bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential of miRNA-Based Nanotherapeutics for Uveal Melanoma
Authors: Yang Chun , Wang Rui , Hardy Pierre
Published: October 2021

Uveal melanoma (UM) is the most common adult intraocular cancer, and metastatic UM remains deadly and incurable. UM is a complex disease associated with the deregulation of numerous genes and redundant intracellular signaling pathways. As understanding of epigenetic dysregulation in the oncogenesis of UM has increased, the abnormal expression of microRNAs (miRNAs) has been found to be an epigenetic mechanism underlying UM tumorigenesis. A growing number of miRNAs are being found to be associated with aberrant signaling pathways in UM, and some have been investigated and functionally characterized in preclinical settings. This review summarizes the miRNAs with promising therapeutic potential for UM treatment, paying special attention to the therapeutic miRNAs (miRNA mimics or inhibitors) used to restore dysregulated miRNAs to their normal levels. However, several physical and physiological limitations associated with therapeutic miRNAs have prevented their translation to cancer therapeutics. With the advent of nanotechnology delivery systems, the development of effective targeted therapies for patients with UM has received great attention. Therefore, this review provides an overview of the use of nanotechnology drug delivery systems, particularly nanocarriers that can be loaded with therapeutic miRNAs for effective delivery into target cells. The development of miRNA-based therapeutics with nanotechnology-based delivery systems may overcome the barriers of therapeutic miRNAs, thereby enabling their translation to therapeutics, enabling more effective targeting of UM cells and consequently improving therapeutic outcomes.
Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models
Authors: Li Sherly X. , Milne Roger L. , Nguyen-Dumont Tú , English Dallas R. , Giles Graham G. , Southey Melissa C. , Antoniou Antonis C. , Lee Andrew , Winship Ingrid , Hopper John L. , Terry Mary Beth , MacInnis Robert J.
Published: October 2021

Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50–65 years and unaffected at commencement of follow-up two (conducted in 2003–2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50–54, 55–59, 60–65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56–0.62) and IBIS (0.57, 95% CI 0.54–0.61) than the other models (p-difference ≤ 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum.
Head and Neck Cancer among American Indian and Alaska Native Populations in California, 2009–2018
Authors: Warren Brooke R. , Grandis Jennifer R. , Johnson Daniel E. , Villa Alessandro
Published: October 2021

The purpose of this study was to determine the incidence of HPV-positive (HPV+) and HPV-negative (HPV-) head and neck cancer (HNC) in the American Indian/Alaska Native (AI/AN) population in California to assess whether incidence is higher among AI/ANs compared to other ethnicities. We analyzed data from the California Cancer Registry, which contains data reported to the Cancer Surveillance Section of the Department of Public Health. A total of 51,289 HNC patients were identified for the years 2009–2018. Outcomes of interest included sex, stage at presentation, 5-year survival rate, tobacco use, and HPV status. AI/AN and White patients had the highest burden of late stage HNC (AI/AN 6.3:100,000; 95% CI 5.3–7.4, White 5.8:100,000; 95% CI 5.7–5.9) compared to all ethnicities or races (Black: 5.2; 95% CI 4.9–5.5; Asian/Pacific Islander: 3.2; 95% CI 3–3.3; and Hispanic: 3.1; 95% CI 3–3.2 per 100,000). Additionally, AI/AN and White patients had the highest burden of HPV+ lip, oral cavity, and pharynx HNC (AI/AN 0.9:100,000; 95% CI 0.6–1.4, White 1.1:100,000; 95% CI 1–1.1) compared to all ethnicities or races (Black: 0.8:100,000; 95% CI 0.7–0.9; Asian/Pacific Islander: 0.4; 95% CI 0.4–0.5; and Hispanic: 0.6; 95% CI 0.5–0.6). AI/ANs had a decreased 5-year survival rate compared to White patients (AI/AN 59.9%; 95% CI 51.9–67.0% and White 67.7%; 95% CI 67.00–68.50%) and a higher incidence of HNC in former and current tobacco users. These findings underscore the disparities that exist in HNC for California AI/AN populations. Future studies should aim to elucidate why the unequal burden of HNC outcomes exists, how to address increased tobacco usage, and HPV vaccination patterns to create culturally and community-based interventions.
HMGA2 Supports Cancer Hallmarks in Triple-Negative Breast Cancer
Authors: Mansoori Behzad , Terp Mikkel Green , Mohammadi Ali , Pedersen Christina Bøg , Ditzel Henrik Jørn , Baradaran Behzad , Gjerstorff Morten Frier
Published: October 2021

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that exhibits a high proliferation rate and early metastasis leading to a poor prognosis. HMGA2 is a DNA binding transcriptional regulator implicated in tumorigenesis. Here, we demonstrate that the HMGA2 promoter is demethylated in TNBC tumors, leading to increased expression of HMGA2 at both mRNA and protein levels. Importantly, high HMGA2 levels in TNBC tumors are correlated with poor prognosis. To detail the role of HMGA2 in TNBC development and progression, we studied its effect on core cancer phenotypes. Stable knockdown of HMGA2 in TNBC cells revealed that HMGA2 may support cell proliferation, cell migration and invasion. In addition, HMGA2 knockdown decreased cancer stem cell (CSC) features. Importantly, we found that silencing HMGA2 inhibited NF-kB signaling and lead to decreased expression of the downstream molecules IL-6 and IL-8 and reduced STAT3 pathway activation. Our results demonstrate that HMGA2 supports cancer hallmarks in TNBC and may represent a promising target for TNBC treatment.
PD-L1 Expression on Circulating Tumour-Derived Microvesicles as a Complementary Tool for Stratification of High-Grade Serous Ovarian Cancer Patients
Authors: Battaglia Alessandra , Piermattei Alessia , Buzzonetti Alexia , Pasciuto Tina , Zampetti Nicole , Fossati Marco , Angelico Giuseppe , Iacobelli Valentina , Nero Camilla , Iannucci Veronica , Scambia Giovanni , Fagotti Anna , Fattorossi Andrea
Published: October 2021

Background: Ovarian cancer (OC) has recently attracted attention for the use of PD-1/PD-L1 axis blocking agents, with durable activity reported only in a subset of patients. The most used biomarker for sensitivity to the PD-1/PD-L1 axis blockade is tumour PD-L1 status by immunohistochemistry. However, patient stratification using this method suffers from intrinsic heterogeneity of OC, likely contributing to the unsatisfactory results obtained so far. Cells communicate with each other by releasing microvesicles (MVs) that carry parental cell surface features. Thus, we hypothesised that PD-L1+ tumour cells (TC) and infiltrating PD-L1+ leukocytes should shed MVs carrying surface PD-L1 that may serve as a proxy for the whole tumour PD-L1 status. Results: We showed for the first time the presence of measurable amounts of TC- and leukocyte-derived PD-L1+ MVs (range: 1.4–178.8 MVs/μL and 6.2–504.8 MVs/μL, respectively) in the plasma of high-grade serous OC (HGSOC) patients (n = 63), using a sensitive flow cytometry platform. The concentration of PD-L1+ MVs of either origin did not associate with the PD-L1 status of TCs and leukocytes in the tumour biopsies, suggesting that the circulating PD-L1+ MVs also included ones from locations not selected for immunohistochemistry analysis and represented the PD-L1 status of the whole tumour mass. In this study, we also describe the serendipitous discovery of circulating PD-L1+ MVs of platelet origin (10.3–2409.6 MVs/μL). Conclusions: The enumeration of circulating PD-L1+ MVs in HGSOC patients may provide a novel direction for assessing the tumour PD-L1 status and contribute to HGSOC patient stratification for immunotherapy interventions. The presence of circulating PD-L1+ MVs of platelet origin, a finding not yet reported in HGSOC patients, warrants further studies.
No Need to Stick Together to Be Connected: Multiple Types of Enhancers’ Networking
Authors: Vitale Emanuele , Gugnoni Mila , Ciarrocchi Alessia
Published: October 2021

The control of gene expression at a transcriptional level requires a widespread landscape of regulatory elements. Central to these regulatory circuits are enhancers (ENHs), which are defined as cis-acting DNA elements able to increase the transcription of a target gene in a distance- and orientation-independent manner. ENHs are not independent functional elements but work in a complex and dynamic cooperative network, constituting the building blocks of multimodular domains of gene expression regulation. The information from each of these elements converges on the target promoter, contributing to improving the precision and sharpness of gene modulation. ENHs’ interplay varies in its nature and extent, ranging from an additive to redundant effect depending on contexts. Moving from super-enhancers that drive the high expression levels of identity genes, to shadow-enhancers, whose redundant functions contribute to buffering the variation in gene expression, this review aims to describe the different modalities of ENHs’ interaction and their role in the regulation of complex biological processes like cancer development.
Second-Generation Jak2 Inhibitors for Advanced Prostate Cancer: Are We Ready for Clinical Development?
Authors: Beinhoff Paul , Sabharwal Lavannya , Udhane Vindhya , Maranto Cristina , LaViolette Peter S. , Jacobsohn Kenneth M. , Tsai Susan , Iczkowski Kenneth A. , Wang Liang , Hall William A. , Dehm Scott M. , Kilari Deepak , Nevalainen Marja T.
Published: October 2021

Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.
The Key Differences between Human Papillomavirus-Positive and -Negative Head and Neck Cancers: Biological and Clinical Implications
Authors: Powell Steven F. , Vu Lexi , Spanos William C. , Pyeon Dohun
Published: October 2021

Head and neck squamous cell carcinoma (HNSCC) is a unique malignancy associated with two distinct risk factors: exposure to typical carcinogens and infection of human papillomavirus (HPV). HPV encodes the potent oncoproteins E6 and E7, which bypass many important oncogenic processes and result in cancer development. In contrast, HPV-negative HNSCC is developed through multiple mutations in diverse oncogenic driver genes. While the risk factors associated with HPV-positive and HPV-negative HNSCCs are discrete, HNSCC patients still show highly complex molecular signatures, immune infiltrations, and treatment responses even within the same anatomical subtypes. Here, we summarize the current understanding of biological mechanisms, treatment approaches, and clinical outcomes in comparison between HPV-positive and -negative HNSCCs.
Improved Immunotherapy Efficacy by Vascular Modulation
Authors: Newport Emma L. , Pedrosa Ana Rita , Njegic Alexandra , Hodivala-Dilke Kairbaan M. , Muñoz-Félix José M.
Published: October 2021

Several strategies have been developed to modulate the tumour vasculature for cancer therapy including anti-angiogenesis and vascular normalisation. Vasculature modulation results in changes to the tumour microenvironment including oxygenation and immune cell infiltration, therefore lending itself to combination with cancer therapy. The development of immunotherapies has led to significant improvements in cancer treatment. Particularly promising are immune checkpoint blockade and CAR T cell therapies, which use antibodies against negative regulators of T cell activation and T cells reprogrammed to better target tumour antigens, respectively. However, while immunotherapy is successful in some patients, including those with advanced or metastatic cancers, only a subset of patients respond. Therefore, better predictors of patient response and methods to overcome resistance warrant investigation. Poor, or periphery-limited, T cell infiltration in the tumour is associated with poor responses to immunotherapy. Given that (1) lymphocyte recruitment requires leucocyte–endothelial cell adhesion and (2) the vasculature controls tumour oxygenation and plays a pivotal role in T cell infiltration and activation, vessel targeting strategies including anti-angiogenesis and vascular normalisation in combination with immunotherapy are providing possible new strategies to enhance therapy. Here, we review the progress of vessel modulation in enhancing immunotherapy efficacy.
ARRDC4 and UBXN1: Novel Target Genes Correlated with Prostate Cancer Gleason Score
Authors: Oh Jong Jin , Ho Jin-Nyoung , Byun Seok-Soo
Published: October 2021

To investigate potential markers of the prostate cancer (PCa) Gleason score (GS), genetic arrays in 841 PCa patients were conducted followed by functional validation in PCa cell lines. A total of 841 PCa patients who received radical prostatectomy (RP) from November 2003 to July 2019 were enrolled. HumanExome BeadChip 12v1-1 (Illumina, Inc.; San Diego, CA, USA) exomic arrays were performed on RP tissue samples. Unconditional logistic regression was used to calculate odds ratios to generate estimates of the relative risk of pathologic GS (≥8); SNPs with the highest association were selected and validated using PCa cell lines (PC3, LNCaP, 22Rv1 and DU145). Following transfection with target-gene siRNA, assays for cell viability, wound healing, and transwell invasion were performed. Mean age of enrolled subjects was 66.34 years and median PSA was 8.43 ng/mL. After RP, 122 patients (14.5%) had pathological Gleason scores ≥8. The results from genotyping with 242,186 SNPs by exomic array revealed that 4 SNPs (rs200944490, rs117555780, rs34625170, and rs61754877) were significantly associated with high pathological GS (≥8) within cut-off level to p < 10−5. The most highly associated rs200944490 in ARRDC4 (p = 1.39 × 10−6) and rs117555780 in UBXN1 (p = 2.92 × 10−5) were selected for further validation. The knockdown of UBXN1 and ARRDC4 led to significantly reduced cell proliferation and suppressed migration and invasiveness in PCa cell lines. Epithelial mesenchymal transition (EMT) markers were significantly down-regulated in si-ARRDC4 and si-UBXN1-transfected cells. The expression levels of PI3K-phosphorylation and Akt phosphorylation and NF-κB were also suppressed following knockdown of UBXN1 and ARRDC4. The rs200944490 (ARRDC4) and rs117555780 (UBXN1) were identified as candidate markers predictive of PCa Gleason score which is strongly associated with cancer aggressiveness. Additional validation in future studies is warranted.
The Prognostic Impact of Histology in Esophageal and Esophago-Gastric Junction Adenocarcinoma
Authors: Fiocca Roberto , Mastracci Luca , Lugaresi Marialuisa , Grillo Federica , D’Errico Antonietta , Malvi Deborah , Spaggiari Paola , Tomezzoli Anna , Albarello Luca , Ristimäki Ari , Bottiglieri Luca , Bonora Elena , Krishnadath Kausilia K. , Raulli Gian Domenico , Rosati Riccardo , Fumagalli Romario Uberto , De Manzoni Giovanni , Räsänen Jari , Mattioli Sandro
Published: October 2021

Stage significantly affects survival of esophageal and esophago-gastric junction adenocarcinomas (EA/EGJAs), however, limited evidence for the prognostic role of histologic subtypes is available. The aim of the study was to describe a morphologic approach to EA/EGJAs and assess its discriminating prognostic power. Histologic slides from 299 neoadjuvant treatment-naïve EA/EGJAs, resected in five European Centers, were retrospectively reviewed. Morphologic features were re-assessed and correlated with survival. In glandular adenocarcinomas (240/299 cases—80%), WHO grade and tumors with a poorly differentiated component ≥6% were the most discriminant factors for survival (both p < 0.0001), distinguishing glandular well-differentiated from poorly differentiated adenocarcinomas. Two prognostically different histologic groups were identified: the lower risk group, comprising glandular well-differentiated (34.4%) and rare variants, such as mucinous muconodular carcinoma (2.7%) and diffuse desmoplastic carcinoma (1.7%), versus the higher risk group, comprising the glandular poorly differentiated subtype (45.8%), including invasive mucinous carcinoma (5.7%), diffuse anaplastic carcinoma (3%), mixed carcinoma (6.7%) (CSS p < 0.0001, DFS p = 0.001). Stage (p < 0.0001), histologic groups (p = 0.001), age >72 years (p = 0.008), and vascular invasion (p = 0.015) were prognostically significant in the multivariate analysis. The combined evaluation of stage/histologic group identified 5-year cancer-specific survival ranging from 87.6% (stage II, lower risk) to 14% (stage IVA, higher risk). Detailed characterization of histologic subtypes contributes to EA/EGJA prognostic prediction.
MSC-Derived Extracellular Vesicles in Tumors and Therapy
Authors: Luo Tianjiao , von der Ohe Juliane , Hass Ralf
Published: October 2021

Exosomes derived from mesenchymal stroma-/stem-like cells (MSCs) as part of extracellular vesicles are considered cell-free biocompatible nanovesicles that promote repair activities of damaged tissues or organs by exhibiting low immunogenic and cytotoxic effects. Contributions to regenerative activities include wound healing, maintenance of stem cell niches, beneficial regenerative effects in various diseases, and reduction of senescence. However, the mode of action in MSC-derived exosomes strongly depends on the biological content like different regulatory microRNAs that are determined by the tissue origin of MSCs. In tumors, MSCs use indirect and direct pathways in a communication network to interact with cancer cells. This leads to mutual functional changes with the acquisition of an aberrant tumor-associated MSC phenotype accompanied by altered cargo in the exosomes. Consequently, MSC-derived exosomes either from normal tissue-originating MSCs or from aberrant tumor-associated MSCs can confer different actions on tumor development. These processes exhibiting tumor-inhibitory and tumor-supportive effects with a focus on exosome microRNA content will be discriminated and discussed within this review.
Sarcomas: New Biomarkers and Therapeutic Strategies
Authors: Nakamura Tomoki
Published: October 2021

Bone and soft tissue sarcoma (STS) are heterogeneous diseases comprised of various molecular and histologic subtypes [...]
A Retrospective Cross-Sectional Cohort Trial Assessing the Prevalence of MTHFR Polymorphisms and the Influence of Diet on Platinum Resistance in Ovarian Cancer Patients
Authors: Phillips-Chavez Caitlin , Coward Jermaine , Watson Michael , Schloss Janet
Published: October 2021

Ovarian cancer has the lowest survival rate in gynaecologic malignancies with a 5-year survival rate of 43%. Platinum resistance is one of the main drivers of ovarian cancer mortality, of which aberrant methylation has been cited as a significant contributor. Understanding the essential role of the methylenetetrahydrofolate reductase enzyme (MTHFR) on DNA synthesis and repair, and how nutrient status can vastly affect its performance, led to the investigation of MTHFR status and dietary influence on platinum response in epithelial ovarian cancer (EOC) patients. Twenty-five adult female patients who completed first-line platinum-based chemotherapy for primary ovarian cancer were selected from Icon Cancer Centres in Australia. Participants were grouped based on platinum response. A full medical and family history, food frequency questionnaire and single blood test were completed, testing for MTHFR polymorphisms, serum folate, serum and active B12 and homocysteine levels. Nineteen of twenty-five participants had an MTHFR polymorphism. Of those, 20% were compound heterozygous, 12% were heterozygous C677T (CT), 4% homozygous C677T, 12% homozygous A1298C and 28% were heterozygous A1298C (AC). Statistically significant associations were found between dietary zinc (p = 0.0086; 0.0030; 0.0189) and B12 intakes in CT genotypes (p = 0.0157; 0.0030; 0.0068) indicating that zinc or vitamin B12 intakes below RDI were associated with this genotype. There were strong associations of vitamin B6 intakes in AC genotypes (p = 0.0597; 0.0547; 0.0610), and dietary folate in compound heterozygotes with sensitive and partially sensitive disease (p = 0.0627; 0.0510). There were also significant associations between serum folate (p = 0.0478) and dietary B12 (p = 0.0350) intakes above RDI and platinum sensitivity in wild-types as well as strong associations with homocysteine levels (p = 0.0886) and zinc intake (p = 0.0514). Associations with dietary B12 (p = 0.0514) and zinc intakes (p = 0.0731) were also strong in resistant wild types. Results indicate that dietary zinc, B12 and B6 intakes may be associated with platinum sensitivity dependent on MTHFR genotype. These results require further research to clarify the dosages necessary to elicit a response; however, they provide a novel foundation for acknowledging the role of diet on treatment response in EOC.
Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View
Authors: Körfer Justus , Lordick Florian , Hacker Ulrich T.
Published: October 2021

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.
Uncommon Variants of Mature T-Cell Lymphomas (MTCLs): Imaging and Histopathologic and Clinical Features with Updates from the Fourth Edition of the World Health Organization (WHO) Classification of Lymphoid Neoplasms
Authors: Salem Ahmed Ebada , Zaki Yehia H. , El-Hussieny Gamal , ElNoueam Khaled I. , Shaaban Akram M. , Koppula Bhasker Rao , Yang Ming , Salama Mohamed , Elsayes Khaled M. , Covington Matthew F.
Published: October 2021

Understanding the pathogenesis and molecular biology of malignant lymphomas is challenging, given the complex nature and incongruity of these disorders. The classification of lymphoma is continually evolving to account for advances in clinical, pathological, molecular biology and cytogenetic aspects, which impact our understanding of these disorders. The latest fourth edition of the WHO classification of lymphoid malignancies was released in 2016 to account for these changes. Additionally, unlike B-cell lymphomas (BCL), T-cell lymphomas (TCL) are uncommon, and may be sporadically experienced in clinical practice. These disorders are rare, thus early diagnosis is challenging for both physicians and radiologists, owing to the overlap in clinical and imaging features with other, more common disorders. We aim to discuss some rare variants of T-cell lymphomas, including clinicopathologic and imaging features, as well as to give a glimpse of the updates contained within the new 2016 WHO classification.
Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review
Authors: Shalata Walid , Abu-salman Amjad , Steckbeck Rachel , Mathew Jacob Binil , Massalha Ismaell , Yakobson Alexander
Published: October 2021

Immune checkpoint inhibitors are immune stimulatory drugs used to treat many types of cancer. These drugs are antibodies against inhibitory proteins, such as CTLA-4 and PD-1/PD-L1, that are expressed on immune cells. When bound, they allow for increased stimulation of T cells to fight tumor cells. However, immune checkpoint inhibitors have several immune-related adverse effects. Many cases have come to light recently of cardiotoxicity as a result of treatment with these drugs. Cardiotoxicity from immune checkpoint inhibitors is unique due to its rarity and high mortality rate. Patients with this toxicity may present with myocarditis, pericarditis, Takotsubo cardiomyopathy, conduction disorders, and others within just a few weeks of starting immune checkpoint inhibitors. We present here a review of the current research on immune checkpoint inhibitors, their associated cardiotoxicities, the timing of presentation of these conditions, lab tests and histology for each condition, and finally the treatment of patients with cardiotoxicity. We observe a positive skew in the onset of presentation, which is significant for the treating physician.
Selection of a Nuclease-Resistant RNA Aptamer Targeting CD19
Authors: Esposito Carla L. , Van Roosbroeck Katrien , Santamaria Gianluca , Rotoli Deborah , Sandomenico Annamaria , Wierda William G. , Ferrajoli Alessandra , Ruvo Menotti , Calin George A. , de Franciscis Vittorio , Catuogno Silvia
Published: October 2021

The transmembrane glycoprotein cluster of differentiation 19 (CD19) is a B cell–specific surface marker, expressed on the majority of neoplastic B cells, and has recently emerged as a very attractive biomarker and therapeutic target for B-cell malignancies. The development of safe and effective ligands for CD19 has become an important need for the development of targeted conventional and immunotherapies. In this regard, aptamers represent a very interesting class of molecules. Additionally referred to as ‘chemical antibodies’, they show many advantages as therapeutics, including low toxicity and immunogenicity. Here, we isolated a nuclease-resistant RNA aptamer binding to the human CD19 glycoprotein. In order to develop an aptamer also useful as a carrier for secondary reagents, we adopted a cell-based SELEX (Systematic Evolution of Ligands by EXponential Enrichment) protocol adapted to isolate aptamers able to internalise upon binding to their cell surface target. We describe a 2′-fluoro pyrimidine modified aptamer, named B85.T2, which specifically binds to CD19 and shows an exquisite stability in human serum. The aptamer showed an estimated dissociation constant (KD) of 49.9 ± 13 nM on purified human recombinant CD19 (rhCD19) glycoprotein, a good binding activity on human B-cell chronic lymphocytic leukaemia cells expressing CD19, and also an effective and rapid cell internalisation, thus representing a promising molecule for CD19 targeting, as well as for the development of new B-cell malignancy-targeted therapies.
FDG-PET/CT in Lymphoma: Where Do We Go Now?
Authors: Al Tabaa Yassine , Bailly Clement , Kanoun Salim
Published: October 2021

18F-fluorodeoxyglucose positron emission tomography combined with computed tomography (FDG-PET/CT) is an essential part of the management of patients with lymphoma at staging and response evaluation. Efforts to standardize PET acquisition and reporting, including the 5-point Deauville scale, have enabled PET to become a surrogate for treatment success or failure in common lymphoma subtypes. This review summarizes the key clinical-trial evidence that supports PET-directed personalized approaches in lymphoma but also points out the potential place of innovative PET/CT metrics or new radiopharmaceuticals in the future.
Cobalt Boride/g-C3N4 Nanosheets-Assisted Electrocatalytic Oxidation of 5-Hydroxymethylfurfural into 2,5-Furandicarboxylic Acid
Authors: Suliman Mohammed A. , Basheer Chanbasha , Farooq Wasif
Published: October 2021

The electrochemical production of 2,5-furandicarboxylic acid (FDCA) from 5-(hydroxymethyl)furfural (HMF) is receiving growing attention. The FDCA-based polyethylene 2,5-furan dicarboxylate (PEF) polymer is a green candidate for substituting polyethylene terephthalate. This work demonstrated a highly efficient CoB/g-C3N4 nanosheet on the surface of the nickel foam as an electrode for the HMF electrooxidation reaction. Electrolysis at a constant potential combined with liquid chromatography showed the formation of FDCA with a yield of 97% with an excellent faradaic efficiency of near 95%. CoB/g-C3N4 achieved a current density of 20 mA cm−2 for HMF oxidation in 1.0 M KOH with 10 mM HMF at 1.37 V vs. RHE before the competing oxygen evolution reaction. The electrocatalyst was effectively reused up to three times without compromising efficiency. This work demonstrates a cheap and active electrocatalyst material for the electrochemical formation of FDCA from HMF and gives perception into the reaction mechanism.
Catalysts and Processes for H2S Conversion to Sulfur
Authors: Barba Daniela
Published: October 2021

Hydrogen sulfide is one of the main waste products of the petrochemical industry; it is produced by the catalytic hydrodesulfurization processes (HDS) of the hydrocarbon feedstocks, and it is a byproduct from the sweetening of sour natural gas and from the upgrading of heavy oils, bitumen, and coals [...]
Photocatalytic Degradation of Antibiotics by Superparamagnetic Iron Oxide Nanoparticles. Tetracycline Case
Authors: Olusegun Sunday Joseph , Larrea Gonzalo , Osial Magdalena , Jackowska Krystyna , Krysinski Pawel
Published: October 2021

The challenges associated with the uncontrolled presence of antibiotics such as tetracycline in the environment have necessitated their removal through different techniques. Tetracycline is hard to degrade in living organisms and can even be converted to more toxic substances. In view of this, we synthesized iron oxide nanoparticles with good magnetization (70 emu g−1) and 15 nm particle size for the adsorption and photocatalytic degradation of tetracycline. Characterization carried out on the synthesized iron oxides revealed a bandgap of 1.83 eV and an isoelectric point at pH 6.8. The results also showed that the pH of the solution does not directly influence the adsorption of tetracycline. The adsorption isotherm was consistent with the model proposed by Langmuir, having 97 mg g−1 adsorption capacity. Combined with the superparamagnetic behavior, this capacity is advantageous for the magnetic extraction of tetracycline from wastewater. The mechanisms of adsorption were proposed to be hydrogen bonding and n-π interactions. Photocatalytic degradation studies showed that approximately 40% of tetracycline degraded within 60 min of irradiation time with UV/vis light. The kinetics of photodegradation of tetracycline followed the pseudo-first-order mechanism, proceeding through hydroxyl radicals generated under illumination. Moreover, the photogenerated hydrogen peroxide could lead to heterogeneous photo-Fenton processes on the surface of iron oxide nanoparticles, additionally generating hydroxyl and hydroperoxyl radicals and facilitating photodegradation of tetracycline.
Dehydroisomerisation of α-Pinene and Limonene to p-Cymene over Silica-Supported ZnO in the Gas Phase
Authors: Alsharif Aliyah , Smith Natalie , Kozhevnikova Elena , Kozhevnikov Ivan
Published: October 2021

Silica-supported zinc oxide possessing acid and dehydrogenation functions is an efficient, noble-metal-free bifunctional catalyst for the environment-friendly synthesis of p-Cymene from renewable monoterpene feedstock by gas-phase dehydroisomerisation of α-pinene and limonene in a fixed-bed reactor. The reaction involves acid-catalysed terpene isomerisation to p-menthadienes followed by dehydrogenation to form p-Cymene. Dehydroisomerisation of α-pinene produces p-Cymene with 90% yield at 100% conversion at 370 °C and WHSV = 0.01–0.020 h−1. The reaction with limonene gives a 100% p-Cymene yield at 325 °C and WHSV = 0.080 h−1. ZnO/SiO2 catalyst shows stable performance for over 70 h without co-feeding hydrogen.
Pt Electrocatalyst Prepared by Hydrothermal Reduction onto the Gas Diffusion Layer for High-Temperature Formic Acid and Ethanol Fuel PEMFC
Authors: da Silva Cardoso Rayane , Sartório de Castro Bruna Sartório , de Andrade Dias Sophya , H. Clemente Maria Clara H. , Dias Sílvia C. L. , A. Dias José A. , Crisafulli Rudy , Linares José J. , Veloso Martins Gesley A.
Published: October 2021

An alternative method for the preparation of PEMFC electrodes is presented in this work based on the direct deposition of Pt particles onto the gas diffusion layer (Pt@GDL) by hydrothermal reduction of the H2PtCl6 precursor from formic acid, ethylene glycol, and ethanol reductive solutions. There is a successful anchorage of Pt particles via the formation of Pt crystal aggregates. The influence of the reducing agent concentration and temperature was studied to analyze their influence on the size, morphology, and distribution of the Pt particles on the gas GDL. The prepared Pt@GDL was tested for formic acid and ethanol high-temperature H3PO4-doped PEMFC. The Pt@GDL prepared in the formic acid reductive atmosphere presented the best performance associated with the formation of smaller Pt crystals and a more homogeneous dispersion of the Pt particles. For formic acid and ethanol-fed high-temperature PEMFC using a H3PO4-doped polybenzimidazole membrane as the solid electrolyte, maximum power densities of 0.025 and 0.007 W cm−2 were drawn at 200 °C, respectively.
The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study
Authors: Palacio Laura C. , Ugarte Juan P. , Saiz Javier , Tobón Catalina
Published: October 2021

Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF.
Challenges and Considerations during In Vitro Production of Porcine Embryos
Authors: Chen Paula R. , Redel Bethany K. , Kerns Karl C. , Spate Lee D. , Prather Randall S.
Published: October 2021

Genetically modified pigs have become valuable tools for generating advances in animal agriculture and human medicine. Importantly, in vitro production and manipulation of embryos is an essential step in the process of creating porcine models. As the in vitro environment is still suboptimal, it is imperative to examine the porcine embryo culture system from several angles to identify methods for improvement. Understanding metabolic characteristics of porcine embryos and considering comparisons with other mammalian species is useful for optimizing culture media formulations. Furthermore, stressors arising from the environment and maternal or paternal factors must be taken into consideration to produce healthy embryos in vitro. In this review, we progress stepwise through in vitro oocyte maturation, fertilization, and embryo culture in pigs to assess the status of current culture systems and address points where improvements can be made.
Chemical Genetic Screen in Drosophila Germline Uncovers Small Molecule Drugs That Sensitize Stem Cells to Insult-Induced Apoptosis
Authors: Ishibashi Julien Roy , Keshri Riya , Taslim Tommy Henry , Brewer Daniel Kennedy , Chan Tung Ching , Lyons Scott , McManamen Anika Marie , Chen Ashley , Del Castillo Debra , Ruohola-Baker Hannele
Published: October 2021

Cancer stem cells, in contrast to their more differentiated daughter cells, can endure genotoxic insults, escape apoptosis, and cause tumor recurrence. Understanding how normal adult stem cells survive and go to quiescence may help identify druggable pathways that cancer stem cells have co-opted. In this study, we utilize a genetically tractable model for stem cell survival in the Drosophila gonad to screen drug candidates and probe chemical-genetic interactions. Our study employs three levels of small molecule screening: (1) a medium-throughput primary screen in male germline stem cells (GSCs), (2) a secondary screen with irradiation and protein-constrained food in female GSCs, and (3) a tertiary screen in breast cancer organoids in vitro. Herein, we uncover a series of small molecule drug candidates that may sensitize cancer stem cells to apoptosis. Further, we have assessed these small molecules for chemical-genetic interactions in the germline and identified the NF-κB pathway as an essential and druggable pathway in GSC quiescence and viability. Our study demonstrates the power of the Drosophila stem cell niche as a model system for targeted drug discovery.
Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases
Authors: Pinto Claudio , Ninfole Elisabetta , Benedetti Antonio , Marzioni Marco , Maroni Luca
Published: October 2021

Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.
Foxd4l1.1 Negatively Regulates Chordin Transcription in Neuroectoderm of Xenopus Gastrula
Authors: Kumar Vijay , Goutam Ravi Shankar , Umair Zobia , Park Soochul , Lee Unjoo , Kim Jaebong
Published: October 2021

Inhibition of the bone morphogenetic proteins (BMPs) is the primary step toward neuroectoderm formation in vertebrates. In this process, the Spemann organizer of the dorsal mesoderm plays a decisive role by secreting several extracellular BMP inhibitors such as Chordin (Chrd). Chrd physically interacts with BMP proteins and inhibits BMP signaling, which triggers the expression of neural-specific transcription factors (TFs), including Foxd4l1.1. Thus, Chrd induces in a BMP-inhibited manner and promotes neuroectoderm formation. However, the regulatory feedback mechanism of Foxd4l1.1 on mesodermal genes expression during germ-layer specification has not been fully elucidated. In this study, we investigated the regulatory mechanism of Foxd4l1.1 on chrd (a mesodermal gene). We demonstrate that Foxd4l1.1 inhibits chrd expression during neuroectoderm formation in two ways: First, Foxd4l1.1 directly binds to FRE (Foxd4l1.1 response elements) within the chrd promoter region to inhibit transcription. Second, Foxd4l1.1 physically interacts with Smad2 and Smad3, and this interaction blocks Smad2 and Smad3 binding to activin response elements (AREs) within the chrd promoter. Site-directed mutagenesis of FRE within the chrd(-2250) promoter completely abolished repressor activity of the Foxd4l1.1. RT-PCR and reporter gene assay results indicate that Foxd4l1.1 strongly inhibits mesoderm- and ectoderm-specific marker genes to maintain neural fate. Altogether, these results suggest that Foxd4l1.1 negatively regulates chrd transcription by dual mechanism. Thus, our study demonstrates the existence of precise reciprocal regulation of chrd transcription during neuroectoderm and mesoderm germ-layer specification in Xenopus embryos.
CRMP2 Is Involved in Regulation of Mitochondrial Morphology and Motility in Neurons
Authors: Brustovetsky Tatiana , Khanna Rajesh , Brustovetsky Nickolay
Published: October 2021

Regulation of mitochondrial morphology and motility is critical for neurons, but the exact mechanisms are unclear. Here, we demonstrate that these mechanisms may involve collapsin response mediator protein 2 (CRMP2). CRMP2 is attached to neuronal mitochondria and binds to dynamin-related protein 1 (Drp1), Miro 2, and Kinesin 1 light chain (KLC1). Treating neurons with okadaic acid (OA), an inhibitor of phosphatases PP1 and PP2A, resulted in increased CRMP2 phosphorylation at Thr509/514, Ser522, and Thr555, and augmented Drp1 phosphorylation at Ser616. The CRMP2-binding small molecule (S)-lacosamide ((S)-LCM) prevented an OA-induced increase in CRMP2 phosphorylation at Thr509/514 and Ser522 but not at Thr555, and also failed to alleviate Drp1 phosphorylation. The increased CRMP2 phosphorylation correlated with decreased CRMP2 binding to Drp1, Miro 2, and KLC1. (S)-LCM rescued CRMP2 binding to Drp1 and Miro 2 but not to KLC1. In parallel with CRMP2 hyperphosphorylation, OA increased mitochondrial fission and suppressed mitochondrial traffic. (S)-LCM prevented OA-induced alterations in mitochondrial morphology and motility. Deletion of CRMP2 with a small interfering RNA (siRNA) resulted in increased mitochondrial fission and diminished mitochondrial traffic. Overall, our data suggest that the CRMP2 expression level and phosphorylation state are involved in regulating mitochondrial morphology and motility in neurons.
Role of Aldynoglia Cells in Neuroinflammatory and Neuroimmune Responses after Spinal Cord Injury
Authors: Buzoianu-Anguiano Vinnitsa , Torres-Llacsa Mabel , Doncel-Pérez Ernesto
Published: October 2021

Aldynoglia are growth-promoting cells with a morphology similar to radial glia and share properties and markers with astrocytes and Schwann cells. They are distributed in several locations throughout the adult central nervous system, where the cells of the aldynoglia interact and respond to the signals of the immune cells. After spinal cord injury (SCI), the functions of resident aldynoglia, identified as ependymocytes, tanycytes, and ependymal stem cells (EpSCs) of the spinal cord are crucial for the regeneration of spinal neural tissue. These glial cells facilitate axonal regrowth and remyelination of injured axons. Here, we review the influence of M1 or M2 macrophage/microglia subpopulations on the fate of EpSCs during neuroinflammation and immune responses in the acute, subacute, and chronic phases after SCI.
A Four-Year Follow-Up Case Report of Hypomineralized Primary Second Molars Rehabilitated with Stainless Steel Crowns
Authors: Bandeira Lopes Luísa , Machado Vanessa , Botelho João
Published: October 2021

Hypomineralized primary second molars (HPSM) are characterized by enamel opacities accompanied by hypersensitivity and atypical caries lesion, on one to four primary second molars. The correct treatment and follow-ups of those teeth have an important impact on a correct eruption of the first permanent molars and future occlusion. Hence, this report aims to describes a case of a severe HPSM in all second molars of a four-year-old girl and subsequent four-year follow-ups. The rehabilitation involved the placement of four stainless steel crowns on all four second primary molars under general anesthesia. Concerning the available literature and the case severity of HPSM, the treatment approach proposed for the case provided good functional outcome.
Parenting and Health: The Major Challenge of Complex Relations
Authors: Pereira Dora
Published: October 2021

Parenting is an interpersonal process associated with taking care and fostering the healthy development of children and young people [...]