bluuebunny/crossref_metadata_2025 huggingface dataset:
Developmental Cognitive Neuroscience in the Era of Networks and Big Data: Strengths, Weaknesses, Opportunities, and Threats
Authors: Fair Damien A. , Dosenbach Nico U.F. , Moore Amy H. , Satterthwaite Theodore D. , Milham Michael P.
Published: September 2021

Developmental cognitive neuroscience is being pulled in new directions by network science and big data. Brain imaging [e.g., functional magnetic resonance imaging (fMRI), functional connectivity MRI], analytical advances (e.g., graph theory, machine learning), and access to large computing resources have empowered us to collect and process neurobehavioral datafaster and in larger populations than ever before. The translational potential from these advances is unparalleled, as a better understanding of complex human brain functions is best grounded in the onset of these functions during human development. However, the maturation of developmental cognitive neuroscience has seen the emergence of new challenges and pitfalls, which have significantly slowed progress and need to be overcome to maintain momentum. In this review, we examine the state of developmental cognitive neuroscience in the era of networks and big data. In addition, we provide a discussion of the strengths, weaknesses, opportunities, and threats (SWOT) of the field to advance developmental cognitive neuroscience's scientific and translational potential.
Emerging Therapeutics, Technologies, and Drug Development Strategies to Address Patient Nonadherence and Improve Tuberculosis Treatment
Authors: Garcia-Cremades Maria , Solans Belen P. , Strydom Natasha , Vrijens Bernard , Pillai Goonaseelan Colin , Shaffer Craig , Thomas Bruce , Savic Rada M.
Published: September 2021

Imperfect medication adherence remains the biggest predictor of treatment failure for patients with tuberculosis. Missed doses during treatment lead to relapse, tuberculosis resistance, and further spread of disease. Understanding individual patient phenotypes, population pharmacokinetics, resistance development, drug distribution to tuberculosis lesions, and pharmacodynamics at the site of infection is necessary to fully measure the impact of adherence on patient outcomes. To decrease the impact of expected variabilityin drug intake on tuberculosis outcomes, an improvement in patient adherence and new forgiving regimens that protect against missed doses are needed. In this review, we summarize emerging technologies to improve medication adherence in clinical practice and provide suggestions on how digital adherence technologies can be incorporated in clinical trials and practice and the drug development pipeline that will lead to more forgiving regimens and benefit patients suffering from tuberculosis.
Childhood Antisocial Behavior: A Neurodevelopmental Problem
Authors: van Goozen Stephanie H.M. , Langley Kate , Hobson Christopher W.
Published: September 2021

Early-onset disruptive, aggressive, and antisocial behavior is persistent, can become increasingly serious as children grow older, and is difficult to change. In 2007, our group proposed a theoretical model highlighting the interplay between neurobiological deficits and cognitive and emotional functioning as mediators of the link between genetic influences and early social adversity, on the one hand, and antisocial behavioral problems in childhood, on the other. In this article, we review the post-2007 evidence relevant to this model. We discuss research on genetics/epigenetics, stress/arousal regulation, and emotion and executive functioning in support of the argument that antisocial children, especially those who persist in engaging in antisocial behavior as they grow older, have a range of neuropsychological characteristics that are important in explaining individual differences in the severity and persistence of antisocial behavior. Current clinical practice tends not to acknowledge these individual neuropsychological risk factors or to target them for intervention. We argue that aggressive and disruptive behavior in childhood should be regarded as a neurodevelopmental problem and that intervening at the level of mediating neuropsychological processes represents a promising way forward in tackling these serious behavioral problems.
Varicella Zoster Virus Meningitis with Absence of Rash in an Immunocompetent Child
Authors: Lagrine Mariam , El fakiri Karima , Rada Noureddine , Draiss Ghizlane , Soraa Nabila , Bouskraoui Mohammed
Published: September 2021

Only a few cases in the literature have ever reported the reactivation of the varicella zoster virus (VZV) in children especially in the case of immunocompetent patients. It is an uncommon situation that may lead to several neurological complications. We report varicella zoster virus (VZV) meningitis in a 14-year-old healthy boy with no antecedent of rash. On his cerebrospinal fluid (CSF) examination, VZV DNA was detected. The rapid HIV test was negative. The treatment using acyclovir (20 mg/kg/8h) was effective, and the child’s clinical condition rapidly improved.
The Dual Effect of Abnormal Serum Uric Acid on Intervertebral Disc Degeneration
Authors: Yang Ming , Wang Naiguo , Zhang Wentao , Sun Tianze , Zhang Dan , Chang Yvang , Li Jingmin , Li Zhonghai
Published: September 2021

An abnormal serum uric acid (SUA) level is associated with many diseases. To our knowledge, there is no research on the association between SUA and intervertebral disc degeneration (IDD). The purpose of this study was to determine the relationship between SUA and IDD. From June 2011 to July 2020, 691 patients undergoing surgery for lumbar disc herniation (LDH) were included in the LDH group, and 684 patients who underwent endoscopic surgery for knee trauma were included in the non‐LDH group. We examined the baseline characteristics of all these patients and divided the SUA level into 10 groups according to the percentiles in males, females, and the total population. Subsequently, the relationship between the SUA level and IDD was further analyzed. There was no statistically significant difference in the baseline characteristics of the two groups (p > 0.05). Among the 10 groups, the LDH rate was higher at both lower and higher SUA levels. In multiple logistic regression analysis, after adjustment for age, sex, body mass index, smoking, and drinking, when the SUA level was <20% or >80%, compared with 60–80%, the odds ratio (OR) and 95% confidence interval (CI) of LDH of the total population were 1.821 (1.125–2.946) and 1.701 (1.186–2.438), respectively, and in the males, they were 1.922 (1.169–3.161) and 2.800 (1.766, 4.439), respectively. In females, when the SUA was <20%, there was a higher LDH rate (OR = 1.951, 95% CI 1.091‐3.486). The present study suggests that there is a U‐shaped relationship between SUA and IDD, being particularly prominent among male. Lower and higher SUA level may be risk factors for IDD.
The Silent Pandemic: The Psychological Burden on Frontline Healthcare Workers during COVID-19
Authors: Froessl Luise J. , Abdeen Yazan
Published: September 2021

This narrative review explores the full scope of harmful psychological effects of the COVID-19 (Coronavirus Disease of 2019) pandemic on FLHCWs (Frontline healthcare workers). Additionally, we highlight the risk factors for worse outcomes. A literature review identified 24 relevant papers included in this synthesis. The majority of studies reported a high number of mental health conditions in HCWs (Healthcare workers) overall. Working in the frontline setting was repeatedly identified as an independent risk factor for poorer mental health. Additional risk factors, such as gender, occupational pressure, and low level of support from hospital administration, family, and the community, were also commonly identified. In the past, defined interventions have been shown to mitigate the psychological impact of high-stress situations on frontline workers. This review is aimed at identifying individuals at higher risk to help effectively target preventative measures in future stress situations in our healthcare system.
Exploring the Extracellular Vesicle MicroRNA Expression Repertoire in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis Treated with TNF Inhibitors
Authors: Wielińska Joanna , Crossland Rachel E. , Łacina Piotr , Świerkot Jerzy , Bugaj Bartosz , Dickinson Anne M. , Bogunia-Kubik Katarzyna
Published: September 2021

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) belong to the most common inflammatory rheumatic diseases. MicroRNAs (miRNAs) are small 18–22 RNA molecules that function as posttranscriptional regulators. They are abundantly present within extracellular vesicles (EVs), small intercellular communication vesicles that can be found in bodily fluids and that have key functions in pathological and physiological pathways. Recently, EVs have gained much interest because of their diagnostic and therapeutic potential. Using NanoString profiling technology, the miRNA repertoire of serum EVs was determined and compared in RA and AS patients before and after anti-TNF therapy to assess its potential use as a diagnostic and prognostic biomarker. Furthermore, possible functional effects of those miRNAs that were characterized by the most significant expression changes were evaluated using in silico prediction algorithms. The analysis revealed a unique profile of differentially expressed miRNAs in RA and AS patient serum EVs. We identified 12 miRNAs whose expression profiles enabled differentiation between RA and AS patients before induction of anti-TNF treatment, as well as 4 and 14 miRNAs whose repertoires were significantly changed during the treatment in RA and AS patients, respectively. In conclusion, our findings suggest that extracellular vesicle miRNAs could be used as potential biomarkers associated with RA and AS response to biological treatment.
A Pan-Cancer Analysis of SLC12A5 Reveals Its Correlations with Tumor Immunity
Authors: Jiang Yi , Liao Hong-li , Chen Li-ya
Published: September 2021

Background. Solute carrier family 12 member 5 (SLC12A5) has been reported to play an oncogenic role in certain malignancies. Its prognostic roles and immune mechanisms of action in human cancers, however, remain largely unknown. Methods. Data derived from TCGA, GEPIA, and TIMER databases were utilized to delve into the expressing patterns, prognostic values, clinical significances, and tumor immunity of SLC12A5 in tumors. Additionally, the association of SLC12A5 expressions with tumor mutation burden (TMB), methyltransferases, and mismatch repairs (MMRs) was also analyzed. Results. Herein, we observed that SLC12A5 was significantly overexpressed in various malignancies, and SLC12A5 levels correlated with overall survival, disease-specific survival, and tumor stage of certain cancers. Furthermore, we noticed that SLC12A5 was distinctly associated with methyltransferases, mismatch repair proteins, TMB, and MSI in human cancers. Conclusions. SLC12A5 may act as a potential prognostic and immunological biomarker and therapeutic target for human cancers.
Bearing Capacity of Recycled Self‐Compacting Concrete‐Filled Circular Steel Tubular Long Columns Subjected to Axial Load
Authors: Yu Feng , Song Jie , Bu Shuangshuang , Wang Jingfeng , Wan Haiying , Shen Wanyu , Huang Wei , Fang Yuan
Published: September 2021

To investigate the ultimate bearing capacity and deformation of the recycled self‐compacting concrete‐filled circular steel tubular (RSCCFCST) long columns subjected to axial load, nine specimens with different recycled self‐compacting concrete (RSCC) strength grades and slenderness ratios are tested. The experimental results indicate that the lateral deflection dominates the buckling failure of the specimens. The ultimate bearing capacity of the specimens is enhanced gradually as the RSCC strength grade increases but decreases as the slenderness ratio rises. The load‐strain curves are linear and basically coincide at the elastic stage. The decrease in the slenderness ratio or increase in the RSCC strength grade contributes to the improvement of the stiffness and ultimate circumferential and axial strains of the columns gradually. Based on the combined tangent modulus theory and bearing capacity of the RSCCFCST short columns, two estimation models are presented to predict the ultimate bearing capacity of the RSCCFCST long columns. Additionally, comparisons between the calculation results of the ultimate strength demonstrate that the prediction models established in this study are more accurate than the other specifications mentioned.
Operation Performance Evaluation of Urban Rail Transit PPP Projects: Based on Best Worst Method and Large‐Scale Group Evaluation Technology
Authors: Wang Yuning , Liang Yingzi , Li Cong , Zhang Xinyuan
Published: September 2021

Urban rail transit project is a kind of typical operating public project. Adopting the PPP model can alleviate local financial pressure and improve capital use efficiency. However, many existing urban rail transit PPP projects have fallen into the dilemma of cost overrun, schedule delay, and poor product quality. The lack of reasonable project performance evaluation is considered as an important cause. This research first clarifies the meaning and characteristics of project performance evaluation by comparing and analyzing several basic concepts and relationships. Secondly, an operation performance evaluation system based on urban rail transit PPP project of a three party is constructed from a multistakeholder perspective. Finally, the best worst method and large‐scale group evaluation technology are used based on the comparison of multistakeholder evaluation application scenarios and evaluation methods. A quantitative model is constructed to evaluate the operating performance of urban rail transit PPP projects and is tested and explained by a specific case study. Most current studies generally focus on the earlier stage of project performance, and this article mainly discusses and researches the operation performance of PPP projects. There, suggestions are provided for the operation performance evaluation theory and urban rail transit PPP project practices. This article focuses on the operation performance evaluation of PPP projects.
Economic Policy Uncertainty and Chinese Stock Market Volatility: A CARR‐MIDAS Approach
Authors: Wu Xinyu , Liu Tianyu , Xie Haibin
Published: September 2021

Intraday range (the difference between intraday high and low prices) is often used to measure volatility, which has proven to be a more efficient volatility estimator than the return‐based one. Meanwhile, a growing body of studies has found that economic policy uncertainty (EPU) has important impact on stock market volatility. In this paper, building on the range‐based volatility model, namely, the conditional autoregressive range (CARR) model, we introduce the CARR‐mixed‐data sampling (CARR‐MIDAS) model framework by considering intraday information to investigate the impact of EPU on the volatility of Chinese stock market and to explore the predictive ability of EPU for Chinese stock market. The empirical results show that both the China EPU (CEPU) and global EPU (GEPU) have a significantly negative effect on the long‐run volatility of Chinese stock market. Furthermore, we find that taking into account the CEPU and GEPU leads to substantial improvement in the ability to forecast the volatility of Chinese stock market. We also find that the CEPU provides superior volatility forecasts compared to the GEPU. Our findings are robust to different forecasting windows.
Seismic Behavior Experimental Study on the Joint of Circular Tubed Steel‐Reinforced Concrete Columns
Authors: Dai Yan , Nie Shaofeng , Zhou Tianhua , Xue Chengfeng , Peng Jingrong
Published: September 2021

A new type joint of Circular Tubed Steel‐Reinforced Concrete (CTSRC) columns was designed in this paper. The structural characteristics, manufacturing process, and mechanical properties of raw materials of the new joint were introduced. In order to simulate the earthquake action, two joint specimens were subjected to low‐cycle cyclic loading at the end of the column. Based on the in‐depth study of the failure characteristics, load‐displacement hysteretic curve, skeleton curve, ductility index, load‐strain hysteretic curve in the core area of the joint, energy dissipation performance, strength and stiffness degradation performance, and shear deformation in the core area of the joint during the whole loading process, the seismic behavior of this new type of joint was investigated. The results show that the new joint has reasonable failure characteristics, high bearing capacity, good ductility, excellent seismic energy dissipation performance, and strong resistance to strength and stiffness degradation, which meets the seismic design principle of “strong joint and weak component” and is suitable for the results with special requirements for seismic performance. In addition, preliminary design recommendations were put forward. The research results of this paper can provide a theoretical basis for the application of this kind of new structure.
Identification and Characterisation of Seed-Borne Fungal Pathogens Associated with Maize (Zea mays L.)
Authors: Goko M. L. , Murimwa J. C. , Gasura E. , Rugare J. T. , Ngadze E.
Published: September 2021

A research study was conducted to identify and characterise seed-borne fungal pathogens associated with maize (Zea mays L.) in storage. Seed-borne fungal pathogenic infections of maize were studied using seed samples collected from Gokwe South District in Zimbabwe. The agar plating method using PDA medium was used to detect fungal pathogens on the maize seeds. A total of 150 treatments were used for this experiment, which were replicated three times in a randomised complete block design (RCBD). Analysis of the grain showed the presence of Fusarium moniliforme, Rhizopus stolonifer, Penicillium citrinum, and mostly Aspergillus species, namely, Aspergillus flavus, Aspergillus parasiticus, Aspergillus niger, and Aspergillus tamarii. Significant differences (

p

 < 0.05) between treatments were detected for the pathogens. A total of ten samples were used for mycotoxin determination, and all of them were 100% positive with aflatoxin total, zearalenone, fumonisin, and deoxynivalenol (DON) having an average of 0.255 ppb, 2.425 ppb, 2.65 ppb, and 0.07 ppb, respectively. The present study showed that most grain samples are contaminated with different species of fungi with mycotoxigenic potential. The data on the diversity and magnitude of pathogen infection by fungal species will have a significant effect even at the regional level for predicting the extent of pre- and postinfections. Measures to reduce mycotoxin contamination are needed for maize grains.
Constructions and Properties for a Finite-Dimensional Modular Lie Superalgebra
K

n
,
m
Authors: Mao Dan , Zheng Keli
Published: September 2021

In this paper, a finite-dimensional Lie superalgebra

K

n
,
m

over a field of prime characteristic is constructed. Then, we study some properties of

K

n
,
m

. Moreover, we prove that

K

n
,
m

is an extension of a simple Lie superalgebra, and if

m

=

n

−

1

, then it is isomorphic to a subalgebra of a restricted Lie superalgebra.
Pericytes of Indirect Contact Coculture Decrease Integrity of Inner Blood-Retina Barrier Model In Vitro by Upgrading MMP-2/9 Activity
Authors: Yang Tianye , Guo Liang , Fang Yuan , Liang Mingli , Zheng Yongzheng , Pan Mingdong , Meng Chun , Liu Guanghui
Published: September 2021

Inner blood-retina barrier (iBRB) is primarily formed of retinal microvascular endothelial cells (ECs) with tight junctions, which are surrounded and supported by retinal microvascular pericytes (RMPs) and basement membrane. Pericytes are believed to be critically involved in the physiology and pathology of iBRB. However, the underlying mechanism remains to be fully elucidated. We developed a novel in vitro iBRB model which was composed of primary cultures of rat retinal ECs and RMPs based on Transwell system. We tested the involvement of pericytes in the migration and invasion of ECs, examined the expression and activity of matrix metalloproteinase- (MMP-) 2/MMP-9 in the culture, evaluated the TEER and permeability of iBRB, and assessed the expression of ZO-1, occludin, claudin-5, and VE-cadherin of endothelial junctions. We found that RMPs with indirect contact of ECs can increase the expression of MMP-2 and upgrade the activity of MMP-2/9 in the coculture, which subsequently decreased TJ protein abundance of ZO-1 and occludin in ECs, promoted the migration of ECs, and finally reduced the integrity of iBRB. Taken together, our data show that RMP relative location with ECs is involved in the integrity of iBRB via MMP-2/9 and has important implications for treating diabetic retinopathy and other retinal disorders involving iBRB dysfunction.
HIV-Related Immune Activation and Inflammation: Current Understanding and Strategies
Authors: Lv Tingxia , Cao Wei , Li Taisheng
Published: September 2021

Although antiretroviral therapy effectively controls human immunodeficiency virus (HIV) replication, a residual chronic immune activation/inflammation persists throughout the disease. This aberrant immune activation and inflammation are considered an accelerator of non-AIDS-related events and one of the driving forces of CD4+ T cell depletion. Unfortunately, HIV-associated immune activation is driven by various factors, while the mechanism of excessive inflammation has not been formally clarified. To date, several clinical interventions or treatment candidates undergoing clinical trials have been proposed to combat this systemic immune activation/inflammation. However, these strategies revealed limited results, or their nonspecific anti-inflammatory properties are similar to previous interventions. Here, we reviewed recent learnings of immune activation and persisting inflammation associated with HIV infection, as well as the current directions to overcome it. Of note, a more profound understanding of the specific mechanisms for aberrant inflammation is still imperative for identifying an effective clinical intervention strategy.
Analyzing the Relationship between the PM2.5 Concentration and the Gini Coefficient Using the Grey Model
Authors: Wu Lifeng , Cai Kai , Chen Yan
Published: September 2021

To explore the relationship between the PM2.5 concentration and the gap between the rich and the poor, the PM2.5 concentration in 26 provincial regions of China is predicted by using the Gini coefficient as the independent variable. The nonequigap fractional grey prediction model (CFNGM (1, 1)) is used for data fitting and predicting. The validity of the model is verified by comparing with the traditional nonequidistant grey model. The predicting results show that the PM2.5 concentration in many provinces of China presents a roughly downward trend. In the past nine years, the Gini coefficients have declined in more than 70% of the 26 provinces. However, the development of the Gini coefficient in Northwest China fluctuates greatly and even has an upward trend in recent years. According to the predictive results, reasonable suggestions can be put forward for the effective control of PM2.5 emission in China.
Investigating Driving Styles: A Validation Study of Multidimensional Driving Styles with British and Chinese Drivers
Authors: Sun Xu , Jiang Ying , Burnett Gary , Wang Qingfeng
Published: September 2021

Culture has a significant impact on driving behaviour and can play an important role in driving safety. The adaptation of traffic‐related psychological instruments, developed elsewhere in new national contexts, should consider the cultural context. This paper validates the multidimensional driving style inventory (MDSI) with two cultural samples consisting of 215 Chinese drivers and 240 British drivers. A factor analysis of the driving style yielded evidence that both datasets present some variations from the original version of the instruments in the factorial structure. The analysis of the UK sample is comparable to the previous MDSI by indicating six driving styles, namely, anxious, risky and dissociative, high‐velocity and angry, patient, careful, and distress‐reduction. The analysis of the Chinese participants’ dataset showed its factorial structure with 40 items of the 44 original items divided over six styles. A new dimension, namely, an inattentive driving style, appeared in the Chinese sample. These differences raise the need to validate and adapt such instruments to consider cultural specificities. Implications were also derived for driver and road safety enhancement solutions through driver behaviour applications.
Organosilane and Lignosulfonate Stabilization of Roads Unbound: Performance during a Two‐Year Time Span
Authors: Barbieri Diego Maria , Lou Baowen , Chen Hao , Shu Benan , Wang Fusong , Hoff Inge
Published: September 2021

The construction of the new Norwegian E39 highway comprises the excavation of extended tunnelling systems, which lead to a tremendous amount of blasted rocks. Among others, a sustainable cost‐benefit application of these resources is represented by their local use as construction material in the unbound layers of the roads. Two types of nontraditional additives are investigated to improve the mechanical properties of aggregates; this is particularly useful for those rocks that do not fulfil the design requirements in their natural status. This work focuses on the field application of two innovative stabilizing technologies based on organosilane and lignosulfonate. The performance of these additive agents is characterized by considering three typical road base layer sections built on purpose according to real practice and added with water (no treatment), organosilane, and lignosulfonate. The test sections are subjected to climatic actions only as neither traffic nor surface courses are applied. With the investigation covering two years, the layers’ stiffness, deformation, and resistance to penetration are evaluated by employing a light‐weight deflectometer and dynamic cone penetrometer. Both organosilane and lignosulfonate significantly enhance the mechanical properties of the treated base layers.
Micromobility Station Placement Optimization for a Rural Setting
Authors: Askarzadeh Taraneh , Bridgelall Raj
Published: September 2021

Micromobility is an evolving form of transportation modality that uses small human- or electric-powered vehicles to move people short distances. Planners expected that bike sharing, the first form of micromobility, would reduce traffic congestion, cut travel cost, reduce pollution, enable connectivity with other modes of transport, and promote public health. However, micromobility options also brought new challenges such as the difficulty of placement decisions to encourage adoption and to minimize conflict with other transport modes. Sound deployment decisions depend on the unique environmental characteristics and demographics of a location. Most studies analyzed deployments in high-density urban areas. This research determines the best locations for 5 new bike-sharing stations in Fargo, North Dakota, a small urban area in the rural United States. The workflow combines a geographic information system (GIS), level of traffic stress (LTS) ratings, and location-allocation optimization models. The spatial analysis considered 18 candidate station locations and eliminated those that fell within the 700-meter isochrone walking distance of the 11 existing stations. This case study demonstrates a scalable workflow that planners can repeat to achieve sustainable micromobility deployments by considering the land use, population density, activity points, and characteristics of the available pathways in their unique setting.
Tumor neuroendocrino, mucocele y adenoma tubulo-velloso: tres lesiones infrecuentes en el apéndice cecal
Authors: Piamo Morales Alberto José , Chávez Jiménez Digna , Arzuaga Anderson Isnerio , Ferrer Marrero Daisy , Palma Machado Lourdes , Montano Loandy Sotolongo
Published: September 2021

Introducción: Los tumores del apéndice cecal constituyen un grupo heterogéneo de neoplasias con evolución y pronóstico variables; representan una pequeña parte de todas las neoplasias gastrointestinales y de las apendicetomías.

Objetivo: Realizar la comunicación de la presentación de tumores infrecuentes del apéndice cecal y revisar la literatura con énfasis la importancia del diagnóstico histopatológico.

Presentación de caso: Durante la necropsia del paciente  HC: 199584 se realizó el diagnóstico histopatológico de un tumor carcinoide y mucocele apendicular y en la pieza quirúrgica del paciente HC: 223360 correspondiente a una apendicectomía se realizó el diagnóstico de adenoma tubulo-velloso, dadas que estas lesiones son poco frecuente se decide su comunicación y la revisión del tema en la literaturaen idioma inglés y español a través de las bases de datos MEDLINE/PubMed, ELSEVIER, SciELO, EBSCO, Hinari y Búsqueda Avanzada en Google Schcolar, encontrándose un total de 29 publicaciones entre 1990 a 2019.

Conclusiones: El diagnóstico de tumores del apéndice cecal se realiza en forma incidental en el estudio anatomopatológico después de una apendicectomía por apendicitis aguda, es por ello que siempre se debe realizar el estudio histológico de la pieza quirúrgica, no solo para confirmar o negar el diagnostico que motivo la apendicetomía sino para descartar la presencia de lesiones neoplásicas benignas o malignas.
caso de aducanumab ¿Más esperanza que ciencia?
Authors: Sánchez-Montoya Eliana , Andresen Max , Corrales Raúl , Gallardo Jorge , Noriega Viviana , Weinstein-Oppenheimer Caroline R.
Published: September 2021

En junio, la Agencia de Alimentos y medicamentos de los Estados Unidos (FDA) otorgó aprobación mediante vía acelerada al medicamento aducanumab, desarrollado por Biogen, Inc.  para tratamiento de la enfermedad de Alzheimer (EA).  Esta autorización no ha estado exenta de controversia, ya que no se basó en un criterio de beneficio clínico demostrado, sino en un resultado de valoración sustituto, como es la reducción de la placa β-amieloide (Aβ). Primero con mecanismo novedoso aprobado para EA desde 2003 (Jaffe, 2021).
Racial/Ethnic Disparities in Childhood Cancer Survival in the United States
Authors: Zhao Jingxuan , Han Xuesong , Zheng Zhiyuan , Nogueira Leticia , Lu Amy D. , Nathan Paul C. , Yabroff K. Robin
Published: September 2021

Background:

Non-white patients with childhood cancer have worse survival than Non-Hispanic (NH) White patients for many childhood cancers in the United States. We examined the contribution of socioeconomic status (SES) and health insurance on racial/ethnic disparities in childhood cancer survival.

Methods:

We used the National Cancer Database to identify NH White, NH Black, Hispanic, and children of other race/ethnicities (<18 years) diagnosed with cancer between 2004 and 2015. SES was measured by the area-level social deprivation index (SDI) at patient residence and categorized into tertiles. Health insurance coverage at diagnosis was categorized as private, Medicaid, and uninsured. Cox proportional hazard models were used to compare survival by race/ethnicity. We examined the contribution of health insurance and SES by sequentially adjusting for demographic and clinical characteristics (age group, sex, region, metropolitan statistical area, year of diagnosis, and number of conditions other than cancer), health insurance, and SDI.

Results:

Compared with NH Whites, NH Blacks and Hispanics had worse survival for all cancers combined, leukemias and lymphomas, brain tumors, and solid tumors (all P < 0.05). Survival differences were attenuated after adjusting for health insurance and SDI separately; and further attenuated after adjusting for insurance and SDI together.

Conclusions:

Both SES and health insurance contributed to racial/ethnic disparities in childhood cancer survival.

Impact:

Improving health insurance coverage and access to care for children, especially those with low SES, may mitigate racial/ethnic survival disparities.
Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer
Authors: Peng Hui , James C. Alston , Cullinan Darren R. , Hogg Graham D. , Mudd Jacqueline L. , Zuo Chong , Takchi Rony , Caldwell Katharine E. , Liu Jingxia , DeNardo David G. , Fields Ryan C. , Gillanders William E. , Goedegebuure S. Peter , Hawkins William G.
Published: September 2021

Purpose:

FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system.

Experimental Design:

Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF).

Results:

Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27−Tbet+ effector/effector memory subsets of CD4 and CD8 T cells.

Conclusions:

Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.
Ovarian Cancer–Specific BRCA-like Copy-Number Aberration Classifiers Detect Mutations Associated with Homologous Recombination Deficiency in the AGO-TR1 Trial
Authors: Schouten Philip C. , Richters Lisa , Vis Daniel J. , Kommoss Stefan , van Dijk Ewald , Ernst Corinna , Kluin Roelof J.C. , Marmé Frederik , Lips Esther H. , Schmidt Sandra , Scheerman Esther , Prieske Katharina , van Deurzen Carolien H.M. , Burges Alexander , Ewing-Graham Patricia C. , Dietrich Dimo , Jager Agnes , de Gregorio Nikolaus , Hauke Jan , du Bois Andreas , Nederlof Petra M. , Wessels Lodewyk F. , Hahnen Eric , Harter Philipp , Linn Sabine C. , Schmutzler Rita K.
Published: September 2021

Purpose:

Previously, we developed breast cancer BRCA1-like and BRCA2-like copy-number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.

Experimental Design: We analyzed DNA copy-number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent The Cancer Genome Atlas dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in HR repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883).

Results:

The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6%. The BRCA2-like classifier performed less accurately, likely due to a smaller training set. Furthermore, three quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non–BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype.

Conclusions:

The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.
HighFGFR1–4mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer
Authors: Sánchez-Guixé Mònica , Hierro Cinta , Jiménez José , Viaplana Cristina , Villacampa Guillermo , Monelli Erika , Brasó-Maristany Fara , Ogbah Zighereda , Parés Mireia , Guzmán Marta , Grueso Judit , Rodríguez Olga , Oliveira Mafalda , Azaro Analía , Garralda Elena , Tabernero Josep , Casanovas Oriol , Scaltriti Maurizio , Prat Aleix , Dienstmann Rodrigo , Nuciforo Paolo , Saura Cristina , Graupera Mariona , Vivancos Ana , Rodon Jordi , Serra Violeta
Published: September 2021

Purpose:

FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multi-tyrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively.

Experimental Design:

Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient–derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence.

Results:

High FGFR1–4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTKIs showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1–4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTKI exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1–4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs.

Conclusions:

Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1–4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.
TAS-116 (Pimitespib), an Oral HSP90 Inhibitor, in Combination with Nivolumab in Patients with Colorectal Cancer and Other Solid Tumors: An Open-Label, Dose-Finding, and Expansion Phase Ib Trial (EPOC1704)
Authors: Kawazoe Akihito , Itahashi Kota , Yamamoto Noboru , Kotani Daisuke , Kuboki Yasutoshi , Taniguchi Hiroya , Harano Kenichi , Naito Yoichi , Suzuki Mitsuko , Fukutani Miki , Higuchi Tsukiko , Ikeno Takashi , Wakabayashi Masashi , Sato Akihiro , Koyama Shohei , Nishikawa Hiroyoshi , Shitara Kohei
Published: September 2021

Purpose:

This is a phase Ib trial of TAS-116, an oral HSP90 inhibitor, plus nivolumab for colorectal cancer and other solid tumors.

Patients and Methods:

Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the recommended dose. Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80–160 mg) was administered for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLT). We also conducted biomarker research using paired samples from repeated blood collections and tumor biopsies.

Results:

A total of 44 patients with colorectal cancer (n = 29), gastric cancer (n = 8), sarcoma (n = 5), non–small cell lung cancer (n = 1), and melanoma (n = 1) were enrolled. Eleven patients had previously received immune-checkpoint inhibitors. No DLTs were observed at all dose levels, and TAS-116 160 mg was determined as recommended dose. The common grade 3 or worse treatment-related adverse events included liver transaminase increased (7%), creatinine increased (5%), and platelet count decreased (5%). Objective tumor response was observed in 6 patients, including 4 microsatellite stable (MSS) colorectal cancers, 1 microsatellite instability-high colorectal cancer, and 1 leiomyosarcoma, resulting in an objective response rate of 16% in MSS colorectal cancer without prior immune-checkpoint inhibitors. Biomarker analysis showed that TAS-116 inhibited the activity of regulatory T cells in peripheral blood mononuclear cells and tumor-infiltrating lymphocytes.

Conclusions:

TAS-116 160 mg plus nivolumab had manageable safety profiles and antitumor activity, especially for MSS colorectal cancer patients.
Phase II Evaluation of Stereotactic Ablative Radiotherapy (SABR) and Immunity in 11C-Choline-PET/CT–Identified Oligometastatic Castration-Resistant Prostate Cancer
Authors: Zhang Henan , Orme Jacob J. , Abraha Feven , Stish B.J. , Lowe Val J. , Lucien Fabrice , Tryggestad Erik J. , Bold Michael S. , Pagliaro Lance C. , Choo C. Richard , Brinkmann Debra H. , Iott Matthew J. , Davis Brian J. , Quevedo J. Fernando , Harmsen William S. , Costello Brian A. , Johnson Geoffrey B. , Nathan Mark A. , Olivier Kenneth R. , Pisansky Thomas M. , Kwon Eugene D. , Dong Haidong , Park Sean S.
Published: September 2021

Purpose:

Outcomes for resistant metastatic castration-resistant prostate cancer (CRPC) are poor. Stereotactic ablative radiotherapy (SABR) induces antitumor immunity in clinical and preclinical studies, but immunologic biomarkers are lacking.

Patients and Methods:

Eighty-nine patients with oligometastatic CRPC were identified by 11C-Choline-PET (Choline-PET) from August 2016 to December 2019 and treated with SABR. Prespecified coprimary endpoints were 2-year overall survival (OS) and PSA progression. Secondary endpoints included 2-year SABR-treated local failure and 6-month adverse events. Correlative studies included peripheral blood T-cell subpopulations before and after SABR.

Results:

128 lesions in 89 patients were included in this analysis. Median OS was 29.3 months, and 1- and 2-year OS were 96% and 80%, respectively. PSA PFS was 40% at 1 year and 21% at 2 years. Local PFS was 84.4% and 75.3% at 1 and 2 years, respectively, and no grade ≥3 AEs were observed. Baseline high levels of tumor-reactive T cells (TTR; CD8+CD11ahigh) predicted superior local, PSA, and distant PFS. Baseline high levels of effector memory T cells (TEM; CCR7−CD45RA−) were associated with improved PSA PFS. An increase in TTR at day 14 from baseline was associated with superior OS.

Conclusions:

This is the first comprehensive effector T-cell immunophenotype analysis in a phase II trial before and after SABR in CRPC. Results are favorable and support the incorporation of immune-based markers in the design of future randomized trials in patients with oligometastatic CRPC treated with SABR.
A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1
Authors: Wirawan Aditya , Tajima Ken , Takahashi Fumiyuki , Mitsuishi Yoichiro , Winardi Wira , Hidayat Moulid , Hayakawa Daisuke , Matsumoto Naohisa , Izumi Kenta , Asao Tetsuhiko , Ko Ryo , Shimada Naoko , Takamochi Kazuya , Suzuki Kenji , Abe Masaaki , Hino Okio , Sekido Yoshitaka , Takahashi Kazuhisa
Published: September 2021

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance.

Implications:

This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.
Quantitative Longitudinal Imaging Reveals that Inhibiting Hedgehog Activity Alleviates the Hypoxic Tumor Landscape
Authors: Lama-Sherpa Tshering D. , Das Shamik , Hinshaw Dominique C. , Kammerud Sarah C. , Song Patrick N. , Alsheikh Heba A. , Sorace Anna G. , Samant Rajeev S. , Shevde Lalita A.
Published: September 2021

Metastases account for the majority of mortalities related to breast cancer. The onset and sustained presence of hypoxia strongly correlates with increased incidence of metastasis and unfavorable prognosis in patients with breast cancer. The Hedgehog (Hh) signaling pathway is dysregulated in breast cancer, and its abnormal activity enables tumor progression and metastasis. In addition to programming tumor cell behavior, Hh activity enables tumor cells to craft a metastasis-conducive microenvironment. Hypoxia is a prominent feature of growing tumors that impacts multiple signaling circuits that converge upon malignant progression. We investigated the role of Hh activity in crafting a hypoxic environment of breast cancer. We used radioactive tracer [18F]-fluoromisonidazole (FMISO) positron emission tomography (PET) to image tumor hypoxia. We show that tumors competent for Hh activity are able to establish a hypoxic milieu; pharmacologic inhibition of Hh signaling in a syngeneic mammary tumor model mitigates tumor hypoxia. Furthermore, in hypoxia, Hh activity is robustly activated in tumor cells and institutes increased HIF signaling in a VHL-dependent manner. The findings establish a novel perspective on Hh activity in crafting a hypoxic tumor landscape and molecularly navigating the tumor cells to adapt to hypoxic conditions.

Implications: Importantly, we present a translational strategy of utilizing longitudinal hypoxia imaging to measure the efficacy of vismodegib in a preclinical model of triple-negative breast cancer.