First Results in the Search for Dark Sectors at NA64 with the CERN SPS High Energy Muon Beam.

We report the first search for dark sectors performed at the NA64 experiment employing a high energy muon beam and a missing energy-momentum technique. Muons from the M2 beamline at the CERN Super Proton Synchrotron with a momentum of 160 GeV/c are directed to an active target. The signal signature consists of a single scattered muon with momentum <80 GeV/c in the final state, accompanied by missing energy, i.e., no detectable activity in the downstream calorimeters. For a total dataset of (1.98±0.02)×10^{10} muons on target, no event is observed in the expected signal region. This allows us to set new limits on the remaining (m_{Z^{'}},g_{Z^{'}}) parameter space of a new Z^{'} (L_{µ}-L_{τ}) vector boson which could explain the muon (g-2)_{µ} anomaly. Additionally, our study excludes part of the parameter space suggested by the thermal dark matter relic abundance. Our results pave the way to explore dark sectors and light dark matter with muon beams in a unique and complementary way to other experiments.

[Oncological results of repeat partial nephrectomy in patients with recurrence after nephron-sparing procedures].

AIM: To carried out a comparative analysis of the risk of complications and oncological results of repeat partial nephrectomy and radical nephrectomy in patients with local recurrence after previous organ-sparing procedures. MATERIALS AND METHODS: Retrospective and prospective data of 64 patients with local recurrence of kidney cancer after nephron-sparing procedures. who underwent surgical treatment in the department of oncourology of the National Medical Research Center of Oncology named after N.N. Blokhin in the period from 2000 to 2022. A total of 37 (57.8%) patients of the main group underwent repeat partial nephrectomy, while in 27 (42.2%) patients in the control group a radical nephrectomy was done. Median follow-up was 35 (3-131; Q1-Q3: 13-57) months. Both groups were comparable in terms of demographic and clinical characteristics (p>0.05). The median time to detect relapse after previous partial nephrectomy was 24 (2-172) months. RESULTS: Complications were noted in 8 (21.6%) patients after repeat partial nephrectomy, compared to 29.6% in the control group (n=8) (p=0.563). A comparative analysis revealed a significant advantage in overall survival in patients of the main group (p=0.042). There were no significant differences between groups in cancer-specific and disease-free survival (p=0.369 and p=0.537, respectively). CONCLUSION: Repeat partial nephrectomy for local recurrence of kidney cancer leads to an increase in overall survival compared to radical nephrectomy, in the absence of significant differences in cancer-specific and relapse-free survival.

Search for Light Dark Matter with NA64 at CERN.

Thermal dark matter models with particle χ masses below the electroweak scale can provide an explanation for the observed relic dark matter density. This would imply the existence of a new feeble interaction between the dark and ordinary matter. We report on a new search for the sub-GeV χ production through the interaction mediated by a new vector boson, called the dark photon A^{'}, in collisions of 100 GeV electrons with the active target of the NA64 experiment at the CERN SPS. With 9.37×10^{11} electrons on target collected during 2016-2022 runs NA64 probes for the first time the well-motivated region of parameter space of benchmark thermal scalar and fermionic dark matter models. No evidence for dark matter production has been found. This allows us to set the most sensitive limits on the A^{'} couplings to photons for masses m_{A^{'}}≲0.35 GeV, and to exclude scalar and Majorana dark matter with the χ-A^{'} coupling α_{D}≤0.1 for masses 0.001≲m_{χ}≲0.1 GeV and 3m_{χ}≤m_{A^{'}}.

The Role of Methylation of a Group of microRNA Genes in the Pathogenesis of Metastatic Renal Cell Carcinoma.

The role of methylation of 9 miRNA genes in the pathogenesis of metastatic clear cell renal cell carcinoma was determined by quantitative methylation-specific PCR (MS-PCR). For 5 genes (MIR125B-1, MIR137, MIR193A, MIR34B/C, and MIR375), a significant correlation of high methylation level with late (III-IV) stages, large size (T3+T4) of the tumor, and metastasis to lymph nodes and/or distant organs was revealed. For another group of genes (MIR125B-1, MIR1258, MIR193A, MIR34B/C, and MIR375), a statistically significant correlation of high methylation level with loss of differentiation in the tumor (G3-G4) was found, and the opposite pattern was found for MIR203A. A total of 7 microRNA genes (MIR125B-1, MIR1258, MIR137, MIR193A, MIR203A, MIR34B/C, and MIR375) were identified, the methylation of which is associated with the progression of metastatic clear cell renal cell carcinoma. For 6 of them (except MIR34B/C) these data were obtained for the first time. Thus, new factors of the development and progression of clear cell renal cell carcinoma were identified as potential biomarkers for the early diagnosis and prognosis of metastatic clear cell renal cell carcinoma.

Results from the Baksan Experiment on Sterile Transitions (BEST).

The Baksan Experiment on Sterile Transitions (BEST) was designed to investigate the deficit of electron neutrinos ν_{e} observed in previous gallium-based radiochemical measurements with high-intensity neutrino sources, commonly referred to as the "gallium anomaly," which could be interpreted as evidence for oscillations between ν_{e} and sterile neutrino (ν_{s}) states. A 3.414-MCi ^{51}Cr ν_{e} source was placed at the center of two nested Ga volumes and measurements were made of the production of ^{71}Ge through the charged current reaction, ^{71}Ga(ν_{e},e^{-})^{71}Ge, at two average distances. The measured production rates for the inner and the outer targets, respectively, are [54.9_{-2.4}^{+2.5}(stat)±1.4(syst)] and [55.6_{-2.6}^{+2.7}(stat)±1.4(syst)] atoms of ^{71}Ge/d. The ratio (R) of the measured rate of ^{71}Ge production at each distance to the expected rate from the known cross section and experimental efficiencies are R_{in}=0.79±0.05 and R_{out}=0.77±0.05. The ratio of the outer to the inner result is 0.97±0.07, which is consistent with unity within uncertainty. The rates at each distance were found to be similar, but 20%-24% lower than expected, thus reaffirming the anomaly. These results are consistent with ν_{e}→ν_{s} oscillations with a relatively large Δm^{2} (>0.5 eV^{2}) and mixing sin^{2}2θ (≈0.4).

Search for a New B-L Z

A search for a new Z^{'} gauge boson associated with (un)broken B-L symmetry in the keV-GeV mass range is carried out for the first time using the missing-energy technique in the NA64 experiment at the CERN SPS. From the analysis of the data with 3.22×10^{11} electrons on target collected during 2016-2021 runs, no signal events were found. This allows us to derive new constraints on the Z^{'}-e coupling strength, which, for the mass range 0.3≲m_{Z^{'}}≲100 MeV, are more stringent compared to those obtained from the neutrino-electron scattering data.

[Molecular Diagnostics of the Involvement of Visually Normal Mucosa in the Malignancy Process in Urothelial Bladder Cancer].

Immunofluorescent method by flow cytometry was used to quantify the expression of the tumor-associated protein ßIII-tubulin (TUBB3) in the tissue of urothelial bladder cancer and visually normal mucosa (56 samples in total). The expression of the marker was detected in 100% of cases, and heterogeneity of the TUBB3 expression level both in tumor tissue and in "normal" mucosa was revealed. The level of TUBB3 in the "normal" mucosa did not depend on the distance from the tumor (1 cm or more than 3 cm) and, on average, it was lower than in the tumor tissue (21.8 ± 10.8% and 24.9 ± 13.2% vs 35.2 ± 12.4%; p = 0.04 and 0.005, respectively). An increase of the TUBB3 expression in the tumor and in the "normal" mucosa was revealed in muscle invasive bladder cancer compared to non-muscle invasive bladder cancer. Therefore, in urothelial bladder cancer, the tumor-associated protein TUBB3 is a molecular marker of bladder mucosa involvement in the malignancy process and predicts the risk of tumor muscle invasion, which may influence indications for early cystectomy.

Panel of Candidate Genes to Predict the Survival of Patients with Clear Cell Renal Cancer on the Basis of Gene Expression Regulated by HIF1α/HIF2α.

The detection of genes related to the lifetime of patients with clear cell renal cancer provides information on the mechanisms of the tumor development and can be the basis for creating approaches to predict patient survival. In this paper, the expression of genes regulated by the HIF2α transcriptional factor was studied. Based on the results obtained here and previously identified genes regulated by the transcriptional factor HIF1α, a new panel of 6 genes, including the BAP1 gene, was proposed. Expression of genes of this panel allows predicting the survival of patients with clear cell renal cancer with high sensitivity (93%), specificity (96%), and relative risk (21.5). After verification, the application of this panel can be useful for personalized treatment of patients with clear cell renal cancer, which will increase the effectiveness of therapy.

Constraints on New Physics in Electron g-2 from a Search for Invisible Decays of a Scalar, Pseudoscalar, Vector, and Axial Vector.

We performed a search for a new generic X boson, which could be a scalar (S), pseudoscalar (P), vector (V), or an axial vector (A) particle produced in the 100 GeV electron scattering off nuclei, e^{-}Z→e^{-}ZX, followed by its invisible decay in the NA64 experiment at CERN. No evidence for such a process was found in the full NA64 dataset of 2.84×10^{11} electrons on target. We place new bounds on the S, P, V, A coupling strengths to electrons, and set constraints on their contributions to the electron anomalous magnetic moment a_{e}, |Δa_{X}|≲10^{-15}-10^{-13} for the X mass region 1 MeV≲m_{X}≲1 GeV. These results are an order of magnitude more sensitive compared to the current accuracy on a_{e} from the electron g-2 experiments and recent high-precision determination of the fine structure constant.

Search for Axionlike and Scalar Particles with the NA64 Experiment.

We carried out a model-independent search for light scalar (s) and pseudoscalar axionlike (a) particles that couple to two photons by using the high-energy CERN SPS H4 electron beam. The new particles, if they exist, could be produced through the Primakoff effect in interactions of hard bremsstrahlung photons generated by 100 GeV electrons in the NA64 active dump with virtual photons provided by the nuclei of the dump. The a(s) would penetrate the downstream HCAL module, serving as a shield, and would be observed either through their a(s)→γγ decay in the rest of the HCAL detector, or as events with a large missing energy if the a(s) decays downstream of the HCAL. This method allows for the probing of the a(s) parameter space, including those from generic axion models, inaccessible to previous experiments. No evidence of such processes has been found from the analysis of the data corresponding to 2.84×10^{11} electrons on target, allowing us to set new limits on the a(s)γγ-coupling strength for a(s) masses below 55 MeV.

Prognostic Role of Matrix Metalloproteinases 2, 7, 8, 9 and Their Type 1 Tissue Inhibitor in Blood Serum of Patients with Kidney Cancer.

The study compared the levels of MMP-2,7,8,9, and TIMP-1 in blood serum of healthy people (N=97) and patients with primary renal cell carcinoma (N=93) to assess relevance of these markers to prognosis of overall survival of these patients, which were followed-up over 1 to 45 months (median 26 months). To evaluate the survival with the Kaplan-Meier estimator, the median values of examined markers in the total group of patients were taken as the threshold levels. This estimator showed that the high levels of serum MMP-7 and MMP-8 were indicative for unfavorable prognosis in the total group of patients with renal cell cancer. Of them, the most significant marker was the level of MMP-7: at its low level (<6.3 ng/ml), a 3-year survival was 93%, whereas survival dropped down to 51% at a higher value of this marker (p<0.001). For MMP-8, the threshold level was 51 ng/ml, and the corresponding survivals were 78 and 58% (p<0.01). The level of MMP-7 was also prognostically significant for the patients with stage I kidney cancer: during a 3-year follow-up, all the patients with low MMP-7 were alive, while the 3-year survival of the patients with a high level of MMP-7 was only 72% (p=0.02). There were the declining trends for survival at high TIMP-1 and low MMP-2. In contrast, the level of MMP-9 virtually did not correlate with survival of the patients with renal cell cancer.

Dark Matter Search in Missing Energy Events with NA64.

A search for sub-GeV dark matter production mediated by a new vector boson A^{'}, called a dark photon, is performed by the NA64 experiment in missing energy events from 100 GeV electron interactions in an active beam dump at the CERN SPS. From the analysis of the data collected in the years 2016, 2017, and 2018 with 2.84×10^{11} electrons on target no evidence of such a process has been found. The most stringent constraints on the A^{'} mixing strength with photons and the parameter space for the scalar and fermionic dark matter in the mass range ≲0.2 GeV are derived, thus demonstrating the power of the active beam dump approach for the dark matter search.

Kidney Injury Molecule-1 (KIM-1) in Blood Plasma of Patients with Clear-Cell Carcinoma.

The concentration of kidney injury molecule-1 (KIM-1) was measured in blood plasma of 99 patients with clear-cell carcinoma and 14 patients with benign renal tumors using a Human Serum TIM-1/KIM-1/HAVCR Quantikine ELISA kit. The control group consisted of 15 healthy male and 14 healthy female subjects. KIM-1 levels in blood plasma of patients with cancer or benign renal tumors were significantly higher than in the control (p<0.00001 and p<0.01, respectively). In patients with benign tumors, this parameter was significantly lower than in patients with cancer (p<0.0001). KIM-1 level significantly increased with disease stage (p<0.0001), and even in stage I cancer, it was higher than in the control group (p<0.0001) or in patients with benign tumors (p<0.01). The best sensitivity/specificity ratio for stage I renal cancer detection (81 and 83% respectively) was achieved at cut-off level 77 pg/ml, the sensitivity of detection of for stages II-IV being 97%. Plasma level of KIM-1 increased with increasing the size and area of the primary tumor (T). This parameter was higher in patients with metastasis in regional lymph nodes irrespective of their number (N1 or N2) in comparison with patients without regional metastasis (N0). It is also higher in patients with distant metastasis (M+). In patients with grade III-IV cancer, KIM-1 level was 7-fold higher than in patients with grade I-II tumor (p<0.0001). Thus, KIM-1 can be regarded as a highly sensitive marker for early detection of clear-cell carcinoma.

[Impact of PD-L1 status on the long-term outcomes of radical treatment of patients with prostate cancer].

A wide range of variables are associated with poor long-term outcomes of radical treatment in patients with prostate cancer (PCa). Expression of the programmed death-1 ligand 1 (PD-L1) in tumor might be a potential novel marker for PCa. AIM: to evaluate the influence of PD-L1 expression status in tumor cells on long-term results of radical treatment in patients with PCa. MATERIALS AND METHODS: a total of 45 patients with pathologically-proven PCa who undergone radical treatment and followed at N.N. Blokhin National Medical Research Center of Oncology were retrospectively analyzed. In all cases PD-L1 expression in tumor cells was evaluated by immunohistochemical studies of paraffin block sections obtained under direct control of pathologist. Positive expression of PD-L1(+) was defined as expression level in tumor cells more or equal 1%, while hyperexpression was diagnosed when expression level L1 more or equal 5%. RESULTS: PD-L1 expression and hyperexpression in tumor cells were identified in 8 (17.8%) and 6 (13.3%) cases. Median metastasis-free survival in patients with positive PD-L1 expression was 48.918 months (95% CI 42.523-55.313) and was less than in patients with negative PD-L1 expression (68.033 months, 95% CI 48.242- 87.824, p=0.090). Cancer-specific survival in patients with negative PD-L1 expression was significantly longer compared to patients with positive expression (p=0.05) and hyperexpression (p=0.024) of PD-L1 in tumor cells. Multivariate Cox analysis confirmed independent predictive value of positive expression and hyperexpression of PD-L1 in tumor cells for metastasis-free survival (HR 3.461, 95% CI 1.171-10.228, p=0.025, and HR 3.916, 95% CI 1.129-13.591, p=0.032) and cancer-specific survival (HR 7.65, 95% CI 0.69-84.51, p=0.097, and HR 9.73, 95% CI 0.87-108.78, p=0.065). CONCLUSION: According to our study and published data, positive PD-L1 expression in tumor cells is associated with poor prognosis of PCa. Given the lack of association of PD-L1 expression in tumor cells with the routine clinical and pathological characteristics of the disease, it seems reasonable to include the status of PD-L1 expression in the current predictive nomograms for patients with PCa. The results may indicate the potential benefits of developing personalized approaches to PCa treatment, particularly with targeting a PD-L1/PD-1 signaling pathway in tumor cells.

[Impact of germline BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-nave prostate cancer].

INTRODUCTION: as shown in previous studies, mutations in the BRCA1/2 and CHEK2 genes are associated with worsened long-term results of the definitive treatment for localized prostate cancer (PCa). AIM: to evaluate the prognostic value of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with metastatic PCa (mPCa), receiving hormonal therapy in the first-line systemic treatment. MATERIALS AND METHODS: A total of 76 patients with mPCa receiving hormonal therapy with luteinizing hormone-releasing hormone analogue (LHRHa) in N.N. Blokhin National Medical Research Center of Oncology were recruited in our prospective study. All patients were genotyped for germline mutations in the BRCA1/2 and CHEK2 genes by real-time polymerase chain reaction using a set "OncoGenetics" (LLC "Research and Production Company DNA-Technology", Russia, registration certificate No 2010/08415) and the Sanger sequencing using a set "Beckman Coulter enomeLab GeXP". In addition, a histologic grade and volume of metastatic disease were evaluated. RESULTS: Pathogenic and possibly pathogenic mutations in the BRCA2 and CHEK2 gene were identified in 19 (25%) patients. No cases of BRCA1 mutations were detected. Median time to castration resistance was significantly lower in BRCA2 and CHEK2 mutation carriers (7.93 mo, 95% confidence interval (CI) 2.62-13.25), than in non-carriers (48,66 mo, 95% CI 31.05-68.26, p<0,001). Cox analysis confirmed three independent unfavorable prognostic factors. DISCUSSION: The results of our study and other publications have confirmed limited efficacy of standard approach to treatment hormone-sensitive mPCa in germline mutation BRCA2 and CHEK2 carriers. However, the main objective of studies was to assess the survival rates in these patients at the stage of castration-resistant mPCa. CONCLUSION: Our results demonstrated that germline BRCA2 and CHEK2 mutations are independent unfavorable predictors in patients with mPCa which are associated with decreased time to castration resistance (HR 3.04, 95% CI 1.63-5.66, p<0.001), particularly in subgroup with low volume metastatic disease (HR 4.59, 95% CI 2.06-10.22, p<0,001). An evaluation of a prognostic value of mutations in other DNA repair genes requires additional research.

Search for a Hypothetical 16.7 MeV Gauge Boson and Dark Photons in the NA64 Experiment at CERN.

We report the first results on a direct search for a new 16.7 MeV boson (X) which could explain the anomalous excess of e^{+}e^{-} pairs observed in the excited ^{8}Be^{*} nucleus decays. Because of its coupling to electrons, the X could be produced in the bremsstrahlung reaction e^{-}Z→e^{-}ZX by a 100 GeV e^{-} beam incident on an active target in the NA64 experiment at the CERN Super Proton Synchrotron and observed through the subsequent decay into a e^{+}e^{-} pair. With 5.4×10^{10} electrons on target, no evidence for such decays was found, allowing us to set first limits on the X-e^{-} coupling in the range 1.3×10^{-4}≲ε_{e}≲4.2×10^{-4} excluding part of the allowed parameter space. We also set new bounds on the mixing strength of photons with dark photons (A^{'}) from nonobservation of the decay A^{'}→e^{+}e^{-} of the bremsstrahlung A^{'} with a mass ≲23 MeV.

AEgIS at ELENA: outlook for physics with a pulsed cold antihydrogen beam.

The efficient production of cold antihydrogen atoms in particle traps at CERN's Antiproton Decelerator has opened up the possibility of performing direct measurements of the Earth's gravitational acceleration on purely antimatter bodies. The goal of the AEgIS collaboration is to measure the value of g for antimatter using a pulsed source of cold antihydrogen and a Moiré deflectometer/Talbot-Lau interferometer. The same antihydrogen beam is also very well suited to measuring precisely the ground-state hyperfine splitting of the anti-atom. The antihydrogen formation mechanism chosen by AEgIS is resonant charge exchange between cold antiprotons and Rydberg positronium. A series of technical developments regarding positrons and positronium (Ps formation in a dedicated room-temperature target, spectroscopy of the n=1-3 and n=3-15 transitions in Ps, Ps formation in a target at 10 K inside the 1 T magnetic field of the experiment) as well as antiprotons (high-efficiency trapping of [Formula: see text], radial compression to sub-millimetre radii of mixed [Formula: see text] plasmas in 1 T field, high-efficiency transfer of [Formula: see text] to the antihydrogen production trap using an in-flight launch and recapture procedure) were successfully implemented. Two further critical steps that are germane mainly to charge exchange formation of antihydrogen-cooling of antiprotons and formation of a beam of antihydrogen-are being addressed in parallel. The coming of ELENA will allow, in the very near future, the number of trappable antiprotons to be increased by more than a factor of 50. For the antihydrogen production scheme chosen by AEgIS, this will be reflected in a corresponding increase of produced antihydrogen atoms, leading to a significant reduction of measurement times and providing a path towards high-precision measurements.This article is part of the Theo Murphy meeting issue 'Antiproton physics in the ELENA era'.

Association of Target Therapy Gene Expression with Metastasizing of Clear-Cell Renal Cell Carcinoma.

We analyzed association of the levels of VEGFA, RAF1, and mTOR gene expression in the tissue of clear-cell renal cell carcinoma (ccRCC) with tumor metastasizing. Significant association with metastases was found only for VEGFA gene: OR=6.641, 95%CI=2.111-20.696. The risk of metastasis associated with reduced expression of VEGFA gene - 2.467, 95%CI=1.238-4.915. An association of VEGFA gene expression with the time to the metastasis appearance was revealed (p=0.0005). Reduced expression of the VEGFA gene is associated with reduction of the time to metastasis appearance; the median of this time is shifted from 46 to 2 months. Analysis of tumor samples with reduced expression of the VEGFA gene revealed association of increased expression of RAF1 (p=0.003) and mTOR genes (p=0.038) with metastasis.

Expression Profiles of Genes-Potential Therapy Targets-and Their Relationship to Survival in Renal Cell Carcinoma.

The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.

[Use of multiparametric magnetic resonance imaging in t-staging of prostate cancer: a multicenter study].

AIM: The study aimed to analyze the diagnostic performance of preoperative multiparametric magnetic resonance imaging (mp-MRI) in the staging of prostate cancer (PCa) versus postoperative histological examination and determine the most sensitive pulse sequence from the mp-MRI protocol in estimating the local extent of PCa. MATERIALS AND METHODS: The study comprised 112 men aged 52 to 84 years with a morphologically verified diagnosis of prostate cancer. All patients underwent pelvic mp-MRI before radical prostatectomy (RPE) no earlier than six weeks after the prostate biopsy. Radical prostatectomy was performed within two weeks after mp-MRI. MP-MRI findings and the results of postoperative histology were compared using a binary logistic regression model. RESULTS: The sensitivity, specificity, diagnostic accuracy, positive (PPV) and negative (NPV) predictive values for predicting extracapsular extension were 87.5, 92.6, 91, 84 and 94.3%, respectively; for predicting seminal vesicles invasion, they were 85, 95, 90, 80.9 and 96.7%, respectively. When stratified by the presence or absence of the pseudocapsule invasion, the reliability of detecting the tumor spread for different types of images decreases in the following order: DWI - T2 + DWI - T2 VI - DCE-MRI. CONCLUSION: mp-MRI has high sensitivity, specificity, general diagnostic accuracy, high NPV, and PPV values in detecting an extracapsular extension of prostate cancer. According to the binary logistic regression model, the greatest contribution to the decision on the presence or absence of extracapsular extension is also made by the DWI.