Experimental Study on the Effect of Urban Road Traffic Noise on Heart Rate Variability of Noise-Sensitive People

Epidemiological studies have confirmed that long-term exposure to road traffic noise can cause cardiovascular diseases (CDs), and when noise exposure reaches a certain level, the risk of related CDs significantly increases. Currently, a large number of Chinese residents are exposed to high noise exposure, which could greatly increase the risk of cardiovascular disease. On the other hand, relevant studies have found that people with high noise sensitivity are more susceptible to noise. And it is necessary to pay more attention to the high noise-sensitive people. This study investigated the acute physiological effect of different noise-sensitive groups by indoor-level noise stimulus experiments under laboratory conditions, by observing heart rate variability (HRV) indicators, including standard deviation of NN intervals (SDNN), low frequency/high frequency (LF/HF), and heart rate (HR). The results showed that (a) there was no significant difference in HRV between the high-sensitive group and the low-sensitive group at the physiological baseline and the different stimulating noise levels. (b) Then, based on the theory of cumulative effect of noise proposed by WHO Regional Office for Europe, non-significant but observable differences between groups were further discussed. By analyzing differences of the variation trends and the within-group significant changes of SDNN and HR between the two groups, the results tended to show that the high-sensitive group is more affected by road traffic noise. In addition, the values of SDNN and HR showed observable between-group differences at 55 dB (A) and 65 dB (A) which corresponding to the SPL associated with a significantly increased risk of cardiovascular disease concerned by epidemiological studies. According to the cumulative effect theory (WHO), these differences in HRV caused by short-term noise stimulation may have the potential to produce physiological response and lead to between-groups differences in prevalence after long-term recurrent effect, and deserve attention and further research.

Evaluation Short-term Efficacy of Cervical Cancer Under Radiotherapy by Shear Wave Elastography: a Preliminary Study

Background To find a reliable, safe, convenient and low-cost imaging technology in evaluation of the short-term clinical efficacy of cervical cancer. Here, we performed a preliminary examination of the value of shear wave elastography (SWE) in assessing short-term efficacy of radiotherapy in cervical cancer. Methods In this study, we used SWE to measure the elastic modulus of cervical masses and healthy paracervical tissues and record the maximum elastic modulus (Emax) and the mean elastic modulus (Emean) in 46 patients with cervical cancer. The 46 patients who were naive to treatment were monitored at 5 time points. We divided those into sensitive and non-sensitive groups based on MRI in combination with RECIST1.1. The relative changes in the elastic modulus of the mass before and after radiotherapy were calculated in all patients. MRI was also combined with gynecological examinations to determine if any residual masses remained. Results In this study, 25 patients completed all 5 time points examinations showing the elastic modulus of the cervix decreased while healthy paracervical tissues first increased and then decreased. Then, all 46 patients underwent SWE at 3 time points: prior to radiotherapy, the 15th radiotherapy session, and at completed radiotherapy. The results revealed that the relative changes in cervical masses in the sensitive group were larger than that in the non-sensitive group (P < 0.05). We further discovered the Emax and the Emean of cervical tissues in the residual group were higher than that in the non-residual group (135.69 ± 35.18, 128.25 ± 35.55 vs 104.13 ± 20.19, 98.14 ± 18.9, respectively; P < 0.05), and the area under the curve (AUCs) of the receiver operating characteristic (ROC)were 0.770 and 0.767, respectively (P < 0.05). Conclusions SWE can be used to monitor changes in cervix and paracervical stiffness, and to assist in assessments of the efficacy of radiotherapy in cervical cancer.

High Serpin Family A Member 10 Expression Confers Platinum Sensitivity and Is Associated With Survival Benefit in High-Grade Serous Ovarian Cancer: Based on Quantitative Proteomic Analysis

This study aims to identify differentially expressed proteins related with platinum sensitivity and to find biomarkers for predicting platinum response and survival outcomes in patients with high-grade serous ovarian cancer (HGSOC). Eligible HGSOC patients were divided into platinum-sensitive and platinum-resistant groups according to platinum-free interval (PFI). Tissue protein lysates from tumor tissues were subjected to an in-solution tryptic digest followed by tandem mass tag (TMT) labeling of the resulting peptides and mass spectrometric analysis. Candidate proteins were identified using differentially expressed protein and gene set enrichment analysis (GSEA) and confirmed by immunohistochemistry (IHC), and their survival relevance was evaluated in The Cancer Genome Atlas (TCGA) ovarian cancer cohort. The results showed that there was a significant difference in the protein expression profiling between the two patient groups. In the GSEA model, a gene set of 239 extracellular matrix (ECM)-related proteins was significantly enriched in the platinum-sensitive group [normalized enrichment score (NES) = 3.82, q &lt; 10−5], and this finding was confirmed in TCGA ovarian cancer cohort. Interestingly, an ECM-related gene expression, serpin family A member 10 (SERPINA10), was identified to be significantly positively correlated with overall survival (OS) and progression-free survival (PFS) in TCGA ovarian cancer cohort (all p &lt; 0.05). IHC results demonstrated that HGSOC patients with high SERPINA10 expression had longer PFI than the patients with low SERPINA10 expression (9 vs. 5 months, p = 0.038), and the SERPINA10 expression had an area under the receiver operating characteristic curve (AUC) value of 0.758 (95% CI = 0.612–0.905; p = 0.005) to discriminate the platinum-sensitive group from the platinum-resistant group. In conclusion, the results suggested that SERPINA10 could be a promising biomarker for predicting the response and survival in platinum-based chemotherapy of HGSOC.

Phosphoproteomic Analysis of Primary Myeloma Patient Samples Identifies Distinct Phosphorylation Signatures Correlating with Chemo-Sensitivity Profiles in an Ex Vivo Drug Sensitivity Testing Platform

Introduction: Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow resulting in end-organ damage. Despite an extensive increase in the five-year survival rate in recent years, MM is still considered an incurable disease as patients will repeatedly relapse and develop resistance to current chemotherapies. A key focus for the personalization of myeloma therapy is understanding the biological mechanisms of drug resistance and identifying clinically useful biomarkers of therapeutic response. Highly efficient techniques for the enrichment of phosphorylated peptides followed by high resolution mass spectrometry facilitates the quantitation of thousands of site-specific phosphorylation events. Here, we have performed a phosphoproteomic analysis on MM cell lysates stratified based on their ex vivo drug response profiles to advance our understanding of drug resistance mechanisms. Materials and Methods: CD138 + plasma cells were isolated from 20 adult MM patient bone marrow aspirates at diagnosis (n=7) or relapse (n=13). Samples were grouped based on ex vivo drug sensitivity and resistance testing (DSRT) as follows: highly sensitive (Group I), sensitive (Group II), resistant (Group III), highly resistant (Group IV) [1]. For the phosphoproteomic analysis, peptides were generated and purified using the filter aided sample preparation (FASP) protocol. Peptide tandem mass tag (TMT) labelling, Fe 3+ immobilized metal ion affinity chromatography (IMAC), synchronous precursor selection (SPS), and triple stage tandem mass spectrometry (MS3) was performed. Nonenriched peptides were used for proteomic analysis. Resulting data was analysed using MaxQuant, followed by normalization of phosphosite intensities using the internal reference scale (IRS) method, and statistical analysis using Perseus. Functional enrichment and kinase enrichment analyses were performed on significant phosphoproteins using g:profiler and KEA2, respectively. Results: Our quantitative MS-based phosphoproteomic analysis identified 2,945 phosphorylation sites on 2,232 phosphopeptides from 690 phosphoproteins. Of these phosphorylation sites, 176 were significantly changed between all four DSRT groups and 267 were significantly changed between Group I and Group IV (False Discovery Rate (FDR) &lt; 0.05). Hierarchical clustering was performed to highlight the distinct phosphoproteomic profiles associated with each DSRT group, of which the very sensitive (Group I) and very resistant (Group IV) subgroups demonstrated a well-defined separation (Fig. 1A, 1B). KEGG pathway analysis and gene ontology (GO) analysis of significantly increased phosphorylated proteins in Group IV compared to Group I MM patients demonstrated an increased phosphorylation of proteins associated with tight junctions, the Rap1 signalling pathway and the phosphatidylinositol signalling system; indicating an upregulation of cell adhesion associated processes in drug resistant MM. Phosphoproteins increased in abundance in Group I compared to Group IV MM patients revealed an increased phosphorylation of proteins involved in translation and RNA processing including the spliceosome, RNA transport and RNA binding pathways (Fig. 1C). We identified filamin A serine 2152, RAS guanyl-releasing protein 2 serine 576 and proto-oncogene tyrosine-protein kinase Src serine 17 as increased in Group IV MM, and nuclease-sensitive element-binding protein 1 (YBX1) serine 165, CD44 serine 697 and Bcl2-associated agonist of cell death (BAD) serine 99 as increased in Group I MM. KEA of the upregulated phosphoproteome in Group IV revealed an enrichment of cyclin dependent kinase 1 (CDK1) and ribosomal s6 kinases (RPS6K) whereas casein kinase 2 (CK2) and the glycolysis-associated kinases were enriched in Group I (Fig. 1D). Conclusion: Our study has generated a phosphoproteomic dataset demonstrating distinct phosphorylation signatures associated with drug sensitivity in clinical MM plasma cells. The identification of phosphorylation events associated with drug resistance provides a basis for further exploration of these events and associated signalling pathways to further understand drug resistance mechanisms in MM and identify potential biomarkers of therapeutic response and targets for drug re-sensitization in MM. References: [1] M. M. Majumder et al., Oncotarget 8(34), 56338 (2017) Figure 1 Figure 1. Disclosures Heckman: Novartis: Research Funding; Orion Pharma: Research Funding; Celgene/BMS: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding.

Autologous Hematopoietic Stem Cell Transplantation for AL Amyloidosis Refractory to Induction Therapy

Background: There has been an increased use of novel agents in the induction therapy for transplant-eligible AL amyloidosis over past decade. Hematologic response after an autologous hematopoietic stem cell transplantation (ASCT) is predictive of better outcomes, including organ response and overall survival. However, limited data exist about the outcomes of patients who are refractory to induction chemotherapy but proceed with upfront ASCT). We present here the outcomes of AL amyloidosis refractory to induction therapy. Methods: This retrospective study included all consecutive AL patients who had their ASCT at our institution between 01/2008 and 12/2018 and received induction therapy. We excluded patients who were untreated at the time of transplant. Primary objective: assess the hematologic response, progression-free survival (PFS) and overall survival (OS). Secondary objective: compare PFS and OS of AL amyloidosis by response to induction therapy (refractory vs sensitive). Refractory disease was defined as patient who had stable disease (SD) or progressive disease (PD) after at least 1 line of induction therapy. Hematologic response was defined per the 2012 consensus criteria. Survival estimates were calculated using Kaplan-Meier method. Results: One-hundred-and-eleven patients with a median age of 61 (range, 27-77) years met eligibility criteria. Thirty-three (30%) were refractory and 78 (70%) were sensitive to induction therapy. Table 1 summarizes patient and disease characteristics of all study patients and for the refractory vs sensitive groups. Overall, the two groups were comparable except for significantly more kidney involvement in the refractory group (97% of patients). Induction therapies were similar in the two groups, with bortezomib/cyclophosphamide/dexamethasone (VCD) being the most commonly used regimen (46%). With a median follow-up of 3.11 (range, 0.18-11.15) years, the 3-year PFS and OS for all study patients were 67% and 78%, respectively. At 3 months after transplant, 74% of the patients in the refractory group achieved an objective hematologic response (OHR; defined as PR or better). Of these, 29% achieved VGPR/CR and 45% achieved PR. As expected, more patients in the sensitive group achieved OHR (97%) and VGPR/CR (76%). The respective 3-year PFS and OS were 49% and 73% in the refractory group compared to 75% and 83% in the sensitive group (p=0.0068 for PFS; p=0.0790 for OS). Univariate analysis (UVA) was performed for the variables listed in Table 1 and multivariable analyses included only factors with p value&lt;0.1 in in the UVA. In MVA, in addition to increased risk for refractory patients (HR 2.885, 95% CI:1.237-6.729; p=0.0142), only elevated beta-2 microglobulin (HR 3.899, 95% CI:1.039-14.629; p=0.0437) was associated with inferior PFS. Regarding OS, age ≥60 (HR 3.812, 95% CI:1.038-14.002; p=0.0438) and revised Mayo stage III/IV (HR 3.886, 95% CI: 1.029-14.679; p=0.0453) were associated with inferior survival. In a subgroup analysis comparing PFS and OS stratifying patients by their response to induction (refractory vs sensitive) and their 3-month hematologic response after transplant, we found no significant differences in the 3-year PFS (86% for refractory vs 80% for sensitive group; p=0.7284) for those with VGPR or better but significantly inferior PFS for refractory patients who achieved &lt;VGPR (27% compared to 74% for the sensitive group; p=0.0196). Conclusion: AL amyloid patients refractory to induction therapy seem to benefit from high-dose chemotherapy and ASCT in terms of both response rates and survival. Durable responses for refractory disease are notable in patients who achieved &gt;VGPR after ASCT. Prospective studies comparing transplant versus non-transplant approaches are warranted for these high-risk patients. Figure 1 Figure 1. Disclosures Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Lee: Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Legend Biotech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Oncopetides: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Regeneron: Research Funding. Orlowski: Asylia Therapeutics, Inc., BioTheryX, Inc., and Heidelberg Pharma, AG.: Other: Laboratory research funding; Asylia Therapeutics, Inc.: Current holder of individual stocks in a privately-held company, Patents & Royalties; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, Forma Therapeutics, Genzyme, GSK Biologicals, Janssen Biotech, Juno Therapeutics, Karyopharm Therapeutics, Inc., Kite Pharma, Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, I: Membership on an entity's Board of Directors or advisory committees; CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Other: Clinical research funding; Amgen, Inc., BioTheryX, Inc., Bristol-Myers Squibb, Celgene, EcoR1 Capital LLC, Genzyme, GSK Biologicals, Janssen Biotech, Karyopharm Therapeutics, Inc., Neoleukin Corporation, Oncopeptides AB, Regeneron Pharmaceuticals, Inc., Sanofi-Aventis, and Takeda P: Consultancy, Honoraria. Qazilbash: Janssen: Research Funding; Biolline: Research Funding; Angiocrine: Research Funding; Amgen: Research Funding; NexImmune: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board.

Genetic aspects of aspirin resistance in patients with cerebrovascular pathology

Введение. Цереброваскулярные заболевания (ЦВЗ) и нарушения мозгового кровообращения (НМК) остаются одной из основных причин смерти во всем мире. Доказана генетическая составляющая возникновения НМК, генетические полиморфизмы могут изменять ответ на фармакологические агенты. Ацетилсалициловая кислота (АСК) — «золотой стандарт» антиагрегантного лечения ЦВЗ. С начала XXI века в мировой науке накопились факты о недостаточном эффекте АСК, в связи с чем возник термин аспиринорезистентность. Цель исследования: оценка вклада гемореологических и генетических факторов в возникновение феномена аспиринорезистентности у пациентов с ЦВЗ. Материалы и методы. В настоящее проспективное рандомизированное контролируемое наблюдательное исследование были включены 186 пациентов с ЦВЗ в возрасте 45–75 лет. Все пациенты получали 75 мг АСК ежедневно. Наряду с комплексным клиническим обследованием, оценкой когнитивного статуса и приверженности к лечению, проводилась лабораторная оценка функции тромбоцитов, развернутый биохимический анализ крови, идентификация полиморфизмов A842G гена циклооксигеназы 1-го типа (ЦОГ-1) (rs 10306114), С50Т ЦОГ-1 (rs3842787) и А1676G ЦОГ-1 (rs1330344). Статистическая обработка выполнена с использованием программ IBM SPSS Statistics. Результаты. Выявлена положительная взаимосвязь между уровнем агрегации тромбоцитов (АТ) с аденозиндифосфатом (АТ-АДФ) и адреналином и (АТ-адр) и пробой АСК in vitro (r = 0,722 и r = 0,689; р < 0,001). Обнаружена отрицательная взаимосвязь между АТ-АДФ и баллом по Монреальской шкале оценки когнитивных функций (англ. Montreal Cognitive Assessment, MoCA) и приверженностью к лечению (r = –0,845; p = 0,001). На основании анализа АТ все обследованные были подразделены на АСК-нечувствительных (группа 1, n = 100) и АСК-чувствительных (группа 2, n = 86). В группе АСК-нечувствительных наблюдалось больше пациентов, несущих хотя бы один аллель G полиморфизма гена ЦОГ-1 rs1330344 по сравнению с пациентами в группе ACK-чувствительных (60,4% против 47,7%; p < 0,01). Наличие rs1330344 часто ассоциировано с сахарным диабетом 2-го типа (отношение шансов = 3,749; 95% доверительный интервал = 1,937–7,254; p = 0,001). Полиморфизм ЦОГ-1 C50T (rs3842787) по данным логистической регрессии связан с АТ-Адр (r = 0,845; р < 0,001). Заключение. Среди причин аспиринорезистентности у пациентов с ЦВЗ следует учитывать генетические аспекты. Background. Cerebrovascular disease (CVD) and stroke remain one of the leading causes of death worldwide. The genetic component of stroke has been proven; genetic polymorphisms can alter the response to pharmacological agents. Acetylsalicylic acid (ASA) is the “gold standard” for antiplatelet treatment of CVD. Since the beginning of the XXI century, the world science has accumulated facts about the insufficient effect of ASA, so the term aspirin resistance appeared. Objectives: to assess hemorheological and genetic factors to the occurrence of the phenomenon of aspirin resistance in patients with CVD. Patients/Methods. This prospective randomized controlled observational study included 186 patients with CVD, aged 45–75 years. All patients received 75 mg ASA daily. Clinical examination, assessment of cognitive status and compliance to treatment, a laboratory assessment of platelet function, a detailed biochemical blood test, identifi cation of A842G polymorphisms of type 1 cyclooxygenase (COX-1) gene (rs 10306114), C50T COX-1 (rs3842787) and A1676G COX-1 (rs3842787) and A1676G COX-1 (rs1330344) were performed. Statistics was carried out using the IBM SPSS Statistics software. Results. The positive correlation was found between platelet aggregation (РА) with adenosine diphosphate (РА-ADP) and adrenaline (РА-Аdr) and an in vitro test with ASA (r = 0.722 and r = 0.689; p < 0.001). A negative correlation was found between РА-ADP and the Montreal Cognitive Assessment (MoCA) score for compliance to treatment (r = –0,845; p = 0,001). Based on the analysis of PA, all examined patients were divided into ASA-insensitive (group 1, n = 100) and ASA-sensitive (group 2, n = 86). In the ASA-insensitive group, there were more patients carrying at least one G allele of the COX-1 gene rs1330344 polymorphism compared with patients in the ACK-sensitive group (60.4% versus 47.7%; p < 0.01). The presence of rs1330344 is often associated with type 2 diabetes mellitus (OR = 3.749; 95% СI = 1.937–7.254; p = 0.001). C50T polymorphism of COX-1 (rs3842787) according to logistic regression is associated with AT-Adr (r = 0.845; p < 0.001). Conclusions. Genetic aspects should be considered among the causes of aspirin resistance in patients with CVD.

Neoadjuvant Chemotherapy Followed by Surgery Versus Abdominal Radical Hysterectomy Alone for Oncological Outcomes of Stage IB3 Cervical Cancer—A Propensity Score Matching Analysis

ObjectiveTo compare the 5-year overall survival (OS) and disease-free survival (DFS) of patients with cervical cancer who received neoadjuvant chemotherapy followed by surgery (NACT) with those who received abdominal radical hysterectomy alone (ARH).MethodsWe retrospectively compared the oncological outcomes of 1410 patients with stage IB3 cervical cancer who received NACT (n=583) or ARH (n=827). The patients in the NACT group were divided into an NACT-sensitive group and an NACT-insensitive group according to their response to chemotherapy.ResultsThe 5-year oncological outcomes were significantly better in the NACT group than in the ARH group (OS: 96.2% vs. 91.2%, respectively, p=0.002; DFS: 92.2% vs. 87.5%, respectively, p=0.016). Cox multivariate analysis suggested that NACT was independently associated with a better 5-year OS (HR=0.496; 95% CI, 0.281-0.875; p=0.015), but it was not an independent factor for 5-year DFS (HR=0.760; 95% CI, 0.505-1.145; p=0.189). After matching, the 5-year oncological outcomes of the NACT group were better than those of the ARH group. Cox multivariate analysis suggested that NACT was still an independent protective factor for 5-year OS (HR=0.503; 95% CI, 0.275-0.918; p=0.025). The proportion of patients in the NACT group who received postoperative radiotherapy was significantly lower than that in the ARH group (p&lt;0.001). Compared to the ARH group, the NACT-sensitive group had similar results as the NACT group. The NACT-insensitive group and the ARH group had similar 5-year oncological outcomes and proportions of patients receiving postoperative radiotherapy.ConclusionAmong patients with stage IB3 cervical cancer, NACT improved 5-year OS and was associated with a reduction in the proportion of patients receiving postoperative radiotherapy. These findings suggest that patients with stage IB3 cervical cancer, especially those who are sensitive to chemotherapy, might consider NACT followed by surgery.

Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.