bluuebunny/crossref_metadata_2025 huggingface dataset:
Air Flow Experiments on a Train Carriage—Towards Understanding the Risk of Airborne Transmission
Authors: Woodward Huw , Fan Shiwei , Bhagat Rajesh K. , Dadonau Maksim , Wykes Megan Davies , Martin Elizabeth , Hama Sarkawt , Tiwari Arvind , Dalziel Stuart B. , Jones Roderic L. , Kumar Prashant , Linden Paul F.
Published: September 2021

A series of experiments was undertaken on an intercity train carriage aimed at providing a “proof of concept” for three methods in improving our understanding of airflow behaviour and the accompanied dispersion of exhaled droplets. The methods used included the following: measuring CO2 concentrations as a proxy for exhaled breath, measuring the concentrations of different size fractions of aerosol particles released from a nebuliser, and visualising the flow patterns at cross-sections of the carriage by using a fog machine and lasers. Each experiment succeeded in providing practical insights into the risk of airborne transmission. For example, it was shown that the carriage is not well mixed over its length, however, it is likely to be well mixed along its height and width. A discussion of the suitability of the fresh air supply rates on UK train carriages is also provided, drawing on the CO2 concentrations measured during these experiments.
Modeling the Impacts of City-Scale “Ventilation Corridor” Plans on Human Exposure to Intra-Urban PM2.5 Concentrations
Authors: Liu Chao , Shu Qian , Huang Sen , Guo Jingwei
Published: September 2021

Increasingly, Chinese cities are proposing city-scale ventilation corridors (VCs) to strengthen wind velocities and decrease pollution concentrations, although their influences are ambiguous. To assess VC impacts, an effort has been made to predict the impact of VC solutions in the high density and diverse land use of the coastal city of Shanghai, China, in this paper. One base scenario and three VC scenarios, with various VC widths, locations, and densities, were first created. Then, the combination of the Weather Research and Forecasting/Single-Layer Urban Canopy Model (WRFv.3.4/UCM) and Community Multiscale Air Quality (CMAQv.5.0.1) numerical simulation models were employed to comprehensively evaluate the impacts of urban spatial form and VC plans on PM2.5 concentrations. The modeling results indicated that concentrations increased within the VCs in both summer and winter, and the upwind concentration decreased in winter. These counter-intuitive results could be explained by decreased planetary boundary layer (PBL), roughness height, deposition rate, and wind speeds induced by land use and urban height modifications. PM2.5 deposition flux decreased by 15–20% in the VCs, which was attributed to the roughness height decrease for it weakens aerodynamic resistance (Ra). PBL heights within the VCs decreased 15–100 m, and the entire Shanghai’s PBL heights also decreased in general. The modeling results suggest that VCs may not be as functional as certain urban planners have presumed.
An Integrated Methodology of Subjective Investigation for a Sustainable Indoor Built Environment. The Case Study of a University Campus in Italy
Authors: Attaianese Erminia , d'Ambrosio Alfano Francesca , Palella Boris , Pepe Daniela , Vanacore Roberto
Published: September 2021

Indoor built environments’ design and management require a holistic approach inspired by ergonomic principles and sustainability criteria. This is especially in case of renovation of existing buildings where any kind of intervention requires the direct feedback of occupants. This work deals with two aspects of these issues, often studied separately: the quality of interior spaces, in terms of Indoor Environmental Quality (IEQ), and the quality of the architecture in terms of orientation and wayfinding. A methodology focused on the subjective evaluation of the IEQ giving relevance to users and their fruition needs is also proposed. Main findings from a specific subjective investigation carried out at the Fisciano Campus of the University of Salerno (Italy) demonstrate that the subjective approach is a valuable tool to make more sustainable intervention strategies. In this way, all multidisciplinary skills can be synergically involved in improving the livability of a complex reality as University Campuses are.
Effect of Elevated CO2 on Seed Yield, Essential Oil Metabolism, Nutritive Value, and Biological Activity of Pimpinella anisum L. Accessions at Different Seed Maturity Stages
Authors: Balkhyour Mansour A. , Hassan Abdelrahim H. A. , Halawani Riyadh F. , Summan Ahmed Saleh , AbdElgawad Hamada
Published: September 2021

Besides the lack of studies regarding applying elevated CO2 (eCO2) as a strategy to improve the chemical composition of anise (Pimpinella anisum L.) seeds, studies on its interaction with seed developmental stages and origin are very limited. The seed yield, chemical composition, and biological activity of 6 aniseed accessions (Egypt, Tunisia, Syria, Turkey, Yemen, and Morocco) were investigated during three developmental stages (immature, premature, and mature) under control and elevated CO2 conditions. Mature seeds from all aniseed accessions had significantly higher (p < 0.05) dry weight (DW) percentages than premature and immature seeds. The highest DW percentages were recorded in Egypt and Morocco accessions. Seed maturation increased nutrients and antioxidant metabolites in most eCO2-treated accessions. In contrast, essential oils were decreased by seed maturation, while eCO2 reversed this effect. Essential oil-related precursors (e.g., phenylalanine) and enzyme activities (3-Deoxy-d-arabino-heptulosonate-7-phosphate synthase (DAHPS) and O–methyltransferase) decreased with seed maturity. However, high CO2 reduced this impact and further induced the other essential oil-related precursors (shikimic and cinnamic acids). Consequently, eCO2 provoked changes in the antioxidant and hypocholesterolemic activities of aniseeds, particularly at mature stages. Overall, eCO2 application, as an efficient way to improve aniseed growth, essential oil metabolism, and chemical composition, was affected by seed maturation and origin. Future studies of eCO2-treated aniseeds as a nutraceutical and pharmaceutical product are suggested.
Effect of Pirfenidone on TGF-β1-Induced Myofibroblast Differentiation and Extracellular Matrix Homeostasis of Human Orbital Fibroblasts in Graves’ Ophthalmopathy
Authors: Wu Shi-Bei , Hou Tzu-Yu , Kau Hui-Chuan , Tsai Chieh-Chih
Published: September 2021

Pirfenidone is a pyridinone derivative that has been shown to inhibit fibrosis in animal models and in patients with idiopathic pulmonary fibrosis. Its effect on orbital fibroblasts remains poorly understood. We investigated the in vitro effect of pirfenidone in transforming growth factor-β1 (TGF-β1)-induced myofibroblast transdifferentiation and extracellular matrix (ECM) homeostasis in primary cultured orbital fibroblasts from patients with Graves’ ophthalmopathy (GO). The expression of fibrotic proteins, including α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), fibronectin, and collagen type I, was determined by Western blots. The activities of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) responsible for the ECM homeostasis were examined. After pretreating the GO orbital fibroblasts with pirfenidone (250, 500, and 750 μg/mL, respectively) for one hour followed by TGF-β1 for another 24 h, the expression of α-SMA, CTGF, fibronectin, and collagen type I decreased in a dose-dependent manner. Pretreating the GO orbital fibroblasts with pirfenidone not only abolished TGF-β1-induced TIMP-1 expression but recovered the MMP-2/-9 activities. Notably, pirfenidone inhibited TGF-β1-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK), the critical mediators in the TGF-β1 pathways. These findings suggest that pirfenidone modulates TGF-β1-mediated myofibroblast differentiation and ECM homeostasis by attenuating downstream signaling of TGF-β1.
Accumulation of CD28null Senescent T-Cells Is Associated with Poorer Outcomes in COVID19 Patients
Authors: Coleman Mia , Zimmerly Kourtney , Yang Xuexian
Published: September 2021

Coronavirus disease 2019 (COVID-19), a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes infectious disease, and manifests in a wide range of symptoms from asymptomatic to severe illness and even death. Severity of infection is related to many risk factors, including aging and an array of underlying conditions, such as diabetes, hypertension, chronic obstructive pulmonary disease (COPD), and cancer. It remains poorly understood how these conditions influence the severity of COVID-19. Expansion of the CD28null senescent T-cell populations, a common phenomenon in aging and several chronic inflammatory conditions, is associated with higher morbidity and mortality rates in COVID-19. Here, we summarize the potential mechanisms whereby CD28null cells drive adverse outcomes in disease and predispose patients to devastating COVID-19, and discuss possible treatments for individuals with high counts of CD28null senescent T-cells.
Fatty Acids Rescue the Thermogenic Function of Sympathetically Denervated Brown Fat
Authors: Cao Qiang , Wang Shirong , Wang Huan , Cui Xin , Jing Jia , Yu Liqing , Shi Hang , Xue Bingzhong
Published: September 2021

Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here we aimed to uncover the physiological factors compensating for maintaining brown fat thermogenesis in the absence of BAT innervation. After an initial decline of body temperature during cold exposure, mice with SNS surgical denervation in interscapular BAT gradually recovered their temperature comparable to that of sham-operated mice. The surgically denervated BAT also maintained a sizable uncoupling protein 1 (UCP1) protein along with basal norepinephrine (NE) at a similar level to that of sham controls, which were associated with increased circulating NE. Furthermore, the denervated mice exhibited increased free fatty acid levels in circulation. Indeed, surgical denervation of mice with CGI-58 deletion in adipocytes, a model lacking lipolytic capacity to release fatty acids from WAT, dramatically reduced BAT UCP1 protein and rendered the mice susceptible to cold. We conclude that circulating fatty acids and NE may serve as key factors for maintaining BAT thermogenic function and body temperature in the absence of BAT sympathetic innervation.
ReCODE: A Personalized, Targeted, Multi-Factorial Therapeutic Program for Reversal of Cognitive Decline
Authors: Rao Rammohan V , Kumar Sharanya , Gregory Julie , Coward Christine , Okada Sho , Lipa William , Kelly Lance , Bredesen Dale E
Published: September 2021

Background: Alzheimer’s disease (AD) is the major cause of age-associated cognitive decline, and in the absence of effective therapeutics is progressive and ultimately fatal, creating a dire need for successful prevention and treatment strategies. We recently reported results of a successful proof-of-concept trial, using a personalized, precision medicine protocol, but whether such an approach is readily scalable is unknown. Objective: In the case of AD, there is not a single therapeutic that exerts anything beyond a marginal, unsustained, symptomatic effect. This suggests that the monotherapeutic approach of drug development for AD may not be an optimal one, at least when used alone. Using a novel, comprehensive, and personalized therapeutic system called ReCODE (reversal of cognitive decline), which proved successful in a small, proof-of-concept trial, we sought to determine whether the program could be scaled to improve cognitive and metabolic function in individuals diagnosed with subjective cognitive impairment, mild cognitive impairment, and early-stage AD. Methods: 255 individuals submitted blood samples, took the Montreal Cognitive Assessment (MoCA) test, and answered intake questions. Individuals who enrolled in the ReCODE program had consultations with clinical practitioners, and explanations of the program were provided. Participants had follow-up visits that included education regarding diet, lifestyle choices, medications, supplements, repeat blood sample analysis, and MoCA testing between 2 and 12 months after participating in the ReCODE program. Pre- and post-treatment measures were compared using the non-parametric Wilcoxon signed rank test. Results and Conclusions: By comparing baseline to follow-up testing, we observed that MoCA scores either significantly improved or stabilized in the entire participant pool—results that were not as successful as those in the proof-of-concept trial, but more successful than anti-amyloid therapies—and other risk factors including blood glucose, high-sensitivity C-reactive protein, HOMA-IR, and vitamin D significantly improved in the participant pool. Our findings provide evidence that a multi-factorial, comprehensive, and personalized therapeutic program designed to mitigate AD risk factors can improve risk factor scores and stabilize or reverse the decline in cognitive function. Since superior results were obtained in the proof-of-concept trial, which was conducted by a small group of highly trained and experienced physicians, it is possible that results from the use of this personalized approach would be enhanced by further training and experience of the practicing physicians. Nonetheless, the current results provide further support indicating the potential of such an approach for the prevention and reversal of cognitive decline.
Irradiation Mediates IFNα and CXCL9 Expression in Non-Small Cell Lung Cancer to Stimulate CD8+ T Cells Activity and Migration toward Tumors
Authors: Cheng Chun-Chia , Chang Yi-Fang , Ho Ai-Sheng , Sie Zong-Lin , Chang Jung-Shan , Peng Cheng-Liang , Chang Chun-Chao
Published: September 2021

Irradiation-broken DNA fragments increase type I interferon and chemokines secretion in tumor cells. Since radiotherapy may augment tumor immunotherapy, we hypothesize that the chemokines increased by irradiation could recruit CD8+ T cells to suppress tumor proliferation. This study intended to unveil the secreted factors activating and recruiting CD8+ T cells in non-small-cell lung cancer (NSCLC). EGFR-positive A549 was selected and treated by X-irradiation (IR) to identify the overexpression of chemokines associated to CD8+ T cell cytotoxicity and recruitment. A transwell assay with Alexa 488-labeled CD8+ T cells was used to evaluate CD8+ T cell motility in vitro. A nuclear imaging platform by In111-labeled nivolumab was used to track CD8+ T cells homing to tumors in vivo. The activation markers GZMB, PRF-1, and IFNγ, migration marker CD183 (CXCR3), and inhibitory marker CD274 (PD-1), were measured and compared in CD8+ T cells with A549 co-cultured, chemokines treated, and patients with late-stage lung cancer. We found that IR not only suppressed A549 proliferation but also induced IFNα and CXCL9 expression (p < 0.05). IFNα majorly increased IFNγ levels in CD8+ T cells (p < 0.05) and synergistically with CXCL9 enhanced CD8+ T cell migration in vitro (p < 0.05). We found that CXCR3 and PD-1 were down-regulated and up-regulated, respectively, in the peripheral blood CD8+ T cells in patients with lung cancer (n = 4 vs. healthy n = 3, both p < 0.05), which exhibited reduction of cell motility (p < 0.05). The in vivo nuclear imaging data indicated highly CD8+ T cells migrated to A549-induced tumors. In addition, we demonstrated that healthy PBMCs significantly suppressed the parallel tumor growth (p < 0.05) and the radioresistant tumor growth in the tumor xenograft mice (p < 0.05), but PBMCs from patients with lung cancer had lost the anti-tumor capacity. We demonstrated that IR induced IFNα and CXCL9 expression in A549 cells, leading to CD8+ T cell migration. This study unveiled a potential mechanism for radiotherapy to activate and recruit CD8+ T cells to suppress lung tumors.
HBeAg Levels Vary across the Different Stages of HBV Infection According to the Extent of Immunological Pressure and Are Associated with Therapeutic Outcome in the Setting of Immunosuppression-Driven HBV Reactivation
Authors: Piermatteo Lorenzo , Alkhatib Mohammad , D’Anna Stefano , Malagnino Vincenzo , Bertoli Ada , Andreassi Eleonora , Basile Elisa , Iuvara Alessandra , De Cristofaro Maria , Cappiello Giuseppina , Cerva Carlotta , Minichini Carmine , Pisaturo Mariantonietta , Starace Mario , Coppola Nicola , Fontana Carla , Grelli Sandro , Ceccherini-Silberstein Francesca , Andreoni Massimo , Gill Upkar S. , Kennedy Patrick T. F. , Sarmati Loredana , Salpini Romina , Svicher Valentina
Published: September 2021

HBeAg is a marker of HBV-activity, and HBeAg-loss predicts a favorable clinical outcome. Here, we characterize HBeAg-levels across different phases of HBV infection, their correlation with virological/biochemical markers and the virological response to anti-HBV therapy. Quantitative HBeAg (qHBeAg, DiaSorin) is assessed in 101 HBeAg+ patients: 20 with acute-infection, 20 with chronic infection, 32 with chronic hepatitis and 29 with immunosuppression-driven HBV-reactivation (HBV-R). A total of 15/29 patients with HBV-R are monitored for >12 months after starting TDF/ETV. qHBeAg is higher in immunosuppression-driven HBV-R (median[IQR]:930[206–1945]PEIU/mL) and declines in chronic hepatitis (481[28–1393]PEIU/mL, p = 0.03), suggesting HBeAg production, modulated by the extent of immunological pressure. This is reinforced by the negative correlation between qHBeAg and ALT in acute infection (Rho = −0.66, p = 0.006) and chronic hepatitis (Rho = −0.35; p = 0.05). Interestingly, qHBeAg strongly and positively correlates with qHBsAg across the study groups, suggesting cccDNA as a major source of both proteins in the setting of HBeAg positivity (with limited contribution of integrated HBV-DNA to HBsAg production). Focusing on 15 patients with HBV-R starting TDF/ETV, virological suppression and HBeAg-loss are achieved in 60% and 53.3%. Notably, the combination of qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL at HBV-R is the only factor predicting no HBeAg loss (HBeAg loss: 0% with vs. 72.7% without qHBeAg > 2000 PEIU/mL + qHBsAg > 52,000 IU/mL, p = 0.03). In conclusion, qHBeAg varies over the natural course of HBV infection, according to the extent of immunological pressure. In the setting of HBV-R, qHBeAg could be useful in predicting the treatment response under immunosuppression.
An Overview on Cognitive Function Enhancement through Physical Exercises
Authors: Srinivas Narayanasamy Sai , Vimalan Vijayaragavan , Padmanabhan Parasuraman , Gulyás Balázs
Published: September 2021

This review is extensively focused on the enhancement of cognitive functions while performing physical exercises categorized into cardiovascular exercises, resistance training, martial arts, racquet sports, dancing and mind-body exercises. Imaging modalities, viz. functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS) and electroencephalography (EEG), have been included in this review. This review indicates that differences are present in cognitive functioning while changing the type of physical activity performed. This study concludes that employing fNIRS helps overcome certain limitations of fMRI. Further, the effects of physical activity on a diverse variety of the population, from active children to the old people, are discussed.
Role of COMT V158M Polymorphism in the Development of Dystonia after Administration of Antipsychotic Drugs
Authors: Nicotera Antonio Gennaro , Di Rosa Gabriella , Turriziani Laura , Costanzo Maria Cristina , Stracuzzi Emanuela , Vitello Girolamo Aurelio , Rando Rosanna Galati , Musumeci Antonino , Vinci Mirella , Musumeci Sebastiano Antonino , Calì Francesco
Published: September 2021

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia; however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient’s genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.
Effectiveness of Mindfulness-Based Relapse Prevention in Individuals with Substance Use Disorders: A Systematic Review
Authors: Ramadas Eduardo , Lima Margarida Pedroso de , Caetano Tânia , Lopes Jessica , Dixe Maria dos Anjos
Published: September 2021

Objectives: This systematic review aimed to understand the current state of the art about the effectiveness of mindfulness-based relapse prevention (MBRP) on individuals with substance use disorders (SUD), taking into account not only SUD variables (e.g., cravings, frequency of use) but also other relevant clinical variables (e.g., anxiety and depressive symptoms, quality of life). Methods: A comprehensive search of electronic databases was conducted to identify studies that investigate MBRP interventions on individuals with SUD. Studies that met the inclusion criteria were synthesized and assessed using systematic review methods. Results: Thirteen studies were included in the present review. The methodological quality of the included studies was moderately strong. Nine studies (69.2%) used the traditional 16 h MBRP program. Six studies (46.1%) chose to use a co-intervention treatment ranging from the treatment as usual (TAU) to cognitive behavioral therapy. All but one study indicated that their interventions produced positive effects on at least one addiction outcome measure. None of the interventions were evaluated across different settings or populations. Conclusions: Despite some heterogeneity regarding the type of MBRP program used, results support the effectiveness of these interventions in the SUD population, especially in reducing cravings, decreasing the frequency of use, and improving depressive symptoms.
First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats
Authors: Bertho Annaïg , Ortiz Ramon , Juchaux Marjorie , Gilbert Cristèle , Lamirault Charlotte , Pouzoulet Frederic , Polledo Laura , Liens Alethea , Warfving Nils , Sebrie Catherine , Jourdain Laurène , Patriarca Annalisa , de Marzi Ludovic , Prezado Yolanda
Published: September 2021

(1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials.
Treatment Strategy for Multiple Myeloma to Improve Immunological Environment and Maintain MRD Negativity
Authors: Suzuki Kazuhito , Nishiwaki Kaichi , Yano Shingo
Published: September 2021

Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.
Detection of Persistent Organic Pollutants in Omental Adipose Tissue from Patients with Diffuse-Gastric Cancer: A Pilot Study
Authors: Perrot-Applanat Martine , Pimpie Cynthia , Cano-Sancho German , Antignac Jean Philippe , Pocard Marc
Published: September 2021

The greater omentum represents a specific adipose tissue resected with gastric surgery for cancer. Diffuse gastric adenocarcinoma (diffuse-GC) is of major relevance among gastric cancers due to its unknown origin, aggressiveness, and metastasis in the peritoneal cavity. We postulated that persistent organic pollutants (POPs) could be detected in the greater omentum. Great omentum from patients with (i) diffuse-GC, or (ii) with other peritoneal metastatic cancer, and (iii) control group without cancer disease were analyzed for the distribution of a large panel of 96 POPs. POPs include polychlorinated dioxins/furans (PCDD/Fs), polychlorobiphenyls (PCBs), polybrominated diphenyl ethers (PBDE), polybrominated biphenyls (PBB), hexabromocyclododecanes, organochlorine pesticides, and polycyclic aromatic hydrocarbons (PAHs). The widespread presence of a substantial list of POPs (PCDDs/Fs, PCBs, and brominated flame retardants) was found in the omentum from patients with aggressive diffuse-GC, with minor presence of some organochlorine pesticides and PAHs at the low analyzed levels. Some chemicals appeared in larger concentrations in diffuse-GC or other cancer groups, including some PCDDs, PCB105, 123, 138, PBDE209, and PBB153. Overall, the present pilot study provides novel information regarding POPs levels in the omental fat, which is an understudied fat depot in terms of POPs load, and diffuse-GC association.
The Role of Cytokines in the Different Stages of Hepatocellular Carcinoma
Authors: Rico Montanari Noe , Anugwom Chimaobi M. , Boonstra Andre , Debes Jose D.
Published: September 2021

Hepatocellular carcinoma (HCC) is the primary form of liver cancer and a leading cause of cancer-related death worldwide. Early detection remains the most effective strategy in HCC management. However, the spectrum of underlying liver diseases preceding HCC, its genetic complexity, and the lack of symptomatology in early stages challenge early detection. Regardless of underlying etiology, unresolved chronic inflammation is a common denominator in HCC. Hence, many inflammatory molecules, including cytokines, have been investigated as potential biomarkers to predict different stages of HCC. Soluble cytokines carry cell-signaling functions and are easy to detect in the bloodstream. However, its biomarkers’ role remains limited due to the dysregulation of immune parameters related to the primary liver process and their ability to differentiate carcinogenesis from the underlying disease. In this review, we discuss and provide insight on cytokines with clinical relevance for HCC differentiating those implicated in tumor formation, early detection, advanced disease, and response to therapy.
Expression Patterns of TOP2A and SIRT1 Are Predictive of Survival in Patients with High-Risk Soft Tissue Sarcomas Treated with a Neoadjuvant Anthracycline-Based Chemotherapy
Authors: Berclaz Luc M. , Altendorf-Hofmann Annelore , Dürr Hans Roland , Klein Alexander , Angele Martin K. , Albertsmeier Markus , Schmidt-Hegemann Nina-Sophie , Di Gioia Dorit , Knösel Thomas , Lindner Lars H.
Published: September 2021

Molecular predictors of response to chemotherapy and survival have not been put into clinical practice in high-risk soft tissue sarcomas (HR-STS) by now. The expression of TOP2A and SIRT1 has implications for the mechanism of action of doxorubicin, which is the backbone of chemotherapy in HR-STS. Pre-treatment samples of 167 patients with HR-STS were collected. Protein expression levels of TOP2A and SIRT1 were evaluated with tissue microarrays and immunohistochemistry and correlated with clinicopathological parameters, including overall survival (OS). The expression of TOP2A and SIRT1 was seen in 47% and 60% of patients with HR-STS, respectively. TOP2A expression was associated with higher tumor grading and shorter 5-year OS. The expression of SIRT1 was correlated with a better 5- and 10-year OS. The combination of high SIRT1 and low TOP2A (“Top survivors”) significantly predicted a better OS compared to other biomarker combinations. A multivariate analysis confirmed the expression of SIRT1 and the “Top survivor” biomarker combination as independent predictive factors of OS. This is the first study to associate SIRT1 overexpression with a statistically significant prolongation of OS in HR-STS. Both individual markers and their combination can be used as predictive indicators for HR-STS patients scheduled for neoadjuvant anthracycline-based chemotherapy.
Psychosocial Care for Adult Cancer Patients: Guidelines of the Italian Medical Oncology Association
Authors: Caminiti Caterina , Diodati Francesca , Annunziata Maria Antonietta , Di Giulio Paola , Isa Luciano , Mosconi Paola , Nanni Maria Giulia , Patrini Adele , Piredda Michela , Santangelo Claudia , Verusio Claudio , Cinquini Michela , Fittipaldo Veronica Andrea , Passalacqua Rodolfo
Published: September 2021

Psychosocial morbidity can have negative consequences for cancer patients, including maladaptive coping, poor treatment adherence, and lower quality of life. Evidence shows that psychosocial interventions can positively impact quality of life, as well as symptoms and side effects; however, they are not always offered to patients who might benefit from them. These guidelines were produced by a multidisciplinary panel of 16 experts, including patients, following GRADE methodology. The panel framed clinical questions and voted on outcomes to investigate. Studies identified by rigorous search strategies were assessed to rate certainty of evidence, and recommendations were formulated by the panel. Although the quality of the evidence found was generally moderate, interventions could be recommended aimed at improving patient information, communication with healthcare professionals and involvement in decision-making; detecting and managing patient psychosocial needs, particularly with non-pharmacological therapy; and supporting families of patients with advanced cancer. The role of nurses as providers of information and psychosocial care is stressed. Most recommended interventions do not appear to necessitate new services or infrastructures, and therefore do not require allocation of additional resources, but predominantly involve changes in clinical staff behavior and/or ward organization. Patients should be made aware of psychosocial care standards so that they can expect to receive them.
Data on Utility in Cost–Utility Analyses of Genetic Screen-and-Treat Strategies for Breast and Ovarian Cancer
Authors: Simões Corrêa Galendi Julia , Vennedey Vera , Kentenich Hannah , Stock Stephanie , Müller Dirk
Published: September 2021

Genetic screen-and-treat strategies for the risk-reduction of breast cancer (BC) and ovarian cancer (OC) are often evaluated by cost–utility analyses (CUAs). This analysis compares data on health preferences (i.e., utility values) in CUAs of targeted genetic testing for BC and OC. Based on utilities applied in fourteen CUAs, data on utility including related assumptions were extracted for the health states: (i) genetic test, (ii) risk-reducing surgeries, (iii) BC/OC and (iv) post cancer. In addition, information about the sources of utility and the impact on the cost-effectiveness was extracted. Utility for CUAs relied on heterogeneous data and assumptions for all health states. The utility values ranged from 0.68 to 0.97 for risk-reducing surgeries, 0.6 to 0.85 for BC and 0.5 to 0.82 for OC. In two out of nine studies, considering the impact of the test result strongly affected the cost–effectiveness ratio. While in general utilities seem not to affect the cost–utility ratio, in future modeling studies the impact of a positive/negative test on utility should be considered mandatory. Women’s health preferences, which may have changed as a result of improved oncologic care and genetic counselling, should be re-evaluated.
Stroma AReactive Invasion Front Areas (SARIFA)—A New Easily to Determine Biomarker in Colon Cancer—Results of a Retrospective Study
Authors: Martin Benedikt , Grosser Bianca , Kempkens Lana , Miller Silvia , Bauer Svenja , Dhillon Christine , Banner Bettina Monika , Brendel Eva-Maria , Sipos Éva , Vlasenko Dmytro , Schenkirsch Gerhard , Schiele Stefan , Müller Gernot , Märkl Bruno
Published: September 2021

Many studies have used histomorphological features to more precisely predict the prognosis of patients with colon cancer, focusing on tumor budding, poorly differentiated clusters, and the tumor–stroma ratio. Here, we introduce SARIFA: Stroma AReactive Invasion Front Area(s). We defined SARIFA as the direct contact between a tumor gland/tumor cell cluster (≥5 cells) and inconspicuous surrounding adipose tissue in the invasion front. In this retrospective, single-center study, we classified 449 adipose-infiltrative adenocarcinomas (not otherwise specified) from two groups based on SARIFA and found 25% of all tumors to be SARIFA-positive. Kappa values between the two pathologists were good/very good: 0.77 and 0.87. Patients with SARIFA-positive tumors had a significantly shorter colon-cancer-specific survival (p = 0.008, group A), absence of metastasis, and overall survival (p < 0.001, p = 0.003, group B). SARIFA was significantly associated with adverse features such as pT4 stage, lymph node metastasis, tumor budding, and higher tumor grade. Moreover, SARIFA was confirmed as an independent prognostic indicator for colon-cancer-specific survival (p = 0.011, group A). SARIFA assessment was very quick (<1 min). Because of low interobserver variability and good prognostic significance, SARIFA seems to be a promising histomorphological prognostic indicator in adipose-infiltrative adenocarcinomas of the colon. Further studies should validate our results and also determine whether SARIFA is a universal prognostic indicator in solid cancers.
Towards Personalized Treatment Strategies for Esophageal Adenocarcinoma; A Review on the Molecular Characterization of Esophageal Adenocarcinoma and Current Research Efforts on Individualized Curative Treatment Regimens
Authors: Hoefnagel Sanne J. M. , Boonstra Jurjen J. , Russchen Marjolein J. A. M. , Krishnadath Kausilia K.
Published: September 2021

Esophageal cancers confer a major health challenge and are highly aggressive malignancies with poor prognosis. Esophageal adenocarcinoma (EAC) is one of the two major histopathological subtypes of esophageal cancer. Despite advances in treatment modalities, the prognosis of patients with EAC remains poor, with a 5-year survival rate that rarely exceeds 30% in patients treated with curative intent. Chemoradiotherapy followed by resection is the treatment of choice for EAC patients, which are deemed to be curable. Current patient stratification and treatments are based on outcomes from clinical trials. Unfortunately, the molecular heterogeneity of EAC which determines the chemo- and radiosensitivity of these cancers are not taken into account. A more personalized approach in the treatment of EAC could improve patient outcomes. This review aims at summarizing literature on translational and clinical research in the field of EAC which could be of importance to develop personalized approaches. As suggested by the TCGA, expression data features molecular classifications by different platforms, including miRNA, genomic mutations and reverse-phase protein arrays. Here, we summarize literature on transcriptomic, data-driven approaches to identify distinct subtypes of EAC associated with molecular features. These novel classifications may determine the responsiveness to chemo(radio)therapy and help to identify novel molecular targets within cell signaling pathways. Moreover, we discuss the current clinical research efforts on tailored treatment regimens for patients with EAC taking into account the heterogeneous response to chemoradiotherapy. We summarize the evidence regarding active surveillance instead of immediate surgical resection after application of neoadjuvant chemo(radio)therapy in EAC. We consider that in future patients with complete response to chemo(radio)therapy, predicted by (transcriptomic) biomarkers, might benefit most from this approach. Finally, challenges to overcome for current findings to be implemented in clinical practice and move the field forward are being discussed.
A Modified Intraperitoneal Chemotherapy Regimen for Ovarian Cancer: Technique and Treatment Outcomes
Authors: Kim Ji Hyun , Ha Hyeong In , Kim Min Hae , Han Mi Ra , Park Sang-Yoon , Lim Myong Cheol
Published: September 2021

This study aimed to investigate treatment outcomes concerning three institutional modifications to intraperitoneal (IP) chemotherapy for patients with ovarian cancer. The medical records of 27 patients treated with IP chemotherapy were retrospectively reviewed. All patients had three IP chemotherapy institutional modifications; modified Gynecologic Oncology Group 172 regimen was used for the chemotherapy regimen. With institutional modifications, 63.0% (17/27) completed all six cycles of IP chemotherapy. Of the 17 and 10 patients with primary and recurrent ovarian cancer, respectively, 55.6% (15/27) underwent left colonic surgery, including low anterior resection. In patients with primary ovarian cancer, the IP chemotherapy completion rate was 76.5% (13/17). In patients with and without left colonic surgery, the IP chemotherapy completion rates were 53.3% (8/15) and 75.0% (9/12), respectively. No complications related to left colonic surgery during IP chemotherapy were identified. The most frequent grade 3–4 toxicities were gastrointestinal toxicities (33.3%) and neutropenia (29.6%). The median progression-free survival was 19.5 months in all patients and 25.2 months in patients with primary ovarian cancer. Three institutional modifications to IP chemotherapy increased the completion rate for planned IP chemotherapy, even after left colonic surgery. Further studies involving a larger study cohort are required to confirm survival outcomes using these modifications.
Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias
Authors: Duchmann Matthieu , Laplane Lucie , Itzykson Raphael
Published: September 2021

Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing—and more recently, of single-cell technologies—has shed light on the intratumoral diversity of leukemic cells. Taking AML as a model disease, we review the multiple sources of genetic, epigenetic, and functional heterogeneity of leukemic cells and discuss the definition of a leukemic clone extending its definition beyond genetics. After introducing the two dimensions contributing to clonal diversity, namely, richness (number of leukemic clones) and evenness (distribution of clone sizes), we discuss the mechanisms at the origin of clonal emergence (mutation rate, number of generations, and effective size of the leukemic population) and the causes of clonal dynamics. We discuss the possible role of neutral drift, but also of cell-intrinsic and -extrinsic influences on clonal fitness. After reviewing available data on the prognostic role of genetic and epigenetic diversity of leukemic cells on patients’ outcome, we discuss how a better understanding of AML as an evolutionary process could lead to the design of novel therapeutic strategies in this disease.
Efficient 1-Hydroxy-2-Butanone Production from 1,2-Butanediol by Whole Cells of Engineered E. coli
Authors: Lin Hui , Xu Jiayin , Sun Wenlian , Hu Wujia , Gao Huifang , Hu Kaihui , Qiu Junzhi , Huang Binbin , Zhang Liaoyuan
Published: September 2021

1-Hydroxy-2-butanone (HB) is a key intermediate for anti-tuberculosis pharmaceutical ethambutol. Commercially available HB is primarily obtained by the oxidation of 1,2-butanediol (1,2-BD) using chemical catalysts. In present study, seven enzymes including diol dehydrogenases, secondary alcohol dehydrogenases and glycerol dehydrogenase were chosen to evaluate their abilities in the conversion of 1,2-BD to HB. The results showed that (2R, 3R)- and (2S, 3S)-butanediol dehydrogenase (BDH) from Serratia sp. T241 could efficiently transform (R)- and (S)-1,2-BD into HB respectively. Furthermore, two biocatalysts co-expressing (2R, 3R)-/(2S, 3S)-BDH, NADH oxidase and hemoglobin protein in Escherichia coli were developed to convert 1,2-BD mixture into HB, and the transformation conditions were optimized. Maximum HB yield of 341.35 and 188.80 mM could be achieved from 440 mM (R)-1,2-BD and 360 mM (S)-1,2-BD by E. coli (pET-rrbdh-nox-vgb) and E. coli (pET-ssbdh-nox-vgb) under the optimized conditions. In addition, two biocatalysts showed the ability in chiral resolution of 1,2-BD isomers, and 135.68 mM (S)-1,2-BD and 112.43 mM (R)-1,2-BD with the purity of 100% could be obtained from 300 and 200 mM 1,2-BD mixture by E. coli (pET-rrbdh-nox-vgb) and E. coli (pET-ssbdh-nox-vgb), respectively. These results provided potential application for HB production from 1,2-BD mixture and chiral resolution of (R)-1,2-BD and (S)-1,2-BD.
TiO2@MOF Photocatalyst for the Synergetic Oxidation of Microcystin-LR and Reduction of Cr(VI) in Aqueous Media
Authors: Wang Yarui , Yu Wanchao , Geng Fanglan , Zhao Lixia , Wang Yawei
Published: September 2021

The coexistence of pollutants presents a great challenge to the implementation of photocatalysts. In this work, a novel MIL-101(Fe)/TiO2 composite prepared by in situ growth of MIL-101(Fe) on TiO2 was developed for the synergetic oxidation of MC-LR and Cr(VI) reduction. The heterojunction material shows elevated photocatalytic behavior under ultraviolet compared with the unary pollutant system. Furthermore, quenching experiments and electron spin resonance confirm that the enhanced photodegradation behavior is related to the synergistic effect between the photocatalytic reduction and oxidation process, in which MC-LR consumes the holes and Cr(VI) captures electrons, followed by efficient charge separation through the conventional double-transfer mechanism between MIL-101(Fe) and TiO2. This investigation provides a deeper understanding of the construction of MOFs/semiconductor heterojunctions for the pollutants removal in multi-component contaminants system.
Inflammatory Cascade in Alzheimer’s Disease Pathogenesis: A Review of Experimental Findings
Authors: de Oliveira Jade , Kucharska Ewa , Garcez Michelle Lima , Rodrigues Matheus Scarpatto , Quevedo João , Moreno-Gonzalez Ines , Budni Josiane
Published: September 2021

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Most AD patients develop the disease in late life, named late onset AD (LOAD). Currently, the most recognized explanation for AD pathology is the amyloid cascade hypothesis. It is assumed that amyloid beta (Aβ) aggregation and deposition are critical pathogenic processes in AD, leading to the formation of amyloid plaques, as well as neurofibrillary tangles, neuronal cell death, synaptic degeneration, and dementia. In LOAD, the causes of Aβ accumulation and neuronal loss are not completely clear. Importantly, the blood–brain barrier (BBB) disruption seems to present an essential role in the induction of neuroinflammation and consequent AD development. In addition, we propose that the systemic inflammation triggered by conditions like metabolic diseases or infections are causative factors of BBB disruption, coexistent inflammatory cascade and, ultimately, the neurodegeneration observed in AD. In this regard, the use of anti-inflammatory molecules could be an interesting strategy to treat, delay or even halt AD onset and progression. Herein, we review the inflammatory cascade and underlying mechanisms involved in AD pathogenesis and revise the anti-inflammatory effects of compounds as emerging therapeutic drugs against AD.
Mechanisms and Clinical Significance of Tumor Lymphatic Invasion
Authors: Fujimoto Noriki , Dieterich Lothar C.
Published: September 2021

Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes “hijacked” by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.