The natural behavior of mesenchymal stem cells (MSCs) and their exosomes in targeting tumors is a promising approach for curative therapy. Human tumor tropic mesenchymal stem cells (MSCs) isolated ...from various tissues and MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase suicide fusion gene (yCD::UPRT‐MSCs) released exosomes in conditional medium (CM). Exosomes from all tissue specific yCD::UPRT‐MSCs contained mRNA of the suicide gene in the exosome's cargo. When the CM was applied to tumor cells, the exosomes were internalized by recipient tumor cells and in the presence of the prodrug 5‐fluorocytosine (5‐FC) effectively triggered dose‐dependent tumor cell death by endocytosed exosomes via an intracellular conversion of the prodrug 5‐FC to 5‐fluorouracil. Exosomes were found to be responsible for the tumor inhibitory activity. The presence of microRNAs in exosomes produced from naive MSCs and from suicide gene transduced MSCs did not differ significantly. MicroRNAs from yCD::UPRT‐MSCs were not associated with therapeutic effect. MSC suicide gene exosomes represent a new class of tumor cell targeting drug acting intracellular with curative potential.
What's new?
Mesenchymal stem cells (MSC) migrate toward tumors and are currently being exploited as conduits for targeted cancer treatment. The authors engineered MSCs to express a suicide gene (yeast cytosine deaminase::uracil phosphoribosyl Transferase) converting a prodrug (5‐fluorocytosine) into a cytotoxic cancer treatment (5‐fluorouracil). They find mRNAs of the suicide gene secreted in exosomes from MSCs and the exosomes to exhibit cytotoxic effects in the presence of prodrug. This study adds MSC‐derived exosomes to the list of targeted cancer drug delivery approaches.
Biobanks have during last two decades gained an important role in the whole process of biomedical research and health care not only in Europe but also worldwide. Biobanks are one of the pillars in ...personalised medicine tackling all its aspects such as prevention, diagnosis, treatment and monitoring closely the specific characteristics of an individual patient. The current and future power of biobanks is the amount of samples of high-quality and related information available for current and future research of diseases, for optimising patients´ prevention, diagnosis, treatment and monitoring. The material stored in biobanks is a treasure for future technologies that will be able to utilise the currently uncovered information and knowledge. A great and growing number of samples and related information also opens new ways in how to tackle the big data problems and population studies. Biobanks play a substantial role in drug discovery, development and validation. Biobanks are not only an issue of biomedical research, but are becoming a public issue involving patients, to actively participate in biobanking with respect to ethical, legal and social issues. And, finally, biobanking as a multidisciplinary and modern field of science requires appropriate education at all levels of society. To be a world leader in the field of biobanking requires wide international and interdisciplinary collaboration. The topic-dedicated programmes released by the European Commission sustainably support biobank development in Europe and the main tool is the biggest European Union (EU) research and innovation programme ever—Horizon 2020. This article reviews the main Horizon 2020 biobanking projects, financing schemes and the future perspectives.
In the early twenty-first century, societies around the world are facing the paradoxal epidemic development of PCa as a non-communicable disease. PCa is the most frequently diagnosed cancer for men ...in several countries such as the USA. Permanently improving diagnostics and treatments in the PCa management causes an impressive divergence between, on one hand, permanently increasing numbers of diagnosed PCa cases and, on the other hand, stable or even slightly decreasing mortality rates. Still, aspects listed below are waiting for innovate solutions in the context of predictive approaches, targeted prevention and personalisation of medical care (PPPM / 3PM).
PCa belongs to the cancer types with the highest incidence worldwide. Corresponding economic burden is enormous. Moreover, the costs of treating PCa are currently increasing more quickly than those of any other cancer. Implementing individualised patient profiles and adapted treatment algorithms would make currently too heterogeneous landscape of PCa treatment costs more transparent providing clear “road map” for the cost saving.
PCa is a systemic multi-factorial disease. Consequently, predictive diagnostics by liquid biopsy analysis is instrumental for the disease prediction, targeted prevention and curative treatments at early stages.
The incidence of metastasising PCa is rapidly increasing particularly in younger populations. Exemplified by trends observed in the USA, prognosis is that the annual burden will increase by over 40% in 2025. To this end, one of the evident deficits is the reactive character of medical services currently provided to populations. Innovative screening programmes might be useful to identify persons in suboptimal health conditions before the clinical onset of metastasising PCa. Strong predisposition to systemic hypoxic conditions and ischemic lesions (e.g. characteristic for individuals with Flammer syndrome phenotype) and low-grade inflammation might be indicative for specific phenotyping and genotyping in metastasising PCa screening and disease management. Predictive liquid biopsy tests for CTC enumeration and their molecular characterisation are considered to be useful for secondary prevention of metastatic disease in PCa patients.
Particular rapidly increasing PCa incidence rates are characteristic for adolescents and young adults aged 15–40 years. Patients with early onset prostate cancer pose unique challenges; multi-factorial risks for these trends are proposed. Consequently, multi-level diagnostics including phenotyping and multi-omics are considered to be the most appropriate tool for the risk assessment, prediction and prognosis. Accumulating evidence suggests that early onset prostate cancer is a distinct phenotype from both aetiological and clinical perspectives deserving particular attention from view point of 3P medical approaches.
Peritonsillar abscess (PTA) is the most common complication of tonsillitis. Cultivation usually reveals a wide spectrum of aerobic and anaerobic microbiota. This retrospective study compared PTA ...incidence and the spectrum of individual microbial findings in groups of patients divided by gender, age, and season. Of the 966 samples cultivated, a positive cultivation finding was detected in 606 patients (62.73%). Cultivation findings were negative in 360 (37.27%), meaning no pathogen was present or only common microbiota was cultivated. The highest incidence of PTA was found in group I patients (19–50 years) (p ≤ 0.0001) and the most frequently cultured pathogens was Streptococcus pyogenes (36.23%). Gender seemed to have an influence on the results, with higher incidence found in males (p ≤ 0.0001). The analysis of correlation between PTA incidence and season did not yield statistically significant results (p = 0.4396) and no statistically significant differences were observed in individual pathogen frequency. PTA had a higher incidence in adult males and a slightly higher incidence in girls in childhood. The following findings are clinically significant and have implications for antibiotic treatment strategy: (1) the most frequently cultivated pathogen was Streptococcus pyogenes; (2) an increased incidence of anaerobes was proven in the oldest group (>50 years).
Colorectal cancer (CRC) belongs to the most common cancers. The liver is a predominant site of CRC dissemination. Novel biomarkers for predicting the survival of CRC patients with liver metastases ...(CLM) undergoing metastasectomy are needed. We examined KRAS mutated circulating cell-free tumor DNA (ctDNA) in CLM patients as a prognostic biomarker, independently or in combination with carcinoembryonic antigen (CEA). Thereby, a total of 71 CLM were retrospectively analyzed. Seven KRAS G12/G13 mutations was analyzed by a ddPCR™ KRAS G12/G13 Screening Kit on QX200 Droplet Digital PCR System (Bio-Rad Laboratories, Hercules, CA, USA) in liver metastasis tissue and preoperative and postoperative plasma samples. CEA were determined by an ACCESS CEA assay with the UniCel DxI 800 Instrument (Beckman Coulter, Brea, CA, USA). Tissue KRAS positive liver metastases was detected in 33 of 69 patients (47.8%). Preoperative plasma samples were available in 30 patients and 11 (36.7%) were KRAS positive. The agreement between plasma- and tissue-based KRAS mutation status was 75.9% (22 in 29; kappa 0.529). Patients with high compared to low levels of preoperative plasma KRAS fractional abundance (cut-off 3.33%) experienced shorter overall survival (OS 647 vs. 1392 days, p = 0.003). The combination of high preoperative KRAS fractional abundance and high CEA (cut-off 3.33% and 4.9 µg/L, resp.) best predicted shorter OS (HR 13.638, 95%CI 1.567–118.725) in multivariate analysis also (OS HR 44.877, 95%CI 1.59–1266.479; covariates: extend of liver resection, biological treatment). KRAS mutations are detectable and quantifiable in preoperative plasma cell-free DNA, incompletely overlapping with tissue biopsy. KRAS mutated ctDNA is a prognostic factor for CLM patients undergoing liver metastasectomy. The best prognostic value can be reached by a combination of ctDNA and tumor marker CEA.
Appetite and gastrointestinal hormones (GIHs) participate in energy homeostasis, feeding behavior and regulation of body weight. We demonstrated previously the superior effect of a hypocaloric diet ...regimen with lower meal frequency (B2) on body weight, hepatic fat content, insulin sensitivity and feelings of hunger compared to the same diet divided into six smaller meals a day (A6). Studies with isoenergetic diet regimens indicate that lower meal frequency should also have an effect on fasting and postprandial responses of GIHs. The aim of this secondary analysis was to explore the effect of two hypocaloric diet regimens on fasting levels of appetite and GIHs and on their postprandial responses after a standard meal. It was hypothesized that lower meal frequency in a reduced-energy regimen leading to greater body weight reduction and reduced hunger would be associated with decreased plasma concentrations of GIHs: gastric inhibitory peptide (GIP), glucagon-like peptide-1(GLP-1), peptide YY(PYY), pancreatic polypeptide (PP) and leptin and increased plasma concentration of ghrelin. The postprandial response of satiety hormones (GLP-1, PYY and PP) and postprandial suppression of ghrelin will be improved.
In a randomized crossover study, 54 patients suffering from type 2 diabetes (T2D) underwent both regimens. The concentrations of GLP-1, GIP, PP, PYY, amylin, leptin and ghrelin were determined using multiplex immunoanalyses.
Fasting leptin and GIP decreased in response to both regimens with no difference between the treatments (p = 0.37 and p = 0.83, respectively). Fasting ghrelin decreased in A6 and increased in B2 (with difference between regimens p = 0.023). Fasting PP increased in B2with no significant difference between regimens (p = 0.17). Neither GLP-1 nor PYY did change in either regimen. The decrease in body weight correlated negatively with changes in fasting ghrelin (r = -0.4, p<0.043) and the postprandial reduction of ghrelin correlated positively with its fasting level (r = 0.9, p<0.001). The postprandial responses of GIHs and appetite hormones were similar after both diet regimens.
Both hypocaloric diet regimens reduced fasting leptin and GIP and postprandial response of GIP comparably. The postprandial responses of GIHs and appetite hormones were similar after both diet regimens. Eating only breakfast and lunch increased fasting plasma ghrelin more than the same caloric restriction split into six meals. The changes in fasting ghrelin correlated negatively with the decrease in body weight. These results suggest that for type 2 diabetic patients on a hypocaloric diet, eating larger breakfast and lunch may be more efficient than six smaller meals during the day.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Colorectal cancer (CRC) ranks among the most common cancers worldwide. Surgical removal remains the best strategy for treatment of resectable tumors. An important part of caring for patients after ...surgery is monitoring for early detection of a possible relapse of the disease. Efforts are being made to improve the sensitivity and specificity of routinely used carcinoembryonic antigen (CEA) with the use of additional biomarkers such as microRNAs. The aim of our study was to evaluate the prognostic potential of microRNAs and their use as markers of disease recurrence. The quantitative estimation of CEA, CA19-9, and 22 selected microRNAs (TaqMan Advanced miRNA Assays) was performed in 85 paired (preoperative and postoperative) blood plasma samples of CRC patients and in samples taken during the follow-up period. We have revealed a statistically significant decrease in plasma levels for miR-20a, miR-23a, miR-210, and miR-223a (
= 0.0093,
= 0.0013,
= 0.0392, and
= 0.0214, respectively) after surgical removal of the tumor tissue. A statistically significant relation to prognosis (overall survival; OS) was recorded for preoperative plasma levels of miR-20a, miR-21, and miR-23a (
= 0.0236,
= 0.0316, and
=0.0271, respectively) in a subgroup of patients who underwent palliative surgery. The best discrimination between patients with favorable and unfavorable outcomes was achieved by a combination of CEA, CA19-9 with miR-21, miR-20a, and miR-23a (
< 0.0001). The use of these microRNAs for early disease recurrence detection was affected by a low specificity in comparison with CEA and CA19-9. CEA and CA19-9 had high specificity but low sensitivity. Our results show the benefit of combining currently used standard biomarkers and microRNAs for precise prognosis estimation.
Background
Detection of tumor cells in lymph nodes (LNs) removed during the treatment of pulmonary tumor by radical surgery is limited by the possibilities of standard histopathological methods. The ...goal of this study was to obtain more accurate pTNM status by a more sensitive detection of micrometastases in LNs.
Methods
A total of 885 LNs, an average of 13.8 LNs per patient, were removed during 64 surgeries. LNs from the same zone were pooled together as a group, five groups of LNs were examined in each patient. A total of 320 groups of LNs were examined. One‐step nucleic acid amplification (OSNA) method was compared to standard histopathological examination with haematoxylin‐eosin (H&E) staining and CK19 immunohistochemistry, specifically by an ultimate analysis of all intraoperatively removed LNs.
Results
Identical results for H&E and OSNA examinations were recorded in 286 groups of LNs (89.4%). In total, positive examinations were recorded in 27 groups of LNs (8.4%) using the OSNA method, which were H&E negative. In seven groups of LNs (2.2%), the H&E examination was positive, while OSNA method produced negative results.
Conclusions
The OSNA examination led to a higher pTNM stage classification in 14 (21.9%) patients. The clinical significance remains the subject of follow‐up research.
Background and Objectives
Utilisation of the one‐step nucleic acid amplification (OSNA) molecular biology method for the detection of the metastatic involvement of sentinel lymph nodes (SLNs) in ...endometrial cancer (EC) patients. A comparison with histopathological ultrastaging and a description of the clinical consequences.
Methods
Surgically treated EC patients underwent detection of SLNs. Nodes greater than 5 mm were cut into sections 2‐mm thick parallel to the short axis of the node. Odd sections were examined according to the OSNA method, while even ones according to an appropriate ultrastaging protocol. Nodes less than or equal to 5 mm were cut into halves along the longitudinal axis with one half examined according to the OSNA method and the other half by ultrastaging.
Results
Fifty‐eight patients were included and 135 SLNs were acquired. Both ultrastaging and OSNA agreed on 116 results. According to the OSNA method, 20.69% more patients were classified into International Federation of Gynecology and Obstetrics (FIGO) stage III. When comparing the results of the OSNA method to the conclusions of ultrastaging as a reference method, sensitivity of 90.9%, specificity of 85.5% and concordance of 85.9% were attained.
Conclusions
The results of the OSNA method showed a higher frequency of detection of micrometastases and included 20.69% more patients into FIGO stage III.
MicroRNAs regulate the expression of genes involved in several important cancer-related processes including cell adhesion, proliferation, and tumour angiogenesis. Bevacizumab is routinely used in the ...treatment of patients with metastatic colorectal cancer, but, so far, no reliable biomarker predicting response to bevacizumab has been established. The aim of our retrospective study was to evaluate the association of miR-126-3p, miR-126-5p and miR-664-3p tumour expression levels with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. The study included 63 patients. For the assessment of microRNA expression, gene-specific TaqMan assays were used. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-3p were 8.8 and 20.6 months versus 13.5 months and median overall survival was not reached for patients with high expression (p = 0.0064 and p = 0.0027), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-126-5p were 9.0 and 22.2 months versus 12.0 and 23.4 months for patients with high expression (p = 0.2113 and 0.6858), respectively. The median progression-free survival and overall survival for patients with low tumour expression of miR-664-3p were 9.1 and 22.5 months versus 8.8 and 23.4 months for patients with high expression (p = 0.2542 and p = 0.1922), respectively. The multivariable Cox proportional hazards model revealed that miR-126-3p expression was significantly associated with progression-free survival (hazard ratio = 0.28, p = 0.0053) and also with overall survival (hazard ratio = 0.18, p = 0.0046). In conclusion, the results of this study suggest that the expression of miR-126-3p in the tumour tissue was associated with outcome of metastatic colorectal cancer patients treated with bevacizumab.
PDF
