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Background. By 2020, breast cancer (BC) has become the most frequent malignancy in the world. The most common type of BC is HR+/HER2-negative cancer,2540% of which harbors PIK3CA mutations that affect the catalytic subunit of the PI3K protein. PIK3CA alterations are actionable, as such neoplasms can be treated with a combination of fulvestrant and the PI3K inhibitor alpelisib. As PIK3CA mutations have an extremely versatile effect on the characteristics of a tumor cell, numerous associations of PIK3CA mutations and various clinico-pathological characteristics of BC can be traced. Aim. Our aim was to clarify the information on the frequency and spectrum of PIK3CA mutations in Russian patients with HR+/HER2- advanced BC, and to study the association of PIK3CA mutations with clinical and pathological parameters of BC. Materials and methods. Tissue samples from 694 patients with HR+/HER2- advanced BC (mixed population of primary metastatic and relapsed tumors) who received any line of anti-cancer treatment in Dec 2020 to June 2021 in Russian Federation were analyzed by high-resolution melting, allele-specific PCR, digital droplet PCR and Sanger sequencing (exons 7,9, and 20 of the PIK3CA gene). Mutation rates in different BC subgroups were compared using the Fishers exact test. The age at diagnosis in patients with different PIK3CA status was compared using the MannWhitney U-test. The relationship between the PIK3CA status and the degree of tumor differentiation was compared using the CochraneArmitage test for trends. Luminal A and B BC expression subtypes were distinguished with surrogate IHC markers according to St.-Gallen recommendations (2013). Results. Mutations were identified in 220/694 (32%) BC patients. The three most frequent missense substitutions in the PIK3CA gene (p.E542K, p.E545K, and p.H1047R) accounted for 190/220 (86%) mutations. Associations of PIK3CA mutations with luminal A subtype of BC, low proliferation index, small size of the primary tumor, and absence of signs of hereditary cancer were revealed. Associations of mutations in the kinase domain of PIK3CA (p.H1047R) with late recurrence of locally advanced BC and with non-Slavic ethnic origin of patients were found. Conclusion. PIK3CA mutation rate of 32% confirms high prevalence of mutation in Russian population, with some differences reflecting the ethnic origin of patients.

Electrically charged particles can be created by the decay of strong enough electric fields, a phenomenon known as the Schwinger mechanism1. By electromagnetic duality, a sufficiently strong magnetic field would similarly produce magnetic monopoles, if they exist2. Magnetic monopoles are hypothetical fundamental particles that are predicted by several theories beyond the standard model3-7 but have never been experimentally detected. Searching for the existence of magnetic monopoles via the Schwinger mechanism has not yet been attempted, but it is advantageous, owing to the possibility of calculating its rate through semi-classical techniques without perturbation theory, as well as that the production of the magnetic monopoles should be enhanced by their finite size8,9 and strong coupling to photons2,10. Here we present a search for magnetic monopole production by the Schwinger mechanism in Pb-Pb heavy ion collisions at the Large Hadron Collider, producing the strongest known magnetic fields in the current Universe11. It was conducted by the MoEDAL experiment, whose trapping detectors were exposed to 0.235 per nanobarn, or approximately 1.8 × 109, of Pb-Pb collisions with 5.02-teraelectronvolt center-of-mass energy per collision in November 2018. A superconducting quantum interference device (SQUID) magnetometer scanned the trapping detectors of MoEDAL for the presence of magnetic charge, which would induce a persistent current in the SQUID. Magnetic monopoles with integer Dirac charges of 1, 2 and 3 and masses up to 75 gigaelectronvolts per speed of light squared were excluded by the analysis at the 95% confidence level. This provides a lower mass limit for finite-size magnetic monopoles from a collider search and greatly extends previous mass bounds.

Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs.Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008).Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.

MET exon 14 skipping (exon 14Δ) mutations are associated with tumor sensitivity to a number of tyrosine kinase inhibitors, however clinical testing for MET gene status remains complicated. We developed a simple allele-specific PCR cDNA-based test, which allowed for the identification of MET exon 14Δ allele in 35 (2.5%) out of 1415 EGFR mutation–negative lung carcinomas (LCs). MET exon 14Δ was significantly associated with elderly age and non-smoking status of the patients. A total of 34 (97%) out of 35 tumors carrying MET exon 14Δ showed preferential expression of the mutated allele; this imbalance was attributed to the down-regulation of the expression of the wild-type gene copy. Sanger sequencing confirmed the presence of genomic exon 14 splice site mutations in 24/35 (68.6%) cases, which showed MET exon 14 skipping by PCR. In addition to LCs described above, some carcinomas demonstrated low-abundance MET exon 14Δ-specific signal. Low-level expression of MET exon 14Δ allele may potentially compromise the results of allele-specific PCR-based tests, therefore comparison of the level of expression of mutated and normal alleles is essential for the reliability of MET gene testing.

Highlights • In patients with ALK-rearranged NSCLC who received lorlatinib within the compassionate use program, the objective tumor response (OR) and disease control (DC) were observed in 43% and 94% cases, respectively. • Lorlatinib showed particularly high efficacy against brain metastases, with OR and DC for intracranial disease reaching 81% and 100%, respectively. • Patients with V.1 and V.3 ALK translocations had similar response to the therapy. • Complete lack of adverse events tended to correlate with poor outcome of lorlatinib treatment., Background Lorlatinib is a novel potent ALK inhibitor, with only a few studies reporting the results of its clinical use. Methods This study describes the outcomes of lorlatinib treatment for 35 non-small cell lung cancer patients with ALK rearrangements, who had 2 (n = 5), 1 (n = 26) or none (n = 4) prior tyrosine kinase inhibitors and received lorlatinib mainly within the compassionate use program. Results Objective tumor response (OR) and disease control (DC) were registered in 15/35 (43%) and 33/35 (94%) patients, respectively; brain metastases were particularly responsive to the treatment (OR: 22/27 (81%); DC: 27/27 (100%)). Median progression free survival (PFS) was estimated to be 21.8 months, and median overall survival (OS) approached to 70.1 months. Only 4 out of 35 patients experienced no adverse effects; two of them were the only subjects who had no clinical benefit from lorlatinib. PFS and OS in the no-adverse-events lorlatinib users were strikingly lower as compared to the remaining patients (1.1 months vs. 23.7 months and 10.5 months vs. not reached, respectively; p < 0.0001 for both comparisons). ALK translocation variants were known for 28 patients; there was no statistical difference between patients with V.1 and V.3 rearrangements with regard to the OS or PFS. Conclusion Use of lorlatinib results in excellent disease outcomes, however caution must be taken for patients experiencing no adverse effects from this drug.

PALB2 is а high-penetrance gene for hereditary breast cancer (BC). Our study aimed to investigate the spectrum of PALB2 mutations in Russian cancer patients. PALB2 sequencing revealed pathogenic variants in 3/190 (1.6%) young-onset and/or familial and/or bilateral BC cases but none in 96 ovarian cancer (OC) or 172 pancreatic cancer patients. Subsequently, seven recurrent PALB2 pathogenic alleles were selected from this and previous Slavic studies and tested in an extended patient series. PALB2 pathogenic variants were detected in 5/585 (0.9%) "high-risk" BC, 10/1508 (0.7%) consecutive BC and 5/1802 (0.3%) OC cases. Haplotyping suggested that subjects with Slavic alleles c.509-510delGA (n = 10) and c.172-175delTTGT (n = 4) as well as carriers of Finnish c.1592delT mutation (n = 4) originated from a single founder each, while PALB2 p.R414X allele (n = 4) had at least two independent founders. Somatic loss of heterozygosity (LOH) was revealed in 5/10 chemonaive BCs and in 0/2 BC samples obtained after neoadjuvant therapy. Multigene sequencing identified somatic PALB2 inactivating point mutation in one out of two tumors without PALB2 LOH but in none of four BCs with PALB2 LOH. Genomic instability, as determined by NGS, was observed in four out of five tumors with biallelic PALB2 inactivation but not in the BC sample with the preserved wild-type PALB2 allele. PALB2 germ-line mutations contribute to a small fraction of cancer cases in Russia. The majority although not all PALB2-driven BCs have somatic inactivation of the remaining PALB2 allele and therefore potential sensitivity to platinum compounds and PARP inhibitors.

The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis. The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and “rare” BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women. Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.

The MoEDAL trapping detector, consists of approximately 800 kg of aluminium volumes. It was exposed during Run-2 of the LHC program to 6.46 fb^-1 of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminium volumes comprising the detector through a SQUID magnetometer. The presence of a trapped dyon would be signalled by a persistent current induced in the SQUID magnetometer. On the basis of a Drell-Yan production model, we exclude dyons with a magnetic charge ranging up to 5 Dirac charges, and an electric charge up to 200 times the fundamental electric charge for mass limits in the range 790 - 3130 GeV., arXiv admin note: text overlap with arXiv:1903.08491

Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. Nineteen patients were prospectively included in the study. Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6–15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

Background: This study evaluated the distribution of epidermal growth factor receptor (EGFR) T790M mutations in treatment-naïve tumor and normal samples obtained from cancer patients. Methods: We utilized allele-specific PCR (AS-PCR), digital droplet PCR (ddPCR) and next generation sequencing (NGS) to detect EGFR T790M allele in several collections of tumor and normal human tissues. Results: AS-PCR analysis of treatment-naïve tumor samples revealed somatic T790M mutation in 3/394 (1%) non-small cell lung carcinomas (NSCLC) carrying the tyrosine kinase inhibitor (TKI)-sensitizing EGFR mutation, but in none of 334 NSCLC lacking EGFR exon 19 deletions (ex19del) or L858R substitutions and in none of 235 non-lung tumors. Use of highly sensitive and quantitative assays, such as ddPCR and NGS, produced a high number of T790M-specific signals even in presumably T790M-negative DNA specimens. This background noise was evidently higher in degraded DNA isolated from formalin-fixed paraffin-embedded tissues as compared to high molecular weight DNA. A combination of AS-PCR, ddPCR and NGS revealed mosaic EGFR T790M allele in 2/68 (3%) NSCLC treated with the first-generation TKI. Both these tumors produced evident and durable response to gefitinib. Conclusion: Detection of mosaic EGFR T790M mutation in treatment-naïve samples may be compromised by yet unresolved technical issues and may have limited clinical value.

Drug treatment of disseminated non small cell lung cancer (NSCLC) is an actual issue today. Both clinical and economic efficacy analysis is needed for optimal therapy selection. We performed economic efficacy assessment of gefitinib (G.) therapy in patients with non operable NSCLC who hase no EGFR mutation using Markov model based on results of clinical studies conducted in N.N. Petrov Research Institute of Oncology.G. increases overall survival of patients with NSCLC with EGFR mutation by 1,05 year. Cost/efficacy coefficient for G. in patients with EGFR mutation is 934 800 rub per 1 acquired year of life. Therapy with G just for patients with genetically proven mutation is dominating strategy when compared to therapy for all NSCLC patients irrespectively to mutation status (saving 211600 – 251800 rub per 1 patient taking into account equal clinical efficacy). Therapy with G. is economically justifying strategy when compared to chemotherapy (additional costs coefficient 960700 – 1010000 rub per 1 gained year of life). Thus, EGFR mutation testing with subsequent G. therapy in non operable NSCLC patients not only prolongs patient’s life but also has acceptable level of medical expenses.

A paper titled ‘Quantised singularities in the electromagnetic field’ by P.A.M. Dirac appeared in 1931 in the Proceedings of the Royal Society A . The paper concerned ‘[ · s ] the reason for the existence of a smallest electric charge.’ Dirac showed that the quantization of the electric charge follows from the existence of at least one free magnetic charge, finding ‘a connection between the smallest electric charge and the smallest magnetic pole’, a connection called since then the ‘Dirac relation’. That seminal paper marked the opening of a new research field that has grown considerably since then. The search for magnetic monopoles in cosmic radiation encompasses many fields, from particle physics to astrophysics, from the extremely small to cosmology. This article is part of a discussion meeting issue ‘Topological avatars of new physics’.

Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch syndrome (LS), is a common cancer-predisposing syndrome. This study aimed to investigate the spectrum of germ-line mutations in Russian LS patients. LS-related mismatch repair (MMR) genes were analyzed in 16 patients, who were forwarded to genetic testing due to strong clinical features of LS and had high-level microsatellite instability (MSI-H) in the tumor (n = 14) or unknown MSI status (n = 2). In addition, 672 consecutive colorectal cancer (CRC) cases were screened for family history; 15 patients were younger than 50 years and reported 2 or more instances of LS-related cancers in 1st- or 2nd-degree relatives. Seven of these cases demonstrated MSI-H and therefore were subjected to DNA germ-line testing. Overall, 17/23 (74%) subjects carried LS-associated gene variants (MLH1: 10; MSH2: 4; MSH6: 2; PMS2: 1), with 2 alleles (MLH1 c.677G > T and MSH2 с.1906G > C) detected twice. Testing for recurrent mutations of 30 consecutive MSI-H CRCs led to the identification of 2 additional subjects with LS. The analysis of all relevant publications identified 28 unrelated LS patients presented in Russian medical literature and 3 unrelated Russian LS subjects described in international journals. Overall, 15/49 (31%) genetic defects revealed in Russian LS patients were represented by six recurrent alleles (MLH1: c.350C > T, c.677G > T, c.1852_1854del; MSH2: c.942+3A > T, c.1861C > T, с.1906G > C). We conclude that the founder effect for LS in Russia is seemingly less pronounced than the one for hereditary breast-ovarian cancer syndrome, however testing for recurrent LS mutations may be considered feasible in some circumstances.

BRCA1 L1705P (c.5114T>C) has been classified in the NCBI SNP database as the variant with uncertain significance and is absent in major BRCA1 databases. BRCA1 W1837X (c.5511G>A) results in a loss of only last 27 residues of BRCA1 protein, thus its pathogenic role still requires a confirmation. This report describes two breast cancer (BC) patients carrying BRCA1 L1705P and W1837X germ-line mutations, respectively. Significant evidence for BC-predisposing impact of the mentioned mutations have been obtained: (1) both index cases presented with the triple-negative receptor status of BC disease; (2) complete segregation with BRCA1-related cancers was observed in the families of these patients; (3) somatic loss of the remaining (wild-type) BRCA1 allele was detected in tumor tissues of the affected women. The results of this study have to be taken into account while providing genetic counseling to cancer patients and while considering the use of BRCA1-specific therapeutic compounds for BC treatment.

Exomes of 27 Russian subjects were analyzed for the presence of medically relevant alleles, such as protein-truncating variants (PTVs) in known recessive disease-associated genes and pathogenic missense mutations included in the ClinVar database. 36 variants (24 PTVs and 12 amino acid substitutions) were identified and then subjected to the analysis in 897 population controls. 9/36 mutations were novel, however only two of them (POLH c.490delG associated with xeroderma pigmentosum variant (XPV) and CATSPER1 c.859_860delCA responsible for spermatogenic failure) were shown to be recurrent. 27 out of 36 pathogenic alleles were already described in prior genetic studies; seven of them occurred only in the index cases, while 20 demonstrated evidence for persistence in Russian population. In particular, non-random occurrence was revealed for SERPINA1 c.1096G > A (alpha-1 antitrypsin deficiency), C8B c.1282C > T and c.1653G > A (complement component 8B deficiency), ATP7B c.3207C > A (Wilson disease), PROP1 c.301_302delAG (combined pituitary hormone deficiency), CYP21A2 c.844G > T (non-classical form of adrenogenital syndrome), EYS c.1155T > A (retinitis pigmentosa), HADHA c.1528G > C (LCHAD deficiency), SCO2 c.418G > A (cytochrome c oxidase deficiency), OTOA c.2359G > T (sensorineural deafness), C2 c.839_866del (complement component 2 deficiency), ACADVL c.848T > C (VLCAD deficiency), TGM5 c.337G > T (acral peeling skin syndrome) and VWF c.2561 G > A (von Willebrand disease, type 2N). These data deserve to be considered in future medical genetic activities.

Background Lung carcinomas (LCs) carrying MET exon 14 skipping (exon 14Δ) mutations are responsive to a number of tyrosine kinase inhibitors. There is a need to incorporate MET analysis in the diagnostic pipeline for LC patients. Methods Nucleic acids were extracted from formalin-fixed paraffin-embedded archival LC samples and subjected to cDNA synthesis. This pool of genomic DNA and cDNA was sequentially tested for EGFR, ALK and MET mutations by PCR-based assays. Results Allele-specific PCR detected MET exon 14 skipping in 35/1415 (2.5%) EGFR mutation–negative LCs. There was a highly pronounced association with the elderly age of the patients (median age 69 years as compared to 62 years in EGFR/ALK/MET mutation-negative cases; p = 1.821e-06). 34/35 (97%) LCs with MET exon 14 skipping mutations showed preferential expression of the affected MET allele, while the wild-type transcript was almost undetectable in these tumors. In addition, we identified a subset of MET wild-type LCs, which produced normal MET transcript but also expressed residual amounts of MET exon 14Δ RNA message, probably due to alternative splicing. Conclusions The mere detection of MET exon 14Δ signal by allele-specific PCR does not warrant the presence of corresponding clonal MET mutation. Comparison of expression of MET exon 14Δ and wild-type alleles is essential for reliable identification of tumors carrying drug-sensitizing MET lesions. Legal entity responsible for the study The authors. Funding Russian Science Foundation (grant 17-75-30027). Disclosure All authors have declared no conflicts of interest.

Detection of ALK rearrangements in patients with non-small cell lung cancer (NSCLC) presents a significant technical challenge due to the existence of multiple translocation partners and break-points. To improve the performance of PCR-based tests, we utilized the combination of 2 assays, i.e. the variant-specific PCR for the 5 most common ALK rearrangements and the test for unbalanced 5'/3'-end ALK expression. Overall, convincing evidence for the presence of ALK translocation was obtained for 34/400 (8.5%) cases, including 14 EML4ex13/ALKex20, 12 EML4ex6/ALKex20, 3 EML4ex18/ALKex20, 2 EML4ex20/ALKex20 variants and 3 tumors with novel translocation partners. 386 (96.5%) out of 400 EGFR mutation-negative NSCLCs were concordant for both tests, being either positive (n = 26) or negative (n = 360) for ALK translocation; 49 of these samples (6 ALK+, 43 ALK-) were further evaluated by FISH, and there were no instances of disagreement. Among the 14 (3.5%) "discordant" tumors, 5 demonstrated ALK translocation by the first but not by the second PCR assay, and 9 had unbalanced ALK expression in the absence of known ALK fusion variants. 5 samples from the latter group were subjected to FISH, and the presence of translocation was confirmed in 2 cases. Next generation sequencing analysis of these 2 samples identified novel translocation partners, DCTN1 and SQSTM1; furthermore, the DCTN1/ALK fusion was also found in another NSCLC sample with unbalanced 5'/3'-end ALK expression, indicating a recurrent nature of this translocation. We conclude that the combination of 2 different PCR tests is a viable approach for the diagnostics of ALK rearrangements. Systematic typing of ALK fusions is likely to reveal new NSCLC-specific ALK partners.

Distribution of cancer-predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ-line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early-onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ-line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next-generation sequencing of 7 APC/MUTYH mutation-negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low-penetrant cancer-associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH-associated polyposis in Russia is likely to be 1:23 000.

MoEDAL is designed to identify new physics in the form of long-lived highly-ionising particles produced in high-energy LHC collisions. Its arrays of plastic nuclear-track detectors and aluminium trapping volumes provide two independent passive detection techniques. We present here the results of a first search for magnetic monopole production in 13 TeV proton-proton collisions using the trapping technique, extending a previous publication with 8 TeV data during LHC run-1. A total of 222 kg of MoEDAL trapping detector samples was exposed in the forward region and analysed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges exceeding half the Dirac charge are excluded in all samples and limits are placed for the first time on the production of magnetic monopoles in 13 TeV $pp$ collisions. The search probes mass ranges previously inaccessible to collider experiments for up to five times the Dirac charge., 6 pages, 1 table, 2 figures, accepted for publication in Phys. Rev. Lett

Two widely used methods of determining the etch-rate ratio in poly-ethylene terephthalate (PET) nuclear track detector are compared. Their application in different regimes of ion$\textquoteright$s energy loss is investigated. A new calibration curve for PET is also presented., Comment: 14 pages, 5 figures

The NESSiE Collaboration has been setup to undertake a conclusive experiment to clarify the {\em muon--neutrino disappearance} measurements at short baselines in order to put severe constraints to models with more than the three--standard neutrinos. To this aim the current FNAL--Booster neutrino beam for a Short--Baseline experiment was carefully evaluated by considering the use of magnetic spectrometers at two sites, near and far ones. The detector locations were studied, together with the achievable performances of two OPERA--like spectrometers. The study was constrained by the availability of existing hardware and a time--schedule compatible with the undergoing project of multi--site Liquid--Argon detectors at FNAL. The settled physics case and the kind of proposed experiment on the Booster neutrino beam would definitively clarify the existing tension between the $\nu_{\mu}$ disappearance and the $\nu_e$ appearance/disappearance at the eV mass scale. In the context of neutrino oscillations the measurement of $\nu_{\mu}$ disappearance is a robust and fast approach to either reject or discover new neutrino states at the eV mass scale. We discuss an experimental program able to extend by more than one order of magnitude (for neutrino disappearance) and by almost one order of magnitude (for antineutrino disappearance) the present range of sensitivity for the mixing angle between standard and sterile neutrinos. These extensions are larger than those achieved in any other proposal presented so far., Comment: 19 pages, published in EPJC

A nonsense mutation, p.Q548X, in the BLM gene has recently been associated with an increased risk for breast cancer. In the present work, we investigated the prevalence of this Slavic founder mutation in 2,561 ovarian cancer cases from Russia, Belarus, Poland, Lithuania or Germany and compared its frequency with 6,205 ethnically matched healthy female controls. The p.Q548X allele was present in nine ovarian cancer patients of Slavic ancestry (0.5 %; including one case with concurrent BRCA1 mutation). The mutation was not significantly more frequent in cases than in controls (Mantel-Haenszel OR 1.14, 95 % CI 0.49; 2.67). Ovarian tumours in p.Q548X carriers were mainly of the serous subtype, and there was little evidence for an early age at diagnosis or pronounced family history of cancer. These findings indicate that the BLM p.Q548X mutation is not a strong risk factor for ovarian cancer.

This article describes an unexpected phenomenon which was revealed during the study of microRNA expression profiles of breast tumors. Hierarchical clustering has distinguished two broad groups of microRNAs with different expression patterns. One of these groups, Group Q (“questionable”), was composed mainly of recently discovered microRNAs and contained a large number of viral microRNA species. This microRNA subset was found to be extremely rich in guanine. The above features suggest that the Group Q is an artifact of microRNA expression profiling. However, the latter explanation is not supported by the evidence for biologically relevant associations observed for the Group Q microRNAs.

In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein-coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild-type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors (n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 (p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers (n = 17) compared to noncarriers (n = 93) (p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation-induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes.

The SLIM experiment at the Chacaltaya high altitude laboratory was sensitive to nuclearites and Q-balls, which could be present in the cosmic radiation as possible Dark Matter components. It was sensitive also to strangelets, i.e. small lumps of Strange Quark Matter predicted at such altitudes by various phenomenological models. The analysis of 427 m^2 of Nuclear Track Detectors exposed for 4.22 years showed no candidate event. New upper limits on the flux of downgoing nuclearites and Q-balls at the 90% C.L. were established. The null result also restricts models for strangelets propagation through the Earth atmosphere., 14 pages, 11 EPS figures

Background Several lines of evidence suggest the involvement of CCND1 and FGFR1 genes in determining breast cancer (BC) resistance to endocrine therapy, however these assumptions still require a validation in clinical data sets. Methods This study included 138 tumors from patients with metastatic BC who received first-line endocrine therapy with aromatase inhibitors (AI, n = 69), tamoxifen (n = 65), goserelin (n = 2) or a combination of goserelin and tamoxifen (n = 2). DNA extracted from formalin-fixed paraffin-embedded archival specimens was tested for CCND1 and FGFR1 amplification by digital droplet PCR. Results CCND1 and FGFR1 status was successfully determined in 134 tumors. CCND1 and FGFR1 amplification was detected in 24 (18%) and 28 (21%) informative cases, respectively; 9 carcinomas had concurrent alterations of two genes. Amplifications were more common in less differentiated tumors (G1: 1/18 (6%) vs. G2-3: 34/86 (40%); p = 0.005, Fisher’s exact test). Median disease-free survival in patients receiving AI with CCND1 amplification was shorter than in cases with the normal gene status (12.3 vs. 14.9 months; p = 0.014, log rank test). Objective response to aromatase inhibitors was observed in 2/13 (15%) BC with FGFR1 amplification compared to 22/46 (48%) tumors with the normal FGFR1 gene copy number (p = 0.054). Noteworthy, among patients receiving AI, CCND1 and/or FGFR1 amplification occurred in 5 out of 7 (71%) women with progressive disease compared to only 4 in 23 (17%) patients with objective response to therapy (p = 0.01). Meanwhile, none of 5 tumors showing resistance to tamoxifen harbored CCND1 or FGFR1 amplification. Conclusions The presence of CCND1 and/or FGFR1 amplification is associated with worse results of AI therapy in breast cancer patients. Legal entity responsible for the study The authors. Funding Russian Foundation for Basic Research (grant 17-04-01281). Disclosure All authors have declared no conflicts of interest.

Background Somatic loss of the wild-type allele is a key event in the pathogenesis of BRCA1-driven carcinomas. BRCA1 deficiency renders pronounced sensitivity of these tumors to platinum compounds and PARP inhibitors. Methods We analyzed BRCA1 loss of heterozygosity (LOH) in serial ovarian cancer (OC) samples, which were obtained from BRCA1 germ-line mutation carriers before neoadjuvant chemotherapy (NACT), at surgery and at disease relapse. Results 26/36 (72%) OC had BRCA1 LOH before NACT. 15 (58%) of these 26 tumors showed retention of the normal BRCA1 allele after NACT. The analysis of linked SNPs and FISH assay strongly indicated, that the restoration of BRCA1 function is caused not by the second mutation, but by the selection of pre-existing BRCA1-proficient cells. Tumor relapses were available in 7 patients with BRCA1 LOH in the chemonaive tumor and/or BRCA-proficiency in the residual post-NACT neoplasm; 6 (86%) of these relapses had BRCA1 LOH thus resembling the primary tumor. Secondary open reading frame (ORF) restoring BRCA1 mutation was detected in 1 recurrent OC. Serial samples retained same TP53 mutation during the treatment course. Whole exome sequencing revealed that chemonaive, post-NACT and relapsed tumors had both shared and individual mutations. Conclusions 1) BRCA1 LOH is not the first event in the pathogenesis of BRCA1-driven cancer: gain of TP53 mutation probably precedes BRCA1 inactivation in order to prevent apoptosis; 2) Chemonaive BRCA1-driven tumors contain a small fraction of BRCA1-proficient cells, which rapidly repopulate the tumor lump during the first weeks of therapy; 3) Change of BRCA1 status during NACT may call to reconsider the existing approaches to adjuvant therapy, as the residual post-NACT tumor masses are likely to be platinum-resistant; 4) The balance between BRCA1-deficient and BRCA1-proficient cells is a subject of fluctuations, depending whether therapy is applied or not; 5) Clinical trials on BRCA1-driven OCs need to address the issue of intratumoral heterogeneity of BRCA1 status. Legal entity responsible for the study The authors. Funding Russian Science Foundation (grant 19-15-00168). Disclosure All authors have declared no conflicts of interest.

This paper describes the design and performance of a computer controlled emulsion Plate Changer for the automatic placement and removal of nuclear emulsion films for the European Scanning System microscopes. The Plate Changer is used for mass scanning and measurement of the emulsions of the OPERA neutrino oscillation experiment at the Gran Sasso lab on the CNGS neutrino beam. Unlike other systems it works with both dry and oil objectives. The film changing takes less than 20 s and the accuracy on the positioning of the emulsion films is about 10 μ m . The final accuracy in retrieving track coordinates after fiducial marks measurement is better than 1 μ m .

SLIM is a large area experiment (440 m2) installed at the Chacaltaya cosmic ray laboratory since 2001, and about 100 m2 at Koksil, Himalaya, since 2003. It is devoted to the search for intermediate mass magnetic monopoles (107-1013 GeV/c2) and nuclearites in the cosmic radiation using stacks of CR39 and Makrofol nuclear track detectors. In four years of operation it will reach a sensitivity to a flux of about 10-15 cm-2 s-1 sr-1. We present the results of the calibration of CR39 and Makrofol and the analysis of a first sample of the exposed detector., Presented at the 22nd ICNTS, Barcelona 2004

Twenty one DNA repair genes were analyzed in a group of 95 BC patients, who displayed clinical features of hereditary disease predisposition but turned out to be negative for mutations in BRCA1 and BRCA2 entire coding region as well as for founder disease-predisposing alleles in CHEK2, NBN/NBS1 and ATM genes. Full-length sequencing of CHEK2 and NBN/NBS1 failed to identify non-founder mutations. The analysis of TP53 revealed a woman carrying the R282W allele; further testing of additional 108 BC patients characterized by a very young age at onset (35 years or earlier) detected one more carrier of the TP53 germ-line defect. In addition, this study confirmed non-random occurrence of PALB2 truncating mutations in Russian hereditary BC patients. None of the studied cases carried germ-line defects in recently discovered hereditary BC genes, BRIP1, FANCC, MRE11A and RAD51C. The analysis of genes with yet unproven BC-predisposing significance (BARD1, BRD7, CHEK1, DDB2, ERCC1, EXO1, FANCG, PARP1, PARP2, RAD51, RNF8, WRN) identified single women carrying a protein-truncating allele, WRN R1406X. DNA sequencing of another set of 95 hereditary BC cases failed to reveal additional WRN heterozygous genotypes. Since WRN is functionally similar to the known BC-predisposing gene, BLM, it deserves to be analyzed in future hereditary BC studies. Furthermore, this investigation revealed a number of rare missense germ-line variants, which are classified as probably protein-damaging by online in silico tools and therefore may require further consideration.

Many galactic and extragalactic astrophysical sources are currently considered promising candidates as high energy neutrino emitters. Astrophysical neutrinos can be detected as upward-going muons produced in charged-current interactions with the medium surrounding the detector. The expected neutrino fluxes from various models start to dominate on the atmospheric neutrino background at neutrino energies above some tens of TeV. We present the results of a search for an excess of high energy upward-going muons among the sample of data collected by MACRO during ~5.8 years of effective running time. No significant evidence for this signal was found. As a consequence, an upper limit on the flux of upward-going muons from high-energy neutrinos was set at the level of 1.7 10^(-14) cm^(-2) s^(-1) sr^(-1). The corresponding upper limit for the diffuse neutrino flux was evaluated assuming a neutrino power law spectrum. Our result was compared with theoretical predictions and upper limits from other experiments., 19 pages, 8 figures, 2 tables

We used CR-39 detectors to evaluate radon activity concentrations in several habitations of Bamako. The calibration factor of the dosimeters was determined experimentally with known radon activity concentrations inside a radon chamber, and was also simulated with MCNPX. The experimental and simulated calibration factorsare,respectively,kexp=0.119 ± 0.017andksim=0.126±0.007tr.cm -2 .d -1 .Bq -1 .m 3 . Indoor radon activity concentrations in Bamako were found to vary from 70 ± 18 to 154 ± 35 Bq.m -3 . No significant differences were observed in the mean radon activity concentrations compared with five other African countries. Taking into account an occupancy factor of 0.8 and an equilibrium factor of 0.4 for radon indoors, the effective dose rate ranges from 1.77 to 2.35 mSv.y -1 . In all cases the radon activity

BACKGROUND Although the molecular analysis of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in archived lung cancer tissues is relatively well established, the genetic testing of cytological material has not yet become a routine. METHODS The current study used cell samples that were obtained by bronchial brushing, transthoracic needle aspiration, or biopsy imprint preparation between 1993 and 2008. Islets of malignant cells were visually located on the archived cytological slides, lysed in situ by a drop of sodium dodecyl sulfate-containing buffer, and subjected to the standard DNA and RNA extraction. Examination of paraffin-embedded tissue blocks (resection specimens or biopsy material) from the same patients was performed in parallel. RESULTS A total of 75 cytological/histological lung adenocarcinoma sample pairs underwent polymerase chain reaction analysis for the EGFR mutation. Two cytological samples and 1 morphological sample failed to produce DNA. Concordance for the wild-type and mutation status was observed in 54 of 72 and 14 of 72 informative pairs, respectively; 3 pairs and 1 pair, respectively, had mutation only in the cytological or histological material. The discrepancies could be explained by the failure to ensure a high percentage of lung cancer cells in the analyzed samples or, alternatively, by the genuine intratumoral molecular heterogeneity of some neoplasms. RNA extraction followed by reverse transcriptase-polymerase chain reaction analysis for the EML4-ALK translocation was performed for 44 EGFR mutation-negative sample pairs; failures were observed for 2 cytological and 6 histological specimens. All informative pairs were concordant either for the norm (32 of 36 pairs) or for the presence of EML4-ALK gene fusion (4 of 36 pairs). CONCLUSIONS Archived cytological slides appear to be well suited both for EGFR and ALK analysis. Cancer (Cancer Cytopathol) 2013;121:370–376. © 2013 American Cancer Society.

In the present study, total and partial charge changing cross-sections of 300 A MeV Fe 26+ ion beam in aluminum target were measured by a new system of analysis installed with the Leica QWin Plus software. The CR39 nuclear track detectors were used to identify the incident charged particles and their fragments. The CR39 detectors just before and just after the target were calibrated and found to have the same charge response and the charge resolution, which were 0.19 e and 0.20 e , respectively. The response points were fitted with a polynomial of degree one and all the points are within the limits of experimental errors. The value of total charge changing cross-section was calculated to be σ tot =(1663±236) mb. To determine the partial charge changing cross-sections for Δ Z =−23,−22,…,−1, number of events corresponding to each fragment were determined from multiple Gaussian fitting of diameter distributions within 95.5% confidence levels and the numbers of incident and survived beam ions were counted within 99.7% confidence levels. Charge pick-up cross-section for Δ Z =+1 was calculated and is (92±6) mb.

Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history-negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02-4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel-Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups.

In the present study, CR39 track etch detector was calibrated with a new system and the total charge changing cross-section of 300 A MeV Fe 26+ ion beam in aluminum target was measured. The CR39 nuclear track detectors were used to identify the incident charged particles and their fragments using an optical microscope DM6000 M and automated image analyzer system installed with Leica QWin Plus software. The CR39 detectors before and after the target were calibrated and found to have the same charge response; the charge resolution in both of the detectors were 0.19e and 0.20e, respectively. The calibration points were fitted with a polynomial of degree one and all the points are within the limits of the experimental errors. The response functions were also obtained and fitted with a polynomial of degree three which are quite good throughout Z / β = 4.6 to 41.4. The value of the total charge changing cross-section is σ tot = (1663 ± 236) mb. The total charge changing cross-section was compared with the experimental results of others and also fitted by the Bradt-Peters geometrical cross-section.

Total charge changing cross-section of 10 A GeV Fe26+ ion beam on polyethylene and CR39 targets was measured. Charge of the fragments of projectiles was detected using CR39 nuclear track detectors by a new technique of one-side etching using an automated optical microscope with an image analysing software. The calculated value of total charge changing cross-section is σtot = (2694 ± 142)mb and is in good agreement with the experimental values by other methods within error. The restricted energy loss (REL) at energy 10 A GeV for all the fragments was theoretically calculated by using Bethe–Bloch equation and then obtained a calibration curve of reduced etch-rate ratio (p) versus REL showing the response of CR39 track detectors to 10 A GeV Fe26+ beam. The curve was fitted by a polynomial showing the relation between p and REL.