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The article discusses the content and results of the international conference of the Association "History and Computer" (AIC) "Historical Informatics as Historical Data Science", held on November 11-13, 2022 at the Faculty of History of Lomonosov Moscow State University. All stages and forms of the conference are described in detail: 2 plenary sessions, breakout sessions, a round table. The conference was dedicated to the 30th anniversary of the AIC and the 10th anniversary of the journal "Historical Informatics". The conference program included over 100 reports, the authors of which represented scientific centers of Russia, Azerbaijan, Belarus, Germany, Kazakhstan, Kyrgyzstan, Norway and Uzbekistan. The main part of the conference consisted of 10 breakout sessions, where reports were presented on topical historical problems, the solution of which was proposed by the authors on the basis of methods and technologies of historical informatics. At the same time, in most reports, considerable attention was paid to the characteristics of the data used, methods of their processing and visualization. Much attention was paid to the creation of databases and information systems, statistical processing of historical data, methods of text analysis, historical geoinformatics, 3-D modeling. The results of archaeological research using digital technologies, methods of historical informatics in the research work of archives and museums, digital technologies in historical education were also considered.

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.

The article discusses the possibilities of using geoinformation technologies to study economic inequality. The methodology and technique of applying geospatial analysis in the study of wage inequality of employees of district cities of the Siberian Territory in 1926-1927 are shown. Statistical bulletins published in 1926-1929 in Novosibirsk were used as sources. Data were selected that characterize the salaries of employees of the district cities of Siberia for 8 quarters, covering almost 2 years – 1926 and 1927. During the development of GIS, a 1:3000000 scale map of the Siberian Region was digitized, on which there is a coordinate grid, the situation (hydrographic network and relief displayed by washing) and administrative division were plotted according to the zoning data of 1929. A series of maps was built reflecting the average salary level of employees in district cities, as well as the dynamics of wages based on quarterly statistics. The highest salary of employees is observed in Novosibirsk. It is noticeable that cities with low wages are concentrated in the south of Western Siberia. The growth rates of wages in cities show a greater variation than the average salary. The largest increase in wages is demonstrated by those cities in which its level was low or average. It can be stated that there are certain prospects in the use of geoinformation technologies to study economic inequality.

Purpose To assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of cetrelimab (JNJ-63723283), a monoclonal antibody programmed cell death protein-1 (PD-1) inhibitor, in patients with advanced/refractory solid tumors in the phase 1/2 LUC1001 study. Methods In phase 1, patients with advanced solid tumors received intravenous cetrelimab 80, 240, 460, or 800 mg every 2 weeks (Q2W) or 480 mg Q4W. In phase 2, patients with melanoma, non-small-cell lung cancer (NSCLC), and microsatellite instability–high (MSI-H)/DNA mismatch repair-deficient colorectal cancer (CRC) received cetrelimab 240 mg Q2W. Response was assessed Q8W until Week 24 and Q12W thereafter. Results In phase 1, 58 patients received cetrelimab. Two dose-limiting toxicities were reported and two recommended phase 2 doses (RP2D) were defined (240 mg Q2W or 480 mg Q4W). After a first dose, mean maximum serum concentrations (Cmax) ranged from 24.7 to 227.0 µg/mL; median time to Cmax ranged from 2.0 to 3.2 h. Pharmacodynamic effect was maintained throughout the dosing period across doses. In phase 2, 146 patients received cetrelimab 240 mg Q2W. Grade ≥ 3 adverse events (AEs) occurred in 53.9% of patients. Immune-related AEs (any grade) occurred in 35.3% of patients (grade ≥ 3 in 6.9%). Overall response rate was 18.6% across tumor types, 34.3% in NSCLC, 52.6% in programmed death ligand 1–high (≥ 50% by immunohistochemistry) NSCLC, 28.0% in melanoma, and 23.8% in centrally confirmed MSI-H CRC. Conclusions The RP2D for cetrelimab was established. Pharmacokinetic/pharmacodynamic characteristics, safety profile, and clinical activity of cetrelimab in immune-sensitive advanced cancers were consistent with known PD-1 inhibitors. Trial registrations NCT02908906 at ClinicalTrials.gov, September 21, 2016; EudraCT 2016–002,017-22 at clinicaltrialsregister.eu, Jan 11, 2017.

Background The genome-wide association study (GWAS) is a common tool to identify genetic variants associated with complex traits, including psychiatric disorders (PDs). However, post-GWAS analyses are needed to extend the statistical inference to biologically relevant entities, e.g., genes, proteins and pathways. To achieve this goal, researchers developed methods that incorporate biologically relevant intermediate molecular phenotypes, such as gene expression and protein abundance, which are posited to mediate the variant-trait association. Transcriptome-wide association study (TWAS) and proteome-wide association study (PWAS) are commonly used methods to test the association between these molecular mediators and the trait. Summary In this review, we discuss the most recent developments in TWAS and PWAS. These methods integrate existing 'omic' information with the GWAS summary statistics for trait(s) of interest. Specifically, they impute transcript/protein data and test the association between imputed gene expression/protein level with phenotype of interest by using i) GWAS summary statistics and ii) reference transcriptomic/proteomic/genomic data sets. TWAS and PWAS are suitable as analysis tools for i) primary association scan and ii) fine-mapping to identify potentially causal genes for PDs. Key Messages As post-GWAS analyses, TWAS and PWAS have the potential to highlight causal genes in PDs. These prioritized genes could indicate targets for the development of novel drug therapies. For researchers attempting such analyses, we recommend Mendelian randomization (MR) tools that use GWAS statistics for both trait and reference data sets, e.g., SMR. We base our recommendation on i) being able to use the same tool for both TWAS and PWAS, ii) not requiring the pre-computed weights (and thus easier to update for larger reference data sets) and iii) most larger transcriptome reference data sets are publicly available and easy to transform into a compatible format for SMR analysis.

This paper deals with a version of the two-timing method which describes various ‘slow’ effects caused by externally imposed ‘fast’ oscillations. Such small oscillations are often called vibrations and the research area can be referred as vibrodynamics. The governing equations represent a generic system of first-order ODEs containing a prescribed oscillating velocity $${\varvec{u}}$$ , given in a general form. Two basic small parameters stand in for the inverse frequency and the ratio of two time-scales; they appear in equations as regular perturbations. The proper connections between these parameters yield the distinguished limits, leading to the existence of closed systems of asymptotic equations. The aim of this paper is twofold: (i) to clarify (or to demystify) the choices of a slow variable, and (ii) to give a coherent exposition which is accessible for practical users in applied mathematics, sciences and engineering. We focus our study on the usually hidden aspects of the two-timing method such as the uniqueness or multiplicity of distinguished limits and universal structures of averaged equations. The main result is the demonstration that there are two (and only two) different distinguished limits. The explicit instruction for practically solving ODEs for different classes of $${\varvec{u}}$$ is presented. The key roles of drift velocity and the qualitatively new appearance of the linearized equations are discussed. To illustrate the broadness of our approach, two examples from mathematical biology are shown.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

AIM: This study aimed to assess the formation of scar tissue after burns under the influence of an anti-scar gel. Understanding of the processes involving scars and the morphofunctional features of the tissue at different stages of development allows targeted selection of therapy and prevention of scars. MATERIALS AND METHODS: We conducted a comparative prospective analysis from 2005 to 2020. Of which two groups were identified. In group 1 (n = 47), burns were treated according to the standard scheme without the use of modern wound coverings. In group 2 (n = 41), early primary prevention of pathological scarring was performed, where the Contractubex gel was applied to the area of burn injury from the moment of epithelialization. Histological examination included the analysis of skin biopsies in the area of damage before and after conservative treatment. RESULTS: Histological examination showed quantitative changes in the cellular composition of the scar tissue in all groups. The average quantitative index of the fibroblast activity was significantly reduced in group 2 using Contractubex gel. Thickness of collagen fibers, according to the morphometric analysis, is most reduced in all layers of the dermis in group 2 (p 0.05). In group 1, collagen fibers are represented as nodular clusters; in some areas of the reticular layer of the dermis, fibers have a more fragmented appearance. In group 2, the use of Contractubex leads to a significant decrease in the level of tumor growth factor- in the papillary and reticular layers of the dermis. CONCLUSION: The use of Contractubex gel in the early prevention of pathological scarring significantly reduces the need for subsequent reconstructive surgical interventions

Relevance. PIK3CA belongs to the top three most frequently mutated genes in breast cancer (BC), especially in estrogen receptor (ER) positive, HER2 negative BC subtype. With an approval of selective PI3K-alpha inhibitor, alpelisib, this alteration has become actionable in ER+HER2- tumors. The frequency and spectrum of PIK3CA alterations in various cohorts is affected by a number of factors, including the distribution of BC expression subtypes, histological types, patient age, and even ethnicity. Aim. Aim of the current study was to characterize the frequency and spectrum of PIK3CA alterations in Russian BC patients. Materials and methods. The analysis of PIK3CA exon 7, 9 and 20 mutations was performed in a cohort of Russian ER+HER2- BC patients by a combination of high-resolution melting analysis, allele-specific PCR, and digital droplet PCR. Results. PIK3CA lesions were identified in 62/206 (30%) patients. Noteworthy, 59/62 (95%) of the identified variants were represented by the three most common p.E542K, p.E545K, and p.H1047R substitutions. The analysis of clinical and morphological characteristics revealed the trends towards association of PIK3CA mutations with older age and more frequent metastatic lung involvement. Conclusion. The obtained data on the frequency and spectrum of PIK3CA somatic aberrations can be helpful when organizing molecular genetic testing of breast cancer patients and using PI3K inhibitors in Russian population.

Purpose. The article is devoted to the 65th anniversary of the famous practitioner and scientist — Professor Alexander Fedorov. It provides brief information about the hero of the day, data on the main directions of his scientific research and published works, and concludes that he formed an intersectoral scientific school of combating crime with an emphasis on the comprehensive approach to the study of law and law enforcement inherent in this researcher. The purpose of the article is to promote the most significant works of famous Russian scientists. Methodology: dialectics, hermeneutics, synergetics. Conclusions. The article shows that it is practice that determines the need for conducting appropriate legal research, since legal science cannot be divorced from the realities of life, but is derived from them, providing the solution of practical problems. In turn, legal practice, first, is largely based on the results of previous scientific activity, and secondly, ultimately aimed at solving practical problems. Scientific and practical significance. The article proves that, on the one hand, legal practice is a source of development of legal science, and on the other hand, legal science largely determines what legal practice should be. At the same time, both science and practice in their combination in this article successfully develop a comprehensive theory of law.

Post-traumatic stress disorder (PTSD), a consequence of psychological trauma, is associated with increased inflammation and an elevated risk of developing comorbid inflammatory diseases. However, the mechanistic link between this mental health disorder and inflammation remains elusive. Using a pre-clinical model of PTSD known as repeated social defeat stress (RSDS), we previously identified that S100a8 and S100a9 mRNA, genes that encode the protein calprotectin, were significantly upregulated in T-lymphocytes after psychological trauma. Calprotectin expression positively correlated with inflammatory gene expression and the mitochondrial redox environment in T-lymphocytes, therefore, we hypothesized that genetic deletion of calprotectin would attenuate the inflammatory and redox phenotype displayed after RSDS. Using pharmacological and genetic manipulation of S100a9 (which functionally eliminates calprotectin) in mice, we unexpectedly observed worsening of behavioral pathology, inflammation, and the mitochondrial redox environment in mice after RSDS compared to wild-type (WT) animals. Furthermore, loss of calprotectin significantly enhanced the metabolic demand on T-lymphocytes suggesting this protein may play an undescribed role in mitochondrial regulation. This was further supported by single-cell RNA sequencing analysis demonstrating that RSDS and loss of S100a9 primarily altered genes associated with mitochondrial function and oxidative phosphorylation. Taken together, these data demonstrate the loss of calprotectin potentiates the RSDS-induced phenotype, which suggests its observed upregulation after psychological trauma may provide previously unexplored protective functions.

Background: Trazimera™ (PF-05280014) is a trastuzumab biosimilar. This multinational, randomized, double-blind, parallel-group study (NCT01989676) compared Trazimera with reference trastuzumab (Herceptin®) sourced from the EU (Herceptin-EU), each plus paclitaxel, in the first-line treatment of HER2-positive metastatic breast cancer (MBC). Equivalence between the two groups was previously demonstrated for the primary efficacy endpoint of objective response rate, evaluating responses achieved by Week 25 and confirmed by Week 33 (Pegram et al, Br J Cancer 2019). Furthermore, using data collected up to 378 days after randomization, there were no notable differences in progression-free survival, overall survival (OS), safety, or immunogenicity. Here, we report additional cumulative safety and OS data collected up to 5 years after the first patient was screened. Methods: Eligible patients were randomized 1:1 to receive intravenous Trazimera or Herceptin-EU, each plus paclitaxel. Randomization was stratified by prior trastuzumab exposure and estrogen receptor status. Trazimera or Herceptin-EU treatment could continue until objective disease progression per RECIST 1.1. In addition to evaluating safety and OS in the overall study population, we assessed safety in the subgroup of patients still ongoing in the study after Day 378 (including only adverse events starting after this time point). We also compared time to discontinuation from Trazimera or Herceptin-EU. Results: Of 707 patients randomized (Trazimera, n=352; Herceptin-EU, n=355), 83 (11.7%) were ongoing in the study as of the data cutoff on February 25, 2019 (Trazimera, n=41 [11.6%]; Herceptin-EU, n=42 [11.8%]). Overall, 637 (90.1%) patients discontinued trastuzumab treatment (Trazimera, n=319 [90.6%]; Herceptin-EU, n=318 [89.6%]). The most frequent reason for discontinuing trastuzumab was objective progression (Trazimera, n=245 [69.6%]; Herceptin-EU, n=245 [69.0%]). Estimated median time to discontinuation from trastuzumab was 12.25 months for Trazimera and 12.06 months for Herceptin-EU (stratified hazard ratio [HR] 1.014; 95% confidence interval [CI] 0.867-1.186; log-rank P=0.569). In total, 58 (16.5%) patients in the Trazimera group and 67 (18.9%) patients in the Herceptin-EU group died. There was no statistically significant difference in OS (stratified HR 0.888; 95% CI 0.624-1.264; log-rank P=0.254). Estimated 2-year survival rates were 82.26% for Trazimera and 77.50% for Herceptin-EU; corresponding estimated 3-year rates were 77.17% and 75.33%. Among patients who received treatment (Trazimera, n=349; Herceptin-EU, n=353), there were no notable differences in incidences of treatment-emergent adverse events (TEAEs; 98.3% vs. 96.6%), grade 3 or higher TEAEs (40.7% vs. 42.5%), or serious TEAEs (19.2% vs. 19.3%). Rates of cardiac failure (1.4% vs. 2.8%), infusion-related reaction (IRR; 9.7% vs. 9.1%), and decreased ejection fraction (13.2% vs. 13.0%) were similar. Comparable proportions of patients had ≥1 occasion of an absolute decrease in left ventricular ejection fraction of ≥16% from baseline (6.3% vs. 5.4%) or ≥10% from baseline and below the lower limit of normal (4.0% vs. 5.1%). In the subgroup ongoing after Day 378 (Trazimera, n=265; Herceptin-EU, n=264), rates of cardiac failure (0.0% vs. 1.1%), IRR (0.0% vs. 0.8%), and decreased ejection fraction (3.4% vs. 4.2%) remained balanced. Conclusion: Long-term safety and OS data were consistent with previous results from this ongoing comparative study of Trazimera and Herceptin-EU, demonstrating no clinically meaningful differences between treatment groups. These results represent the longest known follow-up data reported for a trastuzumab biosimilar study in patients with HER2-positive MBC. Funding: This study was sponsored by Pfizer. Citation Format: Rubi K Li, Oleg Lipatov, Hryhoriy Adamchuk, Vladimir Vladimirov, Eduardo Yanez, Patricia Banchero, Amy Freyman, Fiona Hilton, Alexandra Thiele, Alicia Vana. Trazimera (a trastuzumab biosimilar) in HER2-positive metastatic breast cancer: Long-term safety and overall survival data [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-18-08.

We analyze whether growth firms should delay current investment to hoard cash in order to reduce dilution from external financing. This hoarding motive is the natural counterpart to saving cash as a precaution to help secure funding for future investment opportunities. However, the two motives lead to fundamentally different implications for hoarding and for how cash interacts with key financial and investment decisions. In particular, our paper contributes to understanding why firms choosing private over public financing hoard less, and why product market competition has an ambivalent impact on the public–private choice. This paper was accepted by Gustavo Manso, finance.

We analyze how relationship finance, such as venture capital and relationship lending, affects growth firms’ capital structure choices. We show that relationship investors that obtain a strong bargaining position because of their privileged information about the firm optimally cash in on their dominance by pushing it to finance follow-up investments with equity. The firm underinvests if its owner refuses to accept the associated dilution. However, this problem is mitigated if the firm’s initial relationship financing involves high leverage or offers initial investors preferential treatment in liquidation. By contrast, if initial investors are unlikely to gain a dominant position, firms optimally lever up only in later rounds. Our implications for relationship and venture capital financing highlight that the degree of investor dominance is of key importance for growth firms’ capital structure decisions. This paper was accepted by Gustavo Manso, finance.

Background PF-06439535 is a bevacizumab biosimilar. We aimed to compare the efficacy and safety of PF-06439535 with that of reference bevacizumab (Avastin®) sourced from the EU (bevacizumab-EU), each with paclitaxel and carboplatin, in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC). Methods In this double-blind, parallel-group study, we recruited patients from 159 centers in 27 countries. Participants were randomized 1:1 to receive PF-06439535 plus paclitaxel and carboplatin or bevacizumab-EU plus paclitaxel and carboplatin on day 1 of each 21-day cycle for 4–6 cycles, followed by blinded monotherapy with PF-06439535 or bevacizumab-EU until disease progression, unacceptable toxicity, withdrawal of consent, or the end of the study. Randomization was stratified by region, sex, and smoking history. The primary endpoint was objective response rate (ORR) in accordance with RECIST 1.1, based on responses achieved by week 19 and confirmed by week 25. Results Between 21 May 2015 and 14 November 2016, 719 patients were randomized to the PF-06439535 group (n = 358) or the bevacizumab-EU group (n = 361). As of data cutoff for analysis of the primary endpoint (8 May 2017), 45.3% (95% confidence interval [CI] 40.01–50.57) of patients in the PF-06439535 group and 44.6% (95% CI 39.40–49.89) of patients in the bevacizumab-EU group achieved an objective response by week 19 that was confirmed by week 25. The unstratified ORR risk ratio was 1.015 (95% CI 0.863–1.193; 90% CI 0.886–1.163), and the unstratified ORR risk difference was 0.653% (95% CI − 6.608 to 7.908); all three CIs fell within pre-specified equivalence margins. Using final data after study completion (22 December 2017), no notable differences in progression-free survival or overall survival were observed between the groups. The most frequently reported grade 3 or higher treatment-emergent adverse events were hypertension, neutropenia, and anemia. There were no clinically meaningful differences in safety, pharmacokinetics, or immunogenicity across treatment groups. Conclusion Among patients with advanced non-squamous NSCLC, PF-06439535 demonstrated similarity to bevacizumab-EU in terms of efficacy. Safety profiles for the two treatments were comparable. Trial Registration ClinicalTrials.gov, NCT02364999. Funding Pfizer. Electronic supplementary material The online version of this article (10.1007/s40259-019-00363-4) contains supplementary material, which is available to authorized users.

In recent years, large scale meta-analysis of genome-wide association studies (GWAS) have reliably identified genetic polymorphisms associated with neuropsychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD). However, the majority of disease-associated single nucleotide polymorphisms (SNPs) appear within functionally ambiguous non-coding genomic regions. Recently, increased emphasis has been placed on identifying the functional relevance of disease-associated variants via correlating risk polymorphisms with gene expression levels in etiologically relevant tissues. For neuropsychiatric disorders, the etiologically relevant tissue is brain, which requires robust postmortem sample sizes from varying genetic backgrounds. While small sample sizes are of decreasing concern, postmortem brain databases are composed almost exclusively of Caucasian samples, which significantly limits study design and result interpretation. In this review, we highlight the importance of gene expression and expression quantitative loci (eQTL) studies in clinically relevant postmortem tissue while addressing the current limitations of existing postmortem brain databases. Finally, we introduce future collaborations to develop postmortem brain databases for neuropsychiatric disorders from Chinese and Asian subpopulations.

Aim. The aim of the study is to examine the efficacy and safety of eribulin in HER2-negative metastatic breast cancer (BC) in Russian clinical practice. Materials and methods. The analysis included 459 patients with advanced BC from 44 federal and municipal medical clinics in Russia and received at least 2 courses of treatment with eribulin in accordance with the registered indications for drug. The average age of women was 56 years (between 29 and 81 years), 83% of patients had HER2-negative tumor subtype (49.9% - luminal BC and 33.1% - triple-negative BC) HER2-positive biological tumor subtype was registered in 17% of patients. Visceral metastases were diagnosed in 73% of patients and three-zone and multiple zone metastases were diagnosed in 41.6% of cases. The median number of prior lines of therapy in patients with disseminated disease was 2; anthracycline and taxane chemotherapy was applied in 94.3% of patients, and 38.1% of patients were recived CT plus capecitabine. Standard treatment regimen with eribulin was cotinuing (1.4 mg/m² as a 2-5-minute intravenous infusion administrated on days 1, 8 of a 21-day cycle) until disease progression, unacceptable toxic effects, or impossibility of the drug administration for any other reason. We estimated the efficacy and safety of treatment with eribulin in Russian patients with HER2-negative BC. Results. Objective response rate was achieved in 20.5% of cases, complete response rate was in 3.2%, partial - 17.3%, and the stable disease rate was marked in 52.7% of women, and in 19.7% of these cases was prolonged more than 6 months. The frequency of objective response was higher in luminal BC group compared with triple-negative BC: 23.5% vs 15.8%; tumor growth control 76.9% vs. 67.8%, respectively; p

Epigenome-wide association studies (EWAS) aim to provide evidence that marks of DNA methylation (DNAm) have downstream consequences that can result in the development of human diseases. Although these methods have been successful in identifying DNAm patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE inciswere enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated withtransGE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonicalcisDNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented.

Our lab and others have shown that chronic alcohol use leads to gene and miRNA expression changes across the mesocorticolimbic (MCL) system. Circular RNAs (circRNAs) are noncoding RNAs that form closed-loop structures and are reported to alter gene expression through miRNA sequestration, thus providing a potentially novel neurobiological mechanism for the development of alcohol dependence (AD). Genome-wide expression of circRNA was assessed in the nucleus accumbens (NAc) from 32 AD-matched cases/controls. Significant circRNAs (unadj. p ≤ 0.05) were identified via regression and clustered in circRNA networks via weighted gene co-expression network analysis (WGCNA). CircRNA interactions with previously generated mRNA and miRNA were detected via correlation and bioinformatic analyses. Significant circRNAs (N = 542) clustered in nine significant AD modules (FWER p ≤ 0.05), within which we identified 137 circRNA hubs. We detected 23 significant circRNA-miRNA-mRNA interactions (FDR ≤ 0.10). Among these, circRNA-406742 and miR-1200 significantly interact with the highest number of mRNA, including genes associated with neuronal functioning and alcohol addiction (HRAS, PRKCB, HOMER1, and PCLO). Finally, we integrate genotypic information that revealed 96 significant circRNA expression quantitative trait loci (eQTLs) (unadj. p ≤ 0.002) that showed significant enrichment within recent alcohol use disorder (AUD) and smoking genome-wide association study (GWAS). To our knowledge, this is the first study to examine the role of circRNA in the neuropathology of AD. We show that circRNAs impact mRNA expression by interacting with miRNA in the NAc of AD subjects. More importantly, we provide indirect evidence for the clinical importance of circRNA in the development of AUD by detecting a significant enrichment of our circRNA eQTLs among GWAS of substance abuse.

Do mandatory disclosure requirements make public firms less disruptive and competitive? Not necessarily. We offer a new perspective showing that mandatory disclosure facilitates "co-opetition" --- a strategy of competing on some dimensions while avoiding competition on others. Co-opetition encourages disruption by elevating profitability and lowering financing costs. However, it may undermine commitment to intermediately attractive investments, making the benefit of being public U-shaped in investment attractiveness. Being public is most beneficial when firms compete intensely on disruption and, at the other extreme, when protecting cash-cow businesses. Our results explain evidence that stricter disclosure requirements increase the profitability of disruptive public firms.

Genotype imputation across populations of mixed ancestry is critical for optimal discovery in large‐scale genome‐wide association studies (GWAS). Methods for direct imputation of GWAS summary‐statistics were previously shown to be practically as accurate as summary statistics produced after raw genotype imputation, while incurring orders of magnitude lower computational burden. Given that direct imputation needs a precise estimation of linkage‐disequilibrium (LD) and that most of the methods using a small reference panel for example, ~2,500‐subject coming from the 1000 Genome‐Project, there is a great need for much larger and more diverse reference panels. To accurately estimate the LD needed for an exhaustive analysis of any cosmopolitan cohort, we developed DISTMIX2. DISTMIX2: (a) uses a much larger and more diverse reference panel compared to traditional reference panels, and (b) can estimate weights of ethnic‐mixture based solely on Z‐scores, when allele frequencies are not available. We applied DISTMIX2 to GWAS summary‐statistics from the psychiatric genetic consortium (PGC). DISTMIX2 uncovered signals in numerous new regions, with most of these findings coming from the rarer variants. Rarer variants provide much sharper location for the signals compared with common variants, as the LD for rare variants extends over a lower distance than for common ones. For example, while the original PGC post‐traumatic stress disorder GWAS found only 3 marginal signals for common variants, we now uncover a very strong signal for a rare variant in PKN2, a gene associated with neuronal and hippocampal development. Thus, DISTMIX2 provides a robust and fast (re)imputation approach for most psychiatric GWAS‐studies.

Motivation: Rare variant-based analyses are beginning to identify risk genes for neuropsychiatric disorders and other diseases. However, the identified genes only account for a fraction of predicted causal genes. Recent studies have shown that rare damaging variants are significantly enriched in specific gene-sets. Methods which are able to jointly model rare variants and gene-sets to identify enriched gene-sets and use these enriched gene-sets to prioritize additional risk genes could improve understanding of the genetic architecture of diseases. Results: We propose DECO (Integrated analysis of de novo mutations, rare case/control variants and omics information via gene-sets), an integrated method for rare-variant and gene-set analysis. The method can (i) test the enrichment of gene-sets directly within the statistical model, and (ii) use enriched gene-sets to rank existing genes and prioritize additional risk genes for tested disorders. In simulations, DECO performs better than a homologous method that uses only variant data. To demonstrate the application of the proposed protocol, we have applied this approach to rare-variant datasets of schizophrenia. Compared with a method which only uses variant information, DECO is able to prioritize additional risk genes. Availability: DECO can be used to analyze rare-variants and biological pathways or cell types for any disease. The package is available on Github https://github.com/hoangtn/DECO.

Background Long noncoding RNA (lncRNA) have been implicated in the etiology of alcohol use. Since lncRNA provide another layer of complexity to the transcriptome, assessing their expression in the brain is the first critical step toward understanding lncRNA functions in alcohol use and addiction. Thus, we sought to profile lncRNA expression in the nucleus accumbens (NAc) in a large postmortem alcohol brain sample. Methods LncRNA and protein‐coding gene (PCG) expressions in the NAc from 41 subjects with alcohol dependence (AD) and 41 controls were assessed via a regression model. Weighted gene coexpression network analysis was used to identify lncRNA and PCG networks (i.e., modules) significantly correlated with AD. Within the significant modules, key network genes (i.e., hubs) were also identified. The lncRNA and PCG hubs were correlated via Pearson correlations to elucidate the potential biological functions of lncRNA. The lncRNA and PCG hubs were further integrated with GWAS data to identify expression quantitative trait loci (eQTL). Results At Bonferroni adj. p‐value ≤ 0.05, we identified 19 lncRNA and 5 PCG significant modules, which were enriched for neuronal and immune‐related processes. In these modules, we further identified 86 and 315 PCG and lncRNA hubs, respectively. At false discovery rate (FDR) of 10%, the correlation analyses between the lncRNA and PCG hubs revealed 3,125 positive and 1,860 negative correlations. Integration of hubs with genotype data identified 243 eQTLs affecting the expression of 39 and 204 PCG and lncRNA hubs, respectively. Conclusions Our study identified lncRNA and gene networks significantly associated with AD in the NAc, coordinated lncRNA and mRNA coexpression changes, highlighting potentially regulatory functions for the lncRNA, and our genetic (cis‐eQTL) analysis provides novel insights into the etiological mechanisms of AD., Alcohol use disorder (AUD) is a debilitating disease with no reliable and efficacious treatment. However, studying the brain transcriptome may help elucidate the neuropathology of AUD. Using gene network approaches, we provide a glimpse into the complex interactions between coding and non‐coding RNA from patients with AUD and test the moderating effect of clinically relevant risk genetic elements on these interactions. Furthermore, genes and genetic elements associated with AUD were contextualized by examining past studies and conducting enrichment

Genetic signal detection in genome‐wide association studies (GWAS) is enhanced by pooling small signals from multiple Single Nucleotide Polymorphism (SNP), for example, across genes and pathways. Because genes are believed to influence traits via gene expression, it is of interest to combine information from expression Quantitative Trait Loci (eQTLs) in a gene or genes in the same pathway. Such methods, widely referred to as transcriptomic wide association studies (TWAS), already exist for gene analysis. Due to the possibility of eliminating most of the confounding effects of linkage disequilibrium (LD) from TWAS gene statistics, pathway TWAS methods would be very useful in uncovering the true molecular basis of psychiatric disorders. However, such methods are not yet available for arbitrarily large pathways/gene sets. This is possibly due to the quadratic (as a function of the number of SNPs) computational burden for computing LD across large chromosomal regions. To overcome this obstacle, we propose JEPEGMIX2‐P, a novel TWAS pathway method that (a) has a linear computational burden, (b) uses a large and diverse reference panel (33 K subjects), (c) is competitive (adjusts for background enrichment in gene TWAS statistics), and (d) is applicable as‐is to ethnically mixed‐cohorts. To underline its potential for increasing the power to uncover genetic signals over the commonly used nontranscriptomics methods, for example, MAGMA, we applied JEPEGMIX2‐P to summary statistics of most large meta‐analyses from Psychiatric Genetics Consortium (PGC). While our work is just the very first step toward clinical translation of psychiatric disorders, PGC anorexia results suggest a possible avenue for treatment.