bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders
Authors: Lee Ming-Jen , Lee Inyoul , Wang Kai
Published: January 2022

The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in biochemistry and molecular biology has established a new class of therapeutics—the short RNAs and expressible long RNAs. The sequences of therapeutic RNAs can be optimized to enhance their stability and translatability with reduced immunogenicity. The chemically-modified RNAs can also increase their stability during intracellular trafficking. In addition, the development of safe and high efficiency carriers that preserves the integrity of therapeutic RNA molecules also accelerates the transition of RNA therapeutics into the clinic. For example, for diseases that are caused by genetic defects in a specific protein, an effective approach termed “protein replacement therapy” can provide treatment through the delivery of modified translatable mRNAs. Short interference RNAs can also be used to treat diseases caused by gain of function mutations or restore the splicing aberration defects. Here we review the applications of newly developed RNA-based therapeutics and its delivery and discuss the clinical evidence supporting the potential of RNA-based therapy in single-gene neurological disorders.
Inhibition of DUSP6 Activates Autophagy and Rescues the Retinal Pigment Epithelium in Sodium Iodate-Induced Retinal Degeneration Models In Vivo and In Vitro
Authors: Tsai Hao-Yu , Lai Henkie Isahwan Ahmad Mulyadi , Chen Zhang-Yuan , Lin Tai-Chi , Khor Winnie , Kuo Wen-Chuan , Syu Jia-Pu , Tsai Ping-Hsing , Yang Yi-Ping , Chien Yueh , Chen Shih-Jen , Hwang De-Kuang , Chiou Shih-Hwa , Chou Shih-Jie
Published: January 2022

Autophagy plays a protective role in the retinal pigment epithelium (RPE) by eliminating damaged organelles in response to reactive oxygen species (ROS). Dual-specificity protein phosphatase 6 (DUSP6), which belongs to the DUSP subfamily, works as a negative-feedback regulator of the extracellular signal-regulated kinase (ERK) pathway. However, the complex interplay between DUSP6 and autophagy induced by ROS in RPE is yet to be investigated. To investigate the relationship between DUSP6 and autophagy, we exposed the ARPE-19 cell line and C57BL/6N mice to sodium iodate (NaIO3) as an oxidative stress inducer. Our data showed that the inhibition of DUSP6 activity promotes autophagy flux through the ERK pathway via the upregulation of immunoblotting expression in ARPE-19 cells. Live imaging showed a significant increase in autophagic flux activities, which suggested the restoration autophagy after treatment with the DUSP6 inhibitor. Furthermore, the mouse RPE layer exhibited an irregular structure and abnormal deposits following NaIO3 injection. The retina layer was recovered after being treated with DUSP6 inhibitor; this suggests that DUSP6 inhibitor can rescue retinal damage by restoring the mouse retina’s autophagy flux. This study suggests that the upregulation of DUSP6 can cause autophagy flux malfunctions in the RPE. The DUSP6 inhibitor can restore autophagy induction, which may serve as a potential therapeutic approach for retinal degeneration disease.
Design of Magnetic Nanoplatforms for Cancer Theranostics
Authors: Jiao Wangbo , Zhang Tingbin , Peng Mingli , Yi Jiabao , He Yuan , Fan Haiming
Published: January 2022

Cancer is the top cause of death globally. Developing smart nanomedicines that are capable of diagnosis and therapy (theranostics) in one–nanoparticle systems are highly desirable for improving cancer treatment outcomes. The magnetic nanoplatforms are the ideal system for cancer theranostics, because of their diverse physiochemical properties and biological effects. In particular, a biocompatible iron oxide nanoparticle based magnetic nanoplatform can exhibit multiple magnetic–responsive behaviors under an external magnetic field and realize the integration of diagnosis (magnetic resonance imaging, ultrasonic imaging, photoacoustic imaging, etc.) and therapy (magnetic hyperthermia, photothermal therapy, controlled drug delivery and release, etc.) in vivo. Furthermore, due to considerable variation among tumors and individual patients, it is a requirement to design iron oxide nanoplatforms by the coordination of diverse functionalities for efficient and individualized theranostics. In this article, we will present an up–to–date overview on iron oxide nanoplatforms, including both iron oxide nanomaterials and those that can respond to an externally applied magnetic field, with an emphasis on their applications in cancer theranostics.
Electrochemical Detection Platform Based on RGO Functionalized with Diazonium Salt for DNA Hybridization
Authors: Chiticaru Elena A. , Pilan Luisa , Ioniţă Mariana
Published: January 2022

In this paper, we propose an improved electrochemical platform based on graphene for the detection of DNA hybridization. Commercial screen-printed carbon electrodes (SPCEs) were used for this purpose due to their ease of functionalization and miniaturization opportunities. SPCEs were modified with reduced graphene oxide (RGO), offering a suitable surface for further functionalization. Therefore, aryl-carboxyl groups were integrated onto RGO-modified electrodes by electrochemical reduction of the corresponding diazonium salt to provide enough reaction sites for the covalent immobilization of amino-modified DNA probes. Our final goal was to determine the optimum conditions needed to fabricate a simple, label-free RGO-based electrochemical platform to detect the hybridization between two complementary single-stranded DNA molecules. Each modification step in the fabrication process was monitored by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) using [Fe(CN)6]3−/4− as a redox reporter. Although, the diazonium electrografted layer displayed the expected blocking effect of the charge transfer, the next steps in the modification procedure resulted in enhanced electron transfer properties of the electrode interface. We suggest that the improvement in the charge transfer after the DNA hybridization process could be exploited as a prospective sensing feature. The morphological and structural characterization of the modified electrodes performed by scanning electron microscopy (SEM) and Raman spectroscopy, respectively, were used to validate different modification steps in the platform fabrication process.
Correlation between Mild Traumatic Brain Injury-Induced Inflammatory Cytokines and Emotional Symptom Traits: A Systematic Review
Authors: Malik Shazia , Alnaji Omar , Malik Mahnoor , Gambale Teresa , Rathbone Michel Piers
Published: January 2022

Both mild traumatic brain injuries (mTBI) and systemic injuries trigger a transient neuroinflammatory response that result in similar clinical outcome. The ensuing physical, cognitive, and emotional symptoms fail to subside in approximately 15–20% of the concussed population. Emotional impairments, particularly depression, anxiety, and post-traumatic stress disorder (PTSD), are commonly associated with poor recovery following mTBI. These emotional impairments also have a significant neuroinflammatory component. We hypothesized that the inflammatory cytokines seen in mTBI patients with emotional symptoms would coincide with those commonly seen in patients with emotional symptoms without mTBI. A systematic review was conducted to identify the most common neuroinflammatory cytokines in the mTBI population with psychological symptoms (depression, anxiety, PTSD). The electronic databases EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), PUBMED, and PSYCINFO were searched from data inception to 31 August 2021. A systematic screening approach was employed from screening to data analysis. A total of 994 articles were screened, 108 were selected for full article review, and 8 were selected for data analysis. The included studies consisted of 875 patients of which 81.3% were male. The mean sample size of patients with at least one mTBI was 73.8 ± 70.3 (range, 9–213), with a mean age of 33.9 ± 4.8 years. The most common cytokines associated with poor psychological outcomes involving PTSD and/or depression in the chronic mTBI population were IL-6, TNFα, IL-10, and CRP.
Sensitivity of a 29-Channel MEG Source Montage
Authors: Nenonen Jukka , Helle Liisa , Jaiswal Amit , Bock Elizabeth , Ille Nicole , Bornfleth Harald
Published: January 2022

In this paper, we study the performance of a source montage corresponding to 29 brain regions reconstructed from whole-head magnetoencephalographic (MEG) recordings, with the aim of facilitating the review of MEG data containing epileptiform discharges. Test data were obtained by superposing simulated signals from 100-nAm dipolar sources to a resting state MEG recording from a healthy subject. Simulated sources were placed systematically to different cortical locations for defining the optimal regularization for the source montage reconstruction and for assessing the detectability of the source activity from the 29-channel MEG source montage. The signal-to-noise ratio (SNR), computed for each source from the sensor-level and source-montage signals, was used as the evaluation parameter. Without regularization, the SNR from the simulated sources was larger in the sensor-level signals than in the source montage reconstructions. Setting the regularization to 2% increased the source montage SNR to the same level as the sensor-level SNR, improving the detectability of the simulated events from the source montage reconstruction. Sources producing a SNR of at least 15 dB were visually detectable from the source-montage signals. Such sources are located closer than about 75 mm from the MEG sensors, in practice covering all areas in the grey matter. The 29-channel source montage creates more focal signals compared to the sensor space and can significantly shorten the detection time of epileptiform MEG discharges for focus localization.
Post-Stroke Outcomes of Patients with Chronic Obstructive Pulmonary Disease
Authors: Szylińska Aleksandra , Kotfis Katarzyna , Bott-Olejnik Marta , Wańkowicz Paweł , Rotter Iwona
Published: January 2022

Introduction: Research has shown that patients with ischemic stroke and coexisting obstructive respiratory disorders have worse clinical status on admission and increased long-term mortality. Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of stroke, and the risk is even greater after exacerbation of COPD. Moreover, COPD and stroke share major risk factors, which are advancing age and smoking. The aim of this study was to analyze the incidence of complications and mortality in acute ischemic stroke (AIS) patients with and without COPD. Material and methods: We analyzed prospectively collected data of 1022 patients with acute is-chemic stroke hospitalized in a district general hospital. The patients were divided into two groups—with coexisting COPD and without COPD. Results: Logistic regression analysis, which allowed for potential confounders, showed an association between coexisting COPD and the fol-lowing complications in acute ischemic stroke patients: heart failure (OR = 1.879, p = 0.048), atrial fibrillation (OR = 4.746, p = 0.012), delirium (OR = 2.803, p < 0.001), pneumonia (OR = 2.424, p = 0.005), bronchospasm (OR = 3.400, p = 0.023), and out-hospital mortality (OR = 2.656, p = 0.001). Conclusion: Patients presenting with acute ischemic stroke and coexisting COPD significantly more often had cardiac and pulmonary complications, as well as delirium following stroke. In a long-term follow-up, the probability of one-year survival was significantly lower in AIS patients with co-existing COPD.
Functional Changes in Brain Activity Using Hypnosis: A Systematic Review
Authors: Wolf Thomas Gerhard , Faerber Karin Anna , Rummel Christian , Halsband Ulrike , Campus Guglielmo
Published: January 2022

Hypnosis has proven a powerful method in indications such as pain control and anxiety reduction. As recently discussed, it has been yielding increased attention from medical/dental perspectives. This systematic review (PROSPERO-registration-ID-CRD42021259187) aimed to critically evaluate and discuss functional changes in brain activity using hypnosis by means of different imaging techniques. Randomized controlled trials, cohort, comparative, cross-sectional, evaluation and validation studies from three databases—Cochrane, Embase and Medline via PubMed from January 1979 to August 2021—were reviewed using an ad hoc prepared search string and following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. A total of 10,404 articles were identified, 1194 duplicates were removed and 9190 papers were discarded after consulting article titles/abstracts. Ultimately, 20 papers were assessed for eligibility, and 20 papers were included after a hand search (ntotal = 40). Despite a broad heterogenicity of included studies, evidence of functional changes in brain activity using hypnosis was identified. Electromyography (EMG) startle amplitudes result in greater activity in the frontal brain area; amplitudes using Somatosensory Event-Related Potentials (SERPs) showed similar results. Electroencephalography (EEG) oscillations of θ activity are positively associated with response to hypnosis. EEG results showed greater amplitudes for highly hypnotizable subjects over the left hemisphere. Less activity during hypnosis was observed in the insula and anterior cingulate cortex (ACC).
Hydrogenation and Dehydrogenation of Liquid Organic Hydrogen Carriers: A New Opportunity for Carbon-Based Catalysts
Authors: Ordóñez Salvador , Díaz Eva , Faba Laura
Published: January 2022

The development of a hydrogen-based economy is the perfect nexus between the need of discontinuing the use of fossil fuels (trying to mitigate climate change), the development of a system based on renewable energy (with the use of hydrogen allowing us to buffer the discontinuities produced in this generation) and the achievement of a local-based robust energy supply system [...]
Folinic Acid Potentiates the Liver Regeneration Process after Selective Portal Vein Ligation in Rats
Authors: Gutiérrez Sáenz de Santa María Jorge , Herrero de la Parte Borja , Gutiérrez-Sánchez Gaizka , Ruiz Montesinos Inmaculada , Iturrizaga Correcher Sira , Mar Medina Carmen , García-Alonso Ignacio
Published: January 2022

Liver resection remains the gold standard for hepatic metastases. The future liver remnant (FLR) and its functional status are two key points to consider before performing major liver resections, since patients with less than 25% FLR or a Child–Pugh B or C grade are not eligible for this procedure. Folinic acid (FA) is an essential agent in cell replication processes. Herein, we analyze the effect of FA as an enhancer of liver regeneration after selective portal vein ligation (PVL). Sixty-four male WAG/RijHsd rats were randomly distributed into eight groups: a control group and seven subjected to 50% PVL, by ligation of left portal branch. The treated animals received FA (2.5 m/kg), while the rest were given saline. After 36 h, 3 days or 7 days, liver tissue and blood samples were obtained. FA slightly but significantly increased FLR percentage (FLR%) on the 7th day (91.88 ± 0.61%) compared to control or saline-treated groups (86.72 ± 2.5 vs. 87 ± 3.33%; p < 0.01). The hepatocyte nuclear area was also increased both at 36 h and 7days with FA (61.55 ± 16.09 µm2, and 49.91 ± 15.38 µm2; p < 0.001). Finally, FA also improved liver function. In conclusion, FA has boosted liver regeneration assessed by FLR%, nuclear area size and restoration of liver function after PVL.
BHMPS Inhibits Breast Cancer Migration and Invasion by Disrupting Rab27a-Mediated EGFR and Fibronectin Secretion
Authors: Park Jeong-In , Song Kyung-Hee , Kang Seong-Mook , Lee Jeeyong , Cho Seong-Jun , Choi Hyun Kyung , Ahn Jiyeon , Park Jong-Kuk , Kim Jaesung , Hwang Sang-Gu , Lim Dae-Seog , Kim Joon , Jung Seung-Youn , Song Jie-Young
Published: January 2022

Our previous work demonstrated that (E)-N-benzyl-6-(2-(3, 4-dihydroxybenzylidene) hydrazinyl)-N-methylpyridine-3-sulfonamide (BHMPS), a novel synthetic inhibitor of Rab27aSlp(s) interaction, suppresses tumor cell invasion and metastasis. Here, we aimed to further investigate the mechanisms of action and biological significance of BHMPS. BHMPS decreased the expression of epithelial-mesenchymal transition transcription factors through inhibition of focal adhesion kinase and c-Jun N-terminal kinase activation, thereby reducing the migration and invasion of breast cancer. Additionally, knockdown of Rab27a inhibited tumor migration, with changes in related signaling molecules, whereas overexpression of Rab27a reversed this phenomenon. BHMPS effectively prevented the interaction of Rab27a and its effector Slp4, which was verified by co-localization, immunoprecipitation, and in situ proximity ligation assays. BHMPS decreased the secretion of epidermal growth factor receptor and fibronectin by interfering with vesicle trafficking, as indicated by increased perinuclear accumulation of CD63-positive vesicles. Moreover, administration of BHMPS suppressed tumor growth in Rab27a-overexpressing MDA-MB-231 xenograft mice. These findings suggest that BHMPS may be a promising candidate for attenuating tumor migration and invasion by blocking Rab27a-mediated exocytosis.
The Multidisciplinary Management of Cutaneous Squamous Cell Carcinoma: A Comprehensive Review and Clinical Recommendations by a Panel of Experts
Authors: Stanganelli Ignazio , Spagnolo Francesco , Argenziano Giuseppe , Ascierto Paolo A. , Bassetto Franco , Bossi Paolo , Donato Vittorio , Massi Daniela , Massone Cesare , Patuzzo Roberto , Pellacani Giovanni , Quaglino Pietro , Queirolo Paola , Zalaudek Iris , Palmieri Giuseppe ,   on behalf of Italian Melanoma Intergroup (IMI)
Published: January 2022

Cutaneous squamous cell carcinomas (CSCC) account for about 20% of all keratinocyte carcinomas, which are the most common form of cancer. Heterogeneity of treatments and low mortality are a challenge in obtaining accurate incidence data and consistent registration in cancer registries. Indeed, CSCC mostly presents as an indolent, low-risk lesion, with five-year cure rates greater than 90% after surgical excision, and only few tumors are associated with a high-risk of local or distant relapse; therefore, it is particularly relevant to identify high-risk lesions among all other low-risk CSCCs for the proper diagnostic and therapeutic management. Chemotherapy achieves mostly short-lived responses that do not lead to a curative effect and are associated with severe toxicities. Due to an etiopathogenesis largely relying on chronic UV radiation exposure, CSCC is among the tumors with the highest rate of somatic mutations, which are associated with increased response rates to immunotherapy. Thanks to such strong pre-clinical rationale, clinical trials led to the approval of anti-PD-1 cemiplimab by the FDA (Food and Drug Administration) and EMA (European Medicines Agency), and anti-PD-1 pembrolizumab by the FDA only. Here, we provide a literature review and clinical recommendations by a panel of experts regarding the diagnosis, treatment, and follow-up of CSCC.
Targeting PELP1 Attenuates Angiogenesis and Enhances Chemotherapy Efficiency in Colorectal Cancer
Authors: Zhu Jianlin , Wang Lu , Liu Fan , Pan Jinghua , Yao Zhimeng , Lin Yusheng , Yang Yabing , Xiong Xiao , Li Kai , Yang Yi , Zhang Yiran , Chu Xiaodong , Pan Yunlong , Zhang Hao
Published: January 2022

Abnormal angiogenesis is one of the important hallmarks of colorectal cancer as well as other solid tumors. Optimally, anti-angiogenesis therapy could restrain malignant angiogenesis to control tumor expansion. PELP1 is as a scaffolding oncogenic protein in a variety of cancer types, but its involvement in angiogenesis is unknown. In this study, PELP1 was found to be abnormally upregulated and highly coincidental with increased MVD in CRC. Further, treatment with conditioned medium (CM) from PELP1 knockdown CRC cells remarkably arrested the function of human umbilical vein endothelial cells (HUVECs) compared to those treated with CM from wildtype cells. Mechanistically, the STAT3/VEGFA axis was found to mediate PELP1-induced angiogenetic phenotypes of HUVECs. Moreover, suppression of PELP1 reduced tumor growth and angiogenesis in vivo accompanied by inactivation of STAT3/VEGFA pathway. Notably, in vivo, PELP1 suppression could enhance the efficacy of chemotherapy, which is caused by the normalization of vessels. Collectively, our findings provide a preclinical proof of concept that targeting PELP1 to decrease STAT3/VEGFA-mediated angiogenesis and improve responses to chemotherapy due to normalization of vessels. Given the newly defined contribution to angiogenesis of PELP1, targeting PELP1 may be a potentially ideal therapeutic strategy for CRC as well as other solid tumors.
Differential Gene Expression Profiles between N-Terminal Domain and Ligand-Binding Domain Inhibitors of Androgen Receptor Reveal Ralaniten Induction of Metallothionein by a Mechanism Dependent on MTF1
Authors: Obst Jon K. , Mawji Nasrin R. , Teskey Simon J. L. , Wang Jun , Sadar Marianne D.
Published: January 2022

Hormonal therapies for prostate cancer target the androgen receptor (AR) ligand-binding domain (LBD). Clinical development for inhibitors that bind to the N-terminal domain (NTD) of AR has yielded ralaniten and its analogues. Ralaniten acetate is well tolerated in patients at 3600 mgs/day. Clinical trials are ongoing with a second-generation analogue of ralaniten. Binding sites on different AR domains could result in differential effects on AR-regulated gene expression. Here, we provide the first comparison between AR-NTD inhibitors and AR-LBD inhibitors on androgen-regulated gene expression in prostate cancer cells using cDNA arrays, GSEA, and RT-PCR. LBD inhibitors and NTD inhibitors largely overlapped in the profile of androgen-induced genes that they each inhibited. However, androgen also represses gene expression by various mechanisms, many of which involve protein–protein interactions. De-repression of the transcriptome of androgen-repressed genes showed profound variance between these two classes of inhibitors. In addition, these studies revealed a unique and strong induction of expression of the metallothionein family of genes by ralaniten by a mechanism independent of AR and dependent on MTF1, thereby suggesting this may be an off-target. Due to the relatively high doses that may be encountered clinically with AR-NTD inhibitors, identification of off-targets may provide insight into potential adverse events, contraindications, or poor efficacy.
Polymorphism of VDR Gene and the Sensitivity of Human Leukemia and Lymphoma Cells to Active Forms of Vitamin D
Authors: Gleba Justyna Joanna , Kłopotowska Dagmara , Banach Joanna , Turlej Eliza , Mielko Karolina Anna , Gębura Katarzyna , Bogunia-Kubik Katarzyna , Kutner Andrzej , Wietrzyk Joanna
Published: January 2022

The active forms of vitamin D3 (calcitriol and tacalcitol) coupled to the vitamin D receptor (VDR) are known to exhibit anti-cancer properties. However, not all cancer cells are sensitive to the active forms of vitamin D3 and its analogs. The study aimed to determine whether polymorphism of VDR is responsible for the sensitivity of human leukemia and lymphoma cells to calcitriol and tacalcitol. The impact of calcitriol and tacalcitol on the proliferation and morphology of nine different leukemia and lymphoma cell lines was determined. Only MV-4-11, Thp-1, and HL-60 cell lines sensitive to proliferation inhibition by calcitriol and tacalcitol showed morphology changes. Subsequently, the levels of the VDR and 1,25D3-MARRS proteins of calcitriol and tacalcitol binding receptors and the VDR receptor polymorphism in human leukemia and lymphoma cells were ascertained. Contrary to the current understanding, higher levels of VDR are not responsible for the greater sensitivity of cells to calcitriol and tacalcitol. Importantly, we first showed that sensitivity to calcitriol and tacalcitol in leukemias and lymphomas could be determined by the VDR polymorphism. The FokI polymorphism and the presence of the “bat” haplotype were observed only in the sensitive cells.
Optimizing the Diagnosis and Biomarker Testing for Patients with Intrahepatic Cholangiocarcinoma: A Multidisciplinary Approach
Authors: Cho May T. , Gholami Sepideh , Gui Dorina , Tejaswi Sooraj L. , Fananapazir Ghaneh , Abi-Jaoudeh Nadine , Jutric Zeljka , Samarasena Jason B. , Li Xiaodong , Valerin Jennifer B. , Mercer Jacob , Dayyani Farshid
Published: January 2022

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.
EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma
Authors: Pacini Laura , Cabal Virginia N. , Hermsen Mario A. , Huang Paul H.
Published: January 2022

Recurrent epidermal growth factor receptor (EGFR)-activating mutations have been identified in a rare form of head and neck cancer known as sinonasal squamous cell carcinoma (SNSCC), a malignant disease with a 5-year mortality rate of ~40%. Interestingly, the majority of EGFR mutations identified in patients with primary SNSCC are exon 20 insertions (Ex20ins), which is in contrast to non-small-cell lung cancer (NSCLC), where the EGFR exon 19 deletion and L858R mutations predominate. These studies demonstrate that EGFR Ex20ins mutations are not exclusive to lung cancer as previously believed, but are also involved in driving SNSCC pathogenesis. Here we review the landscape of EGFR mutations in SNSCC, with a particular focus on SNSCC associated with inverted sinonasal papilloma (ISP), a benign epithelial neoplasm. Taking lessons from NSCLC, we also discuss potential new treatment options for ISP-associated SNSCC harbouring EGFR Ex20ins in the context of targeted therapies, drug resistance and precision cancer medicine. Moving forward, further basic and translational work is needed to delineate the biology of EGFR Ex20ins in SNSCC in order to develop more effective treatments for patients with this rare disease.
The Anti-Proliferative Effect of PI3K/mTOR and ERK Inhibition in Monolayer and Three-Dimensional Ovarian Cancer Cell Models
Authors: Dunn Elizabeth , Chitcholtan Kenny , Sykes Peter , Garrill Ashley
Published: January 2022

Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors.
Evaluating Pancreatic and Biliary Neoplasms with Small Biopsy-Based Next Generation Sequencing (NGS): Doing More with Less
Authors: Nikas Ilias P. , Mountzios Giannis , Sydney Guy I. , Ioakim Kalliopi J. , Won Jae-Kyung , Papageorgis Panagiotis
Published: January 2022

Pancreatic cancer and cholangiocarcinoma are lethal diseases mainly diagnosed at an inoperable stage. As pancreatobiliary surgical specimens are often unavailable for further molecular testing, this review aimed to highlight the diagnostic, prognostic, and therapeutic impact of next-generation sequencing (NGS) performed on distinct small biopsies, including endoscopic ultrasound fine-needle aspirations and biopsies of pancreatic solid and cystic lesions, biliary duct brushings, and also “liquid biopsies” such as the pancreatic juice, bile, and blood. NGS could clarify indeterminate pancreatic lesions or biliary strictures, for instance by identifying TP53 or SMAD4 mutations indicating high-grade dysplasia or cancer. It could also stratify pancreatic cystic lesions, by distinguishing mucinous from non-mucinous cysts and identifying high-risk cysts that should be excised in surgically fit patients, whereas the combination of cytology, elevated cystic CEA levels and NGS could improve the overall diagnostic accuracy. When NGS is performed on the pancreatic juice, it could stratify high-risk patients under surveillance. On the plasma, it could dynamically monitor the disease course and response to therapy. Notably, the circulating tumor DNA (ctDNA) levels have been associated with staging, grading, and survival. Lastly, NGS has shown potential in identifying potentially actionable molecular alterations. In conclusion, NGS applied on small biopsies could carry significant diagnostic, prognostic, and therapeutic value.
Socio-Economic Inequalities in Lung Cancer Outcomes: An Overview of Systematic Reviews
Authors: Redondo-Sánchez Daniel , Petrova Dafina , Rodríguez-Barranco Miguel , Fernández-Navarro Pablo , Jiménez-Moleón José Juan , Sánchez Maria-José
Published: January 2022

In the past decade, evidence has accumulated about socio-economic inequalities in very diverse lung cancer outcomes. To better understand the global effects of socio-economic factors in lung cancer, we conducted an overview of systematic reviews. Four databases were searched for systematic reviews reporting on the relationship between measures of socio-economic status (SES) (individual or area-based) and diverse lung cancer outcomes, including epidemiological indicators and diagnosis- and treatment-related variables. AMSTAR-2 was used to assess the quality of the selected systematic reviews. Eight systematic reviews based on 220 original studies and 8 different indicators were identified. Compared to people with a high SES, people with a lower SES appear to be more likely to develop and die from lung cancer. People with lower SES also have lower cancer survival, most likely due to the lower likelihood of receiving both traditional and next-generation treatments, higher rates of comorbidities, and the higher likelihood of being admitted as emergency. People with a lower SES are generally not diagnosed at later stages, but this may change after broader implementation of lung cancer screening, as early evidence suggests that there may be socio-economic inequalities in its use.
Lipases as Effective Green Biocatalysts for Phytosterol Esters’ Production: A Review
Authors: Pereira Adejanildo da S. , de Souza Aline Habibe , Fraga Jully L. , Villeneuve Pierre , Torres Alexandre G. , Amaral Priscilla F. F.
Published: January 2022

Lipases are versatile enzymes widely used in the pharmaceutical, cosmetic, and food industries. They are green biocatalysts with a high potential for industrial use compared to traditional chemical methods. In recent years, lipases have been used to synthesize a wide variety of molecules of industrial interest, and extraordinary results have been reported. In this sense, this review describes the important role of lipases in the synthesis of phytosterol esters, which have attracted the scientific community’s attention due to their beneficial effects on health. A systematic search for articles and patents published in the last 20 years with the terms “phytosterol AND esters AND lipase” was carried out using the Scopus, Web of Science, Scielo, and Google Scholar databases, and the results showed that Candida rugosa lipases are the most relevant biocatalysts for the production of phytosterol esters, being used in more than 50% of the studies. The optimal temperature and time for the enzymatic synthesis of phytosterol esters mainly ranged from 30 to 101 °C and from 1 to 72 h. The esterification yield was greater than 90% for most analyzed studies. Therefore, this manuscript presents the new technological approaches and the gaps that need to be filled by future studies so that the enzymatic synthesis of phytosterol esters is widely developed.
Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies
Authors: Berlansky Sascha , Sallinger Matthias , Grabmayr Herwig , Humer Christina , Bernhard Andreas , Fahrner Marc , Frischauf Irene
Published: January 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This respiratory illness was declared a pandemic by the world health organization (WHO) in March 2020, just a few weeks after being described for the first time. Since then, global research effort has considerably increased humanity’s knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19. However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population and the threat of a complete immune escape variant, alternative strategies in the fight against SARS-CoV-2 are urgently required. Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies. In this review, we introduce the pivotal role of calcium signaling in viral infection cascades. Based on this, we discuss prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.
Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways
Authors: Gutierrez Denisse A. , Contreras Lisett , Villanueva Paulina J. , Borrego Edgar A. , Morán-Santibañez Karla , Hess Jessica D. , DeJesus Rebecca , Larragoity Manuel , Betancourt Ana P. , Mohl Jonathon E. , Robles-Escajeda Elisa , Begum Khodeza , Roy Sourav , Kirken Robert A. , Varela-Ramirez Armando , Aguilera Renato J.
Published: January 2022

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.
Regression of Triple-Negative Breast Cancer in a Patient-Derived Xenograft Mouse Model by Monoclonal Antibodies against IL-12 p40 Monomer
Authors: Kundu Madhuchhanda , Raha Sumita , Roy Avik , Pahan Kalipada
Published: January 2022

Although some therapies are available for regular breast cancers, there are very few options for triple-negative breast cancer (TNBC). Here, we demonstrated that serum level of IL-12p40 monomer (p40) was much higher in breast cancer patients than healthy controls. On the other hand, levels of IL-12, IL-23 and p40 homodimer (p402) were lower in serum of breast cancer patients as compared to healthy controls. Similarly, human TNBC cells produced greater level of p40 than p402. The level of p40 was also larger than p402 in serum of a patient-derived xenograft (PDX) mouse model. Accordingly, neutralization of p40 by p40 mAb induced death of human TNBC cells and tumor shrinkage in PDX mice. While investigating the mechanism, we found that neutralization of p40 led to upregulation of human CD4+IFNγ+ and CD8+IFNγ+ T cell populations, thereby increasing the level of human IFNγ and decreasing the level of human IL-10 in PDX mice. Finally, we demonstrated the infiltration of human cytotoxic T cells, switching of tumor-associated macrophage M2 (TAM2) to TAM1 and suppression of transforming growth factor β (TGFβ) in tumor tissues of p40 mAb-treated PDX mice. Our studies identify a possible new immunotherapy for TNBC in which p40 mAb inhibits tumor growth in PDX mice.
Lipocalin-2 (LCN2) Deficiency Leads to Cellular Changes in Highly Metastatic Human Prostate Cancer Cell Line PC-3
Authors: Schröder Sarah K. , Pinoé-Schmidt Manuela , Weiskirchen Ralf
Published: January 2022

The transporter protein lipocalin-2 (LCN2) also termed neutrophil-gelatinase-associated lipocalin (NGAL) has pleiotropic effects in tumorigenesis in various cancers. Since the precise role of LCN2 in prostate cancer (PCa) is poorly understood, we aimed to elucidate its functions in PCa in vitro. For this purpose, LCN2 was transiently suppressed or permanently depleted in human PC-3 cells using siRNA or CRISPR/Cas9-mediated knockout. Effects of LCN2 suppression on expression of different tumorigenic markers were investigated by Western blot analysis and RT-qPCR. LCN2 knockout cells were analyzed for cellular changes and their ability to cope endoplasmic stress compared to parenteral PC-3 cells. Reduced LCN2 was accompanied by decreased expression of IL-1β and Cx43. In PC-3 cells, LCN2 deficiency leads to reduced proliferation, diminished expression of pro-inflammatory cytokines, lower adhesion, and disrupted F-actin distribution. In addition, IL-1β expression strongly correlated with LCN2 levels. LCN2 knockout cells showed enhanced and sustained activation of unfolded protein response proteins when treated with tunicamycin or cultured under glucose deprivation. Interestingly, an inverse correlation between phosphorylation of eukaryotic initiation factor 2 α subunit (p-eIF2α) and LCN2 expression was observed suggesting that LCN2 triggers protein synthesis under stress conditions. The finding that LCN2 depletion leads to significant phenotypic and cellular changes in PC-3 cells adds LCN2 as a valuable target for the treatment of PCa.
Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes
Authors: Stojanovic Tamara , Velarde Gamez David , Schuld Gabor Jorrid , Bormann Daniel , Cabatic Maureen , Uhrin Pavel , Lubec Gert , Monje Francisco J.
Published: January 2022

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212−/−) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3–CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212−/− mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3–CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212−/− mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212−/− mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.
Revisiting the Non-Coding Nature of Pospiviroids
Authors: Katsarou Konstantina , Adkar-Purushothama Charith Raj , Tassios Emilios , Samiotaki Martina , Andronis Christos , Lisón Purificación , Nikolaou Christoforos , Perreault Jean-Pierre , Kalantidis Kriton
Published: January 2022

Viroids are small, circular, highly structured pathogens that infect a broad range of plants, causing economic losses. Since their discovery in the 1970s, they have been considered as non-coding pathogens. In the last few years, the discovery of other RNA entities, similar in terms of size and structure, that were shown to be translated (e.g., cirRNAs, precursors of miRNA, RNA satellites) as well as studies showing that some viroids are located in ribosomes, have reignited the idea that viroids may be translated. In this study, we used advanced bioinformatic analysis, in vitro experiments and LC-MS/MS to search for small viroid peptides of the PSTVd. Our results suggest that in our experimental conditions, even though the circular form of PSTVd is found in ribosomes, no produced peptides were identified. This indicates that the presence of PSTVd in ribosomes is most probably not related to peptide production but rather to another unknown function that requires further study.
Scaffold-Mediated Immunoengineering as Innovative Strategy for Tendon Regeneration
Authors: Russo Valentina , El Khatib Mohammad , Prencipe Giuseppe , Cerveró-Varona Adrián , Citeroni Maria Rita , Mauro Annunziata , Berardinelli Paolo , Faydaver Melisa , Haidar-Montes Arlette A. , Turriani Maura , Di Giacinto Oriana , Raspa Marcello , Scavizzi Ferdinando , Bonaventura Fabrizio , Liverani Liliana , Boccaccini Aldo R. , Barboni Barbara
Published: January 2022

Tendon injuries are at the frontier of innovative approaches to public health concerns and sectoral policy objectives. Indeed, these injuries remain difficult to manage due to tendon’s poor healing ability ascribable to a hypo-cellularity and low vascularity, leading to the formation of a fibrotic tissue affecting its functionality. Tissue engineering represents a promising solution for the regeneration of damaged tendons with the aim to stimulate tissue regeneration or to produce functional implantable biomaterials. However, any technological advancement must take into consideration the role of the immune system in tissue regeneration and the potential of biomaterial scaffolds to control the immune signaling, creating a pro-regenerative environment. In this context, immunoengineering has emerged as a new discipline, developing innovative strategies for tendon injuries. It aims at designing scaffolds, in combination with engineered bioactive molecules and/or stem cells, able to modulate the interaction between the transplanted biomaterial-scaffold and the host tissue allowing a pro-regenerative immune response, therefore hindering fibrosis occurrence at the injury site and guiding tendon regeneration. Thus, this review is aimed at giving an overview on the role exerted from different tissue engineering actors in leading immunoregeneration by crosstalking with stem and immune cells to generate new paradigms in designing regenerative medicine approaches for tendon injuries.
Large-Scale, Wavelet-Based Analysis of Lysosomal Trajectories and Co-Movements of Lysosomes with Nanoparticle Cargos
Authors: Polev Konstantin , Kolygina Diana V. , Kandere-Grzybowska Kristiana , Grzybowski Bartosz A.
Published: January 2022

Lysosomes—that is, acidic organelles known for degradation/recycling—move through the cytoplasm alternating between bursts of active transport and short, diffusive motions or even pauses. While their mobility is essential for lysosomes’ fusogenic and non-fusogenic interactions with target organelles, their movements have not been characterized in adequate detail. Here, large-scale statistical analysis of lysosomal movement trajectories reveals that lysosome trajectories in all examined cell types—both cancer and noncancerous ones—are superdiffusive and characterized by heavy-tailed distributions of run and flight lengths. Consideration of Akaike weights for various potential models (lognormal, power law, truncated power law, stretched exponential, and exponential) indicates that the experimental data are best described by the lognormal distribution, which, in turn, can be related to one of the space-search strategies particularly effective when “thorough” search needs to balance search for rare target(s) (organelles). In addition, automated, wavelet-based analysis allows for co-tracking the motions of lysosomes and the cargos they carry—particularly the nanoparticle aggregates known to cause selective lysosome disruption in cancerous cells. The methods we describe here could help study nanoparticle assemblies, viruses, and other objects transported inside various vesicle types, as well as coordinated movements of organelles/particles in the cytoplasm. Custom-written code that includes integrated workflow for our analyses is made available for academic use.