bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Circulating lncRNAs Associated with Gallbladder Cancer Risk by Tissue-Based Preselection, Cis-eQTL Validation, and Analysis of Association with Genotype-Based Expression
Authors: Blandino Alice , Scherer Dominique , Rounge Trine B. , Umu Sinan U. , Boekstegers Felix , Barahona Ponce Carol , Marcelain Katherine , Gárate-Calderón Valentina , Waldenberger Melanie , Morales Erik , Rojas Armando , Munoz César , Retamales Javier , de Toro Gonzalo , Barajas Olga , Rivera María Teresa , Cortés Analía , Loader Denisse , Saavedra Javiera , Gutiérrez Lorena , Ortega Alejandro , Bertrán Maria Enriqueta , Gabler Fernando , Campos Mónica , Alvarado Juan , Moisán Fabrizio , Spencer Loreto , Nervi Bruno , Carvajal-Hausdorf Daniel E. , Losada Héctor , Almau Mauricio , Fernández Plinio , Gallegos Ivan , Olloquequi Jordi , Fuentes-Guajardo Macarena , Gonzalez-Jose Rolando , Bortolini Maria Cátira , Gallo Carla , Linares Andres Ruiz , Rothhammer Francisco , Lorenzo Bermejo Justo
Published: January 2022

Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer (GBC) using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence “gallstones → dysplasia → GBC”. In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and GBC risk. AC084082.3 and LINC00662 showed increasing expression levels (p-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to GBC (p-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r2 = 0.26) and three cis-C22orf34-eQTLs (r2 = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with GBC risk (OR = 1.25 per log2 expression unit, 95% CI 1.04–1.52, p-value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.
Neoadjuvant Chemotherapy of Patients with Early Breast Cancer Is Associated with Increased Detection of Disseminated Tumor Cells in the Bone Marrow
Authors: Volmer Léa , Koch André , Matovina Sabine , Dannehl Dominik , Weiss Martin , Welker Ganna , Hahn Markus , Engler Tobias , Wallwiener Markus , Walter Christina Barbara , Oberlechner Ernst , Brucker Sara Yvonne , Pantel Klaus , Hartkopf Andreas
Published: January 2022

Preclinical data suggest that neoadjuvant chemotherapy (NAT) may promote micrometastatic spread. We aimed to compare the detection rate and prognostic relevance of disseminated tumor cells (DTCs) from the bone marrow (BM) of patients with early-stage breast cancer (EBC) after NAT with that of therapy-naive EBC patients. DTCs were identified from BM samples, collected during primary surgery. Patients who received NAT were compared to patients who received chemotherapy after surgery. In total, 809 patients were analyzed. After NAT, 45.4% of patients were DTC-positive as compared to 19.9% of patients in the adjuvant chemotherapy group (p < 0.001). When sampled in patients who had undergone NAT, the detection of DTCs in the BM was significantly increased (OR: 3.1; 95% confidence interval (CI): 2.1–4.4; p < 0.001). After NAT, DTC-positive patients with ≥2 DTCs per 1.5 × 106 mononuclear cells in their BM had an impaired disease-free survival (HR: 4.8, 95% CI: 0.9–26.6; p = 0.050) and overall survival (HR: 4.2; 95% CI: 1.4–12.7; p = 0.005). The higher rate of DTC-positive patients after NAT as compared to a treatment-naive comparable control cohort suggests that NAT supports tumor cell dissemination into the bone marrow. DTC positivity in BM predicted relapse in various distant organs, implying that tumor cell dissemination was not restricted to the bone marrow.
Tumor-Infiltrating Lymphocytes as Biomarkers of Treatment Response and Long-Term Survival in Patients with Rectal Cancer: A Systematic Review and Meta-Analysis
Authors: Orhan Adile , Khesrawi Faisal , Tvilling Madsen Michael , Peuliche Vogelsang Rasmus , Dohrn Niclas , Kanstrup Fiehn Anne-Marie , Gögenur Ismail
Published: January 2022

Neoadjuvant chemoradiotherapy (NCRT) is indicated in locally advanced rectal cancer (LARC) to downstage tumors before surgery. Watchful waiting may be a treatment option to avoid surgery in patients, obtaining a complete clinical response. However, biomarkers predictive of treatment response and long-term prognosis are lacking. Here we investigated tumor-infiltrating lymphocytes (TILs) in pretherapeutic biopsies as predictive and prognostic biomarkers. A systematic review and meta-analysis was performed in accordance with the PRISMA guidelines. In total, 429 articles were identified, of which 19 studies were included in the systematic review and 14 studies in the meta-analysis. Patients with high pretherapeutic CD8+ TILs density had an increased likelihood of achieving a pathological complete response (RR = 2.71; 95% CI: 1.58–4.66) or a complete or near-complete pathological treatment response (RR = 1.86; 95% CI: 1.50–2.29). Furthermore, high CD8+ TILs density was a favorable prognostic factor for disease-free survival (HR = 0.57; 95% CI: 0.38–0.86) and overall survival (HR = 0.43; 95% CI: 0.27–0.69). CD3+, CD4+, and FOXP3+ TILs were not identified as predictive or prognostic biomarkers. Thus, assessing pretherapeutic CD8+ TILs density may assist in identifying patients with increased sensitivity to NCRT and favorable long-term prognosis.
Latest Advances in the Use of Therapeutic Focused Ultrasound in the Treatment of Pancreatic Cancer
Authors: Mouratidis Petros X. E. , ter Haar Gail
Published: January 2022

Traditional oncological interventions have failed to improve survival for pancreatic cancer patients significantly. Novel treatment modalities able to release cancer-specific antigens, render immunologically “cold” pancreatic tumours “hot” and disrupt or reprogram the pancreatic tumour microenvironment are thus urgently needed. Therapeutic focused ultrasound exerts thermal and mechanical effects on tissue, killing cancer cells and inducing an anti-cancer immune response. The most important advances in therapeutic focused ultrasound use for initiation and augmentation of the cancer immunity cycle against pancreatic cancer are described. We provide a comprehensive review of the use of therapeutic focused ultrasound for the treatment of pancreatic cancer patients and describe recent studies that have shown an ultrasound-induced anti-cancer immune response in several tumour models. Published studies that have investigated the immunological effects of therapeutic focused ultrasound in pancreatic cancer are described. This article shows that therapeutic focused ultrasound has been deemed to be a safe technique for treating pancreatic cancer patients, providing pain relief and improving survival rates in pancreatic cancer patients. Promotion of an immune response in the clinic and sensitisation of tumours to the effects of immunotherapy in preclinical models of pancreatic cancer is shown, making it a promising candidate for use in the clinic.
Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway
Authors: Wang Wei , Rana Priyanka S. , Alkrekshi Akram , Bialkowska Katarzyna , Markovic Vesna , Schiemann William P. , Plow Edward F. , Pluskota Elzbieta , Sossey-Alaoui Khalid
Published: January 2022

Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated. Accordingly, we generated a floxed mouse strain by targeting the Fermt2 (K2lox/lox) locus, followed by tissue-specific deletion of Kindlin-2 in the myoepithelial compartment of the mammary glands by crossing the K2lox/lox mice with K14-Cre mice. Loss of Kindlin-2 in mammary epithelial cells (MECs) showed no deleterious effects on mammary gland development, fertility, and lactation in mice bearing Kindlin-2-deletion. However, in a syngeneic mouse model of BC, mammary gland, specific knockout of Kindlin-2 inhibited the growth and metastasis of murine E0771 BC cells inoculated into the mammary fat pads. However, injecting the E0771 cells into the lateral tail vein of Kindlin-2-deleted mice had no effect on tumor colonization in the lungs, thereby establishing a critical role of MEC Kindlin-2 in supporting BC tumor growth and metastasis. Mechanistically, we found the MEC Kindlin-2-mediated inhibition of tumor growth and metastasis is accomplished through its regulation of the TGF-β/ERK MAP kinase signaling axis. Thus, Kindlin-2 within the mammary gland microenvironment facilitates the progression and metastasis of BC.
Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types
Authors: Felip Eudald , Gutiérrez-Chamorro Lucía , Gómez Maica , Garcia-Vidal Edurne , Romeo Margarita , Morán Teresa , Layos Laura , Pérez-Roca Laia , Riveira-Muñoz Eva , Clotet Bonaventura , Fernandez Pedro Luis , Mesía Ricard , Martínez-Cardús Anna , Ballana Ester , Margelí Mireia
Published: January 2022

SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1′s role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1′s role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.
Circulating Tumor Cell Kinetics and Morphology from the Liquid Biopsy Predict Disease Progression in Patients with Metastatic Colorectal Cancer Following Resection
Authors: Kolenčík Drahomír , Narayan Sachin , Thiele Jana-Aletta , McKinley Dillon , Gerdtsson Anna Sandström , Welter Lisa , Hošek Petr , Ostašov Pavel , Vyčítal Ondřej , Brůha Jan , Fiala Ondřej , Šorejs Ondřej , Liška Václav , Pitule Pavel , Kuhn Peter , Shishido Stephanie N.
Published: January 2022

The liquid biopsy has the potential to improve current clinical practice in oncology by providing real-time personalized information about a patient’s disease status and response to treatment. In this study, we evaluated 161 peripheral blood (PB) samples that were collected around surgical resection from 47 metastatic colorectal cancer (mCRC) patients using the High-Definition Single Cell Assay (HDSCA) workflow. In conjunction with the standard circulating tumor cell (CTC) enumeration, cellular morphology and kinetics between time-points of collection were considered in the survival analysis. CTCs, CTC-Apoptotic, and CTC clusters were found to indicate poor survival with an increase in cell count from pre-resection to post-resection. This study demonstrates that CTC subcategorization based on morphological differences leads to nuanced results between the subtypes, emphasizing the heterogeneity within the CTC classification. Furthermore, we show that factoring in the time-point of each blood collection is critical, both for its static enumeration and for the change in cell populations between draws. By integrating morphology and time-based analysis alongside standard CTC enumeration, liquid biopsy platforms can provide greater insight into the pathophysiology of mCRC by highlighting the complexity of the disease across a patient’s treatment.
Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives
Authors: Berois Nora , Pittini Alvaro , Osinaga Eduardo
Published: January 2022

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.
An Integrated In Silico, In Vitro and Tumor Tissues Study Identified Selenoprotein S (SELENOS) and Valosin-Containing Protein (VCP/p97) as Novel Potential Associated Prognostic Biomarkers in Triple Negative Breast Cancer
Authors: Costantini Susan , Polo Andrea , Capone Francesca , Accardo Marina , Sorice Angela , Lombardi Rita , Bagnara Palmina , Zito Marino Federica , Amato Martina , Orditura Michele , Fratelli Maddalena , Ciliberto Gennaro , Budillon Alfredo
Published: January 2022

Background. Triple negative breast cancer (TNBC) is a heterogeneous group of tumors with early relapse, poor overall survival, and lack of effective treatments. Hence, new prognostic biomarkers and therapeutic targets are needed. Methods. The expression profile of all twenty-five human selenoproteins was analyzed in TNBC by a systematic approach.In silicoanalysis was performed on publicly available mRNA expression datasets (Cancer Cell Line Encyclopedia, CCLE and Library of Integrated Network-based Cellular Signatures, LINCS). Reverse transcription quantitative PCR analysis evaluated selenoprotein mRNA expression in TNBC versus non-TNBC and normal breast cells, and in TNBC tissues versus normal counterparts. Immunohistochemistry was employed to study selenoproteins in TNBC tissues. STRING and Cytoscape tools were used for functional and network analysis. Results.GPX1, GPX4, SELENOS, TXNRD1 and TXNRD3 were specifically overexpressed in TNBC cells, tissues and CCLE/LINCS datasets. Network analysis demonstrated that SELENOS-binding valosin-containing protein (VCP/p97) played a critical hub role in the TNBCselenoproteins sub-network, being directly associated with SELENOS expression. The combined overexpression of SELENOS and VCP/p97 correlated with advanced stages and poor prognosis in TNBC tissues and the TCGA dataset. Conclusion. Combined evaluation of SELENOS and VCP/p97 might represent a novel potential prognostic signature and a therapeutic target to be exploited in TNBC.
Hematotoxicity and Nephrotoxicity in Prostate Cancer Patients Undergoing Radioligand Therapy with [177Lu]Lu-PSMA I&T
Authors: Hartrampf Philipp E. , Weinzierl Franz-Xaver , Serfling Sebastian E. , Pomper Martin G. , Rowe Steven P. , Higuchi Takahiro , Seitz Anna Katharina , Kübler Hubert , Buck Andreas K. , Werner Rudolf A.
Published: January 2022

(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [177Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [177Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [99mTc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman’s rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = −0.40, p = 0.005) and the eGFR change with Gleason score (r = −0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [177Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.
Cancer-on-a-Chip: Models for Studying Metastasis
Authors: Zhang Xiaojun , Karim Mazharul , Hasan Md Mahedi , Hooper Jacob , Wahab Riajul , Roy Sourav , Al-Hilal Taslim A.
Published: January 2022

The microfluidic-based cancer-on-a-chip models work as a powerful tool to study the tumor microenvironment and its role in metastasis. The models recapitulate and systematically simplify the in vitro tumor microenvironment. This enables the study of a metastatic process in unprecedented detail. This review examines the development of cancer-on-a-chip microfluidic platforms at the invasion/intravasation, extravasation, and angiogenesis steps over the last three years. The on-chip modeling of mechanical cues involved in the metastasis cascade are also discussed. Finally, the popular design of microfluidic chip models for each step are discussed along with the challenges and perspectives of cancer-on-a-chip models.
A New Tumor Burden Score and Albumin–Bilirubin Grade-Based Prognostic Model for Hepatocellular Carcinoma
Authors: Ho Shu-Yein , Liu Po-Hong , Hsu Chia-Yang , Huang Yi-Hsiang , Liao Jia-I , Su Chien-Wei , Hou Ming-Chih , Huo Teh-Ia
Published: January 2022

The prognosis of hepatocellular carcinoma (HCC) varies widely due to variable tumor extent and liver reserve. We aimed to develop and validate a new prognostic model based on tumor burden score (TBS) and albumin–bilirubin (ALBI) grade for HCC. We prospectively identified 3794 HCC patients who were randomized into derivation and validation groups. Survival predictors were evaluated by a multivariate Cox model. The TBS–ALBI system allocated two points for high TBS and ALBI grade 3, and one point each for the presence of ascites, serum α-fetoprotein ≥ 400 ng/mL, vascular invasion or distant metastasis, performance status 2–4, medium TBS, and ALBI grade 2, with a maximal score of 8 points. Significant survival differences were found across different TBS–ALBI score groups in the validation cohort (all p < 0.001). The TBS–ALBI system had the lowest corrected Akaike information criterion (AICc) and the highest homogeneity compared with other proposed staging models. The discriminative ability of the TBS–ALBI system was consistently stable across different viral etiologies, cancer stages, and treatment strategies. Conclusions: This new TBS–ALBI system is a feasible and robust prognostic system in comparison with other systems; it is a user-friendly tool for long-term outcome assessment independent of treatment modality and cancer stage in HCC.
Targeted Next Generation Sequencing for Human Papillomavirus Genotyping in Cervical Liquid-Based Cytology Samples
Authors: Andersen Karoline , Holm Kasper , Tranberg Mette , Pedersen Cecilie Lebech , Bønløkke Sara , Steiniche Torben , Andersen Berit , Stougaard Magnus
Published: January 2022

At present, human papillomavirus (HPV) testing is replacing morphology-based cytology as the primary tool for cervical cancer screening in several countries. However, the HPV assays approved for screening lack detection for all but one of the possibly carcinogenic HPV types and do not genotype all included HPV types. This study demonstrates the use of a targeted HPV next generation sequencing (NGS) panel to detect and genotype all 25 carcinogenic, probably carcinogenic, and possibly carcinogenic HPV types as well as the low-risk types HPV6 and HPV11. The panel was validated using a cohort of 93 paired liquid-based cytology samples (general practitioner (GP)-collected cervical samples and cervico-vaginal self-samples (SS)). Overall, the targeted panel had a sensitivity (GP = 97.7%, SS = 92.1%) and specificity (GP = 98.0%, SS = 96.4%) similar to the commercial HPV assays, Cobas® 4800 HPV DNA test (Roche) and CLART® HPV4S assay (GENOMICA). Interestingly, of the samples that tested positive with the NGS panel, three (6.4%) of the GP-collected samples and four (9.1%) of the self-samples tested positive exclusively for HPV types only included in the NGS panel. Thus, targeted HPV sequencing has great potential to improve the HPV screening programs since, as shown here, it can identify additional HPV positive cases, cases with HPV integration, variants in the HPV genome, and which HPV type is dominant in multi-infected cases.
Magnetic Resonance Imaging-Based Radiomics for the Prediction of Progression-Free Survival in Patients with Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis
Authors: Lee Sangyun , Choi Yangsean , Seo Min-Kook , Jang Jinhee , Shin Na-Young , Ahn Kook-Jin , Kim Bum-soo
Published: January 2022

Advanced non-metastatic nasopharyngeal carcinoma (NPC) has variable treatment outcomes. However, there are no prognostic biomarkers for identifying high-risk patients with NPC. The aim of this systematic review and meta-analysis was to comprehensively assess the prognostic value of magnetic resonance imaging (MRI)-based radiomics for untreated NPC. The PubMed-Medline and EMBASE databases were searched for relevant articles published up to 12 August 2021. The Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) checklist was used to determine the qualities of the selected studies. Random-effects modeling was used to calculate the pooled estimates of Harrell’s concordance index (C-index) for progression-free survival (PFS). Between-study heterogeneity was evaluated using Higgins’ inconsistency index (I2). Among the studies reported in the 57 articles screened, 10 with 3458 patients were eligible for qualitative and quantitative data syntheses. The mean adherence rate to the TRIPOD checklist was 68.6 ± 7.1%. The pooled estimate of the C-index was 0.762 (95% confidence interval, 0.687–0.837). Substantial between-study heterogeneity was observed (I2 = 89.2%). Overall, MRI-based radiomics shows good prognostic performance in predicting the PFS of patients with untreated NPC. However, more consistent and robust study protocols are necessary to validate the prognostic role of radiomics for NPC.
Stem Cell Theory of Cancer: Rude Awakening or Bad Dream from Cancer Dormancy?
Authors: Tu Shi-Ming , Estecio Marcos R. , Lin Sue-Hwa , Zacharias Niki M.
Published: January 2022

To be dormant or not depends on the origin and nature of both the cell and its niche. Similar to other cancer hallmarks, dormancy is ingrained with stemness, and stemness is embedded within dormancy. After all, cancer dormancy is dependent on multiple factors such as cell cycle arrest, metabolic inactivity, and the microenvironment. It is the net results and sum effects of a myriad of cellular interactions, interconnections, and interplays. When we unite all cancer networks and integrate all cancer hallmarks, we practice and preach a unified theory of cancer. From this perspective, we review cancer dormancy in the context of a stem cell theory of cancer. We revisit the seed and soil hypothesis of cancer. We reexamine its implications in both primary tumors and metastatic lesions. We reassess its roles in cell cycle arrest, metabolic inactivity, and stemness property. Cancer dormancy is particularly revealing when it informs us about the mysteries of late relapse, prolonged remission, and second malignancy. It is paradoxically rewarding when it delivers us the promises and power of cancer prevention and maintenance therapy in patient care.
Effects of Modulated Electro-Hyperthermia (mEHT) on Two and Three Year Survival of Locally Advanced Cervical Cancer Patients
Authors: Minnaar Carrie Anne , Maposa Innocent , Kotzen Jeffrey Allan , Baeyens Ans
Published: January 2022

(1) Background: Modulated electro-hyperthermia (mEHT) is a mild to moderate, capacitive-coupled heating technology that uses amplitude modulation to enhance the cell-killing effects of the treatment. We present three year survival results and a cost effectiveness analysis from an ongoing randomised controlled Phase III trial involving 210 participants evaluating chemoradiotherapy (CRT) with/without mEHT, for the management of locally advanced cervical cancer (LACC) in a resource constrained setting (Ethics Approval: M120477/M704133; ClinicalTrials.gov ID: NCT033320690). (2) Methods: We report hazard ratios (HR); odds ratio (OR), and 95% confidence intervals (CI) for overall survival and disease free survival (DFS) at two and three years in the ongoing study. Late toxicity, quality of life (QoL), and a cost effectiveness analysis (CEA) using a Markov model are also reported. (3) Results: Disease recurrence at two and three years was significantly reduced by mEHT (HR: 0.67, 95%CI: 0.48–0.93, p = 0.017; and HR: 0.70, 95%CI: 0.51–0.98, p = 0.035; respectively). There were no significant differences in late toxicity between the groups, and QoL was significantly improved in the mEHT group. In the CEA, mEHT + CRT dominated the model over CRT alone. (4) Conclusions: CRT combined with mEHT improves QoL and DFS rates, and lowers treatment costs, without increasing toxicity in LACC patients, even in resource-constrained settings.
Batch and Flow Nitroaldol Synthesis Catalysed by Granulicella tundricola Hydroxynitrile Lyase Immobilised on Celite R-633
Authors: Coloma José , Teeuwisse Lidwien , Afendi Muhammad , Hagedoorn Peter-Leon , Hanefeld Ulf
Published: January 2022

Granulicella tundricola hydroxynitrile lyase (GtHNL) catalyses the synthesis of chiral (R)-cyanohydrins and (R)-β-nitro alcohols. The triple variant GtHNL-A40H/V42T/Q110H (GtHNL-3V) was immobilised on Celite R-633 and used in monophasic MTBE saturated with 100 mM KPi buffer pH 7 for the synthesis of (R)-2-nitro-1-phenylethanol (NPE) in batch and continuous flow systems. Nitromethane was used as a nucleophile. A total of 82% of (R)-NPE and excellent enantioselectivity (>99%) were achieved in the batch system after 24 h of reaction time. GtHNL-3V on Celite R-633 was successfully recycled five times. During more recycling steps a significant decrease in yield was observed while the enantioselectivity remained excellent over eight cycles. The use of a flow system enabled the continuous synthesis of (R)-NPE. A total of 15% formation of (R)-NPE was reached using a flow rate of 0.1 mL min−1; unfortunately, the enzyme was not stable, and the yield decreased to 4% after 4 h on stream. A similar yield was observed during 15 h at a rate of 0.01 mL min−1. Surprisingly the use of a continuous flow system did not facilitate the process intensification. In fact, the batch system displayed a space-time-yield (STY/mgenzyme) of 0.10 g L−1 h−1 mgenzyme−1 whereas the flow system displayed 0.02 and 0.003 g L−1 h−1 mgenzyme−1 at 0.1 and 0.01 mL min−1, respectively. In general, the addition of 1 M nitromethane potentially changed the polarity of the reaction mixture affecting the stability of Celite-GtHNL-3V. The nature of the batch system maintained the reaction conditions better than the flow system. The higher yield and productivity observed for the batch system show that it is a superior system for the synthesis of (R)-NPE compared with the flow approach.
Production of Amorphous Silicon Dioxide Derived from Aluminum Fluoride Industrial Waste and Consideration of the Possibility of Its Use as Al2O3-SiO2 Catalyst Supports
Authors: Pyagay Igor N. , Shaidulina Alina A. , Konoplin Rostislav R. , Artyushevskiy Dmitriy I. , Gorshneva Ekaterina A. , Sutyaginsky Michail A.
Published: January 2022

This paper presents the results of the study on the development of a methodology for the production of pure amorphous silicon dioxide containing up to 99.8 wt.% of SiO2. As a starting material, a silica gel with a moisture content of up to 55 wt.% and an SiO2/AlF3 ratio of 4 was used. The silica gel was purified using alkaline and acidic solutions in concentrations ranging from 0.1 to 25 wt.%. The analysis of the experimental data allowed to identify the most suitable purification parameters of the starting material. The initial silica gel and the reaction products were studied using the methods of X-ray fluorescence, X-ray phase analysis, electron scanning microscopy, EDS microanalysis, and particle-size analysis. Amorphous silicon dioxide obtained according to the methodology developed by the authors forms agglomerates of spherical silicon dioxide particles up to 1 μm in size. Amorphous silicon dioxide was involved in the preparation of catalyst supports in order to consider the possibility of replacing part of the expensive raw material in the form of aluminum hydroxide. In the work, the characteristics of the addition of this amorphous silicon dioxide and the supports obtained from the traditionally used raw materials were evaluated.
Tendon Immune Regeneration: Insights on the Synergetic Role of Stem and Immune Cells during Tendon Regeneration
Authors: Russo Valentina , El Khatib Mohammad , Prencipe Giuseppe , Citeroni Maria Rita , Faydaver Melisa , Mauro Annunziata , Berardinelli Paolo , Cerveró-Varona Adrián , Haidar-Montes Arlette A. , Turriani Maura , Di Giacinto Oriana , Raspa Marcello , Scavizzi Ferdinando , Bonaventura Fabrizio , Stöckl Johannes , Barboni Barbara
Published: January 2022

Tendon disorders represent a very common pathology in today’s population, and tendinopathies that account 30% of tendon-related injuries, affect yearly millions of people which in turn cause huge socioeconomic and health repercussions worldwide. Inflammation plays a prominent role in the development of tendon pathologies, and advances in understanding the underlying mechanisms during the inflammatory state have provided additional insights into its potential role in tendon disorders. Different cell compartments, in combination with secreted immune modulators, have shown to control and modulate the inflammatory response during tendinopathies. Stromal compartment represented by tenocytes has shown to display an important role in orchestrating the inflammatory response during tendon injuries due to the interplay they exhibit with the immune-sensing and infiltrating compartments, which belong to resident and recruited immune cells. The use of stem cells or their derived secretomes within the regenerative medicine field might represent synergic new therapeutical approaches that can be used to tune the reaction of immune cells within the damaged tissues. To this end, promising opportunities are headed to the stimulation of macrophages polarization towards anti-inflammatory phenotype together with the recruitment of stem cells, that possess immunomodulatory properties, able to infiltrate within the damaged tissues and improve tendinopathies resolution. Indeed, the comprehension of the interactions between tenocytes or stem cells with the immune cells might considerably modulate the immune reaction solving hence the inflammatory response and preventing fibrotic tissue formation. The purpose of this review is to compare the roles of distinct cell compartments during tendon homeostasis and injury. Furthermore, the role of immune cells in this field, as well as their interactions with stem cells and tenocytes during tendon regeneration, will be discussed to gain insights into new ways for dealing with tendinopathies.
A Distinct Hibiscus sabdariffa Extract Prevents Iron Neurotoxicity, a Driver of Multiple Sclerosis Pathology
Authors: Mishra Manoj Kumar , Wang Jianxiong , Mirzaei Reza , Chan Rigel , Melo Helvira , Zhang Ping , Ling Chang-Chun , Bruccoleri Aldo , Tang Lin , Yong V. Wee
Published: January 2022

Iron deposition in the brain begins early in multiple sclerosis (MS) and continues unabated. Ferrous iron is toxic to neurons, yet the therapies used in MS do not counter iron neurotoxicity. Extracts of Hibiscus sabdariffa (HS) are used in many cultures for medicinal purposes. We collected a distinct HS extract and found that it abolished the killing of neurons by iron in culture; medications used in MS were ineffective when similarly tested. Neuroprotection by HS was not due to iron chelation or anthocyanin content. In free radical scavenging assays, HS was equipotent to alpha lipoic acid, an anti-oxidant being tested in MS. However, alpha lipoic acid was only modestly protective against iron-mediated killing. Moreover, a subfraction of HS without radical scavenging activity negated iron toxicity, whereas a commercial hibiscus preparation with anti-oxidant activity could not. The idea that HS might have altered properties within neurons to confer neuroprotection is supported by its amelioration of toxicity caused by other toxins: beta-amyloid, rotenone and staurosporine. Finally, in a mouse model of MS, HS reduced disability scores and ameliorated the loss of axons in the spinal cord. HS holds therapeutic potential to counter iron neurotoxicity, an unmet need that drives the progression of disability in MS.
Post-mortem Findings of Inflammatory Cells and the Association of 4-Hydroxynonenal with Systemic Vascular and Oxidative Stress in Lethal COVID-19
Authors: Zarkovic Neven , Jakovcevic Antonia , Mataic Ana , Jaganjac Morana , Vukovic Tea , Waeg Georg , Zarkovic Kamelija
Published: January 2022

A recent comparison of clinical and inflammatory parameters, together with biomarkers of oxidative stress, in patients who died from aggressive COVID-19 and survivors suggested that the lipid peroxidation product 4-hydroxynonenal (4-HNE) might be detrimental in lethal SARS-CoV-2 infection. The current study further explores the involvement of inflammatory cells, systemic vascular stress, and 4-HNE in lethal COVID-19 using specific immunohistochemical analyses of the inflammatory cells within the vital organs obtained by autopsy of nine patients who died from aggressive SAR-CoV-2 infection. Besides 4-HNE, myeloperoxidase (MPO) and mitochondrial superoxide dismutase (SOD2) were analyzed alongside standard leukocyte biomarkers (CDs). All the immunohistochemical slides were simultaneously prepared for each analyzed biomarker. The results revealed abundant 4-HNE in the vital organs, but the primary origin of 4-HNE was sepsis-like vascular stress, not an oxidative burst of the inflammatory cells. In particular, inflammatory cells were often negative for 4-HNE, while blood vessels were always very strongly immunopositive, as was edematous tissue even in the absence of inflammatory cells. The most affected organs were the lungs with diffuse alveolar damage and the brain with edema and reactive astrocytes, whereas despite acute tubular necrosis, 4-HNE was not abundant in the kidneys, which had prominent SOD2. Although SOD2 in most cases gave strong immunohistochemical positivity similar to 4-HNE, unlike 4-HNE, it was always limited to the cells, as was MPO. Due to their differential expressions in blood vessels, inflammatory cells, and the kidneys, we think that SOD2 could, together with 4-HNE, be a potential link between a malfunctioning immune system, oxidative stress, and vascular stress in lethal COVID-19.
PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells
Authors: Kwon Sora , Ban Kiwon , Hong Young-Kwon , Sung Jung-Suk , Choi Inho
Published: January 2022

The MTOR signal is known to be activated in various cancer cells including hepatocellular carcinoma (HCC) cells. Rapamycin, a specific inhibitor of MTOR, has been widely used as an immunosuppressant in organ transplant patients, and its clinical application has been recently expanded to cancer therapy. In this study, the anti-proliferative effect of rapamycin was investigated in four different HCC cell lines. Rapamycin effectively inhibited the proliferation of Huh7 or Hep3B, but not that of HepG2 or SNU3160 cells. Interestingly, rapamycin increased Prospero-related homeobox 1 (PROX1) expression at the protein level, but did not affect its transcript in Huh7 as well as Hep3B cells. Moreover, immunoprecipitation assays showed that PROX1 ubiquitination was downregulated by rapamycin. Furthermore, PROX1 over-expression or siRNA knock-down in Huh7 and Hep3B cells reduced or increased proliferation, respectively. The effect of PROX1 over-expression on the sensitivity to rapamycin was not synergistic, but the effect of MTOR inhibition on cell proliferation was diminished by PROX1 siRNA. Finally, Huh7 cells were inoculated into the flanks of nude mice and rapamycin was injected daily for 14 days. The xenograft volume was decreased and PROX1 expression was increased by rapamycin. These results indicate that PROX1 plays a key role in the anti-proliferative effect of rapamycin and suggest that the increased PROX1 by MTOR inhibition can be used as a useful marker for predicting whether HCC cells can be affected by rapamycin.
Characterization of Gfat1 (zeppelin) and Gfat2, Essential Paralogous Genes Which Encode the Enzymes That Catalyze the Rate-Limiting Step in the Hexosamine Biosynthetic Pathway in Drosophila melanogaster
Authors: Cotsworth Shawn , Jackson Catherine J. , Hallson Graham , Fitzpatrick Kathleen A. , Syrzycka Monika , Coulthard Alistair B. , Bejsovec Amy , Marchetti Marcella , Pimpinelli Sergio , Wang Simon J. H. , Camfield Robert G. , Verheyen Esther M. , Sinclair Donald A. , Honda Barry M. , Hilliker Arthur J.
Published: January 2022

The zeppelin (zep) locus is known for its essential role in the development of the embryonic cuticle of Drosophila melanogaster. We show here that zep encodes Gfat1 (Glutamine: Fructose-6-Phosphate Aminotransferase 1; CG12449), the enzyme that catalyzes the rate-limiting step in the hexosamine biosynthesis pathway (HBP). This conserved pathway diverts 2%–5% of cellular glucose from glycolysis and is a nexus of sugar (fructose-6-phosphate), amino acid (glutamine), fatty acid [acetyl-coenzymeA (CoA)], and nucleotide/energy (UDP) metabolism. We also describe the isolation and characterization of lethal mutants in the euchromatic paralog, Gfat2 (CG1345), and demonstrate that ubiquitous expression of Gfat1+ or Gfat2+ transgenes can rescue lethal mutations in either gene. Gfat1 and Gfat2 show differences in mRNA and protein expression during embryogenesis and in essential tissue-specific requirements for Gfat1 and Gfat2, suggesting a degree of functional evolutionary divergence. An evolutionary, cytogenetic analysis of the two genes in six Drosophila species revealed Gfat2 to be located within euchromatin in all six species. Gfat1 localizes to heterochromatin in three melanogaster-group species, and to euchromatin in the more distantly related species. We have also found that the pattern of flanking-gene microsynteny is highly conserved for Gfat1 and somewhat less conserved for Gfat2.
A Study on Impact of Different Surface Treatment Agents on the Durability of Airport Pavement Concrete
Authors: Li Tianlun , Wu Yonggen , Wu Haoxiang
Published: January 2022

Concrete surface treatment is one of effective methods to increase the durability of concrete. This study chose tetraethyl orthosilicate (TEOS), lithium silicate (Li2SiO3), SiO2 nanoparticles (nano-SiO2) as surface treatment agents, tested their resistance to water penetration, chloride ion penetration, frost, sulfate erosion and abrasion of concrete specimens with different strengths, compared and evaluated the impacts to the durability of concrete by using three surface treatment agents, researched the impact of concrete strength on the surface treatment effects, and analyzed the mechanism of these surface treatment agents in connection with microscopic tests. It was found that all three agents can improve the durability of concrete, of which, the treatment effect from using tetraethyl orthosilicate (TEOS) was the best; however, along with the improvement of concrete strength, its other effects were gradually reinforced except for some small improvement effect in resistance to frost, which means it is an ideal concrete surface treatment agent; for lithium silicate (Li2SiO3), the improvement effect of resistance to frost was the best with little impact on the strength of the concrete, however, the other performance improvement effects were a little bit worse than that of tetraethyl orthosilicate (TEOS), which means it is more suitable for airport pavement with a higher concrete resistance to frost; For SiO2 nanoparticles (Nano-SiO2), the surface treatment effect was extreme limited, not recommended to be solely used for airport pavement with its requirement of high resistance to frost. Upon scanning electron microscope (SEM), X-ray diffraction (XRD), fourier transform infrared radiation (FTIR) and thermo gravimetric analyzer (TGA) tests, the surfaced concrete specimens did not produce any new substances, and the effect of the surface treatment agents was mainly to improve the concrete performance by physical filling, or by filling the cavities with the hydrated calcium silicate gel produced in the chemical reaction. These results may direct the selection of surface treatment agents in airport engineering.
Spatial and Temporal Variability of the Floral Scent Emitted by Barlia robertiana (Loisel.) Greuter, a Mediterranean Food-Deceptive Orchid
Authors: Romano Vito Antonio , Rosati Leonardo , Fascetti Simonetta , Cittadini Anna Maria Roberta , Racioppi Rocco , Lorenz Richard , D’Auria Maurizio
Published: January 2022

This study on Barlia robertiana aims to: (1) assess whether scent is variable between populations; (2) evaluate whether scent composition may be related to geographical variables; (3) assess whether there are VOC differences during the flowering phase; and (4) assess whether there are yearly VOC variabilities. SPME sampling was used. Fourteen plants, collected along an ecological gradient, were analyzed. A multivariate analysis was performed through ordination and hierarchical cluster analysis. Compositions versus geographic distances were also analyzed using Mantel test. Seventy compounds were identified. Multivariate analyses and Mantel tests detected no correlations between VOC composition and both geographic and ecological variables. These results may suggest that there is no adaptation of floral scent to local environments. VOC compositions during the flowering phase showed a slight change but a strong variability between individuals. A huge difference was found in the pairwise comparison of the plants analyzed in different years. The high scent variability can be interpreted as a strategy of a non-rewarding but allogamous species to not allow the learning by pollinators. In fact, disrupting the association among floral scent signals with the lack of nectar may enhance the fruit set via a higher probability of being visited by insects.
Designing a Practical Code-Based Signature Scheme from Zero-Knowledge Proofs with Trusted Setup
Authors: Gueron Shay , Persichetti Edoardo , Santini Paolo
Published: January 2022

This paper defines a new practical construction for a code-based signature scheme. We introduce a new protocol that is designed to follow the recent paradigm known as “Sigma protocol with helper”, and prove that the protocol’s security reduces directly to the Syndrome Decoding Problem. The protocol is then converted to a full-fledged signature scheme via a sequence of generic steps that include: removing the role of the helper; incorporating a variety of protocol optimizations (using e.g., Merkle trees); applying the Fiat–Shamir transformation. The resulting signature scheme is EUF-CMA secure in the QROM, with the following advantages: (a) Security relies on only minimal assumptions and is backed by a long-studied NP-complete problem; (b) the trusted setup structure allows for obtaining an arbitrarily small soundness error. This minimizes the required number of repetitions, thus alleviating a major bottleneck associated with Fiat–Shamir schemes. We outline an initial performance estimation to confirm that our scheme is competitive with respect to existing solutions of similar type.
Low Birthweight Beef Bulls Compared with Jersey Bulls Do Not Impact First Lactation and Rebreeding of First-Calving Dairy Heifers—A Case Study in New Zealand
Authors: Coleman Lucy , Martín Natalia , Back Penny , Blair Hugh , López-Villalobos Nicolás , Hickson Rebecca
Published: January 2022

Dairy heifers in New Zealand are typically naturally mated by Jersey bulls to produce low-value non-replacement offspring sold for slaughter a few days after birth. Producing a beef-sired calf from a dairy heifer will increase the value of these calves for beef production but may compromise the subsequent career of the animals, in terms of milk production, rebreeding success, health, or survival of the heifer. This study aimed to determine the impact of low birthweight Angus and Hereford bulls versus breed-average Jersey bulls on the reproduction and production traits of first-calving dairy heifers. The experiment included 304 heifer-calf pairs over 2 years. Calves sired by Angus and Hereford bulls were 3.5–4.4 kg and 3.7–6.8 kg heavier than Jersey-sired calves and had a 4.2% and 9.3% incidence of assistance at birth for normally presented calves over the 2 years, respectively. No normally presented Jersey-sired calves were assisted. There was no difference in body condition score, pre-calving live weight, milk production, pregnancy rate, inter-calving interval, re-calving day, and 21-day re-calving rate of heifers mated to the different breeds of bulls. The results indicate that the Angus and Hereford bulls with low birthweight and high direct calving ease estimated breeding values (EBV) can be used to produce calves of greater value than Jersey-sired calves without impacting dairy heifer production. However, a small increase in assistance at calving could be expected.