bluuebunny/crossref_metadata_2025 huggingface dataset:
Nanodiamonds: Synthesis and Application in Sensing, Catalysis, and the Possible Connection with Some Processes Occurring in Space
Authors: Basso Luca , Cazzanelli Massimo , Orlandi Michele , Miotello Antonio
Published: June 2020

The relationship between the unique characteristics of nanodiamonds (NDs) and the fluorescence properties of nitrogen-vacancy (NV) centers has lead to a tool with quantum sensing capabilities and nanometric spatial resolution; this tool is able to operate in a wide range of temperatures and pressures and in harsh chemical conditions. For the development of devices based on NDs, a great effort has been invested in researching cheap and easily scalable synthesis techniques for NDs and NV-NDs. In this review, we discuss the common fluorescent NDs synthesis techniques as well as the laser-assisted production methods. Then, we report recent results regarding the applications of fluorescent NDs, focusing in particular on sensing of the environmental parameters as well as in catalysis. Finally, we underline that the highly non-equilibrium processes occurring in the interactions of laser-materials in controlled laboratory conditions for NDs synthesis present unique opportunities for investigation of the phenomena occurring under extreme thermodynamic conditions in planetary cores or under warm dense matter conditions.
Insignificant Impact of the “Stay-At-Home” Order on Ambient Air Quality in the Memphis Metropolitan Area, U.S.A.
Authors: Jia Chunrong , Fu Xianqiang , Bartelli Debra , Smith Larry
Published: June 2020

The lockdowns due to the COVID-19 pandemic have been reported to reduce ambient air pollution in many cities globally. This study aims to examine whether air pollution dropped in Memphis, a typical U.S. metropolitan city and transportation hub, during the lockdown from 25 March to 4 May, 2020. Daily air pollution data measured at five representative monitoring stations in the Memphis Metropolitan Area were downloaded from the U.S. Environmental Protection Agency’s Air Quality System. The mean concentrations of fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone during the lockdown were compared with the baseline concentrations measured during the same periods in 2017–2019 using linear regression models. The average vehicle miles traveled (VMT) reduced by 57% in this region during the lockdown compared to that during 1–24 March, 2020. The mean (± standard deviation) concentrations of PM2.5, NO2, and ozone were 7.5 ± 2.6 μg/m3, 16.5 ± 9.4 ppb, and 44.5 ± 8.4 ppb, respectively, during the lockdown. They did not statistically differ from the baseline concentrations, nor were they lower than the mean concentrations in the prior month (25 February–24 March, 2020), after accounting for meteorological conditions. The lack of effect could be explained by the small contribution of traffic emissions to air pollution. The results suggest that the “stay-at-home” order had an insignificant impact on reducing air pollution in Memphis.
The Effects of the Early Start Denver Model for Children with Autism Spectrum Disorder: A Meta-Analysis
Authors: Fuller Elizabeth A. , Oliver Kelsey , Vejnoska Sarah F. , Rogers Sally J.
Published: June 2020

This meta-analysis examined the effects of the Early Start Denver Model (ESDM) for young children with autism on developmental outcome measures. The 12 included studies reported results from 640 children with autism across 44 unique effect sizes. The aggregated effect size, calculated using a robust variance estimation meta-analysis, was 0.357 (p = 0.024), which is a moderate effect size with a statistically significant overall weighted averaged that favored participants who received the ESDM compared to children in control groups, with moderate heterogeneity across studies. This result was largely driven by improvements in cognition (g = 0.412) and language (g = 0.408). There were no significant effects observed for measures of autism symptomology, adaptive behavior, social communication, or restrictive and repetitive behaviors.
Experimental and Clinical Treatment of Subarachnoid Hemorrhage after the Rupture of Saccular Intracranial Aneurysms
Authors: Marbacher Serge , Zhang John H.
Published: June 2020

The Special Issue “Experimental and Clinical Treatment of Subarachnoid Hemorrhage after the Rupture of Saccular Intracranial Aneurysms” provides an excellent insight into the many facets of aneurysmal subarachnoid hemorrhage [...]
Uniportal Full Endoscopic Posterolateral Transforaminal Lumbar Interbody Fusion with Endoscopic Disc Drilling Preparation Technique for Symptomatic Foraminal Stenosis Secondary to Severe Collapsed Disc Space: A Clinical and Computer Tomographic Study with Technical Note
Authors: Wu Pang Hung , Kim Hyeun Sung , Lee Yeon Jin , Kim Dae Hwan , Lee Jun Hyung , Jeon Jun Bok , Raorane Harshavardhan Dilip , Jang Il-Tae
Published: June 2020

Background: Severe collapsed disc secondary to degenerative spinal conditions leads to significant foraminal stenosis. We hypothesized that uniportal posterolateral transforaminal lumbar interbody fusion with endoscopic disc drilling technique could be safely applied to the collapsed disc space to improve patients’ pain score, restore disc height, and correct the segmental angular parameters. Methods: We included patients who met the indication criteria for lumbar fusion and underwent uniportal full endoscopic posterolateral transforaminal lumbar interbody fusion with pre-operative Computer Tomography mid disc height of less than or equal to 5 mm and MRI of Grade 3 Foraminal Stenosis. Visual analogue scale and computer tomography pre-operative and post-operative sagittal disc height in the anterior, middle and posterior part of the disc; sagittal focal segmental angle; mid coronal disc height and coronal wedge angles were evaluated. Results: 30 levels of Endo-TLIF were included, with a mean follow up of 12 months. The mean improvement in decreasing pain score was 2.5 ± 1.1, 3.2 ± 0.9 and 4.3 ± 1.0 at 1 week post operation, 3 months post operation and at final follow up, respectively, p < 0.05. There was significant increase in mid sagittal computer tomographic anterior, middle and posterior disc height of 6.99 ± 2.30, 6.28 ± 1.44, 5.12 ± 1.79 mm respectively, p < 0.05. CT mid coronal disc height showed an increase of 7.13 ± 1.90 mm, p < 0.05. There was a significant improvement in the CT coronal wedge angle of 2.35 ± 4.73 and the CT segmental focal sagittal angle of 1.98 ± 4.69, p < 0.05. Conclusion: Application of Uniportal Endoscopic Posterolateral Lumbar Interbody Fusion in patients with severe foraminal stenosis secondary to severe collapsed disc space significantly relieved patients’ pain and restored disc height without early subsidence or exiting nerve root dysesthesia in our cohort of patients.
Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights
Authors: Chiabotto Giulia , Grignani Giovanni , Todorovic Maja , Martin Valentina , Centomo Maria Laura , Prola Elisa , Giordano Giorgia , Merlini Alessandra , Miglio Umberto , Berrino Enrico , Napione Lucia , Isella Claudio , Capozzi Federica , Basiricò Marco , Marsero Cristina , Gerardi Ilaria , Venesio Tiziana , Sangiolo Dario , Aglietta Massimo , D’Ambrosio Lorenzo , Pignochino Ymera
Published: June 2020

Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.
New Anti-Cancer Strategy to Suppress Colorectal Cancer Growth Through Inhibition of ATG4B and Lysosome Function
Authors: Fu Yuanyuan , Gu Qianqian , Luo Li , Xu Jiecheng , Luo Yuping , Xia Fan , Han Fanghai , Hong Liang , Yin Xiao-Ming , Huang Zhiying , Li Min
Published: June 2020

Autophagy inhibition has been proposed to be a potential therapeutic strategy for cancer, however, few autophagy inhibitors have been developed. Recent studies have indicated that lysosome and autophagy related 4B cysteine peptidase (ATG4B) are two promising targets in autophagy for cancer therapy. Although some inhibitors of either lysosome or ATG4B were reported, there are limitations in the use of these single target compounds. Considering multi-functional drugs have advantages, such as high efficacy and low toxicity, we first screened and validated a batch of compounds designed and synthesized in our laboratory by combining the screening method of ATG4B inhibitors and the identification method of lysosome inhibitors. ATG4B activity was effectively inhibited in vitro. Moreover, 163N inhibited autophagic flux and caused the accumulation of autolysosomes. Further studies demonstrated that 163N could not affect the autophagosome-lysosome fusion but could cause lysosome dysfunction. In addition, 163N diminished tumor cell viability and impaired the development of colorectal cancer in vivo. The current study findings indicate that the dual effect inhibitor 163N offers an attractive new anti-cancer drug and compounds having a combination of lysosome inhibition and ATG4B inhibition are a promising therapeutic strategy for colorectal cancer therapy.
Mass Spectrometric Comparison of HPV-Positive and HPV-Negative Oropharyngeal Cancer
Authors: Wurlitzer Marcus , Möckelmann Nikolaus , Kriegs Malte , Vens Maren , Omidi Maryam , Hoffer Konstantin , von Bargen Clara , Möller-Koop Christina , Witt Melanie , Droste Conrad , Oetting Agnes , Petersen Hannes , Busch Chia-Jung , Münscher Adrian , Schlüter Hartmut , Clauditz Till Sebastian , Rieckmann Thorsten
Published: June 2020

Squamous cell carcinoma of the head and neck (HNSCC) consist of two distinct biological entities. While the numbers of classical, tobacco-induced HNSCC are declining, tumors caused by human papillomavirus (HPV) infection are increasing in many countries. HPV-positive HNSCC mostly arise in the oropharynx and are characterized by an enhanced sensitivity towards radiotherapy and a favorable prognosis. To identify molecular differences between both entities on the protein level, we conducted a mass spectrometric comparison of eight HPV-positive and nine HPV-negative oropharyngeal tumors (OPSCC). Overall, we identified 2051 proteins, of which 31 were found to be differentially expressed. Seventeen of these can be assorted to three functional groups, namely DNA replication, nuclear architecture and cytoskeleton regulation, with the differences in the last group potentially reflecting an enhanced migratory and invasive capacity. Furthermore, a number of identified proteins have been described to directly impact on DNA double-strand break repair or radiation sensitivity (e.g., SLC3A2, cortactin, RBBP4, Numa1), offering explanations for the differential prognosis. The unequal expression of three proteins (SLC3A2, MCM2 and lamin B1) was confirmed by immunohistochemical staining using a tissue microarray containing 205 OPSCC samples. The expression levels of SLC3A2 and lamin B1 were found be of prognostic relevance in patients with HPV-positive and HPV-negative OPSCC, respectively.
Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients
Authors: Peng Hong , Pan Sheng , Yan Yuanqing , Brand Randall E. , Petersen Gloria M. , Chari Suresh T. , Lai Lisa A. , Eng Jimmy K. , Brentnall Teresa A. , Chen Ru
Published: June 2020

Background: Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population. Methods: A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels. Results: Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels. Conclusions: Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
microRNAs and Markers of Neutrophil Activation as Predictors of Early Incidental Post-Surgical Pulmonary Embolism in Patients with Intracranial Tumors
Authors: Oto Julia , Plana Emma , Solmoirago María José , Fernández-Pardo Álvaro , Hervás David , Cana Fernando , España Francisco , Artoni Andrea , Bucciarelli Paolo , Carrabba Giorgio , Navarro Silvia , Merati Giuliana , Medina Pilar
Published: June 2020

Venous thromboembolism (VTE) is a common complication of cancer that severely increases morbidity and mortality. Patients with intracranial tumors are more likely to develop VTE than patients with cancers at other sites. Conversely, limited tools exist to identify patients with high thrombotic risk. Upon activation, neutrophils release their content through different mechanisms triggering thrombosis. We explored the ability of microRNAs (miRNAs) and plasma markers of neutrophil activation measured before surgery to predict the risk of early post-surgical pulmonary embolism (PE) in glioma and meningioma patients. We recruited and prospectively followed 50 patients with glioma and 50 with meningioma, 34% of whom in each group developed an early objectively-diagnosed post-surgical PE. We measured miRNA expression and neutrophil markers (cell-free DNA, nucleosomes, calprotectin and myeloperoxidase) before surgery. In glioma patients, we adjusted and validated a predictive model for post-surgical PE with 6 miRNAs: miR-363-3p, miR-93-3p, miR-22-5p, miR-451a, miR-222-3p and miR-140-3p (AUC = 0.78; 95% Confidence Interval (CI) [0.63, 0.94]) and another with cfDNA and myeloperoxidase as predictors (AUC = 0.71; 95% CI [0.52, 0.90]). Furthermore, we combined both types of markers and obtained a model with myeloperoxidase and miR-140-3p as predictors (AUC = 0.79; 95% CI [0.64, 0.94]). In meningioma patients we fitted and validated a predictive model with 6 miRNAs: miR-29a-3p, miR-660-5p, miR-331-3p, miR-126-5p, miR-23a-3p and miR-23b-3p (AUC = 0.69; 95% CI [0.52, 0.87]). All our models outperformed the Khorana score. This is the first study that analyzes the capability of plasma miRNAs and neutrophil activation markers to predict early post-surgical PE in glioma and meningioma patients. The estimation of the thrombotic risk before surgery may promote a tailored thromboprophylaxis in a selected group of high-risk patients, in order to minimize the incidence of PE and avoid bleedings.
Absence of HTATIP2 Expression in A549 Lung Adenocarcinoma Cells Promotes Tumor Plasticity in Response to Hypoxic Stress
Authors: Li Minghua , Li Jing , Guo Xiaofang , Pan Hua , Zhou Qingyu
Published: June 2020

HIV-1 Tat Interactive Protein 2 (HTATIP2) is a tumor suppressor, of which reduced or absent expression is associated with increased susceptibility to tumorigenesis and enhanced tumor invasion and metastasis. However, whether the absent expression of HTATIP2 is a tumor-promoting factor that acts through improving tumor adaptation to hypoxia is unclear. Here, we established a stable HTATIP2-knockdown A549 human lung adenocarcinoma cell line (A549shHTATIP2) using lentiviral-delivered HTATIP2-targeting short hairpin RNA (shRNA), employed a double subcutaneous xenograft model and incorporated photoacoustic imaging and metabolomics approaches to elucidate the impact of the absent HTATIP2 expression on tumor response to hypoxic stress. Results from the in vivo study showed that A549shHTATIP2 tumors exhibited accelerated growth but decreased intratumoral oxygenation and angiogenesis and reduced sensitivity to sorafenib treatment as compared with their parental counterparts. Moreover, results of the immunoblot and real-time PCR analyses revealed that the HIF2α protein and mRNA levels in vehicle-treated A549shHTATIP2 tumors were significantly increased (p < 0.01 compared with the parental control tumors). Despite the strong HIF2α-c-Myc protein interaction indicated by our co-immunoprecipitation data, the increase in the c-Myc protein and mRNA levels was not significant in the A549shHTATIP2 tumors. Nonetheless, MCL-1 and β-catenin protein levels in A549shHTATIP2 tumors were significantly increased (p < 0.05 compared with the parental control tumors), suggesting an enhanced β-catenin/c-Myc/MCL-1 pathway in the absence of HTATIP2 expression. The finding of significantly decreased E-cadherin (p < 0.01 compared with vehicle-treated A549shHTATIP2 tumors) and increased vimentin (p < 0.05 compared with sorafenib-treated A549 tumors) protein levels in A549shHTATIP2 tumors implicates that the absence of HTATIP2 expression increases the susceptibility of A549 tumors to sorafenib-activated epithelial-mesenchymal transition (EMT) process. Comparison of the metabolomic profiles between A549 and A549shHTATIP2 tumors demonstrated that the absence of HTATIP2 expression resulted in increased tumor metabolic plasticity that enabled tumor cells to exploit alternative metabolic pathways for survival and proliferation rather than relying on glutamine and fatty acids as a carbon source to replenish TCA cycle intermediates. Our data suggest a mechanism by which the absent HTATIP2 expression modulates tumor adaptation to hypoxia and promotes an aggressive tumor phenotype by enhancing the HIF2α-regulated β-catenin/c-Myc/MCL-1 signaling, increasing the susceptibility of tumors to sorafenib treatment-activated EMT process, and improving tumor metabolic plasticity.
The Tristetraprolin Family of RNA-Binding Proteins in Cancer: Progress and Future Prospects
Authors: Saini Yogesh , Chen Jian , Patial Sonika
Published: June 2020

Post-transcriptional regulation of gene expression plays a key role in cellular proliferation, differentiation, migration, and apoptosis. Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer. The tristetraprolin family of RNA-binding proteins (RBPs), which include Zinc Finger Protein 36 (ZFP36; commonly referred to as tristetraprolin (TTP)), Zinc Finger Protein 36 like 1 (ZFP36L1), and Zinc Finger Protein 36 like 2 (ZFP36L2), play key roles in the post-transcriptional regulation of gene expression. Mechanistically, these proteins function by binding to the AU-rich elements within the 3′-untranslated regions of their target mRNAs and, in turn, increasing mRNA turnover. The TTP family RBPs are emerging as key regulators of multiple biological processes relevant to cancer and are aberrantly expressed in numerous human cancers. The TTP family RBPs have tumor-suppressive properties and are also associated with cancer prognosis, metastasis, and resistance to chemotherapy. Herein, we summarize the various hallmark molecular traits of cancers that are reported to be regulated by the TTP family RBPs. We emphasize the role of the TTP family RBPs in the regulation of trait-associated mRNA targets in relevant cancer types/cell lines. Finally, we highlight the potential of the TTP family RBPs as prognostic indicators and discuss the possibility of targeting these TTP family RBPs for therapeutic benefits.
Neutrophil Extracellular Traps (NETs) Promote Pro-Metastatic Phenotype in Human Breast Cancer Cells through Epithelial–Mesenchymal Transition
Authors: Martins-Cardoso Karina , Almeida Vitor H. , Bagri Kayo M. , Rossi Maria Isabel Doria , Mermelstein Claudia S. , König Sandra , Monteiro Robson Q.
Published: June 2020

Neutrophil extracellular traps (NETs) have been associated with several steps of tumor progression, including primary growth and metastasis. One of the key features for the acquisition of the metastatic ability is the epithelial–mesenchymal transition (EMT), a complex cellular program. In this study, we evaluated the ability of isolated NETs in modulating the pro-metastatic phenotype of human breast cancer cells. Tumor cells were treated with isolated NETs and then samples were generated for cell migration, quantitative RT-PCR, western blotting, immunofluorescence, and flow cytometry assays. RNA-seq data from The Cancer Genome Atlas (TCGA) database were assessed. NETs changed the typical epithelial morphology of MCF7 cells into a mesenchymal phenotype, a process that was accompanied by enhanced migratory properties. Additional EMT traits were observed: increased expression of N-cadherin and fibronectin, while the E-cadherin expression was repressed. Notably, NETs positively regulated the gene expression of several factors linked to the pro-inflammatory and pro-metastatic properties. Analyses of TCGA data showed that samples from breast cancer patients exhibit a significant correlation between pro-tumoral and neutrophil signature gene expression, including several EMT and pro-metastatic factors. Therefore, NETs drive pro-metastatic phenotype in human breast cancer cells through the activation of the EMT program.
The Evolution of Care of Cancers of the Head and Neck Region: State of the Science in 2020
Authors: Yan Flora , Knochelmann Hannah M. , Morgan Patrick F. , Kaczmar John M. , Neskey David M. , Graboyes Evan M. , Nguyen Shaun A. , Ogretmen Besim , Sharma Anand K. , Day Terry A.
Published: June 2020

Cancers that arise in the head and neck region are comprised of a heterogeneous group of malignancies that include carcinogen- and human papillomavirus (HPV)-driven mucosal squamous cell carcinoma as well as skin cancers such as cutaneous squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma. These malignancies develop in critical areas for eating, talking, and breathing and are associated with substantial morbidity and mortality despite advances in treatment. Understanding of advances in the management of these various cancers is important for all multidisciplinary providers who care for patients across the cancer care continuum. Additionally, the recent Coronavirus Disease 2019 (COVID-19) pandemic has necessitated adaptations to head and neck cancer care to accommodate the mitigation of COVID-19 risk and ensure timely treatment. This review explores advances in diagnostic criteria, prognostic factors, and management for subsites including head and neck squamous cell carcinoma and the various forms of skin cancer (basal cell carcinoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, and melanoma). Then, this review summarizes emerging developments in immunotherapy, radiation therapy, cancer survivorship, and the delivery of care during the COVID-19 era.
Epidemiology of Signet Ring Cell Adenocarcinomas
Authors: Benesch Matthew G.K. , Mathieson Alexander
Published: June 2020

Signet ring cell adenocarcinomas (SRCCs) are a rare histological subtype of adenocarcinomas with a poor prognosis, typically due to advanced disease at diagnosis. A signet ring cell, mimicking its moniker, contains abundant intracytoplasmic mucin that pushes the nucleus to the periphery. In these cancers, this cell feature comprises more than 50% of the tumor. Despite predilection for the gastrointestinal tract, and in particular the stomach, primary SRCCs are also described in other sites, typically in case reports. This literature, however, lacks a standardized overview of the SRCC disease entity. Using a retrospective cohort approach, we summarize the clinicodemographic and mortality outcomes of SRCCs in thirteen primary sites, comprising 95% of all SRCCs in the Surveillance, Epidemiology, and End Results Program (SEER), a population-level cancer database covering nearly one-third of the United States population. SRCCs general trends compared to matching nonvariant adenocarcinomas are earlier age of onset, with initial presentation favoring higher rates of regional or distant disease presentation and poor tumor differentiation. After multivariable analysis, SRCCs typically have worse overall survivals, but substantial variances exist depending on tumor location. Identifying SRCCs at earlier disease stages is likely the single most important intervention to improving outcomes for these patients.
Clinical Applications of Molecular Biomarkers in Prostate Cancer
Authors: Couñago Felipe , López-Campos Fernando , Díaz-Gavela Ana Aurora , Almagro Elena , Fenández-Pascual Esaú , Henríquez Iván , Lozano Rebeca , Linares Espinós Estefanía , Gómez-Iturriaga Alfonso , de Velasco Guillermo , Quintana Franco Luis Miguel , Rodríguez-Melcón Ignacio , López-Torrecilla José , Spratt Daniel E. , Guerrero Luis Leonardo , Martínez-Salamanca Juan Ignacio , del Cerro Elia
Published: June 2020

There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice.
Low-Dose Aspirin Use Significantly Improves the Survival of Late-Stage NPC: A Propensity Score-Matched Cohort Study in Taiwan
Authors: Luo Sheng-Dean , Chen Wei-Chih , Wu Ching-Nung , Yang Yao-Hsu , Li Shau-Hsuan , Fang Fu-Min , Huang Tai-Lin , Wang Yu-Ming , Chiu Tai-Jan , Wu Shao-Chun
Published: June 2020

Background: Aspirin use has been associated with improved survival rates in various cancers. However, it remains unclear if aspirin confers a survival benefit on patients with nasopharyngeal carcinoma (NPC). The aim of this study was to assess the associations between aspirin use and survival in different stages of NPC. Methods: This is a 10-year retrospective cohort study of NPC patients. A total of 565 NPC patients were recruited after we performed a 1:4 propensity score match between aspirin users and non–users. Cox regression models with adjusted covariates were employed to evaluate factors that influence the survival rate of NPC patients. Results: The Kaplan-Meier analysis revealed that the overall survival (p < 0.0001) and disease-specific survival (p < 0.0001) rates of 180-day aspirin users increased. Increased survival rates were also observed in 180-day aspirin users with Stages III and IV, T, N1 and 2, and N3 categories. Cox regression models indicated that factors, including aspirin use (univariate: HR = 0.28, 95% CI = 0.14–0.55, p < 0.001; multivariate: HR = 0.23, 95% CI = 0.12–0.46, p < 0.001), were independent prognostic factors for survival. Conclusions: Aspirin use for more than 180 days is associated with an increased survival rate and is a positive independent prognostic factor in NPC.
Monoclonal Gammopathy of Undetermined Significance (MGUS)—Not So Asymptomatic after All
Authors: Lomas Oliver C. , Mouhieddine Tarek H. , Tahri Sabrin , Ghobrial Irene M.
Published: June 2020

Monoclonal Gammopathy of Undetermined Significance (MGUS) is considered to be a benign precursor condition that may progress to a lymphoproliferative disease or multiple myeloma. Most patients do not progress to an overt condition, but nevertheless, MGUS is associated with a shortened life expectancy and, in a minority of cases, a number of co-morbid conditions that include an increased fracture risk, renal impairment, peripheral neuropathy, secondary immunodeficiency, and cardiovascular disease. This review aims to consolidate current evidence for the significance of these co-morbidities before considering how best to approach these symptoms and signs, which are often encountered in primary care or within a number of specialties in secondary care.
SRC Kinase in Glioblastoma: News from an Old Acquaintance
Authors: Cirotti Claudia , Contadini Claudia , Barilà Daniela
Published: June 2020

Glioblastoma multiforme (GBM) is one of the most recalcitrant brain tumors characterized by a tumor microenvironment (TME) that strongly supports GBM growth, aggressiveness, invasiveness, and resistance to therapy. Importantly, a common feature of GBM is the aberrant activation of receptor tyrosine kinases (RTKs) and of their downstream signaling cascade, including the non-receptor tyrosine kinase SRC. SRC is a central downstream intermediate of many RTKs, which triggers the phosphorylation of many substrates, therefore, promoting the regulation of a wide range of different pathways involved in cell survival, adhesion, proliferation, motility, and angiogenesis. In addition to the aforementioned pathways, SRC constitutive activity promotes and sustains inflammation and metabolic reprogramming concurring with TME development, therefore, actively sustaining tumor growth. Here, we aim to provide an updated picture of the molecular pathways that link SRC to these events in GBM. In addition, SRC targeting strategies are discussed in order to highlight strengths and weaknesses of SRC inhibitors in GBM management, focusing our attention on their potentialities in combination with conventional therapeutic approaches (i.e., temozolomide) to ameliorate therapy effectiveness.
Well-Differentiated Papillary Mesothelioma of the Peritoneum Is Genetically Distinct from Malignant Mesothelioma
Authors: Shrestha Raunak , Nabavi Noushin , Volik Stanislav , Anderson Shawn , Haegert Anne , McConeghy Brian , Sar Funda , Brahmbhatt Sonal , Bell Robert , Le Bihan Stephane , Wang Yuzhuo , Collins Colin , Churg Andrew
Published: June 2020

Well-differentiated papillary mesothelioma (WDPM) is an uncommon mesothelial proliferation that is most commonly encountered as an incidental finding in the peritoneal cavity. There is controversy in the literature about whether WDPM is a neoplasm or a reactive process and, if neoplastic, whether it is a variant or precursor of epithelial malignant mesothelioma or is a different entity. Using whole exome sequencing of five WDPMs of the peritoneum, we have identified distinct mutations in EHD1, ATM, FBXO10, SH2D2A, CDH5, MAGED1, and TP73 shared by WDPM cases but not reported in malignant mesotheliomas. Furthermore, we show that WDPM is strongly enriched with C > A transversion substitution mutations, a pattern that is also not found in malignant mesotheliomas. The WDPMs lacked the alterations involving BAP1, SETD2, NF2, CDKN2A/B, LASTS1/2, PBRM1, and SMARCC1 that are frequently found in malignant mesotheliomas. We conclude that WDPMs are neoplasms that are genetically distinct from malignant mesotheliomas and, based on observed mutations, do not appear to be precursors of malignant mesotheliomas.
New Therapeutics in HER2-Positive Advanced Breast Cancer: Towards a Change in Clinical Practices?
Authors: Mezni Essia , Vicier Cécile , Guerin Mathilde , Sabatier Renaud , Bertucci François , Gonçalves Anthony
Published: June 2020

Over the last few decades, improved knowledge of oncogenic activation mechanisms of HER2 protein has led to the development of HER2 targeted therapies that are currently commonly used in HER2-positive advanced breast cancer, such as trastuzumab, lapatinib, pertuzumab, and ado-trastuzumab emtansine. The management of this breast cancer subgroup has thus been revolutionized and its prognosis has changed dramatically. Nevertheless, HER2-positive advanced breast cancer remains an incurable disease and resistance to conventional anti-HER2 drugs is almost unavoidable. Nowadays, biochemical and pharmaceutical advances are meeting the challenge of developing increasingly sophisticated therapies directed against HER2, including novel anti HER2 antibodies with increased affinity. New antibody-drug conjugates (ADC) with more advanced pharmacological properties, and dual targeting of epitopes via bispecific monoclonal antibodies are also emerging. In addition, more potent and more specific HER2 tyrosine kinase inhibitors have shown interesting outcomes and are under development. Finally, researchers’ interest in tumor microenvironment, particularly tumor-infiltrating lymphocytes, and the major role that signaling pathways, such as the PI3K/AKT/mTOR pathway, play in the development of resistance to anti-HER2 therapies have spurred the development of clinical trials evaluating innovative combinations of anti-HER2 with PD-1/PDL-1, CDK4/6 and PI3K inhibitors. However, several questions remain unresolved, like the optimal management of HER2-positive/HR-positive advanced breast cancer and the identification of predictive biomarkers to better define populations that can benefit most from these new therapies and approaches.
Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia
Authors: Brinton Lindsey T. , Sher Steven , Williams Katie , Canfield Daniel , Orwick Shelley , Wasmuth Ronni , Cempre Casey , Skinner Jordan , Lehman Amy , Blachly James S. , Byrd John C. , Lapalombella Rosa
Published: June 2020

Acute myeloid leukemia (AML) is a hematopoietic stem-cell-derived leukemia with often successive derived driver mutations. Late onset acquisition of internal tandem duplication in FLT3 (FLT3-ITD) at a high variant allele frequency often contributes to full transformation to a highly proliferative, rapidly progressive disease with poor outcome. The FLT3-ITD mutation is targetable with approved FLT3 small molecule inhibitors, including midostaurin and gilteritinib. However, outside of patients receiving allogeneic transplant, most patients fail to respond or relapse, suggesting alternative approaches of therapy will be required. We employed genome-wide pooled CRISPR knockout screening as a method for large-scale identification of targets whose knockout produces a phenotypic effect that enhances the antitumor properties of FLT3 inhibitors. Among the candidate targets we identified the effect of XPO1 knockout to be synergistic with midostaurin treatment. Next, we validated the genetic finding with pharmacologic combination of the slowly reversible XPO1 inhibitor selinexor with midostaurin and gilteritinib in FLT3-ITD AML cell lines and primary patient samples. Lastly, we demonstrated improved survival with either combination therapy compared to its monotherapy components in an aggressive AML murine model, supporting further evaluation and rapid clinical translation of this combination strategy.
Therapeutic Efficacy of ABN401, a Highly Potent and Selective MET Inhibitor, Based on Diagnostic Biomarker Test in MET-Addicted Cancer
Authors: Kim Jooseok , Park Kyung Eui , Jeong Yoo-Seong , Kim YeongMun , Park Hayeon , Nam Ji-Hye , Jung Kyungsoo , Son Woo Sung , Jung Hun Soon , Lee Jong-Hwa , Jeong Seong Hoon , Kim Nam Ah , Ha Jae Du , Cho Sung Yun , Choi Yoon-La , Chung Suk-Jae , Choi Jun Young , Hong Sungyoul , Shin Young Kee
Published: June 2020

The receptor tyrosine kinase c-MET regulates processes essential for tissue remodeling and mammalian development. The dysregulation of c-MET signaling plays a role in tumorigenesis. The aberrant activation of c-MET, such as that caused by gene amplification or mutations, is associated with many cancers. c-MET is therefore an attractive therapeutic target, and inhibitors are being tested in clinical trials. However, inappropriate patient selection criteria, such as low amplification or expression level cut-off values, have led to the failure of clinical trials. To include patients who respond to MET inhibitors, the selection criteria must include MET oncogenic addiction. Here, the efficacy of ABN401, a MET inhibitor, was investigated using histopathologic and genetic analyses in MET-addicted cancer cell lines and xenograft models. ABN401 was highly selective for 571 kinases, and it inhibited c-MET activity and its downstream signaling pathway. We performed pharmacokinetic profiling of ABN401 and defined the dose and treatment duration of ABN401 required to inhibit c-MET phosphorylation in xenograft models. The results show that the efficacy of ABN401 is associated with MET status and they highlight the importance of determining the cut-off values. The results suggest that clinical trials need to establish the characteristics of each sample and their correlations with the efficacy of MET inhibitors.
8th Edition Tumor, Node, and Metastasis T-Stage Prognosis Discrepancies: Solid Component Diameter Predicts Prognosis Better than Invasive Component Diameter
Authors: Funai Kazuhito , Kawase Akikazu , Mizuno Kiyomichi , Koyama Shin , Shiiya Norihiko
Published: June 2020

The biggest change in the 8th edition of the tumor, lymph node, and metastasis (TNM) classification is the recommendation of the solid component diameter and invasive size for determining the clinical and pathological T-factor, respectively. Here, we validated new proposals for the Lung Cancer TNM classification’s revision and compared clinical and pathological T-stages. We retrospectively analyzed 177 cases of non-small cell lung cancers without lymph node metastasis, and involving complete resection, that occurred in our department between January 2017 and March 2019. We reviewed the overall tumor diameter, solid component diameter, and clinical T-factor on computed tomography (CT), and the pathological tumor diameter, pathological invasion diameter, pathological T-factor, and prognosis. The difference between the pathological invasive size and solid size on CT was within 5 mm in 99 cases (56%). At a two-year recurrence-free survival rate, the clinical T-stage demonstrated a better prognostic outcome than the pathological T-stage. Despite including the benign findings, the solid component diameter was better correlated with prognosis than the invasive size. Therefore, in cases of discrepancies of clinically and pathologically detected tumor size, the solid CT size should also be used for the pathological T classification.
Obesity and the Impact on Cutaneous Melanoma: Friend or Foe?
Authors: Smith Lorey K. , Arabi Shaghayegh , Lelliott Emily J. , McArthur Grant A. , Sheppard Karen E.
Published: June 2020

Excess body weight has been identified as a risk factor for many types of cancers, and for the majority of cancers, it is associated with poor outcomes. In contrast, there are cancers in which obesity is associated with favorable outcomes and this has been termed the “obesity paradox”. In melanoma, the connection between obesity and the increased incidence is not as strong as for other cancer types with some but not all studies showing an association. However, several recent studies have indicated that increased body mass index (BMI) improves survival outcomes in targeted and immune therapy treated melanoma patients. The mechanisms underlying how obesity leads to changes in therapeutic outcomes are not completely understood. This review discusses the current evidence implicating obesity in melanoma progression and patient response to targeted and immunotherapy, and discusses potential mechanisms underpinning these associations.
Blood Flow Measurements Enable Optimization of Light Delivery for Personalized Photodynamic Therapy
Authors: Ong Yi Hong , Miller Joann , Yuan Min , Chandra Malavika , El Khatib Mirna , Vinogradov Sergei A. , Putt Mary E. , Zhu Timothy C. , Cengel Keith A. , Yodh Arjun G. , Busch Theresa M.
Published: June 2020

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.
Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1
Authors: Samaniego Rafael , Domínguez-Soto Ángeles , Ratnam Manohar , Matsuyama Takami , Sánchez-Mateos Paloma , Corbí Ángel L. , Puig-Kröger Amaya
Published: June 2020

As macrophages exhibit a huge functional plasticity under homeostasis and pathological conditions, they have become a therapeutic target for chronic inflammatory diseases. Hence, the identification of macrophage subset-specific markers is a requisite for the development of macrophage-directed therapeutic interventions. In this regard, the macrophage-specific Folate Receptor β (FRβ, encoded by the FOLR2 gene) has been already validated as a target for molecular delivery in cancer as well as in macrophage-targeting therapeutic strategies for chronic inflammatory pathologies. We now show that the transcriptome of human macrophages from healthy and inflamed tissues (tumor; rheumatoid arthritis, RA) share a significant over-representation of the “anti-inflammatory gene set”, which defines the gene profile of M-CSF-dependent IL-10-producing human macrophages (M-MØ). More specifically, FOLR2 expression has been found to strongly correlate with the expression of M-MØ-specific genes in tissue-resident macrophages, tumor-associated macrophages (TAM) and macrophages from inflamed synovium, and also correlates with the presence of the PU.1 transcription factor. In fact, PU.1-binding elements are found upstream of the first exon of FOLR2 and most M-MØ-specific- and TAM-specific genes. The functional relevance of PU.1 binding was demonstrated through analysis of the proximal regulatory region of the FOLR2 gene, whose activity was dependent on a cluster of PU.1-binding sequences. Further, siRNA-mediated knockdown established the importance of PU.1 for FOLR2 gene expression in myeloid cells. Therefore, we provide evidence that FRβ marks tissue-resident macrophages as well as macrophages within inflamed tissues, and its expression is dependent on PU.1.
Targeting the JAK/STAT Signaling Pathway Using Phytocompounds for Cancer Prevention and Therapy
Authors: Bose Sankhadip , Banerjee Sabyasachi , Mondal Arijit , Chakraborty Utsab , Pumarol Joshua , Croley Courtney R. , Bishayee Anupam
Published: June 2020

Cancer is a prevalent cause of mortality around the world. Aberrated activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway promotes tumorigenesis. Natural agents, including phytochemicals, exhibit potent anticancer activities via various mechanisms. However, the therapeutic potency of phytoconstituents as inhibitors of JAK/STAT signaling against cancer has only come into focus in recent days. The current review highlights phytochemicals that can suppress the JAK/STAT pathway in order to impede cancer cell growth. Various databases, such as PubMed, ScienceDirect, Web of Science, SpringerLink, Scopus, and Google Scholar, were searched using relevant keywords. Once the authors were in agreement regarding the suitability of a study, a full-length form of the relevant article was obtained, and the information was gathered and cited. All the complete articles that were incorporated after the literature collection rejection criteria were applied were perused in-depth and material was extracted based on the importance, relevance, and advancement of the apprehending of the JAK/STAT pathway and their relation to phytochemicals. Based on the critical and comprehensive analysis of literature presented in this review, phytochemicals from diverse plant origins exert therapeutic and cancer preventive effects, at least in part, through regulation of the JAK/STAT pathway. Nevertheless, more preclinical and clinical research is necessary to completely comprehend the capability of modulating JAK/STAT signaling to achieve efficient cancer control and treatment.