Induction of the pro-myelocytic leukaemia gene by type I and type II interferons.

The physiological role of the pro-myelocytic leukaemia (PML) gene product is poorly defined. Among other functions, PML is involved in haematopoietic differentiation and in control of cell growth and tumorigenesis. We investigated the regulation of human PML expression by interferons (IFNs) and IL-1 in various human haematopoietic lines (U937, THP1, HL60, NB4), in human diploid fibroblasts and in human peripheral blood leukocytes. Cytokine-induced modulation of PML expression was assessed by Northern blot analyses, flow cytometry studies and in situ immunolabelling. Our data show that IFNs and IL-1 upregulate PML transcript and protein expression in a time and dose-dependent manner. In situ immunolabelling revealed that upregulation of protein expression by IFN-alpha is a consequence of a marked increase in both the number and the intensity of the staining of so-called PML nuclear bodies. Our data suggest that stimulation of PML expression by interferons and IL-1 may account for upregulation of PML proteins observed in inflammatory tissues and in proliferative states

Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response

Marker-free cell discrimination by holographic optical tweezers

We introduce a method for marker-free cell discrimination based on optical tweezers. Cancerous, non-cancerous, and drug-treated cells could be distinguished by measuring the trapping forces using holographic optical tweezers. We present trapping force measurements on different cell lines: normal pre-B lymphocyte cells (BaF3; "normal cells"), their Bcr-Abl transformed counterparts (BaF3-p185; "cancer cells") as a model for chronic myeloid leukaemia (CML) and Imatinib treated BaF3-p185 cells. The results are compared with reference measurements obtained by a commercial flow cytometry system

Spiritual well-being and associated factors in Dutch patients with advanced cancer

CONTEXT: Palliative care aims to support patients' spiritual needs with the intention of promoting their spiritual well-being (SWB), an important dimension of quality of life. SWB is one of the less-studied dimensions of QoL, particularly in a secular country such as the Netherlands. OBJECTIVES: In this study we aimed to get a better understanding of SWB in Dutch patients with advanced cancer. We therefore examined its prominence and associated factors. METHODS: We used the baseline data of a cohort study on experienced quality of care and quality of life (eQuiPe study), which included 1,103 patients with advanced cancer. In addition to sociodemographic and religious/spiritual characteristics, study measures comprised the SWB subscales Meaning, Peace, and Faith of the revised FACIT-Sp-12, spiritual problems and needs (PNPCsv), quality of life (EORTC-QLQ-C30) and satisfaction with healthcare professionals' interpersonal skills (INPATSAT-32). RESULTS: On average, patients experienced quite a bit of Meaning (8.9, SD 2.3), a little bit to somewhat Peace (6.8, SD 2.7), and very low levels of Faith (2.9, SD 3.7). Two-thirds (71%) of patients reported one or more spiritual problems, for which the majority (54%) wanted to receive attention. In the final multivariable models, only a few factors were associated with SWB, such as greater spiritual needs with lower levels of Meaning and Peace. CONCLUSION: Dutch patients with advanced cancer experience medium to low levels of Meaning, Peace, and Faith. More attention for their SWB is warranted

Зміни активності NO-синтаз та аргінази у тканині підшлункової залози при введенні L-аргініну або аміногуанідину за умов стрептозотоцин-індукованої гіперглікемії

При стрептозотоцин-индуцированной гипергликемии у крыс изучали влияние L-аргинина и селективного блокатора индуцибельной NO-синтазы аминогунидина на активность NO-синтаз и аргиназы в ткани поджелудочной железы. Показано, что как L-аргинин, так и аминогуанидин снижают активность индуцибельной NO-синтазы, при этом L-аргинин выражено понижает концентрацию глюкозы в крови и повышает активность аргиназы, что свидетельствует об усилении неокислительного пути его метаболизма.The influence of L-arginine and selective inducible NO-synthase blocker aminoguanidine on the activity of NO-synthases and arginase in pancreatic tissue in rats under conditions of streptozotocin-induced hyperglycemia was investigated. It was shown, that both L-arginine and aminoguanidine decrease the activity of inducible NO-synthase, whereas L-arginine supplementation significantly decreases the glucose concentration in blood and increases the activity of arginase, giving evidence about the enhancement of nonoxidative pathway of its metabolism

Highly variable response to cytotoxic chemotherapy in carcinoma-associated fibroblasts (CAFs) from lung and breast

<p>Abstract</p> <p>Background</p> <p>Carcinoma-associated fibroblasts (CAFs) can promote carcinogenesis and tumor progression. Only limited data on the response of CAFs to chemotherapy and their potential impact on therapy outcome are available. This study was undertaken to analyze the influence of chemotherapy on carcinoma-associated fibroblasts (CAFs) <it>in vitro </it>and <it>in vivo</it>.</p> <p>Methods</p> <p>The <it>in vivo </it>response of stromal cells to chemotherapy was investigated in 22 neoadjuvant treated breast tumors on tissue sections before and after chemotherapy. Response to chemotherapy was analyzed <it>in vitro </it>in primary cultures of isolated CAFs from 28 human lung and 9 breast cancer tissues. The response was correlated to <it>Mdm2</it>, <it>ERCC1 </it>and <it>TP53 </it>polymorphisms and <it>TP53 </it>mutation status. Additionally, the cytotoxic effects were evaluated in an <it>ex vivo </it>experiment using cultured tissue slices from 16 lung and 17 breast cancer specimens.</p> <p>Results</p> <p>Nine of 22 tumors showed a therapy-dependent reduction of stromal activity. Pathological response of tumor or stroma cells did not correlate with clinical response. Isolated CAFs showed little sensitivity to paclitaxel. In contrast, sensitivity of CAFs to cisplatinum was highly variable with a GI50 ranging from 2.8 to 29.0 μM which is comparable to the range observed in tumor cell lines. No somatic <it>TP53 </it>mutation was detected in any of the 28 CAFs from lung cancer tissue. In addition, response to cisplatinum was not significantly associated with the genotype of <it>TP53 </it>nor <it>Mdm2 </it>and <it>ERCC1 </it>polymorphisms. However, we observed a non-significant trend towards decreased sensitivity in the presence of <it>TP53 </it>variant genotype. In contrast to the results obtained in isolated cell culture, in tissue slice culture breast cancer CAFs responded to paclitaxel within their microenvironment in the majority of cases (9/14). The opposite was observed in lung cancer tissues: only few CAFs were sensitive to cisplatinum within their microenvironment (2/15) whereas a higher proportion responded to cisplatinum in isolated culture.</p> <p>Conclusion</p> <p>Similar to cancer cells, CAF response to chemotherapy is highly variable. Beside significant individual/intrinsic differences the sensitivity of CAFs seems to depend also on the cancer type as well as the microenvironment.</p

Continuity of care for patients with de novo metastatic cancer during the COVID-19 pandemic:A population-based observational study

During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1–12 2020: pre-COVID-19, weeks 12–20 2020: 1st peak, weeks 21–41 2020: recovery, weeks 42–53 2020: 2nd peak, weeks 1–20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77–0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72–0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p &lt;.001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.</p

Perceptions of involvement in advance care planning and emotional functioning in patients with advanced cancer

Purpose: Advance Care Planning (ACP) is positively associated with the quality of care, but its impact on emotional functioning is ambiguous. This study investigated the association between perceptions of ACP involvement and emotional functioning in patients with advanced cancer. Methods: This study analyzed baseline data of 1,001 patients of the eQuiPe study, a prospective, longitudinal, multicenter, observational study on quality of care and quality of life in patients with advanced cancer in the Netherlands. Patients with metastatic solid cancer were asked to participate between November 2017 and January 2020. Patients’ perceptions of ACP involvement were measured by three self-administered statements. Emotional functioning was measured by the EORTC-QLQ-C30. A linear multivariable regression analysis was performed while taking gender, age, migrant background, education, marital status, and symptom burden into account. Results: The majority of patients (87%) reported that they were as much involved as they wanted to be in decisions about their future medical treatment and care. Most patients felt that their relatives (81%) and physicians (75%) were familiar with their preferences for future medical treatment and care. A positive association was found between patients’ perceptions of ACP involvement and their emotional functioning (b=0.162, p<0.001, 95%CI[0.095;0.229]) while controlling for relevant confounders. Conclusions: Perceptions of involvement in ACP are positively associated with emotional functioning in patients with advanced cancer. Future studies are needed to further investigate the effect of ACP on emotional functioning. Trial registration number: NTR6584 Date of registration: 30 June 2017 Implications for Cancer Survivors: Patients’ emotional functioning might improve from routine discussions regarding goals of future care. Therefore, integration of ACP into palliative might be promising

Capturing complex tumour biology in vitro: Histological and molecular characterisation of precision cut slices

Precision-cut slices of in vivo tumours permit interrogation in vitro of heterogeneous cells from solid tumours together with their native microenvironment. They offer a low throughput but high content in vitro experimental platform. Using mouse models as surrogates for three common human solid tumours, we describe a standardised workflow for systematic comparison of tumour slice cultivation methods and a tissue microarray-based method to archive them. Cultivated slices were compared to their in vivo source tissue using immunohistochemical and transcriptional biomarkers, particularly of cellular stress. Mechanical slicing induced minimal stress. Cultivation of tumour slices required organotypic support materials and atmospheric oxygen for maintenance of integrity and was associated with significant temporal and loco-regional changes in protein expression, for example HIF-1α. We recommend adherence to the robust workflow described, with recognition of temporal-spatial changes in protein expression before interrogation of tumour slices by pharmacological or other means