the cisplatin cohort (relative risk = 1.69). Conclusion: LA-HNSCC patients treated with concomitant carbo-5FU completed chemotherapy less frequently than patients treated with cisplatin. Treatment regimen was not an independent prognostic factor for OS

Cell-binding IgM in CSF is distinctive of multiple sclerosis and targets the iron transporter SCARA5

Intrathecal IgM production in multiple sclerosis (MS) is associated with a worse disease course. To investigate pathogenic relevance of autoreactive IgM in MS, CSF from two independent cohorts, including MS patients and controls, were screened for antibody binding to induced pluripotent stem cell-derived neurons and astrocytes, and a panel of CNS- related cell lines. IgM binding to a primitive neuro-ectodermal tumour cell line discriminated 10% of MS donors from controls. Transcriptomes of single IgM producing CSF B cells from patients with cell-binding IgM were sequenced and used to produce recombinant monoclonal antibodies for characterisation and antigen identification. We produced 5 cell-binding recombinant IgM antibodies, of which one, cloned from an HLA-DR + plasma-like B cell, mediated antigen-dependent complement activation. Immunoprecipitation and mass spectrometry, and biochemical and transcriptome analysis of the target cells identified the iron transport scavenger protein SCARA5 as the antigen target of this antibody. Intrathecal injection of a SCARA5 antibody led to an increased T cell infiltration in an EAE model. CSF IgM might contribute to CNS inflammation in MS by binding to cell surface antigens like SCARA5 and activating complement, or by facilitating immune cell migration into the brain

Agile XL in Globally Distributed Environments

Agile is a software development approach based on a set of 4 values and 12 principles. Using this set Scrum was developed as a agile framework in the early 1990s, which still remains the most popular framework today. However, Scrum originated to be used by a small number of co-located teams. When the amount of teams and the distance between the teams becomes bigger, issues will start to arise. With the rise of the computer and internet, programming-related work environments have become very large and globally distributed, implying a friction when using agile in these environments. This study aims to explore what challenges occur when using agile in very-large globally distributed environments and explore for practices that can be used to deal with them. To do this, a variety of research methods is used to gain insight, those being a systematic literature review (SLR), interviews and online surveys. We identify 50 challenges that may be encountered and 72 practices that can be used to combat them. Our online survey verified that all found challenges are frequently encountered in practice and the majority have a significant impact when encountered. However we also identified multiple practices that are used often to combat certain high-impact challenges. The most important practices were identified to be training and coaching. Experts were invited to fill in an online survey to generate possible learning goals. These learning goals are used to create an education program prototype for very-large scale globally distributed agile software engineering. As examples, 4 use cases in different environments are provided to show the prototype can be used to construct a matching training program. We provide proposals for further research directions into challenges, practices and the education program based on the steps taken in this study.Computer Scienc

More than a Bubble: Extracellular Vesicle microRNAs in Head and Neck Squamous Cell Carcinoma

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules that play a pivotal regulatory role in a broad variety of biological processes. Dysregulation of miRNAs is associated with several human diseases, particularly cancer. Extracellular vesicles (EVs) are crucial components in intercellular communication. As part of the cargo of EVs, miRNAs are involved in EV-mediated cell-to-cell interactions, including promotion or suppression of tumor development. The knowledge on the molecular mechanisms and clinical importance of EV-miRNAs in head and neck squamous cell carcinoma (HNSCC) has rapidly grown over the past years. In the present review, the current understanding regarding the effect of EV-miRNAs on HNSCC tumorigenesis is summarized, which includes effects on tumor proliferation, angiogenesis, invasion and metastasis, the tumor microenvironment, immune modulation, and treatment resistance. EV-miRNA-based biomarkers in liquid biopsies such as blood and saliva may open up new possibilities for employing EV-miRNAs for screening and early diagnostics as well as disease monitoring. Future perspectives include the promise of EV-miRNAs as a novel therapeutic target