bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia
Authors: Barabino Silvia M. L. , Citterio Elisabetta , Ronchi Antonella Ellena
Published: July 2021

Myeloid neoplasms encompass a very heterogeneous family of diseases characterized by the failure of the molecular mechanisms that ensure a balanced equilibrium between hematopoietic stem cells (HSCs) self-renewal and the proper production of differentiated cells. The origin of the driver mutations leading to preleukemia can be traced back to HSC/progenitor cells. Many properties typical to normal HSCs are exploited by leukemic stem cells (LSCs) to their advantage, leading to the emergence of a clonal population that can eventually progress to leukemia with variable latency and evolution. In fact, different subclones might in turn develop from the original malignant clone through accumulation of additional mutations, increasing their competitive fitness. This process ultimately leads to a complex cancer architecture where a mosaic of cellular clones—each carrying a unique set of mutations—coexists. The repertoire of genes whose mutations contribute to the progression toward leukemogenesis is broad. It encompasses genes involved in different cellular processes, including transcriptional regulation, epigenetics (DNA and histones modifications), DNA damage signaling and repair, chromosome segregation and replication (cohesin complex), RNA splicing, and signal transduction. Among these many players, transcription factors, RNA splicing proteins, and deubiquitinating enzymes are emerging as potential targets for therapeutic intervention.
Cloud Computing Based Immunopeptidomics Utilizing Community Curated Variant Libraries Simplifies and Improves Neo-Antigen Discovery in Metastatic Melanoma
Authors: Prakash Amol , Mahoney Keira E. , Orsburn Benjamin C.
Published: July 2021

Unique peptide neo-antigens presented on the cell surface are attractive targets for researchers in nearly all areas of personalized medicine. Cells presenting peptides with mutated or other non-canonical sequences can be utilized for both targeted therapies and diagnostics. Today’s state-of-the-art pipelines utilize complementary proteogenomic approaches where RNA or ribosomal sequencing data helps to create libraries from which tandem mass spectrometry data can be compared. In this study, we present an alternative approach whereby cloud computing is utilized to power neo-antigen searches against community curated databases containing more than 7 million human sequence variants. Using these expansive databases of high-quality sequences as a reference, we reanalyze the original data from two previously reported studies to identify neo-antigen targets in metastatic melanoma. Using our approach, we identify 79 percent of the non-canonical peptides reported by previous genomic analyses of these files. Furthermore, we report 18-fold more non-canonical peptides than previously reported. The novel neo-antigens we report herein can be corroborated by secondary analyses such as high predicted binding affinity, when analyzed by well-established tools such as NetMHC. Finally, we report 738 non-canonical peptides shared by at least five patient samples, and 3258 shared across the two studies. This illustrates the depth of data that is present, but typically missed by lower statistical power proteogenomic approaches. This large list of shared peptides across the two studies, their annotation, non-canonical origin, as well as MS/MS spectra from the two studies are made available on a web portal for community analysis.
Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance
Authors: Rio-Vilariño Anxo , del Puerto-Nevado Laura , García-Foncillas Jesús , Cebrián Arancha
Published: July 2021

Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications.
Detection of Tumor Recurrence via Circulating Tumor DNA Profiling in Patients with Localized Lung Cancer: Clinical Considerations and Challenges
Authors: Ulrich Bryan , Pradines Anne , Mazières Julien , Guibert Nicolas
Published: July 2021

Approximately 30% of patients with non-small-cell lung cancer (NSCLC) present with localized/non-metastatic disease and are eligible for surgical resection or other “treatment with curative intent”. Due to the high prevalence of recurrence after treatment, adjuvant therapy is standard care for most patients. The effect of adjuvant chemotherapy is, however, modest, and new tools are needed to identify candidates for adjuvant treatments (chemotherapy, immunotherapy, or targeted therapies), especially since expanded lung cancer screening programs will increase the rate of patients detected with localized NSCLC. Circulating tumor DNA (ctDNA) has shown strong potential to detect minimal residual disease (MRD) and to guide adjuvant therapies. In this manuscript, we review the technical aspects and performances of the main ctDNA sequencing platforms (TRACERx, CAPP-seq) investigated in this purpose, and discuss the potential of this approach to guide or spare adjuvant therapies after definitive treatment of NSCLC.
Reply to Auclin et al. Comment on “Hopkins et al. Value of the Lung Immune Prognostic Index in Patients with Non-Small Cell Lung Cancer Initiating First-Line Atezolizumab Combination Therapy: Subgroup Analysis of the IMPOWER150 Trial. Cancers 2021, 13, 1176”
Authors: Hopkins Ashley M. , Kichenadasse Ganessan , Abuhelwa Ahmad Y. , McKinnon Ross A. , Rowland Andrew , Sorich Michael J.
Published: July 2021

We thank Auclin et al. [...]
Neuroendocrine Carcinomas of the Digestive Tract: What Is New?
Authors: Pellat Anna , Cottereau Anne Ségolène , Terris Benoit , Coriat Romain
Published: July 2021

Neuroendocrine carcinomas (NEC) are rare tumors with a rising incidence. They show poorly differentiated morphology with a high proliferation rate (Ki-67 index). They frequently arise in the lung (small and large-cell lung cancer) but rarely from the gastrointestinal tract. Due to their rarity, very little is known about digestive NEC and few studies have been conducted. Therefore, most of therapeutic recommendations are issued from work on small-cell lung cancers (SCLC). Recent improvement in pathology and imaging has allowed for better detection and classification of high-grade NEN. The 2019 World Health Organization (WHO) classification has described a new entity of well-differentiated grade 3 neuroendocrine tumors (NET G-3), with better prognosis, that should be managed separately from NEC. NEC are aggressive neoplasms often diagnosed at a metastatic state. In the localized setting, surgery can be performed in selected patients followed by adjuvant platinum-based chemotherapy. Concurrent chemoradiotherapy is also an option for NEC of the lung, rectum, and esophagus. In metastatic NEC, chemotherapy is administered with a classic combination of platinum salts and etoposide in the first-line setting. Peptide receptor radionuclide therapy (PRRT) has shown positive results in high-grade NEN populations and immunotherapy trials are still ongoing. Available therapies have improved the overall survival of NEC but there is still an urgent need for improvement. This narrative review sums up the current data on digestive NEC while exploring future directions for their management.
Clinical Significance of Telomerase Reverse-Transcriptase Promoter Mutations in Hepatocellular Carcinoma
Authors: Pezzuto Francesca , Izzo Francesco , De Luca Pasquale , Biffali Elio , Buonaguro Luigi , Tatangelo Fabiana , Buonaguro Franco Maria , Tornesello Maria Lina
Published: July 2021

Telomerase reactivation during hepatocarcinogenesis is recurrently caused by two point mutations occurring most frequently at the nucleotide −124 (95%) and occasionally at the nucleotide −146 (<5%) upstream of the TERT translational start site in hepatocellular carcinoma (HCC). In this study, we designed a droplet digital PCR (ddPCR) assay to detect TERT promoter (TERTp) nucleotide change G>A at position −124 and to quantify the mutant allele frequency (MAF) in 121 primary liver cancers, including 114 HCC along with 23 autologous cirrhotic tissues, five cholangiocarcinoma (CC), and two hepato-cholangiocarcinoma (HCC-CC). All cases were evaluated for tumour markers such as α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA). We compared the sensitivity of ddPCR and Sanger sequencing and investigated the prognostic relevance of TERTp mutations. The TERTp G>A transition was identified in 63.6% and 52.1% of HCC samples by ddPCR and Sanger sequencing, respectively. One out of 23 (4.3%) peri-tumour tissues tested positive only by ddPCR. One out of five CC (20%) and none of the HCC-CC were found concordantly mutated by the two methods. The TERTp MAF ranged from 2% to 66%, and the large majority (85.5%) of mutated samples showed a value above 20%. A statistically significant correlation was found between TERTp mutation and tumour size (p = 0.048), while an inverse correlation was observed with CA19-9 levels (p = 0.0105). Moreover, HCC patients with TERTp −124A had reduced survival. In conclusion, the single nucleotide variation G>A at position −124 in TERTp, detected either by ddPCR or by Sanger sequencing, showed a remarkable high frequency in HCC. Such mutation is associated with lower levels of CA19-9 and reduced survival in HCC patients suggesting that the TERTp status may represent a distinct signature of liver cancer subgroups.
Association of the Lung Immune Prognostic Index with Immunotherapy Outcomes in Mismatch Repair Deficient Tumors
Authors: Auclin Edouard , Vuagnat Perrine , Smolenschi Cristina , Taieb Julien , Adeva Jorge , Nebot-Bral Laetitia , Garcia de Herreros Marta , Vidal Tocino Rosario , Longo-Muñoz Federico , El Dakdouki Yola , Martín-Romano Patricia , Gaba Lydia , Saurí Tamara , Oliveres Helena , Castañón Eduardo , Garcia-Carbonero Rocio , Besse Benjamin , Massard Christophe , Mezquita Laura , Hollebecque Antoine
Published: July 2021

Background: MSI-H/dMMR is considered the first predictive marker of efficacy for immune checkpoint inhibitors (ICIs). However, around 39% of cases are refractory and additional biomarkers are needed. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients treated with ICIs, including identification of fast-progressors. Methods: A multicenter retrospective study of patients with metastatic MSI-H/dMMR tumors treated with ICIs between April 2014 and May 2019 was performed. LIPI was calculated based on dNLR > 3 and LDH > upper limit of normal. LIPI groups were good (zero factors), intermediate (one factor) and poor (two factors). The primary endpoint was overall survival (OS), including the fast-progressor rate (OS < 3 months). Results: A total of 151 patients were analyzed, mainly female (59%), with median age 64 years, performance status (PS) 0 (42%), and sporadic dMMR status (68%). ICIs were administered as first or second-line for 59%. The most frequent tumor types were gastrointestinal (66%) and gynecologic (22%). LIPI groups were good (47%), intermediate (43%), and poor (10%). The median follow-up was 32 months. One-year OS rates were 81.0%, 67.1%, and 21.4% for good, intermediate, and poor-risk groups (p < 0.0001). After adjustment for tumor site, metastatic sites and PS, LIPI remained independently associated with OS (HR, poor-LIPI: 3.50, 95%CI: 1.46–8.40, p = 0.02. Overall, the fast-progressor rate was 16.0%, and 35.7% with poor-LIPI vs. 7.5% in the good-LIPI group (p = 0.02). Conclusions: LIPI identifies dMMR patients who do not benefit from ICI treatment, particularly fast-progressors. LIPI should be included as a stratification factor for future trials.
Selective Internal Radiation Therapy in Breast Cancer Liver Metastases: Outcome Assessment Applying a Prognostic Score
Authors: Schatka Imke , Tschernig Monique , Rogasch Julian M. M. , Bluemel Stephanie , Graef Josefine , Furth Christian , Sehouli Jalid , Blohmer Jens-Uwe , Gebauer Bernhard , Fehrenbach Uli , Amthauer Holger
Published: July 2021

Selective internal radiation therapy (SIRT) is a therapy option in patients with breast cancer liver metastasis (BCLM). This analysis aimed at identifying a prognostic score regarding overall survival (OS) after SIRT using routine pretherapeutic parameters. Retrospective analysis of 38 patients (age, 59 (39–84) years) with BCLM and 42 SIRT procedures. Cox regression for OS included clinical factors (age, ECOG and prior treatments), laboratory parameters, hepatic tumor load and dose reduction due to hepatopulmonary shunt. Elevated baseline ALT and/or AST was present if CTCAE grade ≥ 2 was fulfilled (>3 times the upper limit of normal). Median OS after SIRT was 6.4 months. In univariable Cox, ECOG ≥ 1 (hazard ratio (HR), 3.8), presence of elevated baseline ALT/AST (HR, 3.8), prior liver surgery (HR, 10.2), and dose reduction of 40% (HR, 8.1) predicted shorter OS (each p < 0.05). Multivariable Cox confirmed ECOG ≥ 1 (HR, 2.34; p = 0.012) and elevated baseline ALT/AST (HR, 4.16; p < 0.001). Combining both factors, median OS decreased from 19.2 months (0 risk factors; n = 14 procedures) to 5.9 months (1 factor; n = 20) or 2.2 months (2 factors; n = 8; p < 0.001). The proposed score may facilitate pretherapeutic identification of patients with unfavorable OS after SIRT. This may help to balance potential life prolongation with the hazards of invasive treatment and hospitalization.
Therapeutic Potential of EWSR1–FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma
Authors: Cervera Saint T. , Rodríguez-Martín Carlos , Fernández-Tabanera Enrique , Melero-Fernández de Mera Raquel M. , Morin Matias , Fernández-Peñalver Sergio , Iranzo-Martínez Maria , Amhih-Cardenas Jorge , García-García Laura , González-González Laura , Moreno-Pelayo Miguel Angel , Alonso Javier
Published: July 2021

Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1–FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1–FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1–FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1–FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1–FLI1 at the cell level should be considered a therapeutic approach to develop in the future.
Electrochemical Detection of Global DNA Methylation Using Biologically Assembled Polymer Beads
Authors: Soda Narshone , Gonzaga Zennia Jean , Pannu Amandeep Singh , Kashaninejad Navid , Kline Richard , Salomon Carlos , Nguyen Nam-Trung , Sonar Prashant , Rehm Bernd H. A. , Shiddiky Muhammad J. A.
Published: July 2021

DNA methylation is a cell-type-specific epigenetic marker that is essential for transcriptional regulation, silencing of repetitive DNA and genomic imprinting. It is also responsible for the pathogenesis of many diseases, including cancers. Herein, we present a simple approach for quantifying global DNA methylation in ovarian cancer patient plasma samples based on a new class of biopolymer nanobeads. Our approach utilises the immune capture of target DNA and electrochemical quantification of global DNA methylation level within the targets in a three-step strategy that involves (i) initial preparation of target single-stranded DNA (ss-DNA) from the plasma of the patients’ samples, (ii) direct adsorption of polymer nanobeads on the surface of a bare screen-printed gold electrode (SPE-Au) followed by the immobilisation of 5-methylcytosine (5mC)-horseradish peroxidase (HRP) antibody, and (iii) immune capture of target ss-DNA onto the electrode-bound PHB/5mC-HRP antibody conjugates and their subsequent qualification using the hydrogen peroxide/horseradish peroxidase/hydroquinone (H2O2/HRP/HQ) redox cycling system. In the presence of methylated DNA, the enzymatically produced (in situ) metabolites, i.e., benzoquinone (BQ), binds irreversibly to cellular DNA resulting in the unstable formation of DNA adducts and induced oxidative DNA strand breakage. These events reduce the available BQ in the system to support the redox cycling process and sequel DNA saturation on the platform, subsequently causing high Coulombic repulsion between BQ and negatively charged nucleotide strands. Thus, the increase in methylation levels on the electrode surface is inversely proportional to the current response. The method could successfully detect as low as 5% methylation level. In addition, the assay showed good reproducibility (% RSD ≤ 5%) and specificity by analysing various levels of methylation in cell lines and plasma DNA samples from patients with ovarian cancer. We envision that our bioengineered polymer nanobeads with high surface modification versatility could be a useful alternative platform for the electrochemical detection of varying molecular biomarkers.
Potential of Immunotherapies in Treating Hematological Cancer-Infection Comorbidities—A Mathematical Modelling Approach
Authors: Ottesen Johnny T. , Andersen Morten
Published: July 2021

Background: The immune system attacks threats like an emerging cancer or infections like COVID-19 but it also plays a role in dealing with autoimmune disease, e.g., inflammatory bowel diseases, and aging. Malignant cells may tend to be eradicated, to appraoch a dormant state or escape the immune system resulting in uncontrolled growth leading to cancer progression. If the immune system is busy fighting a cancer, a severe infection on top of it may compromise the immunoediting and the comorbidity may be too taxing for the immune system to control. Method: A novel mechanism based computational model coupling a cancer-infection development to the adaptive immune system is presented and analyzed. The model maps the outcome to the underlying physiological mechanisms and agree with numerous evidence based medical observations. Results and Conclusions: Progression of a cancer and the effect of treatments depend on the cancer size, the level of infection, and on the efficiency of the adaptive immune system. The model exhibits bi-stability, i.e., virtual patient trajectories gravitate towards one of two stable steady states: a dormant state or a full-blown cancer-infection disease state. An infectious threshold curve exists and if infection exceed this separatrix for sufficiently long time the cancer escapes. Thus, early treatment is vital for remission and severe infections may instigate cancer progression. CAR T-cell Immunotherapy may sufficiently control cancer progression back into a dormant state but the therapy significantly gains efficiency in combination with antibiotics or immunomodulation.
Green Synthesis of Metallic Nanoparticles: Applications and Limitations
Authors: Dikshit Pritam , Kumar Jatin , Das Amit , Sadhu Soumi , Sharma Sunita , Singh Swati , Gupta Piyush , Kim Beom
Published: July 2021

The past decade has witnessed a phenomenal rise in nanotechnology research due to its broad range of applications in diverse fields including food safety, transportation, sustainable energy, environmental science, catalysis, and medicine. The distinctive properties of nanomaterials (nano-sized particles in the range of 1 to 100 nm) make them uniquely suitable for such wide range of functions. The nanoparticles when manufactured using green synthesis methods are especially desirable being devoid of harsh operating conditions (high temperature and pressure), hazardous chemicals, or addition of external stabilizing or capping agents. Numerous plants and microorganisms are being experimented upon for an eco–friendly, cost–effective, and biologically safe process optimization. This review provides a comprehensive overview on the green synthesis of metallic NPs using plants and microorganisms, factors affecting the synthesis, and characterization of synthesized NPs. The potential applications of metal NPs in various sectors have also been highlighted along with the major challenges involved with respect to toxicity and translational research.
Development of an Iron-Based Fischer—Tropsch Catalyst with High Attrition Resistance and Stability for Industrial Application
Authors: Lin Quan , Cheng Meng , Zhang Kui , Li Weizhen , Wu Peng , Chang Hai , Lv Yijun , Men Zhuowu
Published: July 2021

In order to develop an iron-based catalyst with high attrition resistance and stability for Fischer–Tropsch synthesis (FTS), a series of experiments were carried out to investigate the effects of SiO2 and its hydroxyl content and a boron promoter on the attrition resistance and catalytic behavior of spray-dried precipitated Fe/Cu/K/SiO2 catalysts. The catalysts were characterized by means of N2 physisorption, nuclear magnetic resonance (NMR), X-ray diffraction (XRD), Raman spectrum, X-ray photoelectron spectroscopy (XPS), H2-thermogravimetric analysis (H2-TGA), temperature-programmed reduction and hydrogenation (TPR and TPH), and scanning and transmission electron microscopy (SEM and TEM). The FTS performance of the catalysts was tested in a slurry-phase continuously stirred tank reactor (CSTR), while the attrition resistance study included a physical test with the standard method and a chemical attrition test under simulated reaction conditions. The results indicated that the increase in SiO2 content enhances catalysts’ attrition resistance and FTS stability, but decreases activity due to the suppression of further reduction of the catalysts. Moreover, the attrition resistance of the catalysts with the same silica content was greatly improved with an increase in hydroxyl number within silica sources, as well as the FTS activity and stability to some degree. Furthermore, the boron element was found to show remarkable promotion of FTS stability, and the promotion mechanism was discussed with regard to probable interactions between Fe and B, K and B, and SiO2 and B, etc. An optimized catalyst based on the results of this study was finalized, scaled up, and successfully applied in a megaton industrial slurry bubble FTS unit, exhibiting excellent FTS performance.
Evaluation of Micro Satellite Instability and Mismatch Repair Status in Different Solid Tumors: A Multicenter Analysis in a Real World Setting
Authors: Malapelle Umberto , Parente Paola , Pepe Francesco , De Luca Caterina , Pisapia Pasquale , Sgariglia Roberta , Nacchio Mariantonia , Gragnano Gianluca , Russo Gianluca , Conticelli Floriana , Bellevicine Claudio , Vigliar Elena , Iaccarino Antonino , Covelli Claudia , Balistreri Mariangela , Clemente Celeste , Perrone Giovanni , Danza Angela , Scaramuzzi Fabio , Fassan Matteo , Troncone Giancarlo , Graziano Paolo
Published: July 2021

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.
Optimizing Active Tumor Targeting Biocompatible Polymers for Efficient Systemic Delivery of Adenovirus
Authors: Lee Jun Young , Hong Jin Woo , Thambi Thavasyappan , Yoon A-Rum , Choi Joung-Woo , Li Yi , Bui Quang Nam , Lee Doo Sung , Yun Chae-Ok
Published: July 2021

Adenovirus (Ad) has risen to be a promising alternative to conventional cancer therapy. However, systemic delivery of Ad, which is necessary for the treatment of metastatic cancer, remains a major challenge within the field, owing to poor tumor tropism and nonspecific hepatic tropism of the virus. To address this limitation of Ad, we have synthesized two variants of folic acid (FA)-conjugated methoxy poly(ethylene glycol)-b-poly{N-[N-(2-aminoethyl)-2-aminoethyl]-L-glutamate (P5N2LG-FA and P5N5LG-FA) using 5 kDa poly(ethylene glycol) (PEG) with a different level of protonation (N2 < N5 in terms of charge), along with a P5N5LG control polymer without FA. Our findings demonstrate that P5N5LG, P5N2LG-FA, and P5N5LG-FA exert a lower level of cytotoxicity compared to 25 kDa polyethyleneimine. Furthermore, green fluorescent protein (GFP)-expressing Ad complexed with P5N2LG-FA and P5N5LG-FA (Ad/P5N2LG-FA and Ad/P5N5LG-FA, respectively) exerted superior transduction efficiency compared to naked Ad or Ad complexed with P5N5LG (Ad/P5N5LG) in folate receptor (FR)-overexpressing cancer cells (KB and MCF7). All three nanocomplexes (Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA) internalized into cancer cells through coxsackie adenovirus receptor-independent endocytic mechanism and the cell uptake was more efficient than naked Ad. Importantly, the cell uptake of the two FA functionalized nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) was dependent on the complementary interaction of FA–FR. Systemically administered Ad/P5N5LG, Ad/P5N2LG-FA, and Ad/P5N5LG-FA showed exponentially higher retainment of the virus in blood circulation up to 24 h post-administration compared with naked Ad. Both tumor-targeted nanocomplexes (Ad/P5N2LG-FA and Ad/P5N5LG-FA) showed significantly higher intratumoral accumulation than naked Ad or Ad/P5N5LG via systemic administration. Both tumor-targeted nanocomplexes accumulated at a lower level in liver tissues compared to naked Ad. Notably, the nonspecific accumulation of Ad/P5N2LG-FA was significantly lower than Ad/P5N5LG-FA in several normal organs, while exhibiting a significantly higher intratumoral accumulation level, showing that careful optimization of polyplex surface charge is critical to successful tumor-targeted systemic delivery of Ad nanocomplexes.
The Role of Alveolar Edema in COVID-19
Authors: Yuan Shu , Jiang Si-Cong , Zhang Zhong-Wei , Fu Yu-Fan , Hu Jing , Li Zi-Lin
Published: July 2021

The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (conservative fluid management, exogenous surfactant replacements and ethanol–oxygen vapor therapy hypothetically) may be greatly helpful for reducing the occurrences of severe cases. Given that late mechanical ventilation may cause mucus (edema fluid) to be blown deep into the small airways, oxygen therapy should be given at the early stages. The optimal time and blood oxygen saturation (SpO2) threshold for oxygen therapy are also discussed.
Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma
Authors: Lee Ho-Yeop , Nga Ha Thi , Tian Jingwen , Yi Hyon-Seung
Published: July 2021

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPRmt). The mitokines FGF21 and GDF15 are upregulated during UPRmt and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.
Intermediate Filaments from Tissue Integrity to Single Molecule Mechanics
Authors: van Bodegraven Emma J. , Etienne-Manneville Sandrine
Published: July 2021

Cytoplasmic intermediate filaments (IFs), which together with actin and microtubules form the cytoskeleton, are composed of a large and diverse family of proteins. Efforts to elucidate the molecular mechanisms responsible for IF-associated diseases increasingly point towards a major contribution of IFs to the cell’s ability to adapt, resist and respond to mechanical challenges. From these observations, which echo the impressive resilience of IFs in vitro, we here discuss the role of IFs as master integrators of cell and tissue mechanics. In this review, we summarize our current understanding of the contribution of IFs to cell and tissue mechanics and explain these results in light of recent in vitro studies that have investigated physical properties of single IFs and IF networks. Finally, we highlight how changes in IF gene expression, network assembly dynamics, and post-translational modifications can tune IF properties to adapt cell and tissue mechanics to changing environments.
Malformations of Cortical Development, Cognitive Involvementand Epilepsy: A Single Institution Experience in 19 Young Patients
Authors: Venti Valeria , Consentino Maria Chiara , Smilari Pierluigi , Greco Filippo , Oliva Claudia Francesca , Fiumara Agata , Falsaperla Raffaele , Ruggieri Martino , Pavone Piero
Published: July 2021

Background. Malformations of cortical development (MCD) include a wide range of congenital disorders mostly causing severe cognitive dysfunction and epilepsy. Objective: to report on clinical features including cognitive involvement, epileptic seizures with response to antiseizure medications, comorbidities in young patients affected by MCD and followed in a single tertiary hospital. Patients and methods: A retrospective review of the medical records and magnetic resonance images (MRI) of 19 young patients with an age ranging between eight days and fifteen years affected by MCD and admitted to Pediatrics Department University of Catania, Italy from October 2009 and October 2020 were selected. Patients were distinguished in three groups following the Barcovich et al. 2012 classification for MCD: 4 (21%) in Group I; 8 (42%) in Group II; and, and 7 (37%) in Group III. Clinical features and MRI of the patients including cognitive involvement, epilepsy type and response to drugs treatment were analyzed. Results: In Group I, two patients showed cortical dysplasia and two dysembryoplastic neuroepithelial tumors plus focal cortical dysplasia; developmental delay/intellectual disability (DD/ID) was severe in one, moderate in one and absent in two; the type of seizures was in all the cases focal to bilateral tonic-clonic (FBTCs), and drug resistant was found in one case. In Group II, three patients showed neuronal hetero-topias and five had pachygyria-lissencephaly: DD/ID was severe in four, moderate in two, and absent in two; the type of seizure was focal (FS) in five, focal to bilateral tonic-clonic (FBTCs) in two, infantile spasms (IS) in one, and drug resistant was found in three. In Group III, six showed polymicrogyria and one schizencephaly: DD/ID was found severe in five, moderate in two, and the type of seizure was focal (FS) in five, FBTCS in two, and drug resistance was found in three.
Capacity of the CCC-2 to Discriminate ASD from Other Neurodevelopmental Disorders
Authors: de la Torre Carril Alba , Durán-Bouza Montserrat , Pérez-Pereira Miguel
Published: July 2021

The Children’s Communication Checklist (CCC-2) has demonstrated its usefulness as an instrument to assess discrepancies between the use of structural dimensions of language and the pragmatic and sociointeractive uses of language. The aims of the present paper are: (1) to test the capacity of the Galician adaptation of the CCC-2 to discriminate the linguistic profiles of children with different disorders and (2) to test whether the capacity of the CCC-2 to discriminate the linguistic abilities of children with different disorders is the same at different ages: earlier development and later development. The sample is of 117 children previously diagnosed with different disorders: autism spectrum disorder (ASD), developmental language disorder (DLD), attention deficit with hyperactivity disorder (ADHD), Down syndrome children (DS) and typically developing children (TD). The children were divided into two different age groups: from 4 to 6 and from 7 to 16 years of age. The results indicate that the Galician CCC-2 (1) accurately identified children with and without communicative impairments, (2) distinguished between profiles with a predominance of pragmatic (ASD and ADHD) and structural disorders (DS and DLD) and (3) distinguished between different profiles of pragmatic impairment. The CCC-2 equally identified these profiles at both earlier and later ages. The Galician CCC-2 seems to be a useful instrument for differentiating among different clinical groups and for assessing pragmatic disorders from an early age, which can be valuable for planning early intervention.
The Soundscape of Neonatal Intensive Care: A Mixed-Methods Study of the Parents’ Experience
Authors: Chifa Maria , Hadar Tamar , Politimou Nina , Reynolds Gemma , Franco Fabia
Published: July 2021

Parents who have infants hospitalised in neonatal intensive care units (NICUs) experience high levels of stress, including post-traumatic stress disorder (PTSD) symptoms. However, whether sounds contribute to parents’ stress remains largely unknown. Critically, researchers lack a comprehensive instrument to investigate the relationship between sounds in NICUs and parental stress. To address this gap, this report presents the “Soundscape of NICU Questionnaire” (SON-Q), which was developed specifically to capture parents’ perceptions and beliefs about the impact that sound had on them and their infants, from pre-birth throughout the NICU stay and in the first postdischarge period. Parents of children born preterm (n = 386) completed the SON-Q and the Perinatal PTSD Questionnaire (PPQ). Principal Component Analysis identifying underlying dimensions comprising the parental experience of the NICU soundscape was followed by an exploration of the relationships between subscales of the SON-Q and the PPQ. Moderation analysis was carried out to further elucidate relationships between variables. Finally, thematic analysis was employed to analyse one memory of sounds in NICU open question. The results highlight systematic associations between aspects of the NICU soundscape and parental stress/trauma. The findings underscore the importance of developing specific studies in this area and devising interventions to best support parents’ mental health, which could in turn support infants’ developmental outcomes.
The Immunohistochemical Expression of MCM-3, -5, and -7 Proteins in the Uterine Fibroids
Authors: Rubisz Piotr , Hirnle Lidia , Kobierzycki Christopher
Published: July 2021

Uterine fibroids are the most common mesenchymal uterine neoplasms; their prevalence is estimated in 40%–60% of women under 35 and in 70%–80% of women over 50 years of age. The current research aims to focus on the etiopathogenesis of uterine fibroids, the factors that affect their growth, and markers with diagnostic and prognostic properties. The MCM (minichromosome maintenance) protein family consists of peptides whose primary function is participation in the molecular mechanism of creating replication forks while regulating DNA synthesis. The aim of this work was to determine the proliferative potential of uterine fibroid cells based on the expression of the Ki-67 antigen and the MCMs—i.e., MCM-3, MCM-5, and MCM-7. In addition, the expression of estrogen (ER) and progesterone (PgR) receptors was evaluated and correlated with the expression of the abovementioned observations. Ultimately, received results were analyzed in terms of clinical and pathological data. Materials and methods: In forty-four cases of uterine fibroids, immunohistochemical reactions were performed. A tissue microarray (TMA) technique was utilized and analyzed cases were assessed in triplicate. Immunohistochemistry was performed using antibodies against Ki-67 antigen, ER, PgR, MCM-3, MCM-5, and MCM-8 on an automated staining platform. Reactions were digitalized by a histologic scanner and quantified utilizing dedicated software for nuclear analysis. Assessment was based on quantification expression of the three histiospots, each representing one case in TMA. Results: In the study group (uterine fibroids), statistically significant stronger expression of all the investigated MCMs was observed, as compared to the control group. In addition, moderate and strong positive correlations were found between all tested proliferative markers. The expression of the MCM-7 protein also correlated positively with ER and PgR. With regard to clinical and pathological data, there was a negative correlation between the expression of MCMs and the number of both pregnancies and births. Significant reductions in MCM-5 and MCM-7 expression were observed in the group of women receiving oral hormonal contraceptives, while smoking women showed an increase in MCM-7, ER, and PgR. Conclusions: Uterine fibroid cells have greater proliferative potential, as evaluated by expression of the Ki-67 antigen and MCMs, than unaltered myometrial cells of the uterine corpus. The expression of MCM-7 was found to have strong or moderate correlations in all assessed relations. In the context of the clinical data, as well evident proliferative potential of MCMs, further studies are strongly recommended.
A High-Cholesterol Diet Increases Toll-like Receptors and Other Harmful Factors in the Rabbit Myocardium: The Beneficial Effect of Statins
Authors: Kapelouzou Alkistis , Katsimpoulas Michalis , Kontogiannis Christos , Lidoriki Irene , Georgiopoulos Georgios , Kourek Christos , Papageorgiou Christos , Mylonas Konstantinos S. , Dritsas Spyridon , Charalabopoulos Alexandros , Cokkinos Dennis V.
Published: July 2021

Background: A high-cholesterol diet (HCD) induces vascular atherosclerosis through vascular inflammatory and immunological processes via TLRs. The aim of this study is to investigate the mRNA expression of TLRs and other noxious biomarkers expressing inflammation, fibrosis, apoptosis, and cardiac dysfunction in the rabbit myocardium during (a) high-cholesterol diet (HCD), (b) normal diet resumption and (c) fluvastatin or rosuvastatin treatment. Methods: Forty-eight male rabbits were randomly divided into eight groups (n = 6/group). In the first experiment, three groups were fed with HCD for 1, 2 and 3 months. In the second experiment, three groups were fed with HCD for 3 months, followed by normal chow for 1 month and administration of fluvastatin or rosuvastatin for 1 month. Control groups were fed with normal chow for 90 and 120 days. The whole myocardium was removed; total RNA was isolated from acquired samples, and polymerase chain reaction, reverse transcription PCR and quantitative real-time PCR were performed. Results: mRNA of TLRs 2, 3, 4 and 8; interleukin-6; TNF-a; metalloproteinase-2; tissue inhibitor of metalloproteinase-1; tumor protein 53; cysteinyl aspartate specific proteinase-3; and brain natriuretic peptide (BNP) increased in HCD. Statins but not resumption of a normal diet decreased levels of these biomarkers and increased levels of antifibrotic factors. Conclusions: HCD increases the levels of TLRs; inflammatory, fibrotic and apoptotic factors; and BNP in the rabbit myocardium. Atherogenic diets adversely affect the myocardium at a molecular level and are reversed by statins.
In-Process Monitoring of Laser Surface Modification
Authors: Marimuthu Sundar , Pathak Sunil , Radhakrishnan Jagdheesh , Kamara Alhaji M.
Published: July 2021

The laser cleaning process has the potential to become an alternative to the existing chemical-based cleaning process if integrated with an effective in-process monitoring system that could serve as a control mechanism over surface damages or contaminants through which the desired surface cleanliness could be achieved. This paper presents results of an investigation into the characteristics and viability of utilizing probe beam reflection (PBR) and laser plume-emission spectroscopy (PES) as respective integrated monitoring systems during and after cleaning of titanium alloy sheets using a frequency-tripled Nd:YAG laser. The results present the probe beam reflection as a better system with the ability to differentiate between cleaned and un-cleaned surfaces for both small and large surface areas.
Preparation of Surface-Modified Nano Zinc Sulfide/Polyurethane Inorganic-Organic Transparent Coating and Its Application in Resin Lens
Authors: Du Weiping , Ding Yingying , Zhang Yang , Chen Huifang
Published: July 2021

The surface modified hydrophilic zinc sulfide nano powder was prepared by hydrothermal method, and the corresponding zinc sulfide/polyurethane organic-inorganic composite transparent coating via in-situ polymerization. The structure of ZnS Nanoparticles and organic-inorganic composite coating were characterized by Infrared Spectroscopy, X-Ray Diffraction, Laser Particle Size Analyzer and Scanning Electron Microscopy. The optical properties were measured by Ultraviolet-Visible spectrophotometer and ellipsometry. The results show that the monodisperse hydrophilic nano zinc sulfide powder with a particle size of about 70 nm can be obtained by thioglycolic acid (TGA) modification, which has good compatibility with waterborne polyurethane. Nano zinc sulfide increased the refractive index of the coating significantly and the refractive index of the coatings could be controlled in the region of 1.46–1.71 organic-inorganic composite coating by adding ZnS. When the amount of nano ZnS added was 30%, the refractive index of the hybrid coating can reach 1.71, and the transmittance was more than 90%. The cured coatings were smooth and no agglomeration between nano ZnS particles could be found. After application on the surfaces of resin lens, the coatings presented better impact resistance, which indicated that the coating has application prospects in the field of fine processing of lens’ surfaces.
Insecticidal and Antiprotozoal Properties of Lichen Secondary Metabolites on Insect Vectors and Their Transmitted Protozoal Diseases to Humans
Authors: Muhoro Arthur M. , Farkas Edit É.
Published: July 2021

Since the long-term application of synthetic chemicals as insecticides and the chemotherapy of protozoal diseases have had various negative effects (non-target effects, resistance), research on less harmful biological products is underway. This review is focused on lichens with potential insecticidal and antiprotozoal activity. Literature sources (27) were surveyed from five bibliographic databases and analyzed according to the taxonomic group of the insect, the protozoal disease and the lichen, the type of bioactive compounds (including method of application and mount applied), and the potential bioactivity based on mortalities caused after 24 h of exposure on insects and on parasitic protozoa. Six species of protozoa and five species of mosquitoes, three kinds of larval stages of insects and three protozoa stages were tested. Insecticidal and antiprotozoal effects of crude extracts and seven lichen secondary metabolites (mostly usnic acid) of 32 lichen species were determined. Physiological and morphological changes on parasitic protozoa were observed. Mortality rates caused by LSMs on insect vectors closer to (or somewhat above) the WHO threshold were considered to be insecticides. The results are based on laboratory experiments; however, the efficacy of metabolites should be confirmed in the field and on non-human primates to control the insect vectors and human protozoal diseases transmitted by insects.