bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification and Monitoring of the Effect of Botulinum Toxin A on Paretic Calf Muscles of Children With Cerebral Palsy With MRI: A Preliminary Study
Authors: Weidensteiner Claudia , Madoerin Philipp , Deligianni Xeni , Haas Tanja , Bieri Oliver , Akinci D'Antonoli Tugba , Bracht-Schweizer Katrin , Romkes Jacqueline , De Pieri Enrico , Santini Francesco , Rutz Erich , Brunner Reinald , Garcia Meritxell
Published: April 2021

Background: Muscles from patients with cerebral palsy (CP) are often spastic and form contractures that limit the range of motion. Injections of botulinum toxin A (BTX) into the calf muscles are an important treatment for functional equinus; however, improvement in gait function is not always achieved. BTX is also used to test muscle weakening for risk evaluation of muscle lengthening surgery. Our aim was to assess the effect of BTX over time on calf muscle properties in pediatric CP patients with MRI.

Material and Methods: Six toe-walking CP patients (mean age 11.6 years) with indication for lengthening surgery were prospectively enrolled and received BTX injections into the gastrocnemius and soleus muscles. MRI scans at 3T of the lower legs and clinical examinations were performed pre-BTX, 6 weeks (6w), and 12 weeks (12w) post-BTX. A fat-suppressed 2D multi-spin-echo sequence was used to acquire T2 maps and for segmentation. Fat fraction maps were calculated from 3D multi-echo Dixon images. Diffusion tensor imaging (DTI) with a 2D echo-planar imaging (EPI) sequence yielded maps of the mean apparent diffusion coefficient (ADC) and of the fractional anisotropy (FA). Hyperintense regions of interest (ROIs) on the T2-weighted (T2w) images at 6w were segmented in treated muscles. Mean values of T2, fat fraction, ADC, and FA were calculated in hyperintense ROIs and in reference ROIs in non-treated muscles.

Results: Hyperintensity on T2w scans and increased T2 (group mean ± standard deviation: 35 ± 1 ms pre-BTX, 45 ± 2 ms at 6w, and 44 ± 2 ms at 12w) were observed in all patients at the injection sites. The T2 increase was spatially limited to parts of the injected muscles. FA increased (0.30 ± 0.03 pre-BTX, 0.34 ± 0.02 at 6w, and 0.36 ± 0.03 at 12w) while ADC did not change in hyperintense ROIs, indicating a BTX-induced increase in extracellular space and a simultaneous decrease of muscle fiber diameter. Fat fraction showed a trend for increase at 12w. Mean values in reference ROIs remained unchanged.

Conclusion: MRI showed limited spatial distribution of the BTX-induced effects in pediatric CP patients. It could be a promising non-invasive tool for future studies to test BTX treatment protocols.
CSF and Serum Biomarkers of Cerebral Damage in Autoimmune Epilepsy
Authors: Nass Robert Daniel , Akgün Katja , Dague Karmele Olaciregui , Elger Christian Erich , Reichmann Heinz , Ziemssen Tjalf , Surges Rainer
Published: April 2021

Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders.

Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array.

Results: We identified suitable samples from patients with AIE (n = 13) with different antibodies and compared them to HS (n = 13), GGE (n = 7), and PNES (n = 8). The NFL levels were significantly elevated in the serum (p = 0.0009) and CSF (p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere.

Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.
Safety, Tolerability, and Effect of Nusinersen in Non-ambulatory Adults With Spinal Muscular Atrophy
Authors: Elsheikh Bakri , Severyn Steven , Zhao Songzhu , Kline David , Linsenmayer Matthew , Kelly Kristina , Tellez Marco , Bartlett Amy , Heintzman Sarah , Reynolds Jerry , Sterling Gary , Weaver Tristan , Rajneesh Kiran , Kolb Stephen J. , Arnold W. David
Published: April 2021

Objective: Investigation of the safety, tolerability, and treatment effect of nusinersen treatment in non-ambulatory adults with spinal muscular atrophy (SMA).

Methods: Non-ambulatory individuals, aged 18 years or older with genetically confirmed 5q SMA were enrolled. In participants with spinal fusion, fluoroscopy guided cervical C1–C2 lateral approach was used. Outcomes at 2, 6, 10, and 14 months post-treatment were compared with baseline assessment. Forced vital capacity (FVC) was the primary outcome, and RULM, HFMSE, the modified SMA-FRS, and ulnar nerve electrophysiology [compound muscle action potential (CMAP), single motor unit size, and motor unit number] were secondary. Adverse and serious adverse events and clinically significant vital sign or lab abnormalities were recorded.

Results: Results from 12 women and 7 men (mean age: 39.7 ± 13.9, range: 21–64 years) were analyzed. No clinically significant changes of vital signs or laboratory parameters were observed. Five participants were hospitalized for pneumonia. Other adverse events included headache, back pain, cervical injection site pain, and upper respiratory and urinary tract infections. High baseline protein/creatinine ratio without significant change on treatment noted in 4 participants. FVC was feasible in all participants. HFMSE and RULM were not feasible in the majority of participants. FVC and functional outcomes were stable without improvement. CMAP and single motor unit potential sizes showed enlargement while motor unit numbers were stable.

Conclusions: Nusinersen, including C1/C2 delivery, was safe overall and well-tolerated. Several outcome measures were limited by floor effect. Overall, treatment resulted in stability of motor outcomes, but motor unit and CMAP size were increased.
Probable REM Sleep Behavior Disorder Is a Risk Factor for Symptom Progression in Parkinson Disease
Authors: Barasa Ashley , Wang Jijia , Dewey Richard B.
Published: April 2021

Background: The literature is conflicting on whether rapid eye movement sleep behavior disorder (RBD) is associated with more rapid progression of Parkinson disease (PD).

Objective: We aimed to determine (1) how stable probable RBD (pRBD) is over time and (2) whether it predicts faster PD progression.

Methods: We evaluated participants in the Parkinson's Disease Biomarker Project (PDBP) who were prospectively assessed every 6–12 months with a series of motor, non-motor, disability, and health status scales. For aim 1, we calculated the incidence and disappearance rates of pRBD and compared stability of pRBD in PD with control subjects. For aim 2, we developed multiple regression models to determine if pRBD at baseline influenced the rate of change or average value at 48 months of 10 outcome variables.

Results: We found that pRBD was a less stable diagnosis for PD than controls. In pRBD+ subjects, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score progressed 2.78 points per year faster (p < 0.01), MDS-UPDRS total score progressed 3.98 points per year faster (p < 0.01), a global composite outcome (GCO) worsened by 0.09 points per year faster (p = 0.02), and Parkinson's Disease Questionnaire (PDQ-39) mobility score progressed 2.57 percentage points per year faster (p < 0.01). The average scores at 48 months were 8.89 (p = 0.02) and 14.3 (p = 0.01) points higher for pRBD+ in MDS-UPDRS part III and total scores, respectively.

Conclusions: Our study confirms that pRBD detected at the start of a study portends more rapid progression of PD. Knowing this could be useful for enriching clinical trials with fast progressors to accelerate discovery of a disease modifying agent.
How Processing of Sensory Information From the Internal and External Worlds Shape the Perception and Engagement With the World in the Aftermath of Trauma: Implications for PTSD
Authors: Harricharan Sherain , McKinnon Margaret C. , Lanius Ruth A.
Published: April 2021

Post-traumatic stress disorder (PTSD) is triggered by an individual experiencing or witnessing a traumatic event, often precipitating persistent flashbacks and severe anxiety that are associated with a fearful and hypervigilant presentation. Approximately 14–30% of traumatized individuals present with the dissociative subtype of PTSD, which is often associated with repeated or childhood trauma. This presentation includes symptoms of depersonalization and derealization, where individuals may feel as if the world or self is “dream-like” and not real and/or describe “out-of-body” experiences. Here, we review putative neural alterations that may underlie how sensations are experienced among traumatized individuals with PTSD and its dissociative subtype, including those from the outside world (e.g., touch, auditory, and visual sensations) and the internal world of the body (e.g., visceral sensations, physical sensations associated with feeling states). We postulate that alterations in the neural pathways important for the processing of sensations originating in the outer and inner worlds may have cascading effects on the performance of higher-order cognitive functions, including emotion regulation, social cognition, and goal-oriented action, thereby shaping the perception of and engagement with the world. Finally, we introduce a theoretical neurobiological framework to account for altered sensory processing among traumatized individuals with and without the dissociative subtype of PTSD.
Restoration of Two-Photon Ca2+ Imaging Data Through Model Blind Spatiotemporal Filtering
Authors: Luo Liyong , Xu Yuanxu , Pan Junxia , Wang Meng , Guan Jiangheng , Liang Shanshan , Li Yurong , Jia Hongbo , Chen Xiaowei , Li Xingyi , Zhang Chunqing , Liao Xiang
Published: April 2021

Two-photon Ca2+ imaging is a leading technique for recording neuronal activities in vivo with cellular or subcellular resolution. However, during experiments, the images often suffer from corruption due to complex noises. Therefore, the analysis of Ca2+ imaging data requires preprocessing steps, such as denoising, to extract biologically relevant information. We present an approach that facilitates imaging data restoration through image denoising performed by a neural network combining spatiotemporal filtering and model blind learning. Tests with synthetic and real two-photon Ca2+ imaging datasets demonstrate that the proposed approach enables efficient restoration of imaging data. In addition, we demonstrate that the proposed approach outperforms the current state-of-the-art methods by evaluating the qualities of the denoising performance of the models quantitatively. Therefore, our method provides an invaluable tool for denoising two-photon Ca2+ imaging data by model blind spatiotemporal processing.
miR-139-5p Loss-Mediated WTAP Activation Contributes to Hepatocellular Carcinoma Progression by Promoting the Epithelial to Mesenchymal Transition
Authors: Liu Wenli , Gao Xuewei , Chen Xiaolong , Zhao Na , Sun Ying , Zou Yawen , Guan Yize , Yang Lin , Pei Xiaoxian , Wang Guozhen , Wang Bin , Li Mingcheng , Song Wengang
Published: April 2021

Background: Hepatocellular carcinoma (HCC) is a primary aggressive gastrointestinal neoplasm that affects patients worldwide. It has been shown that Wilms' tumor 1-associating protein (WTAP) is frequently upregulated in various cancers. However, the potential role of WTAP in HCC remains largely unknown.

Methods: The expression levels of WTAP in human HCC tissues were determined by the western blotting and immunohistochemical (IHC) staining. A correlation between the WTAP expression, clinicopathological features, and the HCC prognosis was analyzed. The WTAP expression was silenced by short hairpin RNA (shRNA), and effects of the knockdown of WTAP on the proliferation and invasion of HCC cells were assessed. The microRNAs (miRNAs) involved in the regulation of the WTAP expression were identified by a bioinformatics analysis and further confirmed by in vitro assays.

Results: The expression levels of WTAP in liver cancer tissues were significantly elevated and compared with those in the adjacent normal tissues and significantly correlated with the clinical stage and prognosis in patients with HCC. Further investigation revealed that the knockdown of WTAP drastically suppressed HCC cell proliferation and invasion abilities. Luciferase reporter assay and validation experiments confirmed that WTAP was a direct target of miR-139-5p. Moreover, the overexpression of WTAP could partly abolish the inhibitory effects of miR-139-5p on the HCC cell growth and invasion. Mechanistically, we revealed that the miR-139-5p/WTAP axis regulated the HCC progression by controlling the epithelial to mesenchymal transition (EMT).

Conclusions: In summary, the results indicate that WTAP is a potential oncogene in HCC and miR-139-5p negatively regulates the WTAP expression. MiR-139-5p/WTAP can be utilized as a potential therapeutic target for HCC.
Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer
Authors: Liu Chun-Yu , Huang Tzu-Ting , Chen Ji-Lin , Chu Pei-Yi , Lee Chia-Han , Lee Hsin-Chen , Lee Yu-Hsuan , Chang Yuan-Ya , Yang Shung-Haur , Jiang Jeng-Kai , Chen Wei-Shone , Chao Yee , Teng Hao-Wei
Published: April 2021

Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan–kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness.
Identification of UL69 Gene and Protein in Cytomegalovirus-Transformed Human Mammary Epithelial Cells
Authors: Haidar Ahmad Sandy , Al Moussawi Fatima , El Baba Ranim , Nehme Zeina , Pasquereau Sébastien , Kumar Amit , Molimard Chloé , Monnien Franck , Algros Marie-Paule , Karaky Racha , Stamminger Thomas , Diab Assaf Mona , Herbein Georges
Published: April 2021

A growing body of evidence addressing the involvement of human cytomegalovirus (HCMV) in malignancies had directed attention to the oncomodulation paradigm. HCMV-DB infected human mammary epithelial cells (HMECs) in culture showed the emergence of clusters of rapidly proliferating, spheroid-shaped transformed cells named CTH (CMV-Transformed HMECs) cells. CTH cells assessment suggests a direct contribution of HCMV to oncogenesis, from key latent and lytic genes activating oncogenic pathways to fueling tumor evolution. We hypothesized that the presence of HCMV genome in CTH cells is of pivotal importance for determining its oncogenic potential. We previously reported the detection of a long non-coding (lnc) RNA4.9 gene in CTH cells. Therefore, we assessed here the presence of UL69 gene, located nearby and downstream of the lncRNA4.9 gene, in CTH cells. The HCMV UL69 gene in CTH cells was detected using polymerase chain reaction (PCR) and sequencing of UL69 gene was performed using Sanger method. The corresponding amino acid sequence was then blasted against the UL69 sequence derived from HCMV-DB genome using NCBI Protein BLAST tool. A 99% identity was present between the nucleotide sequence present in CTH cells and HCMV-DB genome. UL69 transcript was detected in RNA extracts of CTH cells, using a reverse transcription polymerase chain reaction (RT-PCR) assay, and pUL69 protein was identified in CTH lysates using western blotting. Ganciclovir-treated CTH cells showed a decrease in UL69 gene detection and cellular proliferation. In CTH cells, the knockdown of UL69 with siRNA was assessed by RT-qPCR and western blot to reveal the impact of pUL69 on HCMV replication and CTH cell proliferation. Finally, UL69 gene was detected in breast cancer biopsies. Our results indicate a close link between the UL69 gene detected in the HCMV-DB isolate used to infect HMECs, and the UL69 gene present in transformed CTH cells and tumor biopsies, further highlighting a direct role for HCMV in breast tumor development.
Proliferation of Highly Cytotoxic Human Natural Killer Cells by OX40L Armed NK-92 With Secretory Neoleukin-2/15 for Cancer Immunotherapy
Authors: Guo Meng , Sun Chen , Qian Yuping , Zhu Liye , Ta Na , Wang Guangjian , Zheng Jianming , Guo Fengfu , Liu Yanfang
Published: April 2021

Adoptive natural killer (NK) cell transfer has been demonstrated to be a promising immunotherapy approach against malignancies, but requires the administration of sufficient activated cells for treatment effectiveness. However, the paucity of clinical-grade to support the for large-scale cell expansion limits its feasibility. Here we developed a feeder-based NK cell expansion approach that utilizes OX40L armed NK-92 cell with secreting neoleukin-2/15 (Neo-2/15), a hyper-stable mimetic with a high affinity to IL-2Rβγ. The novel feeder cells (NK92-Neo2/15-OX40L) induced the expansion of NK cells with a 2180-fold expansion (median; 5 donors; range, 1767 to 2719) after 21 days of co-culture without added cytokines. These cells were highly cytotoxic against Raji cells and against several solid tumorsin vivo. Mechanistically, NK92-Neo2/15-OX40L induced OX40 and OX40L expression on expanded NK cells and promoted the OX40-OX40L positive feedback loop, thus boosting NK cell function. Our data provided a novel NK cell expansion mechanism and insights into OX40-OX40L axis regulation of NK cell expansion.
Comparison of Diffusion Kurtosis Imaging and Amide Proton Transfer Imaging in the Diagnosis and Risk Assessment of Prostate Cancer
Authors: Yin Huijia , Wang Dongdong , Yan Ruifang , Jin Xingxing , Hu Ying , Zhai Zhansheng , Duan Jinhui , Zhang Jian , Wang Kaiyu , Han Dongming
Published: April 2021

Objectives

This study aims to evaluate and compare the diagnostic value of DKI and APT in prostate cancer (PCa), and their correlation with Gleason Score (GS).

Materials and Methods

DKI and APT imaging of 49 patients with PCa and 51 patients with benign prostatic hyperplasia (BPH) were collected and analyzed, respectively. According to the GS, the patients with PCa were divided into high-risk, intermediate-risk and low-risk groups. The mean kurtosis (MK), mean diffusion (MD) and magnetization transfer ratio asymmetry (MTRasym, 3.5 ppm) values among PCa, BPH, and different GS groups of PCa were compared and analyzed respectively. The diagnostic accuracy of each parameter was evaluated by using the receiver operating characteristic (ROC) curve. The correlation between each parameter and GS was analyzed by using Spearman’s rank correlation.

Results

The MK and MTRasym (3.5 ppm) values were significantly higher in PCa group than in BPH group, while the MD value was significantly lower than in BPH group. The differences of MK/MD/MTRasym (3.5 ppm) between any two of the low-risk, intermediate-risk, and high-risk groups were all statistically significant (p <0.05). The MK value showed the highest diagnostic accuracy in differentiating PCa and BPH, BPH and low-risk, low-risk and intermediate-risk, intermediate-risk and high-risk (AUC = 0.965, 0.882, 0.839, 0.836). The MK/MD/MTRasym (3.ppm) values showed good and moderate correlation with GS (r = 0.844, −0.811, 0.640, p <0.05), respectively.

Conclusion

DKI and APT imaging are valuable in the diagnosis of PCa and demonstrate strong correlation with GS, which has great significance in the risk assessment of PCa.
Machine Learning Applicability for Classification of PAD/VCD Chemotherapy Response Using 53 Multiple Myeloma RNA Sequencing Profiles
Authors: Borisov Nicolas , Sergeeva Anna , Suntsova Maria , Raevskiy Mikhail , Gaifullin Nurshat , Mendeleeva Larisa , Gudkov Alexander , Nareiko Maria , Garazha Andrew , Tkachev Victor , Li Xinmin , Sorokin Maxim , Surin Vadim , Buzdin Anton
Published: April 2021

Multiple myeloma (MM) affects ~500,000 people and results in ~100,000 deaths annually, being currently considered treatable but incurable. There are several MM chemotherapy treatment regimens, among which eleven include bortezomib, a proteasome-targeted drug. MM patients respond differently to bortezomib, and new prognostic biomarkers are needed to personalize treatments. However, there is a shortage of clinically annotated MM molecular data that could be used to establish novel molecular diagnostics. We report new RNA sequencing profiles for 53 MM patients annotated with responses on two similar chemotherapy regimens: bortezomib, doxorubicin, dexamethasone (PAD), and bortezomib, cyclophosphamide, dexamethasone (VCD), or with responses to their combinations. Fourteen patients received both PAD and VCD; six received only PAD, and 33 received only VCD. We compared profiles for the good and poor responders and found five genes commonly regulated here and in the previous datasets for other bortezomib regimens (all upregulated in the good responders): FGFR3, MAF, IGHA2, IGHV1-69, and GRB14. Four of these genes are linked with known immunoglobulin locus rearrangements. We then used five machine learning (ML) methods to build a classifier distinguishing good and poor responders for two cohorts: PAD + VCD (53 patients), and separately VCD (47 patients). We showed that the application of FloWPS dynamic data trimming was beneficial for all ML methods tested in both cohorts, and also in the previous MM bortezomib datasets. However, the ML models build for the different datasets did not allow cross-transferring, which can be due to different treatment regimens, experimental profiling methods, and MM heterogeneity.
A Nomogram Model to Predict Prognosis of Patients With Genitourinary Sarcoma
Authors: Li Linde , Liang Jiayu , Song Turun , Yin Saifu , Zeng Jun , Zhong Qiang , Feng Xiaobing , Jia Zihao , Fan Yu , Wang Xianding , Lin Tao
Published: April 2021

Objectives

The aim of this study is to evaluate the significant factors influencing the overall survival (OS) and recurrence free survival (RFS) and make an attempt to develop a nomogram for predicting the prognosis of patients with genitourinary sarcoma (GS).

Methods

Data on adult GS from 1985 to 2010 were collected. The impact of clinical factors on OS and RFS were estimated by Kaplan–Meier (KM) analysis, and differences between groups were analyzed by the log-rank test. To establish a nomogram, all patients were randomly divided into a training set (n = 125) and a testing set (n = 63). Cox proportion hazard model was utilized to assess the prognostic effect of variables. Then, a nomogram was established to estimate 1-, 3-, and 5-year OS based on Cox regression model. Subsequently, the nomogram was validated by a training set and a validation set.

Results

A total of 188 patients were enrolled into our study. Male patients with bladder sarcoma had better OS rather than RFS when stratified by gender (P = 0.022). According to histological subtypes, patients with leiomyosarcoma (LMS) undergoing chemotherapy were associated with favorable OS (P = 0.024) and RFS (P = 0.001). Furthermore, LMS in kidney sarcoma were associated with lower recurrence rate in comparison to rhabdomyosarcoma (RMS) (P = 0.043). Margin status after surgical excision markedly influenced the OS and RFS of GS patients and negative margins presented optimal prognosis. Chemotherapy was associated with improved OS for patients without surgery (P = 0.029) and patients with positive margins (P = 0.026). Based on the multivariate analysis of the training cohort, age, gender, surgery status, histological subtype, and chemotherapy were included in our nomogram for prediction of OS. The nomogram had sufficient power with concordance index (C-index) of OS: 0.770, 95%CI: 0.760–0.772 and area under curve (AUC) of OS: 0.759, 95%CI: 0.658–0.859 in the training set and with C-index of OS: 0.741, 95%CI: 0.740–0.765, and AUC of OS: 0.744, 95%CI: 0.576–0.913 in the validation set.

Conclusions

Adults GS is a group of extremely rare tumors with poor prognosis. Of all histological types, LMS is sensitive to chemotherapy. We highlighted the cardinal role of surgical resection and the importance of achieving negative margins. We identified the efficacy of chemotherapy for patients with positive margins and those without surgery as well. A nomogram is validated as an effective tool predicting short-term outcomes.
A Super-Enhancer Driven by FOSL1 Controls miR-21-5p Expression in Head and Neck Squamous Cell Carcinoma
Authors: Wan Yuehan , Hoyle Rosalie G. , Xie Nan , Wang Wenjin , Cai Hongshi , Zhang Ming , Ma Zhikun , Xiong Gan , Xu Xiuyun , Huang Zhengxian , Liu Xiqiang , Li Jiong , Wang Cheng
Published: April 2021

MiR-21-5p is one of the most common oncogenic miRNAs that is upregulated in many solid cancers by inhibiting its target genes at the posttranscriptional level. However, the upstream regulatory mechanisms of miR-21-5p are still not well documented in cancers. Here, we identify a super-enhancer associated with the MIR21 gene (MIR21-SE) by analyzing the MIR21 genomic regulatory landscape in head and neck squamous cell carcinoma (HNSCC). We show that the MIR21-SE regulates miR-21-5p expression in different HNSCC cell lines and disruption of MIR21-SE inhibits miR-21-5p expression. We also identified that a key transcription factor, FOSL1 directly controls miR-21-5p expression by interacting with the MIR21-SE in HNSCC. Moreover, functional studies indicate that restoration of miR-21-5p partially abrogates FOSL1 depletion-mediated inhibition of cell proliferation and invasion. Clinical studies confirmed that miR-21-5p expression is positively correlated with FOSL1 expression. These findings suggest that FOSL1-SE drives miR-21-5p expression to promote malignant progression of HNSCC
Terminating Cancer by Blocking VISTA as a Novel Immunotherapy: Hasta la vista, baby
Authors: Yum Ji-Eun Irene , Hong Young-Kwon
Published: April 2021

VISTA is an up-and-coming immune checkpoint molecule that can become the target of new cancer immunotherapy treatments. Immune cells in the tumor microenvironment can largely influence the progression of cancer through inhibitory and stimulatory pathways. Indeed, VISTA is expressed on many immune cells, including T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and dendritic cells. VISTA has predominantly been shown to act in an immune-suppressing manner that enables cancer progression. This review will delve into results from preclinical murine studies of anti-VISTA monoclonal antibody treatments, bring together recent studies that detect VISTA expression on immune cells from patient tumors of various cancers, and discuss ongoing clinical trials involving VISTA.
Suppression of Heterogeneous Nuclear Ribonucleoprotein C Inhibit Hepatocellular Carcinoma Proliferation, Migration, and Invasion via Ras/MAPK Signaling Pathway
Authors: Hu Jiejun , Cai Dong , Zhao Zhibo , Zhong Guo-Chao , Gong Jianping
Published: April 2021

Hepatocellular carcinoma (HCC), the most common malignant tumor, has high fatality and recurrence rates. Accumulating evidence shows that heterogeneous nuclear ribonucleoprotein C (HNRNPC), which is mainly involved in RNA splicing, export, and translation, promotes progression and metastasis of multiple tumor types; however, the effects of HNRNPC in HCC are unknown. In the present study, high levels of HNRNPC were detected in tumor tissues compared with para-tumor tissues by immunohistochemical and western blot assays. Furthermore, Cox proportional hazards regression models, the Kaplan–Meier method, and clinicopathologic features analysis showed that HNRNPC was not only an independent prognostic factor for both overall and disease-free survival in HCC but also a predictor of large tumor size and advanced tumor stage. Functional experiments revealed that silencing of HNRNPC not only led to arrest of more HCC cells at G0/G1 phase to inhibit their proliferation, but also suppressed EMT process to block their invasion, and migration in vitro; this was related to the Ras/MAPK signaling pathway. In addition, blocking of HCC cell proliferation regulated by HNRNPC silencing was observed in vivo. Finally, rescue tests showed that after recovery of Ras/MAPK signaling pathway activity by treatment with Ras agonists, the proliferation, migration, and invasion suppression of Huh-7 and Hep 3B cell lines caused by HNRNPC knockdown was partially reversed. Taken together, these results indicate that HNRNPC knockdown inhibits HCC cell proliferation, migration and invasion, in part via the Ras/MAPK signaling pathway. Thus, HNRNPC may have an important role in the progression of HCC and represents a promising biomarker for evaluation of prognosis and a potential therapeutic target in HCC patients.
A Novel Prognostic Model and Practical Nomogram for Predicting the Outcomes of Colorectal Cancer: Based on Tumor Biomarkers and Log Odds of Positive Lymph Node Scheme
Authors: Zhu Jun , Hao Jun , Ma Qian , Shi Tingyu , Wang Shuai , Yan Jingchuan , Chen Rujie , Xu Dong , Jiang Yu , Zhang Jian , Li Jipeng
Published: April 2021

Background

Emerging evidence shows that serum tumor biomarkers (TBs) and log odds of positive lymph node scheme (LODDS) are closely associated with the prognosis of colorectal cancer (CRC) patients. The aim of our study is to validate the predictive value of TBs and LODDS clinically and to develop a robust prognostic model to predict the overall survival (OS) of patients with CRC.

Methods

CRC patients who underwent radical resection and with no preoperative chemotherapy were enrolled in the study. The eligible population were randomized into training (70%) and test (30%) cohorts for the comprehensive evaluation of the prognostic model. Clinical implications of serum biomarkers and LODDS were identified by univariate and multivariate Cox proportion regression analysis. The predictive ability and discriminative performance were evaluated by Kaplan–Meier (K–M) curves and receiver operating characteristic (ROC) curves. Clinical applicability of the prognostic model was assessed by decision curve analysis (DCA), and the corresponding nomogram was constructed based on the above factors.

Results

A total of 1,202 eligible CRC patients were incorporated into our study. Multivariable COX analysis demonstrated that CA199 (HR = 1.304), CA125 (HR = 1.429), CEA (HR = 1.307), and LODDS (HR = 1.488) were independent risk factors for OS (all P < 0.0001). K–M curves showed that the high-risk group possessed a shorter OS than the low-risk counterparts. The area under curves (AUCs) of the model for 1-, 3- and 5-year OS were 86.04, 78.70, and 76.66% respectively for the train cohort (80.35, 77.59, and 74.26% for test cohort). Logistic DCA and survival DCA confirmed that the prognostic model displayed more clinical benefits than the conventional AJCC 8th TNM stage and CEA model. The nomograms were built accordingly, and the calibration plot for the probability of survival at 3- or 5-years after surgery showed an optimal agreement between prediction and actual observation.

Conclusions

Preoperative serum TBs and LODDS have significant clinical implications for CRC patients. A novel prognostic model incorporating common TBs (CA199, CA125, and CEA) and LODDS displayed better predictive performance than both single factor and the TNM classification. A novel nomogram incorporating TBs and LODDS could individually predict OS in patients with CRC.
Chlorpromazine Sensitizes Progestin-Resistant Endometrial Cancer Cells to MPA by Upregulating PRB
Authors: Cui Yunxia , Wu Huiwen , Yang Linlin , Huang Ting , Li Jian , Gong Xiaodi , Li Lijuan , Sun Xiao , Mao Fei , Wang Yudong
Published: April 2021

Medroxyprogesterone acetate (MPA) is the main conservative treatment for endometrial cancer (EC) patients desirable to preserve fertility and those who cannot suffer from surgery. Considering the high incidence of progestin resistance and recurrence of MPA treatment, we reproposed antipsychotics chlorpromazine (CPZ) as a new strategy for both progestin-sensitive and -resistant endometrial cancer. Cytobiology experiments indicated that CPZ could significantly suppress proliferation, migration/invasion and induce apoptosis in Ishikawa (ISK) and KLE EC cell lines. And xenograft mouse models were constructed to validate the antitumor effect and toxicity of CPZ in-vivo. CPZ inhibited the growth at a low dose of 3mg/kg and the mice exhibited no signs of toxicity. Next, concomitant treatment and sequential treatment with CPZ and MPA were proceeded to analysis the synergistic effect in EC cells. Concomitant treatment only performed a limited synergistic effect on apoptosis in ISK and KLE cells. Nevertheless, sequential treatment showed favorable synergistic effects in progestin-resistant KLE cells. Finally, a stable MPA-resistant cell line shRNA was established to explore the mechanism of CPZ reversing progestin resistance. Immunoblot data showed that CPZ inhibited the activation of PI3K/AKT signal in ISK and KLE cells and upregulated PRB expression in progestin-resistant cells, by which CPZ overcame progestin resistance to MPA. Thus, CPZ might act as a candidate drug for conservative treatment and sequential treatment with CPZ and MPA could be a suitable therapeutic option for progestin resistant patients.
Genetic Manipulation of Sirtuin 3 Causes Alterations of Key Metabolic Regulators in Melanoma
Authors: Singh Chandra K. , George Jasmine , Chhabra Gagan , Nihal Minakshi , Chang Hao , Ahmad Nihal
Published: April 2021

The mitochondrial sirtuin SIRT3 plays key roles in cellular metabolism and energy production, which makes it an obvious target for the management of cancer, including melanoma. Previously, we have demonstrated that SIRT3 was constitutively upregulated in human melanoma and its inhibition resulted in anti-proliferative effects in vitro in human melanoma cells and in vivo in human melanoma xenografts. In this study, we expanded our data employing knockdown and overexpression strategies in cell culture and mouse xenografts to further validate and establish the pro-proliferative function of SIRT3 in melanocytic cells, and its associated potential mechanisms, especially focusing on the metabolic regulation. We found that short-hairpin RNA (shRNA) mediated SIRT3 knockdown in G361 melanoma cells showed diminished tumorigenesis in immunodeficient Nu/Nu mice. Conversely, SIRT3 overexpressing Hs294T melanoma cells showed increased tumor growth. These effects were consistent with changes in markers of proliferation (PCNA), survival (Survivin) and angiogenesis (VEGF) in xenografted tissues. Further, in in vitro culture system, we determined the effect of SIRT3 knockdown on glucose metabolism in SK-MEL-2 cells, using a PCR array. SIRT3 knockdown caused alterations in a total of 37 genes involved in the regulation and enzymatic pathways of glucose (32 genes) and glycogen (5 genes) metabolism. Functions annotation of these identified genes, using the ingenuity pathway analysis (IPA), predicted cumulative actions of decreased cell viability/proliferation, tumor growth and reactive oxygen species (ROS), and increased apoptosis in response to SIRT3 knockdown. Further, IPA gene network analysis of SIRT3 modulated genes revealed the interactions among these genes in addition to several melanoma-associated genes. Sirtuin pathway was identified as one of the top canonical pathways showing the interaction of SIRT3 with metabolic regulatory genes along with other sirtuins. IPA analysis also predicted the inhibition of HIF1α, PKM, KDM8, PPARGC1A, mTOR, and activation of P53 and CLPP; the genes involved in major cancer/melanoma-associated signaling events. Collectively, these results suggest that SIRT3 inhibition affects cellular metabolism, to impart an anti-proliferative response against melanoma.
Case Report: The Complexities of Managing Medications and the Importance of Deprescribing Anticholinergics in Older Adults
Authors: Elliott Taylor , Eckmann Lynne , Moga Daniela C.
Published: April 2021

Potentially inappropriate anticholinergic medications (including over-the-counter products), polypharmacy, and the existence of communication barriers among members of the interprofessional team frequently contribute to clinical complexity in older adults. We present the case of a frail 86-year old female from the perspective of a community pharmacist managing outpatient medications and transitions of care. CD’s past medical history is significant for dementia, multiple falls, recurrent urinary tract infections, depression, cardiac arrhythmia, macular degeneration, chronic pain, depression, and cerebrovascular disease.
Aptamer-Driven Toxin Gene Delivery in U87 Model Glioblastoma Cells
Authors: di Leandro Luana , Giansanti Francesco , Mei Sabrina , Ponziani Sara , Colasante Martina , Ardini Matteo , Angelucci Francesco , Pitari Giuseppina , d’Angelo Michele , Cimini Annamaria , Fabbrini Maria Serena , Ippoliti Rodolfo
Published: April 2021

A novel suicide gene therapy approach was tested in U87 MG glioblastoma multiforme cells. A 26nt G-rich double-stranded DNA aptamer (AS1411) was integrated into a vector at the 5′ of a mammalian codon-optimized saporin gene, under CMV promoter. With this plasmid termed “APTSAP”, the gene encoding ribosome-inactivating protein saporin is driven intracellularly by the glioma-specific aptamer that binds to cell surface-exposed nucleolin and efficiently kills target cells, more effectively as a polyethyleneimine (PEI)-polyplex. Cells that do not expose nucleolin at the cell surface such as 3T3 cells, used as a control, remain unaffected. Suicide gene-induced cell killing was not observed when the inactive saporin mutant SAPKQ DNA was used in the (PEI)-polyplex, indicating that saporin catalytic activity mediates the cytotoxic effect. Rather than apoptosis, cell death has features resembling autophagic or methuosis-like mechanisms. These main findings support the proof-of-concept of using PEI-polyplexed APTSAP for local delivery in rat glioblastoma models.
Chinese Herbal Medicine Usage Reduces Overall Mortality in HIV-Infected Patients With Osteoporosis or Fractures
Authors: Ho Mao-Wang , Li Te-Mao , Li Ju-Pi , Chiou Jian-Shiun , Chiu Mu-Lin , Chen Chao-Jung , Cheng Chi-Fung , Tsai Fuu-Jen , Wu Yang-Chang , Lin Ting-Hsu , Liao Chiu-Chu , Huang Shao-Mei , Lin Yu-Ning , Chou Chen-Hsing , Liang Wen-Miin , Lin Ying-Ju
Published: April 2021

The survival of patients with HIV has greatly improved, due to Anti-Retroviral Therapy (ART). However, long-term HIV survivors often develop serious bone abnormalities, possibly due to the interplay of osteoblasts, osteoclasts, HIV ad ART. We evaluated in a nation-wide study in Taiwan the effect of Chinese herbal medicine (CHM) on overall mortality in HIV patients with osteoporosis or fractures. Enrollment period was between 1998 and 2011. Patients with osteoporosis or fractures before the HIV infection, and those with less than 14 days CHM use, were excluded. This left 498 patients, 160 CHM users, 338 without CHM. Univariate Kaplan-Meier and multivariate Cox regression analysis were used to compare the overall mortality in these 2 groups. Due to the nature of Chinese medicine, CHMs inevitably varied. We therefore also used rule mining and network analysis to determine which major CHM clusters were prescribed to the patients. CHM users had a much Lower mortality (hazard ratio (HR) = 0.43, 95% confidence interval (CI): 0.24–0.77, p < 0.005) and higher survival (p = 0.004, log-rank test). Although the CHMs greatly varied, network analysis identified one main cluster of strongly related CHM combinations (Chuan-Xiong-Cha-Tiao-San (CXCTS), Gan-Cao (GC; Glycyrrhiza uralensis Fisch.), Liu-He-Tang (LHT), Huang-Qin-Tang (HQT), Jia-Wei-Ping-Wei-San (JWPWS), and Dang-Gui-Long-Hui-Wan (DGLHuiW)). CHM as an additional treatment strongly improves overall survival in HIV-infected patients with osteoporosis and fractures.
Cystic Fibrosis Lung Disease in the Aging Population
Authors: Künzi Lisa , Easter Molly , Hirsch Meghan June , Krick Stefanie
Published: April 2021

The demographics of the population with cystic fibrosis (CF) is continuously changing, with nowadays adults outnumbering children and a median predicted survival of over 40 years. This leads to the challenge of treating an aging CF population, while previous research has largely focused on pediatric and adolescent patients. Chronic inflammation is not only a hallmark of CF lung disease, but also of the aging process. However, very little is known about the effects of an accelerated aging pathology in CF lungs. Several chronic lung disease pathologies show signs of chronic inflammation with accelerated aging, also termed “inflammaging”; the most notable being chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In these disease entities, accelerated aging has been implicated in the pathogenesis via interference with tissue repair mechanisms, alterations of the immune system leading to impaired defense against pulmonary infections and induction of a chronic pro-inflammatory state. In addition, CF lungs have been shown to exhibit increased expression of senescence markers. Sustained airway inflammation also leads to the degradation and increased turnover of cystic fibrosis transmembrane regulator (CFTR). This further reduces CFTR function and may prevent the novel CFTR modulator therapies from developing their full efficacy. Therefore, novel therapies targeting aging processes in CF lungs could be promising. This review summarizes the current research on CF in an aging population focusing on accelerated aging in the context of chronic airway inflammation and therapy implications.
Transcriptomic and Metabolomic Profiling Reveals the Protective Effect of Acanthopanax senticosus (Rupr. & Maxim.) Harms Combined With Gastrodia elata Blume on Cerebral Ischemia-Reperfusion Injury
Authors: Lin Bingfeng , Chen Renhao , Wang Qi , Li Zhifeng , Yang ShiLin , Feng YuLin
Published: April 2021

The effects of current treatment strategies used in ischemic stroke are weakened by cerebral ischemia-reperfusion (CIR) injury. Suitable treatment regimens targeting CIR injury are still lacking. Two herbs, namely, Acanthopanax senticosus (Rupr. & Maxim.) Harms (ASE) and Gastrodia elata Blume (GEB), have been used as traditional Chinese medicine and are indicated in the treatment of stroke and cerebrovascular diseases. However, there are no studies that report the effects of ASE combined with GEB in the treatment of CIR injury. In this study, we used the Zea Longa method to induce CIR injury in male Wistar rats. Results of the pharmacodynamic studies revealed that co-administration of ASE and GEB may improve neuronal injury and prevent neuronal apoptosis by reducing oxidative stress and inflammation, and also help prevent CIR injury. On the basis of our hypothesis, we combined the results from transcriptomic and metabonomic analyses and found that ASE and GEB could prevent CIR injury by targeting phenylalanine, pyrimidine, methionine, and sphingolipid metabolism. Therefore, our study provides the basis for the compatibility and efficacy of ASE and GEB.
Na+/K+-ATPase as a Target of Cardiac Glycosides for the Treatment of SARS-CoV-2 Infection
Authors: Souza e Souza Kauê Francisco Corrêa , Moraes Bianca Portugal Tavares , Paixão Izabel Christina Nunes de Palmer , Burth Patrícia , Silva Adriana Ribeiro , Gonçalves-de-Albuquerque Cassiano Felippe
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified for the first time in Wuhan, China, causes coronavirus disease 2019 (COVID-19), which moved from epidemic status to becoming a pandemic. Since its discovery in December 2019, there have been countless cases of mortality and morbidity due to this virus. Several compounds such as chloroquine, hydroxychloroquine, lopinavir-ritonavir, and remdesivir have been tested as potential therapies; however, no effective treatment is currently recommended by regulatory agencies. Some studies on respiratory non-enveloped viruses such as adenoviruses and rhinovirus and some respiratory enveloped viruses including human respiratory syncytial viruses, influenza A, parainfluenza, SARS-CoV, and SARS-CoV-2 have shown the antiviral activity of cardiac glycosides, correlating their effect with Na+/K+-ATPase (NKA) modulation. Cardiac glycosides are secondary metabolites used to treat patients with cardiac insufficiency because they are the most potent inotropic agents. The effects of cardiac glycosides on NKA are dependent on cell type, exposure time, and drug concentration. They may also cause blockage of Na+ and K+ ionic transport or trigger signaling pathways. The antiviral activity of cardiac glycosides is related to cell signaling activation through NKA inhibition. Nuclear factor kappa B (NFκB) seems to be an essential transcription factor for SARS-CoV-2 infection. NFκB inhibition by cardiac glycosides interferes directly with SARS-CoV-2 yield and inflammatory cytokine production. Interestingly, the antiviral effect of cardiac glycosides is associated with tyrosine kinase (Src) activation, and NFκB appears to be regulated by Src. Src is one of the main signaling targets of the NKA α-subunit, modulating other signaling factors that may also impair viral infection. These data suggest that Src-NFκB signaling modulated by NKA plays a crucial role in the inhibition of SARS-CoV-2 infection. Herein, we discuss the antiviral effects of cardiac glycosides on different respiratory viruses, SARS-CoV-2 pathology, cell signaling pathways, and NKA as a possible molecular target for the treatment of COVID-19.