Five latent factors underlie response to immunotherapy.

Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are.

Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of hematologic malignancies, cardiovascular diseases, and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking.

Discovery of recessive effect of human polymerase δ proofreading deficiency through mutational analysis of POLD1-mutated normal and cancer cells.

Constitutional heterozygous pathogenic variants in the exonuclease domain of POLE and POLD1, which affect the proofreading activity of the corresponding polymerases, cause a cancer predisposition syndrome characterized by increased risk of gastrointestinal polyposis, colorectal cancer, endometrial cancer and other tumor types. The generally accepted explanation for the connection between the disruption of the proofreading activity of polymerases epsilon and delta and cancer development is through an increase in the somatic mutation rate. Here we studied an extended family with multiple members heterozygous for the pathogenic POLD1 variant c.

Identification of Clonal Hematopoiesis Driver Mutations through In Silico Saturation Mutagenesis.

Clonal hematopoiesis (CH) is a phenomenon of clonal expansion of hematopoietic stem cells driven by somatic mutations affecting certain genes. Recently, CH has been linked to the development of a number of hematologic malignancies, cardiovascular diseases and other conditions. Although the most frequently mutated CH driver genes have been identified, a systematic landscape of the mutations capable of initiating this phenomenon is still lacking.

Highly selective and sensitive detection of glutamate by an electrochemical aptasensor.

An electrochemical aptamer-based sensor was developed for glutamate, the major excitatory neurotransmitter in the central nervous system. Determining glutamic acid release and glutamic acid levels is crucial for studying signal transmission and for diagnosing pathological conditions in the brain. Glutamic acid-selective oligonucleotides were isolated from an ssDNA library using the Capture-SELEX protocol in complex medium.

Logic Gates Based on DNA Aptamers.

DNA bio-computing is an emerging trend in modern science that is based on interactions among biomolecules. Special types of DNAs are aptamers that are capable of selectively forming complexes with target compounds. This review is devoted to a discussion of logic gates based on aptamers for the purposes of medicine and analytical chemistry.

Integration of a field effect transistor-based aptasensor under a hydrophobic membrane for bioelectronic nose applications.

A new bioelectronic nose based on a field effect transistor coupled with an aptamer as the sensing element was developed. The gas-to-liquid extraction interface required for appropriate aptamer function was integrated into standard CMOS technology. It was developed with the use of a sacrificial aluminium etching technique combined with surface modifications by silanes for wettability control.

Selection, Characterization, and Application of ssDNA Aptamer against Furaneol.

Furaneol is an aroma compound which occurs naturally in foods and is used as an artificial flavor. Detection of furaneol is required in food science and food processing industry. Capture- Systematic Evolution of Ligands by EXponential enrichment (SELEX) protocol was applied for the isolation of an aptamer binding to furaneol, a small volatile organic substance contributing to the flavor of various products.

Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations.

Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis.

CMOS-compatible biosensor for L-carnitine detection.

A CMOS-compatible ISFET with a TaO sensitive surface was developed. The structure was optimized for achieving high sensitivity using a subthreshold operation mode and by reducing the influence of the capacitances on the value of subthreshold swing. The developed ISFET was used as a basis for a biosensor for L-carnitine detection.

Aptamer based vanillin sensor using an ion-sensitive field-effect transistor.

An aptamer for vanillin was obtained and then used for the development of an aptasensor based on an ion-sensitive field-effect transistor (ISFET). This aptamer (a single-stranded DNA;ssDNA) was selected using the Capture-SELEX protocol, which suites well for selection of aptamers to small molecules. Among six aptamer candidates, the aptamer Van_74 with the highest affinity for vanillin was chosen (elution of 35% of the aptamer from a solid support in the presence of 2 mM of vanillin).

Are Nonsense Alleles of Drosophila melanogaster Genes under Any Selection?

A gene which carries a bona fide loss-of-function mutation effectively becomes a functionless pseudogene, free from selective constraint. However, there is a number of molecular mechanisms that may lead to at least a partial preservation of the function of genes carrying even drastic alleles. We performed a direct measurement of the strength of negative selection acting on nonsense alleles of protein-coding genes in the Zambian population of Drosophila melanogaster.

Amplified Detection of the Aptamer-Vanillin Complex with the Use of Bsm DNA Polymerase.

The electrochemical detection of interactions between aptamers and low-molecular-weight targets often lacks sensitivity. Signal amplification improves the detection of the aptamer-analyte complex; Bsm DNA polymerase was used to amplify the signal from the interaction of vanillin and its aptamer named Van_74 on an ion-sensitive field-effect transistor (ISFET)-based biosensor. The aptamer was immobilized on the ISFET sensitive surface.

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma.

Field-effect transition sensor for KI detection based on self-assembled calixtube monolayers.

A series of novel calixarene-based tubes comprising different numbers of silatrane anchoring groups was synthesized. For the first time, a self-assembled monolayer (SAM) derived from calixtubes was formed on a SiO surface. The formation of the SAM was confirmed by X-ray photoelectron spectroscopy, scanning electron microscopy-energy dispersive X-ray analysis, and contact angle measurements.

Human mismatch repair system balances mutation rates between strands by removing more mismatches from the lagging strand.

Mismatch repair (MMR) is one of the main systems maintaining fidelity of replication. Differences in correction of errors produced during replication of the leading and the lagging DNA strands were reported in yeast and in human cancers, but the causes of these differences remain unclear. Here, we analyze data on human cancers with somatic mutations in two of the major DNA polymerases, delta and epsilon, that replicate the genome.

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context.

APOBEC3A/B cytidine deaminase is responsible for the majority of cancerous mutations in a large fraction of cancer samples. However, its role in heritable mutagenesis remains very poorly understood. Recent studies have demonstrated that both in yeast and in human cancerous cells, most APOBEC3A/B-induced mutations occur on the lagging strand during replication and on the nontemplate strand of transcribed regions.

Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016.

O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y.

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained.

Extensive hydrolysis of phosphonates as unexpected behaviour of the known His6-organophosphorus hydrolase.

The catalytic activity of hexahistidine-tagged organophosphorus hydrolase (His6-OPH) in hydrolytic reactions of methylphosphonic acid (MPA) and its monoesters and diesters being decomposition products of R-VX was demonstrated for the first time. The catalytic constants of enzyme in such reactions were determined. The mechanism of C-P bond cleavage in the MPA by His6-OPH was proposed.

[Discrete plasmapheresis for coronary heart disease].

Aim: To provide a rationale for the expediency and efficiency of discrete plasmapheresis (PA) in the package of therapeutic measures for coronary heart disease (CHD).

Subjects And Methods: 585 sessions or 120 cycles of low-volume therapeutic PA were performed in 91 patients with CHD. The parameters of blood lipid composition, hemocoagulation, rheology, and endotoxicosis were studied.

[Possibilities of pharmacological correction of the arterial hypertension in elderly patients with gout].

The aim of this work was a detailed study of questions connected with the peculiarities of circadian blood pressure profile, efficiency of amlodipine in elderly patients with gout and arterial hypertension. We used 24-hour blood pressure monitoring before and after 3 and 6-months treatment. Patients with gout showed the disturbances of circadian blood pressure profile.

[The role of magnesium in the implementation of vascular reactions during anesthesia in cardiac surgery patients].

Unlabelled: The purpose of the study is to examine the relationship between the concentration of magnesium in plasma and vascular reactions during cardiac surgery.

Materials And Methods: The study included 77 patients with coronary artery disease who underwent myocardial revascularization surgery. In the first group (n = 44) during the entire operation infusion solution "potassium and magnesium asparginate" (Berlin-Chemie) was carried out at a rate of 1.

[Use of a potassium and magnesium asparaginate solution to maintain the balance of potassium and magnesium during cardiosurgical interventions under extracorporeal circulation].

The study included 42 patients with coronary heart disease operated on the coronary arteries. A potassium and magnesium asparaginate (PMA) solution, 450-1000 ml, was injected in 30 patients for 5-7 hours; other crystalloid solutions was used in a control group (n = 12). The concentrations of potassium and magnesium were measured prior to surgery, following initial anesthesia, before and after extracorporeal circulation (EC).