bluuebunny/crossref_metadata_2025 huggingface dataset:
Target-Specific Effects of Deep Brain Stimulation for Tourette Syndrome: A Systematic Review and Meta-Analysis
Authors: Wehmeyer Laura , Schüller Thomas , Kiess Jana , Heiden Petra , Visser-Vandewalle Veerle , Baldermann Juan Carlos , Andrade Pablo
Published: October 2021

Background: Extended research has pointed to the efficacy of deep brain stimulation (DBS) in treatment of patients with treatment-refractory Tourette syndrome (TS). The four most commonly used DBS targets for TS include the centromedian nucleus–nucleus ventrooralis internus (CM-Voi) and the centromedian nucleus–parafascicular (CM-Pf) complexes of the thalamus, and the posteroventrolateral (pvIGPi) and the anteromedial portion of the globus pallidus internus (amGPi). Differences and commonalities between those targets need to be compared systematically.

Objective: Therefore, we evaluated whether DBS is effective in reducing TS symptoms and target-specific differences.

Methods: A PubMed literature search was conducted according to the PRISMA guidelines. Eligible literature was used to conduct a systematic review and meta-analysis.

Results: In total, 65 studies with 376 patients were included. Overall, Yale Global Tic Severity Scale (YGTSS) scores were reduced by more than 50 in 69% of the patients. DBS also resulted in significant reductions of secondary outcome measures, including the total YGTSS, modified Rush Video-Based Tic Rating Scale (mRVRS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and Becks Depression Inventory (BDI). All targets resulted in significant reductions of YGTSS scores and, with the exception of the CM-Pf, also in reduced YBOCS scores. Interestingly, DBS of pallidal targets showed increased YGTSS and YBOCS reductions compared to thalamic targets. Also, the meta-analysis including six randomized controlled and double-blinded trials demonstrated clinical efficacy of DBS for TS, that remained significant for GPi but not thalamic stimulation in two separate meta-analyses.

Conclusion: We conclude that DBS is a clinically effective treatment option for patients with treatment-refractory TS, with all targets showing comparable improvement rates. Future research might focus on personalized and symptom-specific target selection.
Case Report: Serial MR Vessel Wall Imaging Visualizes the Response of Intracranial Plaques and Assists in Decision-Making
Authors: Xiao Jiayu , Padrick Matthew M. , Song Shlee S. , Fan Zhaoyang , Schlick Konrad H.
Published: October 2021

Intracranial atherosclerotic disease (ICAD) is a dynamic process that leads to ischemic stroke. Symptomatic ICAD patients still suffer a high recurrent rate even under standard treatment. In this case report, to better understand the response of intracranial atherosclerotic plaques to medication, serial MR imaging was added to standard clinical workup in a 47-year-old male patient with acute occipital lobe infarction at baseline, 3-month, 6-month, and 12-month post index stroke to directly visualize the morphology and signal change of plaques. We noticed that one of the plaques showed dramatic worsening at 3-month imaging follow-up despite a decrease in low-density lipoprotein level. Early identification of patients who do not respond well to medication is critical to prevent the recurrence of cardiovascular events in ICAD patients.
Conserved and Divergent Principles of Planar Polarity Revealed by Hair Cell Development and Function
Authors: Deans Michael R.
Published: October 2021

Planar polarity describes the organization and orientation of polarized cells or cellular structures within the plane of an epithelium. The sensory receptor hair cells of the vertebrate inner ear have been recognized as a preeminent vertebrate model system for studying planar polarity and its development. This is principally because planar polarity in the inner ear is structurally and molecularly apparent and therefore easy to visualize. Inner ear planar polarity is also functionally significant because hair cells are mechanosensors stimulated by sound or motion and planar polarity underlies the mechanosensory mechanism, thereby facilitating the auditory and vestibular functions of the ear. Structurally, hair cell planar polarity is evident in the organization of a polarized bundle of actin-based protrusions from the apical surface called stereocilia that is necessary for mechanosensation and when stereociliary bundle is disrupted auditory and vestibular behavioral deficits emerge. Hair cells are distributed between six sensory epithelia within the inner ear that have evolved unique patterns of planar polarity that facilitate auditory or vestibular function. Thus, specialized adaptations of planar polarity have occurred that distinguish auditory and vestibular hair cells and will be described throughout this review. There are also three levels of planar polarity organization that can be visualized within the vertebrate inner ear. These are the intrinsic polarity of individual hair cells, the planar cell polarity or coordinated orientation of cells within the epithelia, and planar bipolarity; an organization unique to a subset of vestibular hair cells in which the stereociliary bundles are oriented in opposite directions but remain aligned along a common polarity axis. The inner ear with its complement of auditory and vestibular sensory epithelia allows these levels, and the inter-relationships between them, to be studied using a single model organism. The purpose of this review is to introduce the functional significance of planar polarity in the auditory and vestibular systems and our contemporary understanding of the developmental mechanisms associated with organizing planar polarity at these three cellular levels.
Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment
Authors: Jiang Peizhou , Gan Ming , Yen Shu-Hui , Dickson Dennis W.
Published: October 2021

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. It is characterized pathologically by the aggregation of α-synuclein (αS) in the form of Lewy bodies and Lewy neurites. A major challenge in PD therapy is poor efficiency of drug delivery to the brain due to the blood–brain barrier (BBB). For this reason, nanomaterials, with significant advantages in drug delivery, have gained attention. On the other hand, recent studies have shown that nanoparticles can promote αS aggregation in salt solution. Therefore, we tested if nanoparticles could have the same effect in cell models. We found that nanoparticle can induce cells to form αS inclusions as shown in immunocytochemistry, and detergent-resistant αS aggregates as shown in biochemical analysis; and nanoparticles of smaller size can induce more αS inclusions. Moreover, the induction of αS inclusions is in part dependent on endolysosomal impairment and the affinity of αS to nanoparticles. More importantly, we found that the abnormally high level of endogenous lysosomotropic biomolecules (e.g., sphingosine), due to impairing the integrity of endolysosomes could be a determinant factor for the susceptibility of cells to nanoparticle-induced αS aggregation; and deletion of GBA1 gene to increase the level of intracellular sphingosine can render cultured cells more susceptible to the formation of αS inclusions in response to nanoparticle treatment. Ultrastructural examination of nanoparticle-treated cells revealed that the induced inclusions contained αS-immunopositive membranous structures, which were also observed in inclusions seeded by αS fibrils. These results suggest caution in the use of nanoparticles in PD therapy. Moreover, this study further supports the role of endolysosomal impairment in PD pathogenesis and suggests a possible mechanism underlying the formation of membrane-associated αS pathology.
Photobiomodulation With Blue Laser Inhibits Bladder Cancer Progression
Authors: Xia Yuqi , Yu Weimin , Cheng Fan , Rao Ting , Ruan Yuan , Yuan Run , Ning Jinzhuo , Zhou Xiangjun , Lin Fangyou , Zheng Di
Published: October 2021

Blue lasers are becoming more widely used in the diagnosis and treatment of bladder cancer; however, their photobiomodulation effects on bladder cancer cells remains unclear. The purpose of the current study was to explore the photobiomodulation effect of blue laser irradiation on bladder cancer progression and the associated mechanisms. The human uroepithelial cell line SV-HUC-1 and human bladder cancer cell lines T24 and EJ were exposed to blue laser irradiation (450 nm) at various energy densities, and cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and the levels of the proteins associated with the MAPK pathway proteins were determined. A significant decrease in cell viability was observed in a density-dependent manner after blue laser irradiation at > 4 J/cm2 in both bladder cancer cell lines. However, the blue laser did not reduce cell viability in SV-HUC-1 cells until the energy density exceeded 16 J/cm2. Meanwhile, Ki67 levels, reflecting cell proliferation and senescence, were also significantly decreased after blue laser irradiation at 4 J/cm2 and 8 J/cm2 in the absence of cell cycle arrest. Moreover, blue laser irradiation at 4 J/cm2 and 8 J/cm2 caused a reduction in cell migration and invasion and also reduced the expression levels of MMP-2, MMP-9, Snail, N-cadherin, phospho-MEK and phospho-ERK, and elevated the expression levels of E-cadherin. Meanwhile ERK activator(tBHQ) significantly reversed the irradiation-induced suppression of proliferation, migration and invasion in T24 and EJ cell lines. The present study showed that blue laser irradiation inhibited bladder cancer proliferation in a density-dependent manner and inhibited bladder cancer progression by suppressing migration, invasion, and the EMT process in T24 and EJ cell lines. This inhibition was possibly mediated via suppression of the MAPK/MEK/ERK pathway. Thus, the use of a low-energy blue laser in the diagnosis and treatment of bladder cancer is possibly safe and may have an anti-tumor effect.
Identification of Prognostic Model Based on Immune-Related LncRNAs in Stage I-III Non-Small Cell Lung Cancer
Authors: Li Qiaxuan , Yao Lintong , Lin Zenan , Li Fasheng , Xie Daipeng , Li Congsen , Zhan Weijie , Lin Weihuan , Huang Luyu , Wu Shaowei , Zhou Haiyu
Published: October 2021

Background

Long non-coding RNAs (lncRNAs) participate in the regulation of immune response and carcinogenesis, shaping tumor immune microenvironment, which could be utilized in the construction of prognostic signatures for non-small cell lung cancer (NSCLC) as supplements.

Methods

Data of patients with stage I-III NSCLC was downloaded from online databases. The least absolute shrinkage and selection operator was used to construct a lncRNA-based prognostic model. Differences in tumor immune microenvironments and pathways were explored for high-risk and low-risk groups, stratified by the model. We explored the potential association between the model and immunotherapy by the tumor immune dysfunction and exclusion algorithm.

Results

Our study extracted 15 immune-related lncRNAs to construct a prognostic model. Survival analysis suggested better survival probability in low-risk group in training and validation cohorts. The combination of tumor, node, and metastasis staging systems with immune-related lncRNA signatures presented higher prognostic efficacy than tumor, node, and metastasis staging systems. Single sample gene set enrichment analysis showed higher infiltration abundance in the low-risk group, including B cells (p<0.001), activated CD8+ T cells (p<0.01), CD4+ T cells (p<0.001), activated dendritic cells (p<0.01), and CD56+ Natural killer cells (p<0.01). Low-risk patients had significantly higher immune scores and estimated scores from the ESTIMATE algorithm. The predicted proportion of responders to immunotherapy was higher in the low-risk group. Critical pathways in the model were enriched in immune response and cytoskeleton.

Conclusions

Our immune-related lncRNA model could describe the immune contexture of tumor microenvironments and facilitate clinical therapeutic strategies by improving the prognostic efficacy of traditional tumor staging systems.
High-Risk HPV16 E6 Activates the cGMP/PKG Pathway Through Glycosyltransferase ST6GAL1 in Cervical Cancer Cells
Authors: Wang Jun , Liu Gao , Liu Mei , Cai Qinzhen , Yao Cong , Chen Hao , Song Neng , Yuan Chunhui , Tan Decai , Hu Yuhai , Xiang Yun , Xiang Tian
Published: October 2021

Alterations in glycosylation regulate fundamental molecular and cellular processes of cancer, serving as important biomarkers and therapeutic targets. However, the potential association and regulatory mechanisms of E6 oncoprotein on glycosylation of cervical cancer cells are still unclear. Here, we evaluated the glycomic changes via using Lectin microarray and determined the corresponding enzymes associated with endogenous high-risk HPV16 E6 expression in cervical cancer cells. α-2,6 sialic acids and the corresponding glycosyltransferase ST6GAL1 were significantly increased in E6 stable-expressing HPV− cervical cancer C33A cells. Clinical validation further showed that the expression of ST6GAL1 was significantly increased in patients infected with high-risk HPV subtypes and showed a positive association with E6 in cervical scraping samples. Interfering ST6GAL1 expression markedly blocked the oncogenic effects of E6 on colony formulation, proliferation, and metastasis. Importantly, ST6GAL1 overexpression enhanced tumorigenic activities of both E6-positive and E6-negative cells. Mechanistical investigations revealed that E6 depended on activating YAP1 to stimulate ST6GAL1 expression, as verteporfin (inhibitor of YAP1) significantly suppressed the E6-induced ST6GAL1 upregulation. E6/ST6GAL1 triggered the activation of downstream cGMP/PKG signaling pathway and ODQ (inhibitor of GMP production) simultaneously suppressed the oncogenic activities of both E6 and ST6GAL1 in cervical cancer cells. Taken together, these findings indicate that ST6GAL1 is an important mediator for oncogenic E6 protein to activate the downstream cGMP/PKG signaling pathway, which represents a novel molecular mechanism and potential therapeutic targets for cervical cancer.
Aesthetical and Accuracy Outcomes of Reconstruction of Maxillary Defect by 3D Virtual Surgical Planning
Authors: Wang Yang , Qu Xingzhou , Jiang Junjian , Sun Jian , Zhang Chenping , He Yue
Published: October 2021

Background

Reconstruction of maxillary defect resulting from trauma or oncology surgery is of great importance for patients with physical and psychological complications. The virtual surgical planning (VSP) and 3D printing technics had been used in recent years which simplified the surgical procedure and promoted success and accuracy. To assess the accuracy and outcome of VSP surgery, here we report our experience in maxillary reconstruction retrospectively.

Method

Patients who received maxillary defect reconstruction from 2013 to 2020 were analyzed retrospectively. These patients were divided into two groups. Group 1 received VSP and 3D printed guiding plates in the surgery, while group 2 underwent free-hand surgery (FHS). Patients with different vertical and horizontal defects were classified according to Brown and Shaw classification. Clinical information and postoperative complications of all patients were collected. For patients with unilateral maxillary defect, orbit volume, orbit height, and the contour of the reconstructed side were compared with the normal side.

Result

Thirty-four patients who achieved the criteria were analyzed, of which 20 patients underwent VSP surgery. There were primary and secondary reconstruction cases in both two groups. Vascularized iliac crest flap was used in three cases, and fibula flap was performed in the other cases. One flap collapse occurred in FHS group. Seven patients in VSP group received dental implants, while the number in FHS group was 0. In vertical class III cases, the differences in orbit height (ΔD) and orbit volume (ΔV) between normal side and reconstructed side were measured and compared in the two groups. The mean ΔD is 1.78 ± 1.33 mm in VSP group and 4.25 ± 0.95 mm in FHS group, while the mean ΔV is 2.04 ± 0.85 cm3 in VSP group and 3.25 ± 0.17 cm3 in FHS group. The alterations of orbit height and volume in VSP group were much smaller than that in FHS group with statistical significance. From the perspective of aesthetics, the color-gradient map indicates a more symmetric and smoother curve of post-operation appearance in VSP group.

Conclusion

Compared with traditional free-hand surgical technics, VSP and 3D printing guiding plates can allow for a more accurate maxillary reconstruction with improved aesthetics.
Survival of Neoadjuvant and Adjuvant Therapy Compared With Surgery Alone for Resectable Esophageal Squamous Cell Carcinoma: A Systemic Review and Network Meta-Analysis
Authors: Ma Zeliang , Yuan Meng , Bao Yongxing , Wang Yang , Men Yu , Hui Zhouguang
Published: October 2021

Objective

The optimal treatment for resectable esophageal squamous cell carcinoma (ESCC) remains controversial. Surgery is the primary treatment but with poor results. Attempts to improve patient survival have been made by introducing chemotherapy, radiotherapy, or both. However, randomized comparisons for all these strategies are not always available. This network meta-analysis compared the overall survival of neoadjuvant and adjuvant therapy with surgery alone to identify the most effective approach.

Methods

We systematically searched electronic databases (PubMed, Embase, and Cochrane Library) for relevant studies published before April 2021. Only phase II and III randomized controlled trials comparing the following treatments were included: surgery alone, neoadjuvant chemotherapy (NCT), radiotherapy (NRT) or chemoradiotherapy (NCRT), adjuvant chemotherapy (ACT), radiotherapy (ART), or chemoradiotherapy (ACRT). The hazard ratios (HR) and 95% confidence intervals (CIs) of overall survival (OS) was identified as the measurement of effectiveness. A network meta-analysis was conducted to synthesize the evidence under the Bayesian framework, and the relative effects of all possible comparisons were made. The ranking analysis was performed to support the decision in clinical practice.

Results

A total of 19 relevant trials with 3,749 patients were identified. Compared with surgery alone, NCRT (HR 0.76, 95% CI 0.65–0.89) and NCT (HR 0.81, 95% CI 0.70–0.94) significantly improved OS, while other treatments, including NRT (HR 0.86, 95% CI 0.66–1.08), ACRT (HR 0.73, 95% CI 0.49–1.08), ACT (HR 0.96, 95% CI 0.75–1.21), and ART (HR 0.86, 95% CI 0.66–1.14), provided no significant survival advantage. None of the neoadjuvant and adjuvant treatments showed a statistically significant difference in OS to each other when compared in pairs.

Conclusion

For resectable esophageal squamous cell carcinoma, this network meta-analysis showed that NCRT may be the optimal strategy, NCT may be the second choice, while other multimodality treatments could not improve OS compared with surgery alone. It remains unclear whether ESCC will benefit from adding radiotherapy into the neoadjuvant treatment.

Systematic Review Registration

We registered this meta-analysis protocol at the prospective register of systematic reviews, PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=172745 (Identification code: CRD42020172745).
Systematic Analysis and Identification of Dysregulated Panel lncRNAs Contributing to Poor Prognosis in Head-Neck Cancer
Authors: Tang Shang-Ju , You Guo-Rong , Chang Joseph T. , Cheng Ann-Joy
Published: October 2021

Head and neck cancer (HNC) is one of the most prevalent cancers worldwide, accounting for approximately 5% of all cancers. While the underlying molecules and their pathogenetic mechanisms in HNC have yet to be well elucidated, recent studies have shown that dysregulation of lncRNAs may disrupt the homeostasis of various biological pathways. However, the understanding of lncRNAs in HNC is still limited by the lack of expression profiling. In the present study, we employed a systematic strategy to identify a panel of lncRNA associated with HNC. A cancer-related lncRNA profile PCR array was screened to explore potential molecules specific for HNC. A total of 55 lncRNAs were found to be dysregulated in HNC cells when compared to normal keratinocytes. Further analysis of the prognostic significance using The Cancer Genome Atlas (TCGA) database revealed 15 lncRNAs highly correlated with overall survival in HNC patients. Additionally, clinical sample expression analysis of the TCGA-HNSC cohort revealed 16 highly dysregulated lncRNAs in HNC, resulting in a combined 31-lncRNA signature panel that could predict prognosis. Validation of these molecules confirmed the considerable level of altered expressions in HNC cells, with XIST, HOXA11-AS, TSIX, MALAT1, WT1-AS, and IPW being the most prominently dysregulated. We further selected a molecule from our panel (XIST) to confirm the validity of these lncRNAs in the regulation of cancer aggressiveness. Gene ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses demonstrated that XIST participated in various cancer-related functions, including cell proliferation and metastasis. XIST silencing with the RNAi technique substantially reduced invasion and migration in several HNC cell lines. Thus, our study defined a 31-lncRNA panel as prognostic signatures in HNC. These perspective results provide a knowledge foundation for further application of these molecules in precision medicine.
CDCA7 Facilitates Tumor Progression by Directly Regulating CCNA2 Expression in Esophageal Squamous Cell Carcinoma
Authors: Li Hongyi , Weng Yongjia , Wang Shaojie , Wang Fang , Wang Yanqiang , Kong Pengzhou , Zhang Ling , Cheng Caixia , Cui Heyang , Xu Enwei , Wei Shuqing , Guo Dinghe , Chen Fei , Bi Yanghui , Meng Yongsheng , Cheng Xiaolong , Cui Yongping
Published: October 2021

Background

CDCA7 is a copy number amplified gene identified not only in esophageal squamous cell carcinoma (ESCC) but also in various cancer types. Its clinical relevance and underlying mechanisms in ESCC have remained unknown.

Methods

Tissue microarray data was used to analyze its expression in 179 ESCC samples. The effects of CDCA7 on proliferation, colony formation, and cell cycle were tested in ESCC cells. Real-time PCR and Western blot were used to detect the expression of its target genes. Correlation of CDCA7 with its target genes in ESCC and various SCC types was analyzed using GSE53625 and TCGA data. The mechanism of CDCA7 was studied by chromatin immunoprecipitation (ChIP), luciferase reporter assays, and rescue assay.

Results

The overexpression of CDCA7 promoted proliferation, colony formation, and cell cycle in ESCC cells. CDCA7 affected the expression of cyclins in different cell phases. GSE53625 and TCGA data showed CCNA2 expression was positively correlated with CDCA7. The knockdown of CCNA2 reversed the malignant phenotype induced by CDCA7 overexpression. Furthermore, CDCA7 was found to directly bind to CCNA2, thus promoting its expression.

Conclusions

Our results reveal a novel mechanism of CDCA7 that it may act as an oncogene by directly upregulating CCNA2 to facilitate tumor progression in ESCC.
Knowledge-Based Planning for Robustly Optimized Intensity-Modulated Proton Therapy of Head and Neck Cancer Patients
Authors: Xu Yihang , Cyriac Jonathan , De Ornelas Mariluz , Bossart Elizabeth , Padgett Kyle , Butkus Michael , Diwanji Tejan , Samuels Stuart , Samuels Michael A. , Dogan Nesrin
Published: October 2021

Purpose

To assess the performance of a proton-specific knowledge-based planning (KBP) model in the creation of robustly optimized intensity-modulated proton therapy (IMPT) plans for treatment of advanced head and neck (HN) cancer patients.

Methods

Seventy-three patients diagnosed with advanced HN cancer previously treated with volumetric modulated arc therapy (VMAT) were selected and replanned with robustly optimized IMPT. A proton-specific KBP model, RapidPlanPT (RPP), was generated using 53 patients (20 unilateral cases and 33 bilateral cases). The remaining 20 patients (10 unilateral and 10 bilateral cases) were used for model validation. The model was validated by comparing the target coverage and organ at risk (OAR) sparing in the RPP-generated IMPT plans with those in the expert plans. To account for the robustness of the plan, all uncertainty scenarios were included in the analysis.

Results

All the RPP plans generated were clinically acceptable. For unilateral cases, RPP plans had higher CTV_primary V100 (1.59% ± 1.24%) but higher homogeneity index (HI) (0.7 ± 0.73) than had the expert plans. In addition, the RPP plans had better ipsilateral cochlea Dmean (−5.76 ± 6.11 Gy), with marginal to no significant difference between RPP plans and expert plans for all other OAR dosimetric indices. For the bilateral cases, the V100 for all clinical target volumes (CTVs) was higher for the RPP plans than for the expert plans, especially the CTV_primary V100 (5.08% ± 3.02%), with no significant difference in the HI. With respect to OAR sparing, RPP plans had a lower spinal cord Dmax (−5.74 ± 5.72 Gy), lower cochlea Dmean (left, −6.05 ± 4.33 Gy; right, −4.84 ± 4.66 Gy), lower left and right parotid V20Gy (left, −6.45% ± 5.32%; right, −6.92% ± 3.45%), and a lower integral dose (−0.19 ± 0.19 Gy). However, RPP plans increased the Dmax in the body outside of CTV (body-CTV) (1.2 ± 1.43 Gy), indicating a slightly higher hotspot produced by the RPP plans.

Conclusion

IMPT plans generated by a broad-scope RPP model have a quality that is, at minimum, comparable with, and at times superior to, that of the expert plans. The RPP plans demonstrated a greater robustness for CTV coverage and better sparing for several OARs.
TFDP3 as E2F Unique Partner, Has Crucial Roles in Cancer Cells and Testis
Authors: Huang Jiahao , Wang Yini , Liu Jinlong , Chu Ming , Wang Yuedan
Published: October 2021

Transcription factor DP family member 3 (TFDP3) is a cancer-testis antigen, mainly expressed in normal testis and multiple cancers.TFDP3gene (Gene ID: 51270) is located on the chromosome X and shares a high degree of sequence homology with TFDP1 and TFDP2, which can form heterodimers with E2F family members and enhance DNA-binding activity of E2Fs. In contrast to TFDP1 and TFDP2, TFDP3 downregulates E2F-mediated transcriptional activation. During DNA damage response in cancer cells, TFDP3 is induced and can inhibit E2F1-mediated apoptosis. Moreover, TFDP3 is involved in cell autophagy and epithelial-mesenchymal transition. Regarding cancer therapy opportunity, the transduction of dendritic cells with recombinant adenovirus-encoding TFDP3 can activate autologous cytotoxic T lymphocytes to target hepatoma cells. Here, we review the characterization of TFDP3, with an emphasis on the biological function and molecular mechanism. A better understanding of TFDP3 will provide new insights into the pathological mechanisms and therapeutic strategies for cancers.
Targeting Sphingolipids for Cancer Therapy
Authors: Companioni Osmel , Mir Cristina , Garcia-Mayea Yoelsis , LLeonart Matilde E.
Published: October 2021

Sphingolipids are an extensive class of lipids with different functions in the cell, ranging from proliferation to cell death. Sphingolipids are modified in multiple cancers and are responsible for tumor proliferation, progression, and metastasis. Several inhibitors or activators of sphingolipid signaling, such as fenretinide, safingol, ABC294640, ceramide nanoliposomes (CNLs), SKI-II, α-galactosylceramide, fingolimod, and sonepcizumab, have been described. The objective of this review was to analyze the results from preclinical and clinical trials of these drugs for the treatment of cancer. Sphingolipid-targeting drugs have been tested alone or in combination with chemotherapy, exhibiting antitumor activity alone and in synergism with chemotherapy in vitro and in vivo. As a consequence of treatments, the most frequent mechanism of cell death is apoptosis, followed by autophagy. Aslthough all these drugs have produced good results in preclinical studies of multiple cancers, the outcomes of clinical trials have not been similar. The most effective drugs are fenretinide and α-galactosylceramide (α-GalCer). In contrast, minor adverse effects restricted to a few subjects and hepatic toxicity have been observed in clinical trials of ABC294640 and safingol, respectively. In the case of CNLs, SKI-II, fingolimod and sonepcizumab there are some limitations and absence of enough clinical studies to demonstrate a benefit. The effectiveness or lack of a major therapeutic effect of sphingolipid modulation by some drugs as a cancer therapy and other aspects related to their mechanism of action are discussed in this review.
Improving Quality Indicator of Melanoma Management – Change of Melanoma Mortality-to-Incidence Rate Ratio Based on a Hungarian Nationwide Retrospective Study
Authors: Várnai Máté , Kiss Zoltán , Gyulai Rolland , Oláh Judit , Holló Péter , Emri Gabriella , Csejtei András , Kenessey István , Benedek Angéla , Polányi Zoltán , Nagy-Erdei Zsófia , Dániel Andrea , Knollmajer Kata , Rokszin György , Fábián Ibolya , Barcza Zsófia , Polgár Csaba , Nagy Balázs , Liszkay Gabriella , Vokó Zoltán
Published: October 2021

Introduction

The incidence of melanoma has been increasing in the last decades. A retrospective Hungarian epidemiological study provided real-world data on incidence and mortality rates. There have been changing trends in incidence in Hungary in the last decade and mortality decreased, shifting mortality-to-incidence rate ratios (MIR). MIR is an indicator of cancer management quality.

Objectives

Our aim is to show the changes of melanoma MIR in Hungary between 2011 and 2018 and to compare the real-world evidence-based results of our Hungarian nationwide retrospective study with other European countries.

Methods

MIR is calculated from the age-specific standardized incidence and mortality rates from our study. Annual MIR values are presented for the total population and for both sexes between 2011 and 2018, along with 95% confidence intervals. Comparison with European countries are shown for 2012 and 2018 based on the GLOBOCAN database and Eurostat health care expenditure per capita data.

Results

MIR decreased by 0.035 during the study years. The decrease was same in both sexes (0.031). Male had higher MIRs in all study years. In both 2012 and 2018, Hungarian MIR in both sexes was lower than the European Union average (males: 0.192 vs. 0.212 and 0.148 vs. 0.174 respectively, women: 0.107 vs. 0.129 and 0.083 vs. 0.107 respectively).

Discussion

Hungarian mortality-to-incidence ratio is the lowest in Central and Eastern Europe and is close to the level of Western and Northern European countries. The results are driven by the high number of new diagnosed melanoma cases.
Executive Summary of Clinical and Technical Guidelines for Esophageal Cancer Proton Beam Therapy From the Particle Therapy Co-Operative Group Thoracic and Gastrointestinal Subcommittees
Authors: Chuong Michael D. , Hallemeier Christopher L. , Li Heng , Zhu Xiaorong Ronald , Zhang Xiaodong , Tryggestad Erik J. , Yu Jen , Yang Ming , Choi J. Isabelle , Kang Minglei , Liu Wei , Knopf Antje , Meijers Arturs , Molitoris Jason K. , Apisarnthanarax Smith , Giap Huan , Hoppe Bradford S. , Lee Percy , Chang Joe Y. , Simone Charles B. , Lin Steven H.
Published: October 2021

Radiation therapy (RT) is an integral component of potentially curative management of esophageal cancer (EC). However, RT can cause significant acute and late morbidity due to excess radiation exposure to nearby critical organs, especially the heart and lungs. Sparing these organs from both low and high radiation dose has been demonstrated to achieve clinically meaningful reductions in toxicity and may improve long-term survival. Accruing dosimetry and clinical evidence support the consideration of proton beam therapy (PBT) for the management of EC. There are critical treatment planning and delivery uncertainties that should be considered when treating EC with PBT, especially as there may be substantial motion-related interplay effects. The Particle Therapy Co-operative Group Thoracic and Gastrointestinal Subcommittees jointly developed guidelines regarding patient selection, treatment planning, clinical trials, and future directions of PBT for EC.
Influence of Sex in the Molecular Characteristics and Outcomes of Malignant Tumors
Authors: Araujo Jhajaira M. , Rosas Gina , Belmar-López Carolina , Raez Luis E. , Rolfo Christian D. , Schwarz Luis J. , Infante-Huaytalla Ulises , Paez Kevin J. , García Luis R. , Alvarado Hober , Ramos Fany P. , Delgado-Espinoza Sheyla S. , Cardenas-Farfan Jhon B. , Cornejo Melanie , Zanabria Daniel , Colonio-Cossio Christian , Rojas-Jefferson Mario , Pinto Joseph A.
Published: October 2021

Background

Sex is frequently underestimated as a prognostic biomarker in cancer. In this study, we evaluated a large cohort of patients and public datasets to determine the influence of sex on clinical outcomes, mutational status, and activation of immune pathways in different types of cancer.

Methods

A cohort of 13,619 Oncosalud-affiliated patients bearing sex-unrelated cancers was followed over a 20-year period. Hazard ratios (HRs) for death were estimated for female vs. male patients for each cancer type and then pooled in a meta-analysis to obtain an overall HR. In addition, the mutational status of the main actionable genes in melanoma (MEL), colorectal cancer (CRC), and lung cancer was compared between sexes. Finally, a gene set enrichment analysis (GSEA) of publicly available data was conducted, to assess differences in immune processes between sexes in MEL, gastric adenocarcinoma (GC), head and neck cancer (HNC), colon cancer (CC), liver cancer (LC), pancreatic cancer (PC), thyroid cancer (TC), and clear renal cell carcinoma (CCRCC).

Results

Overall, women had a decreased risk of death (HR = 0.73, CI95: 8%–42%), with improved overall survival (OS) in HNC, leukemia, lung cancer, lymphoma, MEL, multiple myeloma (MM), and non-melanoma skin cancer. Regarding the analysis of actionable mutations, only differences in EGFR alterations were observed (27.7% for men vs. 34.4% for women, p = 0.035). The number of differentially activated immune processes was higher in women with HNC, LC, CC, GC, MEL, PC, and TC and included cellular processes, responses to different stimuli, immune system development, immune response activation, multiorganism processes, and localization of immune cells. Only in CCRCC was a higher activation of immune pathways observed in men.

Conclusions

The study shows an improved survival rate, increased activation of immune system pathways, and an enrichment of EGFR alterations in female patients of our cohort. Enhancement of the immune response in female cancer patients is a phenomenon that should be further explored to improve the efficacy of immunotherapy.
Androgen Receptors Act as a Tumor Suppressor Gene to Suppress Hepatocellular Carcinoma Cells Progression via miR-122-5p/RABL6 Signaling
Authors: Tang Neng , Dou Xiaolin , You Xing , Li Yixiong , Li Xi , Liu Guodong
Published: October 2021

Hepatocellular carcinoma (HCC) is a malignant tumor with a high degree of malignancy and a poor prognosis. Androgen receptor (AR) has been reported to play important roles in the regulation of the progression of HCC, but the underlying mechanisms of how AR regulates HCC initiation, progression, metastasis, and chemotherapy resistance still need further study. Our study found that AR could act as a tumor suppression gene to suppress HCC cells invasion and migration capacities via miR-122-5p/RABL6 signaling, and the mechanism study further confirmed that miR-122-5p could suppress the expression of RABL6 to influence HCC cells progression by directly targeting the 3’UTR of the mRNA of RABL6. The preclinical study using an in vivo mouse model with orthotopic xenografts of HCC cells confirmed the in vitro data, and the clinical data gotten from online databases based on TCGA samples also confirmed the linkage of AR/miR-122-5p/RABL6 signaling to the HCC progression. Together, these findings suggest that AR could suppress HCC invasion and migration capacities via miR-122-5p/RABL6 signaling, and targeting this newly explored signaling may help us find new therapeutic targets for better treatment of HCC.
Sigma-1 Receptor Changes Observed in Chronic Pelvic Pain Patients: A Pilot PET/MRI Study
Authors: Yoon Daehyun , Fast Angela M. , Cipriano Peter , Shen Bin , Castillo Jessa B. , McCurdy Christopher R. , Mari Aparici Carina , Lum Deirdre , Biswal Sandip
Published: October 2021

Introduction: Chronic pelvic pain is a highly prevalent pain condition among women, but identifying the exact cause of pelvic pain remains a significant diagnostic challenge. In this study, we explored a new diagnostic approach with PET/MRI of the sigma-1 receptor, a chaperone protein modulating ion channels for activating nociceptive processes.

Methods: Our approach is implemented by a simultaneous PET/MRI scan with a novel radioligand [18F]FTC-146, which is highly specific to the sigma-1 receptor. We recruited 5 chronic pelvic pain patients and 5 healthy volunteers and compared our PET/MRI findings between these two groups.

Results: All five patients showed abnormally increased radioligand uptake on PET compared to healthy controls at various organs, including the uterus, vagina, pelvic bowel, gluteus maximus muscle, and liver. However, on MRI, only 2 patients showed abnormalities that could be potentially associated with the pain symptoms. For a subset of patients, the association of pain and the abnormally increased radioligand uptake was further validated by successful pain relief outcomes following surgery or trigger point injections to the identified abnormalities.

Conclusion: In this preliminary study, sigma-1 receptor PET/MRI demonstrated potential for identifying abnormalities associated with chronic pelvic pain. Future studies will need to correlate samples with imaging findings to further validate the correlation between S1R distribution and pathologies of chronic pelvic pain.

Trial Registration: The clinical trial registration date is June 2, 2018, and the registration number of the study is NCT03195270 (https://clinicaltrials.gov/ct2/show/NCT03556137).
The Need for Special Education Among ELBW and SGA Preterm Children: A Cohort Study
Authors: van Beek Pauline E. , van de Par Kaylee , van der Horst Iris E. , van Baar Anneloes L. , Vugs Brigitte , Andriessen Peter
Published: October 2021

Background: Preterm infants with pre- or postnatal growth restriction may have an additional risk of adverse neurodevelopmental outcome. Whereas reduced cognitive ability and behavioral problems have consistently been associated with prematurity, a more comprehensive evaluation is necessary to identify those preterm infants who are at increased risk for difficulties in school performance. This study evaluated the association between extremely low birth weight (ELBW) and the need for special education and determined if there is an additional risk for the need for special education among small for gestational age (SGA) children.

Methods: This is a single-center cohort study including singleton children born below 30 weeks' gestation between 1990 and 2011 and followed into 2019. ELBW + was defined as a birth weight below 1,000 g, which was compared to ELBW–. Within all ELBW+ children, SGA+ was defined as a birth weight <10th percentile according to Fenton, which was compared to SGA–. The dichotomous outcome measurement was the need for special education at 8 years of age or not, reflecting if the children required a special educational setting designed to accommodate educational, behavioral, and/or medical needs.

Results: In total, 609 children were eligible for follow-up, of whom 390 (64%) children were assessed at 8 years. Of these, 56 (14%) children needed special education, most often determined by cognitive deficiency (43%), behavioral problems (29%), or both (16%). Among the 191 ELBW+ children, 35 (18%) attended special education, compared to 21 (11%) among ELBW– children (p-value 0.041). A decreasing risk for the need for special education was found from 25% in ELBW+/SGA+ children to 16% in ELBW+/SGA– children and 11% in ELBW–/SGA– children (p-value 0.025). Multivariable logistic regression showed an odds ratio of 2.88 (95% CI 1.20–6.78) for ELBW+/SGA+ children vs. ELBW–/SGA– children for the need for special education.

Conclusions: This study showed that ELBW children are at increased risk for the need for special education compared to non-ELBW children. In addition, children that are both ELBW and SGA do have the highest risk for the need for special education. Classifying children as ELBW and SGA can be useful in follow-up for identifying preterm children with an additional risk for adverse long-term outcome.
The Efficacy and Safety of Revefenacin for the Treatment of Chronic Obstructive Pulmonary Disease: A Systematic Review
Authors: Zhang Jiaxing , Xie Yihong , Kwong Joey Sum-wing , Ge Long , He Rui , Zheng Wenyi , Han Jing , Zhang Rui , Zhao Huaye , He Yuru , Li Xiaosi
Published: October 2021

BackgroundRevefenacin (REV) is a novel once-daily long-acting muscarinic antagonist (LAMA) in the treatment of moderate to very severe chronic obstructive pulmonary disease (COPD). This systematic review incorporating a dose-response meta-analysis aimed to assess the efficacy and safety of REV.

MethodsPubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP database, and Wanfang database were searched from their inception to April 2020. We included randomized controlled trials (RCTs) which evaluated the efficacy and safety of REV in COPD patients. Two reviewers independently performed study screening, data extraction, and risk of bias assessment. Outcomes consisted of the mean change in trough Forced Expiratory Volume in 1 second (FEV1) from baseline, adverse events (AEs), and serious adverse events (SAEs). A dose-response meta-analysis using the robust error meta-regression method was conducted. We used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of evidence.

ResultsNine RCTs (3,121 participants) were included in this systematic review. The meta-analyses indicated that 175 μg/day REV could significantly improve the trough FEV1(MD=143.67, 95%CI: 129.67 to 157.68; I2=96%; 809 participants; studies=4; low quality) without increasing the risk of AEs (OR=0.98, 95%CI: 0.81 to 1.18; I2=34%; 2,286 participants; studies=7; low quality) or SAEs (OR=0.89, 95%CI: 0.55 to 1.46; I2=0%; 2,318 participants; studies=7; very low quality) compared to placebo. Furthermore, the effect of REV in increasing trough FEV1was dose-dependent with an effective threshold of 88 μg/day (R2= 0.7017). Nevertheless, only very low-quality to low-quality evidence showed that REV at a dose of 175 μg/day was inferior to tiotropium regarding the long-term efficacy, and its safety profile was not superior to tiotropium or ipratropium.

ConclusionCurrent evidence shows that REV is a promising option for the treatment of moderate to very severe COPD. Due to most evidence graded as low quality, further studies are required to compare the efficacy, long-term safety and cost-effectiveness between REV and other LAMAs in different populations.

Clinical Trial Registration: [PROSPERO], identifier [CRD42020182793]
AGEs-Induced Calcification and Apoptosis in Human Vascular Smooth Muscle Cells Is Reversed by Inhibition of Autophagy
Authors: He Hu-Qiang , Qu Yuan-Qing , Kwan Law Betty Yuen , Qiu Cong-ling , Han Yu , Ricardo de Seabra Rodrigues Dias Ivo , Liu Yong , Zhang Jie , Wu An-Guo , Wu Cheng-Wen , Fai Mok Simon Wing , Cheng Xin , He Yan-Zheng , Wai Wong Vincent Kam
Published: October 2021

Vascular calcification (VC) in macrovascular and peripheral blood vessels is one of the main factors leading to diabetes mellitus (DM) and death. Apart from the induction of vascular calcification, advanced glycation end products (AGEs) have also been reported to modulate autophagy and apoptosis in DM. Autophagy plays a role in maintaining the stabilization of the external and internal microenvironment. This process is vital for regulating arteriosclerosis. However, the internal mechanisms of this pathogenic process are still unclear. Besides, the relationship among autophagy, apoptosis, and calcification in HASMCs upon AGEs exposure has not been reported in detail. In this study, we established a calcification model of SMC through the intervention of AGEs. It was found that the calcification was upregulated in AGEs treated HASMCs when autophagy and apoptosis were activated. In the country, AGEs-activated calcification and apoptosis were suppressed in Atg7 knockout cells or pretreated with wortmannin (WM), an autophagy inhibitor. These results provide new insights to conduct further investigations on the potential clinical applications for autophagy inhibitors in the treatment of diabetes-related vascular calcification.
Polyphenols as Antitumor Agents Targeting Key Players in Cancer-Driving Signaling Pathways
Authors: Cháirez-Ramírez Manuel Humberto , de la Cruz-López Karen Griselda , García-Carrancá Alejandro
Published: October 2021

Polyphenols constitute an important group of natural products that are traditionally associated with a wide range of bioactivities. These are usually found in low concentrations in natural products and are now available in nutraceuticals or dietary supplements. A group of polyphenols that include apigenin, quercetin, curcumin, resveratrol, EGCG, and kaempferol have been shown to regulate signaling pathways that are central for cancer development, progression, and metastasis. Here, we describe novel mechanistic insights on the effect of this group of polyphenols on key elements of the signaling pathways impacting cancer. We describe the protein modifications induced by these polyphenols and their effect on the central elements of several signaling pathways including PI3K, Akt, mTOR, RAS, and MAPK and particularly those affecting the tumor suppressor p53 protein. Modifications of p53 induced by these polyphenols regulate p53 gene expression and protein levels and posttranslational modifications such as phosphorylation, acetylation, and ubiquitination that influence stability, subcellular location, activation of new transcriptional targets, and the role of p53 in response to DNA damage, apoptosis control, cell- cycle regulation, senescence, and cell fate. Thus, deep understanding of the effects that polyphenols have on these key players in cancer-driving signaling pathways will certainly lead to better designed targeted therapies, with less toxicity for cancer treatment. The scope of this review centers on the regulation of key elements of cancer signaling pathways by the most studied polyphenols and highlights the importance of a profound understanding of these regulations in order to improve cancer treatment and control with natural products.