bluuebunny/crossref_metadata_2025 huggingface dataset:
Selection of Logistics Service Provider for the E-Commerce Companies in Pakistan Based on Integrated GRA-TOPSIS Approach
Authors: Naseem Muhammad Hamza , Yang Jiaqi , Xiang Ziquan
Published: August 2021

Recently, the demand for third-party logistics providers has become extremely relevant and the key subject for businesses to enhance their service quality and minimize logistics costs. The key success factor for an e-commerce business is product delivery, and the third-party logistics service provider is responsible for that. Each 3PLP has its own business characteristics, meaning it is important to select the most suitable logistics provider for the e-commerce business. This study uses a combination of grey relational analysis (GRA) and the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method, assisting decision makers in choosing the best logistics service provider for their e-business. A case study of an e-commerce company based in Faisalabad, Pakistan, was selected to demonstrate the steps of the proposed methods. In this process, seven criteria of logistics suppliers were considered, and then the best alternatives among four logistics provider companies were selected using the proposed method.
Personalized Evaluation of Atrial Complexity of Patients Undergoing Atrial Fibrillation Ablation: A Clinical Computational Study
Authors: Sánchez de la Nava Ana , González Mansilla Ana , González-Torrecilla Esteban , Ávila Pablo , Datino Tomás , Bermejo Javier , Arenal Ángel , Fernández-Avilés Francisco , Atienza Felipe
Published: August 2021

Current clinical guidelines establish Pulmonary Vein (PV) isolation as the indicated treatment for Atrial Fibrillation (AF). However, AF can also be triggered or sustained due to atrial drivers located elsewhere in the atria. We designed a new simulation workflow based on personalized computer simulations to characterize AF complexity of patients undergoing PV ablation, validated with non-invasive electrocardiographic imaging and evaluated at one year after ablation. We included 30 patients using atrial anatomies segmented from MRI and simulated an automata model for the electrical modelling, consisting of three states (resting, excited and refractory). In total, 100 different scenarios were simulated per anatomy varying rotor number and location. The 3 states were calibrated with Koivumaki action potential, entropy maps were obtained from the electrograms and compared with ECGi for each patient to analyze PV isolation outcome. The completion of the workflow indicated that successful AF ablation occurred in patients with rotors mainly located at the PV antrum, while unsuccessful procedures presented greater number of driving sites outside the PV area. The number of rotors attached to the PV was significantly higher in patients with favorable long-term ablation outcome (1-year freedom from AF: 1.61 ± 0.21 vs. AF recurrence: 1.40 ± 0.20; p-value = 0.018). The presented workflow could improve patient stratification for PV ablation by screening the complexity of the atria.
Extracellular Vesicles in Regeneration and Rehabilitation Recovery after Stroke
Authors: Gualerzi Alice , Picciolini Silvia , Rodà Francesca , Bedoni Marzia
Published: August 2021

Patients that survive after a stroke event may present disabilities that can persist for a long time or permanently after it. If stroke prevention fails, the prompt and combinatorial intervention with pharmacological and rehabilitation therapy is pivotal for the optimal recovery of patients and the reduction of disabilities. In the present review, we summarize some key features of the complex events that occur in the brain during and after the stroke event, with a special focus on extracellular vesicles (EVs) and their role as both carriers of biomarkers and potential therapeutics. EVs have already demonstrated their ability to be used for diagnostic purposes for multiple brain disorders and could represent valuable tools to track the regenerative and inflammatory processes occurring in the injured brain after stroke. Last, but not least, the use of artificial or stem cell-derived EVs were proved to be effective in stimulating brain remodeling and ameliorating recovery after stroke. Still, effective biomarkers of recovery are needed to design robust trials for the validation of innovative therapeutic strategies, such as regenerative rehabilitation approaches.
Genetic Mutations and Non-Coding RNA-Based Epigenetic Alterations Mediating the Warburg Effect in Colorectal Carcinogenesis
Authors: Abi Zamer Batoul , Abumustafa Wafaa , Hamad Mawieh , Maghazachi Azzam A. , Muhammad Jibran Sualeh
Published: August 2021

Colorectal cancer (CRC) development is a gradual process defined by the accumulation of numerous genetic mutations and epigenetic alterations leading to the adenoma-carcinoma sequence. Despite significant advances in the diagnosis and treatment of CRC, it continues to be a leading cause of cancer-related deaths worldwide. Even in the presence of oxygen, CRC cells bypass oxidative phosphorylation to produce metabolites that enable them to proliferate and survive—a phenomenon known as the “Warburg effect”. Understanding the complex glucose metabolism in CRC cells may support the development of new diagnostic and therapeutic approaches. Here we discuss the most recent findings on genetic mutations and epigenetic modulations that may positively or negatively regulate the Warburg effect in CRC cells. We focus on the non-coding RNA (ncRNA)-based epigenetics, and we present a perspective on the therapeutic relevance of critical molecules and ncRNAs mediating the Warburg effect in CRC cells. All the relevant studies were identified and assessed according to the genes and enzymes mediating the Warburg effect. The findings summarized in this review should provide a better understanding of the relevance of genetic mutations and the ncRNA-based epigenetic alterations to CRC pathogenesis to help overcome chemoresistance.
H2S as a Bridge Linking Inflammation, Oxidative Stress and Endothelial Biology: A Possible Defense in the Fight against SARS-CoV-2 Infection?
Authors: Gorini Francesca , Del Turco Serena , Sabatino Laura , Gaggini Melania , Vassalle Cristina
Published: August 2021

The endothelium controls vascular homeostasis through a delicate balance between secretion of vasodilators and vasoconstrictors. The loss of physiological homeostasis leads to endothelial dysfunction, for which inflammatory events represent critical determinants. In this context, therapeutic approaches targeting inflammation-related vascular injury may help for the treatment of cardiovascular disease and a multitude of other conditions related to endothelium dysfunction, including COVID-19. In recent years, within the complexity of the inflammatory scenario related to loss of vessel integrity, hydrogen sulfide (H2S) has aroused great interest due to its importance in different signaling pathways at the endothelial level. In this review, we discuss the effects of H2S, a molecule which has been reported to demonstrate anti-inflammatory activity, in addition to many other biological functions related to endothelium and sulfur-drugs as new possible therapeutic options in diseases involving vascular pathobiology, such as in SARS-CoV-2 infection.
The Association between the Binding Processes of Working Memory and Vascular Risk Profile in Adults
Authors: Bika Eirini , Moraitou Despina , Masoura Elvira , Kolios George , Papantoniou Georgia , Sofologi Maria , Papaliagkas Vasileios , Ntritsos Georgios
Published: August 2021

Episodic buffer (EB), a key component of working memory, seems to have a rather complicated function as part of binding processes. Recent papers on the field claim that binding processes of working memory (WM) are assisted by attention and executive functions. On the same page, vascular pathology is gaining more ground as the main underlying cause for many brain pathologies. Hypercholesterolemia, hypertension, obesity, diabetes, lack of exercise and smoking are the most common risk factors that people of all ages suffer from and constitute the main vascular risk factors responsible for a possible decline in executive functions and attention. Thus, this research is an attempt to examine the relation between the binding functions of WM and the existence of vascular risk factors via a computerized test focusing on feature binding. The study comprised adults (n = 229) with and without vascular risk factors. The main tools used were a biomarker questionnaire and a feature binding test (FBT). The results showed that participants who report suffering from one or more vascular risk factors had significantly lower performance on specific subtasks of the FBT in comparison to the participants who were healthy. This allows us to assume that there might be a positive association between feature binding and a vascular risk profile in adults, and such a test could be a useful diagnostic tool for early cognitive impairment due to incipient vascular pathology.
Rat 50 kHz Trill Calls Are Tied to the Expectation of Social Interaction
Authors: Burke Candace J. , Markovina Mariya , Pellis Sergio M. , Euston David R.
Published: August 2021

Rats emit a variety of calls in the 40–80 kHz range (50 kHz calls). While these calls are generally associated with positive affect, it is unclear whether certain calls might be used selectively in certain contexts. To examine this, we looked at ultrasonic calls in 30–40 day old male rats during the expectation of either play or food, both of which are reinforcing. Behavior and vocalizations were recorded while rats were in a test chamber awaiting the arrival of a play partner or food over seven days of testing. Control groups were included for the non-specific effects of food deprivation and social isolation. Play reward led to an increase in 50 kHz vocalizations, generally, with specific increases in trill and “trill with jump” calls not seen in other groups. Expectation of food reward did not lead to a significant increase in vocalizations of any type, perhaps due to the young age of our study group. Further, rats that were food deprived for the food expectation study showed markedly lower calls overall and had a different profile of call types compared to rats that were socially isolated. Taken together, the results suggest that trill-associated calls may be used selectively when rats are socially isolated and/or expecting a social encounter.
Erratum: Tejeda-Bayron et al. Activation of Glutamate Transporter-1 (GLT-1) Confers Sex-Dependent Neuroprotection in Brain Ischemia. Brain Sci. 2021, 11, 76
Authors: Tejeda-Bayron Flavia A. , Rivera-Aponte David E. , Malpica-Nieves Christian J. , Maldonado-Martínez Gerónimo , Maldonado Héctor M. , Skatchkov Serguei N. , Eaton Misty J.
Published: August 2021

The authors wish to make the following corrections to this paper [...]
Obese Subjects without Eating Disorders Experience Binge Episodes Also Independently of Emotional Eating and Personality Traits among University Students of Southern Italy
Authors: Villano Ines , Ilardi Ciro Rosario , Arena Stefania , Scuotto Chiara , Gleijeses Maria Gloria , Messina Giovanni , Messina Antonietta , Monda Vincenzo , Monda Marcellino , Iavarone Alessandro , Chieffi Sergio , La Marra Marco
Published: August 2021

It is widely acknowledged that obesity is a growing public clinical issue involving both physical and psychological well-being. Nevertheless, the relationship between psychological features and weight gain is still unclear. Although emotional eating (EE) and personality traits are considered significant predictors of eating disorders, their role in obesity without eating disorders (OB-wed) is far from proven. The present study aimed at investigating the cumulative effect of EE and personality traits on overeating behavior in a sample of 266 university students (169 female; mean age = 21.85, SD = 2.39) stratified based on their body mass index (BMI; normal weight, overweight, obese). They were enrolled during free screening days promoted by the Human Dietetic and Sport Service of a Southern Italian university. The results show a psychological pattern of increasing overeating behavior and lower Self-Directedness combined with higher Sadness and Anger. However, OB-wed subjects overate regardless of this emotional/personological configuration.
Now or Later? Stress-Induced Increase and Decrease in Choice Impulsivity Are Both Associated with Elevated Affective and Endocrine Responses
Authors: Simon Lisa , Jiryis Talita , Admon Roee
Published: August 2021

Exposure to acute stress elicit physiological and psychological responses that can impact decision-making, often expressed as an increased tendency to act in an impulsive manner following stress. Delay discounting (DD) task has emerged as a reliable measure of impulsive behavior in the form of choice impulsivity (CI). Interestingly, studies that examined the effect of acute stress on DD performance reported mixed results. To address this, we conducted a within-subject examination of the impact of acute stress on CI, focusing on individual differences in response patterns. One hundred and fifty healthy female participants completed the DD task twice, before and after undergoing an acute laboratory stress induction procedure. Saliva samples and self-report mood and affect measures were collected at four time points throughout the session. Fifty-nine matched healthy control participants completed only the DD task twice, with no stress in between. Results indicate that the acute stress procedure elicited the expected effects of increased cortisol release and increased negative mood and affect, at the group level. With respect to DD, stress indeed increased CI at the group level, yet participants differed in the magnitude and direction of this effect. Interestingly, regression analysis revealed quadratic relations between stress-induced changes in CI and cortisol release. Indeed, dividing the sample into three sub-groups based on the impact of stress on CI revealed that, compared to participants that exhibited no substantial change in their CI following stress, participants that exhibited either stress-induced increase or decrease in their CI also exhibited more stress-induced cortisol release, as well as more negative affect. Taken together, these findings suggest that elevated physiological and psychological responses to stress are associated with either increased or decreased choice impulsivity, thus depicting quadratic relations between stress and impulsivity.
Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging
Authors: Alotaibi Abdulmajeed , Podlasek Anna , AlTokhis Amjad , Aldhebaib Ali , Dineen Rob A. , Constantinescu Cris S.
Published: August 2021

Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.
Reaction Time and Visual Memory in Connection to Alcohol Use in Persons with Bipolar Disorder
Authors: Mazumder Atiqul Haq , Barnett Jennifer , Isometsä Erkki Tapio , Lindberg Nina , Torniainen-Holm Minna , Lähteenvuo Markku , Lahdensuo Kaisla , Kerkelä Martta , Ahola-Olli Ari , Hietala Jarmo , Kampman Olli , Kieseppä Tuula , Jukuri Tuomas , Häkkinen Katja , Cederlöf Erik , Haaki Willehard , Kajanne Risto , Wegelius Asko , Männynsalo Teemu , Niemi-Pynttäri Jussi , Suokas Kimmo , Lönnqvist Jouko , Tiihonen Jari , Paunio Tiina , Vainio Seppo Juhani , Palotie Aarno , Niemelä Solja , Suvisaari Jaana , Veijola Juha
Published: August 2021

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol-related disorder in persons with bipolar disorder (BD). The study population included 1268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol-related disorder including alcohol use disorder (AUD). Hazardous drinking was screened with the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) screening tool. Alcohol-related disorder diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on A tablet computer: the 5-choice serial reaction time task, or reaction time (RT) test and the Paired Associative Learning (PAL) test. Depressive symptoms were assessed with the Mental Health Inventory with five items (MHI-5). However, no assessment of current manic symptoms was available. Association between RT-test and alcohol use was analyzed with log-linear regression, and eβ with 95% confidence intervals (CI) are reported. PAL first trial memory score was analyzed with linear regression, and β with 95% CI are reported. PAL total errors adjusted was analyzed with logistic regression and odds ratios (OR) with 95% CI are reported. After adjustment of age, education, housing status and depression, hazardous drinking was associated with lower median and less variable RT in females while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores in females. Our findings of positive associations between alcohol use and cognition in persons with bipolar disorder are difficult to explain because of the methodological flaw of not being able to separately assess only participants in euthymic phase.
Building Information Modeling Based Building Sustainability Assessment Framework for Kazakhstan
Authors: Akhanova Gulzhanat , Nadeem Abid , Kim Jong R. , Azhar Salman , Khalfan Malik
Published: August 2021

The use of building information modeling (BIM) for building sustainability assessment (BSA) is a thriving topic within the architecture, engineering, and construction industry. Despite the various research approaches to employing BSA with BIM support, the research is limited to the BIM implications of BSA methods in developing countries. This paper presents how BIM can assist the BSA processes in Kazakhstan, using a previously developed building sustainability assessment framework for Kazakhstan (KBSAF). This framework has 46 assessment indicators grouped into nine assessment categories. The categories and assessment indicators of KBSAF were derived considering the regional variations and country-specific differences in the assessment factors. In this paper, BIM functions for BSA were identified through literature review; their applicability for KBSAF was evaluated by mapping the functions with the assessment indicators of KBSAF and a BIM-based BSA framework (BIM-KBSAF) was proposed. The proposed framework was validated through a three-round Delphi survey. One of the results demonstrates that for KBSAF, BIM can assess 24 out of 46 assessment indicators. The proposed framework could serve as a systematic guide to the application of BIM for BSA. Furthermore, it can facilitate the BSA process and save considerable time and effort.
Earthquake Damage Repair Loss Estimation in New Zealand: What Other Variables Are Essential Based on Experts’ Opinions?
Authors: Kahandawa Ravindu K. A. V. D. , Domingo Niluka D. , Chawynski Gregory , Uma S. R.
Published: August 2021

Major earthquakes can cause extensive damage to buildings and alter both the natural and built environments. Accurately estimating the financial impact from these events is complex, and the damage is not always visible to the naked eye. PACT, SLAT, and HAZUS are some of the computer-based tools designed to predict probable damage before an earthquake. However, there are no identifiable models built for post-earthquake use. This paper focuses on verifying the significance and usage of variables that specifically need to be considered for the post-earthquake cost estimation of earthquake damage repair work (CEEDRW). The research was conducted using a questionnaire survey involving 92 participants who have experience in cost estimating earthquake damage repair work in New Zealand. The Weighted Average, Relative Importance Index (RII), and Exploratory Factor Analysis were used to analyse the data. The research verified that eleven major variables that are significant to the CEEDRW and should be incorporated to cost estimation models. Verified variables can be used to develop a post-earthquake repair cost estimation tool and can be used to improve the pre-earthquake loss prediction tools.
Radium-223 Treatment of Patients with Metastatic Castration Resistant Prostate Cancer: Biomarkers for Stratification and Response Evaluation
Authors: van der Zande Kim , Oyen Wim J. G. , Zwart Wilbert , Bergman Andries M.
Published: August 2021

Radium-223 dichloride ([223Ra]RaCl2; Ra-223) is a targeted alpha-emitting radiopharmaceutical which results in an overall survival and health related quality of life (HRQoL) benefit in symptomatic patients with metastatic castration resistant prostate cancer (mCRPC) and predominantly bone metastasis. Although effective, options to select patients who will derive treatment benefit and to monitor and predict treatment outcomes are limited. PSA response and radiographic evaluation are commonly used in mCRPC treatment assessment but are not informative in Ra-223 treated patients. Consequently, there is a clear need for predictive and prognostic tools. In this review, we discuss the physiology of bone metastases and the mechanism of action and efficacy of Ra-223 treatment, as well as offering an outline of current innovative prognostic and predictive biomarkers.
Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer
Authors: Cherkasova Viktoriia , Kovalchuk Olga , Kovalchuk Igor
Published: August 2021

Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world’s disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
Germline CDH1 G212E Missense Variant: Combining Clinical, In Vitro and In Vivo Strategies to Unravel Disease Burden
Authors: Figueiredo Joana , Mercadillo Fátima , Melo Soraia , Barroso Alicia , Gonçalves Margarida , Díaz-Tasende José , Carneiro Patrícia , Robles Luis , Colina Francisco , Ibarrola Carolina , Perea José , Morais-de-Sá Eurico , Seruca Raquel , Urioste Miguel
Published: August 2021

E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metastasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.
Genetic Alterations and Resectability Predict Outcome in Patients with Neuroblastoma Assigned to High-Risk Solely by MYCN Amplification
Authors: Berthold Frank , Ernst Angela , Ackermann Sandra , Bartenhagen Christoph , Christiansen Holger , Hero Barbara , Rosswog Carolina , von Schweinitz Dietrich , Klingebiel Thomas , Schmid Irene , Simon Thorsten , Fischer Matthias
Published: August 2021

Background: To identify variables predicting outcome in neuroblastoma patients assigned to the high-risk group solely by the presence of MYCN oncogene amplification (MNA). Methods: Clinical characteristics, genomic information, and outcome of 190 patients solely assigned to high-risk neuroblastoma by MNA were analyzed and compared to 205 patients with stage 4 neuroblastoma aged ≥18 months with MNA (control group). Results: Event-free survival (EFS) and overall survival (OS) at 10 years were 47% (95%-CI 39–54%) and 56% (95%-CI 49–63%), respectively, which was significantly better than EFS and OS of the control group (EFS 25%, 95%-CI 18–31%, p < 0.001; OS 32% 95%-CI 25–39%, p < 0.001). The presence of RAS-/p53-pathway gene alterations was associated with impaired 10-year EFS and OS (19% vs. 55%, and 19% vs. 67%, respectively; both p < 0.001). In time-dependent multivariable analyses, alterations of RAS-/p53-pathway genes and the extent of the best primary tumor resection were the only independent prognostic variables for OS (p < 0.001 and p = 0.011, respectively). Conclusions: Neuroblastoma patients attributed to high risk solely by MYCN amplification have generally a more favorable outcome. Mutations of genes of the RAS and/or p53 pathways and incomplete resection are the main risk factors predicting poor outcome.
Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance
Authors: Neophytou Christiana M. , Trougakos Ioannis P. , Erin Nuray , Papageorgis Panagiotis
Published: August 2021

The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI3K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype.
miR-22 Modulates Lenalidomide Activity by Counteracting MYC Addiction in Multiple Myeloma
Authors: Caracciolo Daniele , Riillo Caterina , Juli Giada , Scionti Francesca , Todoerti Katia , Polerà Nicoletta , Grillone Katia , Fiorillo Lucia , Arbitrio Mariamena , Di Martino Maria Teresa , Neri Antonino , Tagliaferri Pierosandro , Tassone Pierfrancesco
Published: August 2021

Background: MYC is a master regulator of multiple myeloma (MM) by orchestrating several pro-tumoral pathways, including reprograming of the miRNA transcriptome. MYC is also involved in the acquirement of resistance to anti-MM drugs, including immunomodulatory imide drugs (IMiDs). Methods: In silico analysis was performed on MM proprietary and on public MMRF-CoMMpass datasets. Western blot and chromatin immunoprecipitation (ChIP) experiments were performed to validate miR-22 repression induced by MYC. Cell viability and apoptosis assays were used to evaluate lenalidomide sensitization after miR-22 overexpression. Results: We found an inverse correlation between MYC and miR-22 expression, which is associated with poor outcome in IMiD-treated MM patients. Mechanistically, we showed that MYC represses transcription of miR-22, which, in turn, targets MYC, thus establishing a feed-forward loop. Interestingly, we found that IMiD lenalidomide increases miR-22 expression by reducing MYC repression and, most importantly, that the combination of lenalidomide with miR-22 mimics results in a synergistic direct and NK-mediated cytotoxic activity. Conclusions: Taken together, our findings indicate that: (1) low miR-22 expression could represent a potential predictive biomarker of poor lenalidomide response in MM patients; and (2) miR-22 reduces MYC oncogenic activity, thus triggering a novel synthetic lethality loop, which sensitizes MM cells to lenalidomide.
Broad-Spectrum Antibiotic Use and Disease Progression in Early-Stage Melanoma Patients: A Retrospective Cohort Study
Authors: Acharya Mahip , Kim Thomas , Li Chenghui
Published: August 2021

Animal studies and a few clinical studies have reported mixed findings on the association between antibiotics and cancer incidence. Antibiotics may inhibit tumor cell growth, but could also alter the gut-microbiome-modulated immune system and increase the risk of cancer. Studies that assess how antibiotics affect the progression of cancer are limited. We evaluated the association between broad-spectrum antibiotic use and melanoma progression. We conducted a retrospective cohort study using IQVIA PharMetrics® Plus data (2008–2018). We identified patients with malignant melanoma who underwent wide local excision or Mohs micrographic surgery within 90 days of first diagnosis. Surgery date was the index date. Patients were excluded if they had any other cancer diagnosis or autoimmune disorders in 1 year before the index date (“baseline”). Exposure to broad-spectrum antibiotics was identified in three time windows using three cohorts: 3 months prior to the index date, 1 month after the index date, and 3 months after the index date. The covariates were patients’ demographic and clinical characteristics identified in the 1-year baseline period. The patients were followed from the index date until cancer progression, loss of enrollment, or the end of 2 years after the index date. Progression was defined as: (i) any hospice care after surgery, (ii) a new round of treatment for melanoma (surgery, chemotherapy, immunotherapy, targeted therapy, or radiotherapy) 180 days after prior treatment, or (iii) a metastasis diagnosis or a diagnosis of a new nonmelanoma primary cancer at least 180 days after first melanoma diagnosis or prior treatment. A high-dimensional propensity score approach with inverse weighting was used to adjust for the patients’ baseline differences. Cox proportional hazard regression was used for estimating the association. The final samples included 3930, 3831, and 3587 patients (mean age: 56 years). Exposure to antibiotics was 16% in the prior-3-months, 22% in the post-1-month, and 22% in the post-3-months. In the pre-3-months analysis, 9% of the exposed group and 9% of the unexposed group had progressed. Antibiotic use was not associated with melanoma progression (HR: 0.81; 95% CI: 0.57–1.14). However, antibiotic use in subsequent 1 month and subsequent 3 months was associated with 31% reduction (HR: 0.69; 95% CI: 0.51–0.92) and 32% reduction (HR: 0.68; 95% CI: 0.51–0.91) in progression, respectively. In this cohort of patients with likely early-stage melanoma cancer, antibiotic use in 1 month and 3 months after melanoma surgery was associated with a lower risk of melanoma progression. Future studies are warranted to validate the findings.
Enhancement of Neuroblastoma NK-Cell-Mediated Lysis through NF-kB p65 Subunit-Induced Expression of FAS and PVR, the Loss of Which Is Associated with Poor Patient Outcome
Authors: Brandetti Elisa , Focaccetti Chiara , Pezzolo Annalisa , Ognibene Marzia , Folgiero Valentina , Cotugno Nicola , Benvenuto Monica , Palma Paolo , Manzari Vittorio , Rossi Paolo , Fruci Doriana , Bei Roberto , Cifaldi Loredana
Published: August 2021

High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of FAS and/or PVR genes correlated with low survival independently of the disease stage. Our data identify the status of the FAS and PVR genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB.
Sterculic Acid Alters Adhesion Molecules Expression and Extracellular Matrix Compounds to Regulate Migration of Lung Cancer Cells
Authors: Peláez Rafael , Ochoa Rodrigo , Pariente Ana , Villanueva-Martínez Ángela , Pérez-Sala Álvaro , Larráyoz Ignacio M.
Published: August 2021

Sterculic acid (SA) is a cyclopropenoid fatty acid isolated from Sterculia foetida seeds. This molecule is a well-known inhibitor of SCD1 enzyme, also known as ∆9-desaturase, which main function is related to lipid metabolism. However, recent studies have demonstrated that it also modifies many other pathways and the underlying gene expression. SCD overexpression, or up-regulated activity, has been associated with tumor aggressiveness and poor prognosis in many cancer types. Scd1 down-regulation, with different inhibitors or molecular strategies, reduces tumor cell survival and cell proliferation, as well as the chemoresistance associated with cancer stem cell presence. However, SA effects over cancer cell migration and extracellular matrix or adhesion molecules have not been described in cancer cells up to now. We used different migration assays and qPCR gene expression analysis to evaluate the effects of SA treatment in cancer cells. The results reveal that SA induces tumoral cell death at high doses, but we also observed that lower SA-treatments induce cell adhesion-migration capacity reduction as a result of modifications in the expression of genes related to integrins and extracellular matrix compounds. Overall, the functional and transcriptomic findings suggest that SA could represent a new inhibitor activity of epithelial to mesenchymal transition.
Contrast-Enhanced Mammographic Features of In Situ and Invasive Ductal Carcinoma Manifesting Microcalcifications Only: Help to Predict Underestimation?
Authors: Cheung Yun-Chung , Chen Kueian , Yu Chi-Chang , Ueng Shir-Hwa , Li Chia-Wei , Chen Shin-Cheh
Published: August 2021

Background: The contrast-enhanced mammographic features of ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) manifesting microcalcifications only on mammograms were evaluated to determine whether they could predict IDC underestimation. Methods: We reviewed patients who underwent mammography-guided biopsy on suspicious breast microcalcifications only and received contrast-enhanced spectral mammography (CESM) within 2 weeks before the biopsy. Those patients who were proven to have cancers (DCIS or IDC) by biopsy and subsequently had surgical treatment in our hospital were included for analysis. The presence or absence, size, morphology and texture of enhancement on contrast-enhanced spectral mammography were reviewed by consensus of two radiologists. Results: A total of 49 patients were included for analysis. Forty patients (81.6%) showed enhancement, including 18 (45%) DCIS and 22 (55%) IDC patients. All nine unenhanced cancers were pure DCIS. Pure DCIS showed 72.22% nonmass enhancement and 83.33% pure ground glass enhancement. IDC showed more mass (72.2% vs. 27.8%) and solid enhancements (83.33% vs. 16.67%). The cancer and texture of enhancement were significantly different between pure DCIS and IDC, with moderate diagnostic performance for the former (p-value < 0.01, AUC = 0.66, sensitivity = 93%, specificity = 39%) and the latter (p-value < 0.01, AUC = 0.74, sensitivity = 65%, specificity = 83%). Otherwise, pure DCIS showed a significant difference in enhanced texture compared with upgraded IDC and IDC (p = 0.0226 and 0.0018, respectively). Conclusions: Nonmass and pure ground glass enhancements were closely related to pure DCIS, and cases showing mass and unpurified solid enhancements should be suspected as IDC. Unenhanced DCIS with microcalcifications only has a low DCIS upgrade rate. The CESM-enhanced features could feasibly predict IDC underestimation.
Glutamine Availability Controls BCR/Abl Protein Expression and Functional Phenotype of Chronic Myeloid Leukemia Cells Endowed with Stem/Progenitor Cell Potential
Authors: Poteti Martina , Menegazzi Giulio , Peppicelli Silvia , Tusa Ignazia , Cheloni Giulia , Silvano Angela , Mancini Caterina , Biagioni Alessio , Tubita Alessandro , Mazure Nathalie M. , Lulli Matteo , Rovida Elisabetta , Dello Sbarba Persio
Published: August 2021

This study was directed to characterize the role of glutamine in the modulation of the response of chronic myeloid leukemia (CML) cells to low oxygen, a main condition of hematopoietic stem cell niches of bone marrow. Cells were incubated in atmosphere at 0.2% oxygen in the absence or the presence of glutamine. The absence of glutamine markedly delayed glucose consumption, which had previously been shown to drive the suppression of BCR/Abl oncoprotein (but not of the fusion oncogene BCR/abl) in low oxygen. Glutamine availability thus emerged as a key regulator of the balance between the pools of BCR/Abl protein-expressing and -negative CML cells endowed with stem/progenitor cell potential and capable to stand extremely low oxygen. These findings were confirmed by the effects of the inhibitors of glucose or glutamine metabolism. The BCR/Abl-negative cell phenotype is the best candidate to sustain the treatment-resistant minimal residual disease (MRD) of CML because these cells are devoid of the molecular target of the BCR/Abl-active tyrosine kinase inhibitors (TKi) used for CML therapy. Therefore, the treatments capable of interfering with glutamine action may result in the reduction in the BCR/Abl-negative cell subset sustaining MRD and in the concomitant rescue of the TKi sensitivity of CML stem cell potential. The data obtained with glutaminase inhibitors seem to confirm this perspective.
Socio-Territorial Inequities in the French National Breast Cancer Screening Programme—A Cross-Sectional Multilevel Study
Authors: Rollet Quentin , Guillaume Élodie , Launay Ludivine , Launoy Guy
Published: August 2021

Background. France implemented in 2004 the French National Breast Cancer Screening Programme (FNBCSP). Despite national recommendations, this programme coexists with non-negligible opportunistic screening practices. Aim. Analyse socio-territorial inequities in the 2013–2014 FNBCSP campaign in a large sample of the eligible population. Method. Analyses were performed using three-level hierarchical generalized linear model. Level one was a 10% random sample of the eligible population in each département (n = 397,598). For each woman, age and travel time to the nearest accredited radiology centre were computed. These observations were nested within 22,250 residential areas called “Îlots Regroupés pour l’Information Statistique” (IRIS), for which the European Deprivation Index (EDI) is defined. IRIS were nested within 41 départements, for which opportunistic screening rates and gross domestic product based on purchasing power parity were available, deprivation and the number of radiology centres for 100,000 eligible women were computed. Results. Organized screening uptake increased with age (OR1SD = 1.05 [1.04–1.06]) and decreased with travel time (OR1SD = 0.94 [0.93–0.95]) and EDI (OR1SD = 0.84 [0.83–0.85]). Between départements, organized screening uptake decreased with opportunistic screening rate (OR1SD = 0.84 [0.79–0.87]) and départements deprivation (OR1SD = 0.91 [0.88–0.96]). Association between EDI and organized screening uptake was weaker as opportunistic screening rates and as département deprivation increased. Heterogeneity in FNBCSP participation decreased between IRIS by 36% and between départements by 82%. Conclusion. FNBCSP does not erase socio-territorial inequities. The population the most at risk of dying from breast cancer is thus the less participating. More efforts are needed to improve equity.
Targeting Amino Acid Metabolic Reprogramming via L-Type Amino Acid Transporter 1 (LAT1) for Endocrine-Resistant Breast Cancer
Authors: Shindo Haruhiko , Harada-Shoji Narumi , Ebata Akiko , Sato Miku , Soga Tomoyoshi , Miyashita Minoru , Tada Hiroshi , Kawai Masaaki , Kosaka Shinkichi , Onuki Koji , Usami Shin , Furumoto Shozo , Hayashi Shinichi , Abe Takaaki , Suzuki Takashi , Ishida Takanori , Sasano Hironobu
Published: August 2021

The PI3K/Akt/mTOR pathway has been well known to interact with the estrogen receptor (ER)-pathway and to be also frequently upregulated in aromatase inhibitor (AI)-resistant breast cancer patients. Intracellular levels of free amino acids, especially leucine, regulate the mammalian target of rapamycin complex 1 (mTORC1) activation. L-type amino acid transporters such as LAT1 and LAT3 are associated with the uptake of essential amino acids. LAT1 expression could mediate leucine uptake, mTORC1 signaling, and cell proliferation. Therefore, in this study, we explored amino acid metabolism, including LAT1, in breast cancer and clarified the potential roles of LAT1 in the development of therapeutic resistance and the eventual clinical outcome of the patients. We evaluated LAT1 and LAT3 expression before and after neoadjuvant hormone therapy (NAH) and examined LAT1 function and expression in estrogen deprivation-resistant (EDR) breast carcinoma cell lines. Tumors tended to be in advanced stages in the cases whose LAT1 expression was high. LAT1 expression in the EDR cell lines was upregulated. JPH203, a selective LAT1 inhibitor, demonstrated inhibitory effects on cell proliferation in EDR cells. Hormone therapy changed the tumor microenvironment and resulted in metabolic reprogramming through inducing LAT1 expression. LAT1 expression then mediated leucine uptake, enhanced mTORC1 signaling, and eventually resulted in AI resistance. Therefore, LAT1 could be the potential therapeutic target in AI-resistant breast cancer patients.
Whole-Genome Analysis of De Novo Somatic Point Mutations Reveals Novel Mutational Biomarkers in Pancreatic Cancer
Authors: Ghareyazi Amin , Mohseni Amir , Dashti Hamed , Beheshti Amin , Dehzangi Abdollah , Rabiee Hamid R. , Alinejad-Rokny Hamid
Published: August 2021

It is now known that at least 10% of samples with pancreatic cancers (PC) contain a causative mutation in the known susceptibility genes, suggesting the importance of identifying cancer-associated genes that carry the causative mutations in high-risk individuals for early detection of PC. In this study, we develop a statistical pipeline using a new concept, called gene-motif, that utilizes both mutated genes and mutational processes to identify 4211 3-nucleotide PC-associated gene-motifs within 203 significantly mutated genes in PC. Using these gene-motifs as distinguishable features for pancreatic cancer subtyping results in identifying five PC subtypes with distinguishable phenotypes and genotypes. Our comprehensive biological characterization reveals that these PC subtypes are associated with different molecular mechanisms including unique cancer related signaling pathways, in which for most of the subtypes targeted treatment options are currently available. Some of the pathways we identified in all five PC subtypes, including cell cycle and the Axon guidance pathway are frequently seen and mutated in cancer. We also identified Protein kinase C, EGFR (epidermal growth factor receptor) signaling pathway and P53 signaling pathways as potential targets for treatment of the PC subtypes. Altogether, our results uncover the importance of considering both the mutation type and mutated genes in the identification of cancer subtypes and biomarkers.