Methods for obtaining and processing biocompatible medical materials

The article is devoted to the scientific problem associated with the production and processing of biocompatible medical materials with improved mechanical and functional properties. Processing biocompatible materials is one of the key processes to achieve operational properties. The study presents the results of microhardness and microstructure, which showed that electroplastic treatment, together with subsequent annealing, helps to obtain a homogeneous nanocrystalline structure and improve a number of operational properties that play an important role when using biocompatible medical materials

High-Throughput Mutation Data Now Complement Transcriptomic Profiling: Advances in Molecular Pathway Activation Analysis Approach in Cancer Biology

We recently reviewed the current progress in the use of high-throughput molecular “omics” data for the quantitative analysis of molecular pathway activation. These quantitative metrics may be used in many ways, and we focused on their application as tumor biomarkers. Here, we provide an update of the most recent conceptual findings related to pathway analysis in tumor biology, which were not included in the previous review. The major novelties include a method enabling calculation of pathway-scale tumor mutation burden termed “Pathway Instability” and its application for scoring of anticancer target drugs. A new technique termed Shambhala emerged that enables accurate common harmonization of any number of gene expression profiles obtained using any number of experimental platforms. This may be helpful for merging various gene expression data sets and for comparing their pathway activation characteristics. Another recent bioinformatics method, termed FLOating-Window Projective Separator (FloWPS), has the potential to significantly enhance the value of pathway activation profiles as biomarkers of cancer response to treatments. It reduces the minimum required number of training samples needed to construct a machine-learning-based classifier. Finally, several documented clinical cases have been recently published, in which gene-expression-based pathway analysis was successfully used for personalized off-label prescription of target drugs to metastatic cancer patients

Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs

Personalized prescription of tyrosine kinase inhibitors in unresectable metastatic cholangiocarcinoma

Abstract Background Cholangiocarcinoma is an aggressive tumor with poor prognosis. Most of the cases are not available for surgery at the stage of the diagnosis and the best clinical practice chemotherapy results in about 12-month median survival. Several tyrosine kinase inhibitors (TKIs) are currently under investigation as an alternative treatment option for cholangiocarcinoma. Thus, the report of personalized selection of effective inhibitor and case outcome are of clinical interest. Case presentation Here we report a case of aggressive metastatic cholangiocarcinoma (MCC) in 72-year-old man, sequentially treated with two targeted chemotherapies. Initially disease quickly progressed during best clinical practice care (gemcitabine in combination with cisplatin or capecitabine), which was accompanied by significant decrease of life quality. Monotherapy with TKI sorafenib was prescribed to the patient, which resulted in stabilization of tumor growth and elimination of pain. The choice of the inhibitor was made based on high-throughput screening of gene expression in the patient’s tumor biopsy, utilized by Oncobox platform to build a personalized rating of potentially effective target therapies. However, time to progression after start of sorafenib administration did not exceed 6 months and the regimen was changed to monotherapy with Pazopanib, another TKI predicted to be effective for this patient according to the same molecular test. It resulted in disease progression according to RECIST with simultaneous elimination of sorafenib side effects such as rash and hand-foot syndrome. After 2 years from the diagnosis of MCC the patient was alive and physically active, which is substantially longer than median survival for standard therapy. Conclusion This case evidences that sequential personalized prescription of different TKIs may show promising efficacy in terms of survival and quality of life in MCC

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.status: publishe

A systematic review of nerve-sparing surgery for high-risk prostate cancer

We provide a systematic analysis of nerve-sparing surgery (NSS) to assess and summarize the risks and benefits of NSS in high-risk prostate cancer (PCa)

Large-scale assessment of pros and cons of autopsy-derived or tumor-matched tissues as the norms for gene expression analysis in cancers.

Normal tissues are essential for studying disease-specific differential gene expression. However, healthy human controls are typically available only in postmortal/autopsy settings. In cancer research, fragments of pathologically normal tissue adjacent to tumor site are frequently used as the controls. However, it is largely underexplored how cancers can systematically influence gene expression of the neighboring tissues. Here we performed a comprehensive pan-cancer comparison of molecular profiles of solid tumor-adjacent and autopsy-derived healthy normal tissues. We found a number of systemic molecular differences related to activation of the immune cells, intracellular transport and autophagy, cellular respiration, telomerase activation, p38 signaling, cytoskeleton remodeling, and reorganization of the extracellular matrix. The tumor-adjacent tissues were deficient in apoptotic signaling and negative regulation of cell growth including G2/M cell cycle transition checkpoint. We also detected an extensive rearrangement of the chemical perception network. Molecular targets of 32 and 37 cancer drugs were over- or underexpressed, respectively, in the tumor-adjacent norms. These processes may be driven by molecular events that are correlated between the paired cancer and adjacent normal tissues, that mostly relate to inflammation and regulation of intracellular molecular pathways such as the p38, MAPK, Notch, and IGF1 signaling. However, using a model of macaque postmortal tissues we showed that for the 30 min - 24-hour time frame at 4ºC, an RNA degradation pattern in lung biosamples resulted in an artifact differential expression profile for 1140 genes, although no differences could be detected in liver. Thus, such concerns should be addressed in practice

A single-lead ECG based cardiotoxicity detection in patients on polychemotherapy

Background: Anti-cancer treatment can be fraught with cardiovascular complications, which is the most common cause of death among oncological survivors. Without appropriate cardiomonitoring during anti-cancer treatment, it becomes challenging to detect early signs of cardiovascular complications. In order to achieve higher survival rates, it is necessary to monitor oncological patients outpatiently after anti-cancer treatment administration. In this regard, we aim to evaluate the efficacy of single-lead ECG remote monitoring to detect cardiotoxicity in cancer patients with minimal cardiovascular diseases after the first cycle of polychemotherapy. Materials and methods: The study included patients 162 patients over 18 years old with first diagnosed different types of solid tumors, planed for adjuvant (within 8 weeks after surgery) or neoadjuvant polychemotherapy. All patients were monitored, outpatiently, during 14–21 days (depending on the regimen of polychemotherapy) after polychemotherapy administration using single-lead ECG. Results: QTc > 500 mc prolongation was detected in 8 patients (6.6 %), first-diagnosed arial fibrillation was detected in 11 patients (9 %) in period after chemotherapy administration. Moreover, left ventricular diastolic dysfunction using single-lead ECG after polychemotherapy was detected in 49 (40.1 %) patients with sensitivity 80 %, specificity 95 %, AUC 0.88 (95 % CI, 0.82–0.93). Conclusions: The side effects of cancer treatment may cause life-threatening risks. Early identification of cardiotoxicity plays a vital role in the solution of this problem. Using portable devices to detect early cardiotoxicity is a simple, convenient and affordable screening method, that can be used for promptly observation of patients