bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of the Ballast Long Guiding Sheath for Neuroendovascular Procedures: Institutional Experience in 68 Cases
Authors: Hassan Ameer E. , Burke Elizabeth M. , Monayao Marlon , Tekle Wondwossen G.
Published: May 2021

Background: The rise of neurointerventional devices has created a demand for guide systems capable of navigating to the carotid artery consistently regardless of tortuosity. The shift toward large distal access catheters (DACs) and desire for greater trackability have inspired the creation of flexible, supportive, large-lumen long guiding sheaths. Recently, the Ballast long guiding sheath was introduced to provide stability and flexibility while navigating neurointerventional devices through tortuous intracranial anatomy.

Objective: To report our experience using the Ballast long guiding sheath in a series of patients undergoing a variety of neuroendovascular procedures.

Methods: We retrospectively identified all patients who underwent neuroendovascular treatment with a long guiding sheath were selected from a prospectively maintained endovascular database from January 2019 to November 2019. Baseline clinical characteristics and procedural details were collected.

Results: A total of 68 patients were included, mean patient age 67.6 ± 13.6 years. Of the patients treated, 52.9% (36/68) presented with stenosis, 25% (17/68) with aneurysms, 13.2% (9/68) with stroke or emboli, 1.5% (1/68) with a tumor, 1.5% (1/68) with an arteriovenous fistula (AVF), and 4.4% (3/68) with a carotid web. Of the patients with stenosis, 20/36 (55.6%) were extracranial, and 16/36 (44.4%) were intracranial. The Ballast long guiding sheath was used to deliver treatment devices for stenting (37/68, 54.4%), flow diversion (12/68, 17.6%), mechanical thrombectomy (8/68, 11.8%), endovascular coiling (5/68, 7.4%), liquid embolization (3/68, 4.4%), balloon angioplasty (2/68, 2.9%), and balloon angioplasty with stenting (1/68, 1.5%). No Ballast-related complications or adverse events were encountered.

Conclusions: We demonstrate the feasibility of the Ballast long guiding sheath to successfully deliver modern neurointerventional treatment devices through tortuous anatomy.
Outcome and Complications of MR Guided Focused Ultrasound for Essential Tremor: A Systematic Review and Meta-Analysis
Authors: Agrawal Mohit , Garg Kanwaljeet , Samala Raghu , Rajan Roopa , Naik Vikas , Singh Manmohan
Published: May 2021

Background: Magnetic resonance guided focused ultrasound (MRgFUS) is a relatively novel technique to treat essential tremor (ET). The objective of this review was to analyze the efficacy and the safety profile of MRgFUS for ET.

Methods: A systematic literature review was done. The post procedure changes in the Clinical Rating Scale for Tremor (CRST) score, hand score, disability and quality of life scores were analyzed.

Results: We found 29 studies evaluating 617 patients. DTI based targeting was utilized in six cohorts. A significant difference was observed in the pooled standard mean difference between the pre and postoperative total CRST score (p-value < 0.001 and 0.0002), hand score (p-value 0.03 and 0.02); and the disability at 12 months (p-value 0.01). Head pain and dizziness were the most in procedure complications. The immediate pooled proportion of ataxia was 50%, while it was 20% for sensory complications, which, respectively, declined to 31 and 13% on long term follow up. A significant reduction (p = 0.03) in immediate ataxia related complications was seen with DTI targeting.

Conclusion: MRgFUS for ET seems to be an effective procedure for relieving unilateral tremor. Use of DTI based targeting revealed a significant reduction in post procedure ataxia related complications as compared to traditional targeting techniques. Analysis of other complications further revealed a decreasing trend on follow up.
Initiation of Experimental Temporal Lobe Epilepsy by Early Astrocyte Uncoupling Is Independent of TGFβR1/ALK5 Signaling
Authors: Henning Lukas , Steinhäuser Christian , Bedner Peter
Published: May 2021

Blood–brain barrier (BBB) dysfunction following brain insults has been associated with the development and progression of focal epilepsy, although the underlying molecular mechanisms are not fully elucidated yet. Activation of transforming growth factor beta (TGFβ) signaling in astrocytes by extravasated albumin impairs the ability of astrocytes to properly interact with neurons, eventually leading to epileptiform activity. We used the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) to gain further insights into the role of BBB leakage in status epilepticus (SE)-induced epileptogenesis. Immunohistochemical examination revealed pronounced albumin extravasation already 4 h after SE induction. Astrocytes were virtually devoid of albumin immunoreactivity (IR), indicating the lack of uptake by this time point. Inhibition of the TGFβ pathway by the specific TGFβ receptor 1 (TGFβR1) kinase inhibitor IPW-5371 did not prevent seizure-induced reduction of astrocytic gap junction coupling. Thus, loss of coupling, which is thought to play a causative role in triggering TLE-HS, is most likely not mediated by extravasated albumin. Continuous telemetric EEG recordings and video monitoring performed over a period of 4 weeks after epilepsy induction revealed that inhibition of the TGFβ pathway during the initial phase of epileptogenesis slightly attenuated acute and chronic epileptiform activity, but did not reduce the extent of HS. Together, these data indicate that albumin extravasation due to increased BBB permeability and TGFβ pathway activation during the first hours after SE induction are not significantly involved in initiating TLE.
Risk Factors of Hypoperfusion on MRI of Ischemic Stroke Patients Within 7 Days of Onset
Authors: Xiao Jingjing , Liang Huazheng , Wang Yue , Wang Shaoshi , Wang Yi , Bi Yong
Published: May 2021

Objective: Hypoperfusion is an important factor determining the prognosis of ischemic stroke patients. The present study aimed to investigate possible predictors of hypoperfusion on MRI of ischemic stroke patients within 7 days of stroke onset.

Methods: Ischemic stroke patients, admitted to the comprehensive Stroke Center of Shanghai Fourth People's Hospital affiliated to Tongji University within 7 days of onset between January 2016 and June 2017, were recruited to the present study. Magnetic resonance imaging (MRI), including both diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI), was performed within 7 days of the symptom onset. Time to maximum of the residue function (Tmax) maps were automatically evaluated using the RAPID software. The volume of hypoperfusion was measured outside the infarct area based on ADC < 620 × 10−6 mm2/s. The 90 d mRS score was assessed through either clinic visits or telephone calls. Multivariate step-wise analysis was used to assess the correlation between MR findings and clinical variables, including the demographic information, cardio-metabolic characteristics, and functional outcomes.

Results: Among 635 patients admitted due to acute ischemic stroke within 7 days of onset, 241 met the inclusion criteria. Hypoperfusion volume of 38 ml was the best cut-off value for predicting poor prognosis of patients with cerebral infarction (90 d-mRS score ≥ 2). The incidences of MR perfusion Tmax > 4–6 s maps with a volume of 0–38 mL or >38 mL were 51.9% (125/241) and 48.1% (116/241), respectively. Prior stroke and vascular stenosis (≥70%) were associated with MR hypoperfusion. Multivariate step-wise analysis showed that prior stroke and vascular stenosis (≥70%) were risk factors of Tmax > 4–6 s maps, and the odds ratios (OR) were 3.418 (adjusted OR 95% CI: 1.537–7.600), and 2.265 (adjusted OR, 95% CI: 1.199–4.278), respectively.

Conclusion: Our results suggest that prior stroke and vascular stenosis (≥70%) are strong predictors of hypoperfusion in patients with acute ischemic stroke within 7 days of stroke onset.
Adaptive Algorithms as Control Strategies of Smart Upper Limb Orthosis: A Protocol for a Systematic Scoping Review
Authors: Holanda Ledycnarf J. , Fernandes Ana Paula M. , de Amorim Júlia A. , Matias Aryel M. , Nunes Netto Severino P. , Nagem Danilo A. P. , Valentim Ricardo A. de M. , Morya Edgard , Lindquist Ana Raquel
Published: May 2021

Introduction: Adaptive algorithms for controlling orthosis emerged to overcome significant problems with automatic biosignal classification and personalized rehabilitation. Smart orthoses are evolving fast and need a better human-machine interaction performance since biosignals, feedback, and motor control dynamically change and must be adaptive. This manuscript outlines a scoping review protocol to systematically review the smart upper limb (UL) orthoses based on adaptive algorithms and feasibility tests.

Materials and Methods: This protocol was developed based on the York framework. A field-specific structure was defined to achieve each phase. Eleven scientific databases (PubMed, Web of Science, SciELO, Koreamed, Jstage, AMED, CENTRAL, PEDro, IEEE, Scopus, and Arxiv) and five patent databases (Patentscope, Patentlens, Google Patents, Kripis, J-platpat) were searched. The developed framework will extract data (i.e., orthosis description, adaptive algorithms, tools used in the usability test, and benefits to the general population) from the selected studies using a rigorous approach. Data will be described quantitatively using frequency and trend analysis methods. Heterogeneity between the included studies will be assessed using the Chi-test and I-statistic. The risk of bias will be summarized using the latest Prediction Model Study Risk of Bias Assessment Tool.

Discussion: This review will identify, map, and synthesize the advances about the description of adaptive algorithms for control strategies of smart UL orthosis using data extracted from patents and articles.
Beta-Elemene Reduces the Malignancy of Non-Small Cell Lung Cancer by Enhancing C3orf21 Expression
Authors: Cai Hu , Ren Lili , Wang Ying , Zhang Yongjun
Published: May 2021

Background

Beta-elemene has potent anti-tumor effect, but its anti-tumor mechanism remains unclear. Chromosome 3 open reading frame 21 (C3orf21) acts as a tumor suppressor. This study tested whether the anti-tumor effect of beta-elemene was associated with modulating C3orf21 expression in non-small cell lung cancer (NSCLC).

Materials and Methods

The impact of beta-elemene on C3orf21 expression in NSCLC cells was quantified. The stable C3orf21 silencing A549 and over-expressing PC-9 cells were established and their effects on the beta-elemene-attenuated proliferation, wound healing and invasion of NSCLC cells as well as the expression of key regulators and signal events were determined.

Results

Beta-elemene significantly up-regulated C3orf21 expression in NSCLC cells. Beta-elemene treatment significantly attenuated the proliferation, wound healing and invasion of NSCLC cells, which were significantly mitigated by C3orf21 silencing, but enhanced by C3orf21 over-expression. Similar patterns of beta-elemene-modulated cyclinD1, c-Myc, COX2, MMP2, MMP9, VEGF, PTEN and Notch1 expression were detected in NSCLC cells.

Conclusions

Such data indicated that beta-elemene treatment attenuated the malignancy of NSCLC cells by up-regulating C3orf21 expression. Our findings may provide new mechanisms underlying the pharmacological action of beta-elemene.
Comparison of Lobectomy and Sublobar Resection for Stage IA Elderly NSCLC Patients (≥70 Years): A Population-Based Propensity Score Matching’s Study
Authors: Zhang Bo , Liu Renwang , Ren Dian , Li Xiongfei , Wang Yanye , Huo Huandong , Zhu Shuai , Chen Jun , Song Zuoqing , Xu Song
Published: May 2021

Background

To investigate the differences in survival between lobectomy and sub-lobar resection for elderly stage I non-small-cell lung cancer (NSCLC) patients using the Surveillance, Epidemiology, and End Results (SEER) registry.

Method

The data of stage IA elderly NSCLC patients (≥ 70 years) with tumors less than or equal to 3 cm in diameter were extracted. Propensity-matched analysis was used. Lung cancer-specific survival (LCSS) was compared among the patients after lobectomy and sub-lobar resection. The proportional hazards model was applied to identify multiple prognostic factors.

Results

A total of 3,504 patients met criteria after propensity score matching (PSM). Although the LCSS was better for lobectomy than for sub-lobar resection in patients with tumors ≤ 3 cm before PSM (p < 0.001), no significant difference in the LCSS was identified between the two treatment groups after PSM (p = 0.191). Multivariate Cox regression showed the elder age, male gender, squamous cell carcinoma (SQC) histology type, poor/undifferentiated grade and a large tumor size were associated with poor LCSS. The subgroup analysis of tumor sizes, histologic types and lymph nodes (LNs) dissection, there were also no significant difference for LCSS between lobectomy and sub-lobar resection. The sub-lobar resection was further divided into segmentectomy or wedge resection, and it demonstrated that no significant differences in LCSS were identified among the treatment subgroups either. Multivariate Cox regression analysis showed that the elder age, poor/undifferentiated grade and a large tumor size were a statistically significant independent factor associated with survival.

Conclusion

In terms of LCSS, lobectomy has no significant advantage over sub-lobar resection in elderly patients with stage IA NSCLC if lymph node assessment is performed adequately. The present data may contribute to develop a more suitable surgical treatment strategy for the stage IA elderly NSCLC patients.
Immune Microenvironment in Langerhans Cell Histiocytosis: Potential Prognostic Indicators
Authors: Feng Chuchu , Li Yang , Ke Huang , Peng Xiaomin , Guo Haixia , Zhan Liping , Xiong Xilin , Weng Wenjun , Li Jiaqiang , Fang Jianpei
Published: May 2021

In this study, the immune microenvironment in Langerhans cell histiocytosis (LCH) was characterized to determine if immune indices are predictive of severity. Serum samples from 54 treatment-naïve patients were analyzed quantitatively for inflammatory cytokines and immunoglobulins before and after the induction of chemotherapy. The initial serum sIL-2R, TNF-α, and IL-10 of untreated LCH patients with risk organ involvement (RO+) were significantly higher than those with single-system (SS) involvement. LCH patients with hematologic involvement exhibited a significantly higher sIL-2R, TNF-α, IL-10, and IL-1β expression, as compared to the group without involvement. sIL-2R, TNF-α, and IL-10 were increased in patients with liver or spleen involvement. Th cells have decreased in the liver+ and spleen+ group, and Ts cells were significantly decreased in non-response group after induction chemotherapy. The serum level of immune indices represents, to some extent, the severity of the disease. Pertinent laboratory inspections can be used to improve risk stratification and guide immunotherapy.
Endoscopic, Endonasal Transsphenoidal Surgery for Tumors of the Sellar and Suprasellar Region: A Monocentric Historical Cohort Study of 369 Patients
Authors: Van Gerven Laura , Qian Zhen , Starovoyt Anastasiya , Jorissen Mark , Meulemans Jeroen , van Loon Johannes , De Vleeschouwer Steven , Lambert Julie , Bex Marie , Vander Poorten Vincent
Published: May 2021

Background

The endoscopic endonasal transsphenoidal approach (EETA) is an established technique for the resection of a large variety of benign sellar and suprasellar lesions, mostly pituitary adenomas. It has clear advantages over the microscopic approach, like a superior close-up view of the relevant anatomy and the tumor-gland interface, an enlarged working angle, as well as an increased panoramic vision inside the surgical area. We have been performing the EETA for over a decade, and this study will focus on perioperative and postoperative outcomes and complications and their association with the learning curve.

Material and Methods

All patients in our tertiary referral center (n = 369) undergoing an EETA for a lesion of the sellar and suprasellar region between January 1st 2008 and December 31st 2018 were included, and data were retrospectively retrieved from the electronic patient records.

Results

Median follow-up after surgery was 55 months. Pituitary adenomas (n = 322) were the most frequent pathology. Headache (43.4%) and loss of vision (29.3%) were the most common presenting symptoms. Median procedure duration was significantly longer during the initial 5 years (106 versus 79 minutes; p <0.0001), but incidence of peri- and postoperative CSF leaks in the early years was not significantly higher. Knosp grade >2 was associated with perioperative CSF leak (p =0.002), and perioperative CSF leak was associated with postoperative CSF leak (p <0.001). Almost all cases of meningitis were preceded by a postoperative CSF leak. In 22.4% of patients, tumor recurrence required additional therapy. Perioperative (iatrogenic) mortality was 0.8%. The overall hospital stay decreased over time from an average of 7 to 5 days, and the case load increased yearly (p =0.015).

Conclusion

The EETA is an excellent technique with complication rates comparable to or even lower than those in large microsurgical series in the literature. EETA has a significant learning curve affecting the procedure duration. Throughout the first 10 years following the transition from the microscopic approach to the EETA in our cohort, the caseload increased and hospital stay was reduced, while no increase in peri- and postoperative complications was observed.
Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications
Authors: Sun Wei , Zhang Qing , Wang Runkun , Li Yang , Sun Yue , Yang Lin
Published: May 2021

DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.
Combined Anti-Cancer Effects of Platycodin D and Sorafenib on Androgen-Independent and PTEN-Deficient Prostate Cancer
Authors: Lu Zongliang , Song Wei , Zhang Yaowen , Wu Changpeng , Zhu Mingxing , Wang He , Li Na , Zhou Yong , Xu Hongxia
Published: May 2021

Castration-resistant (androgen-independent) and PTEN-deficient prostate cancer is a challenge in clinical practice. Sorafenib has been recommended for the treatment of this type of cancer, but is associated with several adverse effects. Platycodin D (PD) is a triterpene saponin with demonstrated anti-cancer effects and a good safety profile. Previous studies have indicated that PC3 cells (PTEN -/-, AR -/-) are sensitive to PD, suggesting that it may also be a useful treatment for castration-resistance prostate cancer. We herein investigated the effects of combining PD with sorafenib to treat PTEN-deficient prostate cancer cells. Our data show that PD promotes sorafenib-induced apoptosis and cell cycle arrest in PC3 cells. Of interest, PD only promoted the anti-cancer effects of sorafenib in Akt-positive and PTEN-negative prostate cancer cells. Mechanistic studies revealed that PD promoted p-Akt ubiquitination by increasing the p-Akt level. PD also increased the protein and mRNA expression of FOXO3a, the downstream target of Akt. Meanwhile, PD promoted the activity of FOXO3a and increased the protein expression of Fasl, Bim and TRAIL. Interestingly, when FOXO3a expression was inhibited, the antitumor effects of both PD and sorafenib were individually inhibited, and the more potent effects of the combination treatment were inhibited. Thus, the combination of PD and sorafenib may exert potent anti-cancer effects specifically via FOXO3a. The use of Akt inhibitors or FOXO3a agonists, such as PD, may represent a promising approach for the treatment of androgen-independent and PTEN-deficient prostate cancer.
Long Noncoding RNA KCNMB2-AS1 Promotes SMAD5 by Targeting miR-3194-3p to Induce Bladder Cancer Progression
Authors: Chen Yong-Sheng , Xu Yong-Peng , Liu Wen-Hua , Li De-Chao , Wang Huan , Li Chang-Fu
Published: May 2021

Purpose

Bladder cancer is a common malignant tumor of the urinary system, with the fourth-highest incidence of male malignant tumors in Europe and the United States. So far, the mechanism of bladder cancer progression and metastasis has not been clarified. The aim of our study was to validate the way of long noncoding RNA (lncRNA) KCNMB2-AS1 on the metabolism and growth of bladder cancer cells by miR-3194-3p/SMAD5.

Patients and Methods

The Gene Expression was analyzed by qRT-PCR in bladder cancer tissues and cell lines, with the highly expressed KCNMB2-AS1 screened out. Cell proliferation was detected by Edu staining and clone formation assay, cell migration, and invasion by wound healing and transwell assays. Cell stemness was determined by assessing sphere-forming ability and stemness marker. Correlation between miRNA and lncRNA/gene was verified by dual‐luciferase assay and RIP, and the effect of KCNMB2-AS1 on bladder cancer growth by nude mice tumor formation experiment.

Results

Here, we revealed the increased level of KCNMB2-AS1 in bladder cancer for the first time. Knockdown of KCNMB2-AS1 in vitro prevented the ability of proliferation, metastasis, and stemness of cancer cells. In vivo, the silencing of KCNMB2-AS1 also prevented tumor growth in vivo. Next, we revealed that KCNMB2-AS1 could interact with miR-3194-3p and uncovered that SAMD5 was a downstream target of miR-3194-3p.

Conclusion

In conclusion, KCNMB2-AS1 mediated the bladder cancer cells progress by regulating the miR-3194-3p/SAMD5 signal pathway, which would provide a new target for bladder cancer research.
More Severe COVID-19 in Patients With Active Cancer: Results of a Multicenter Cohort Study
Authors: Monari Caterina , Sagnelli Caterina , Maggi Paolo , Sangiovanni Vincenzo , Numis Fabio Giuliano , Gentile Ivan , Masullo Alfonso , Rescigno Carolina , Calabria Giosuele , Megna Angelo Salomone , Gambardella Michele , Manzillo Elio , Russo Grazia , Esposito Vincenzo , Camaioni Clarissa , Messina Vincenzo , Pisaturo Mariantonietta , Allegorico Enrico , Pinchera Biagio , Pisapia Raffaella , Catalano Mario , Salzillo Angela , Porta Giovanni , Signoriello Giuseppe , Coppola Nicola
Published: May 2021

Background

The aim of the study was to compare coronavirus disease 2019 (COVID-19) severity presentation between oncologic and non-oncologic patients and to evaluate the impact of cancer type and stage on COVID-19 course.

Methods

We performed a multicentre, retrospective study involving 13 COVID-19 Units in Campania region from February to May 2020. We defined as severe COVID-19 presentation the cases that required mechanical ventilation and/or admission to Intensive Care Units (ICU) and/or in case of death.

Results

We enrolled 371 COVID-19 patients, of whom 34 (9.2%) had a history or a diagnosis of cancer (24 solid, 6 onco-hematological). Oncologic patients were older (p<0.001), had more comorbidities (p<0.001) and showed a higher rate of severe COVID-19 presentation (p=0.001) and of death (p<0.001). Compared to 12 patients with non-active cancer and to 337 without cancer, the 17 patients with active cancer had more comorbidities and showed a higher rate of severe COVID-19 and of mortality (all p values <0.001). Compared to the 281 non-severe patients, the 90 subjects with a severe presentation of COVID-19 were older (p<0.01), with more comorbidities (p<0.001) and with a higher rate of cancer (p=0.001). At multivariate analysis, age (OR 1.08, 95% CI: 1.04-1.11) and suffering from cancer in an active stage (OR 5.33, 95% CI: 1.77-16.53) were independently associated with severe COVID-19.

Conclusions

Since the higher risk of severe evolution of COVID-19, cancer patients, especially those with an active malignancy, should be candidates for early evaluation of symptoms and early treatment for COVID-19.
Case Report: Prolonged Survival Following EGFRvIII CAR T Cell Treatment for Recurrent Glioblastoma
Authors: Durgin Joseph S. , Henderson Fraser , Nasrallah MacLean P. , Mohan Suyash , Wang Sumei , Lacey Simon F. , Melenhorst Jan Joseph , Desai Arati S. , Lee John Y. K. , Maus Marcela V. , June Carl H. , Brem Steven , O’Connor Roddy S. , Binder Zev , O’Rourke Donald M.
Published: May 2021

Autologous chimeric antigen receptor (CAR) T cells targeted to epidermal growth factor receptor variant III (CAR T-EGFRvIII) have been developed and administered experimentally to treat patients with IDH1 wildtype recurrent glioblastoma (rGBM) (NCT02209376). We report the case of a 59-year-old patient who received a single peripheral infusion of CAR T-EGFRvIII cells and survived 36 months after disease recurrence, exceeding expected survival for recurrent glioblastoma. Post-infusion histopathologic analysis of tissue obtained during a second stage surgical resection revealed immunosuppressive adaptive changes in the tumor tissue as well as reduced EGFRvIII expression. Serial brain imaging demonstrated a significant reduction in relative cerebral blood volume (rCBV), a measure strongly associated with tumor proliferative activity, at early time points following CAR T treatment. Notably, CAR T-EGFRvIII cells persisted in her peripheral circulation during 29 months of follow-up, the longest period of CAR T persistence reported in GBM trials to date. These findings in a long-term survivor show that peripherally administered CAR T-EGFRvIII cells can persist for years in the circulation and suggest that this cell therapy approach could be optimized to achieve broader efficacy in recurrent GBM patients.
Tumor Treating Fields for Glioblastoma Therapy During the COVID-19 Pandemic
Authors: Gatson Na Tosha N. , Barnholtz-Sloan Jill , Drappatz Jan , Henriksson Roger , Hottinger Andreas F. , Hinoul Piet , Kruchko Carol , Puduvalli Vinay K. , Tran David D. , Wong Eric T. , Glas Martin
Published: May 2021

Background

The COVID-19 pandemic has placed excessive strain on health care systems and is especially evident in treatment decision-making for cancer patients. Glioblastoma (GBM) patients are among the most vulnerable due to increased incidence in the elderly and the short survival time. A virtual meeting was convened on May 9, 2020 with a panel of neuro-oncology experts with experience using Tumor Treating Fields (TTFields). The objective was to assess the risk-to-benefit ratio and provide guidance for using TTFields in GBM during the COVID-19 pandemic.

Panel Discussion

Topics discussed included support and delivery of TTFields during the COVID-19 pandemic, concomitant use of TTFields with chemotherapy, and any potential impact of TTFields on the immune system in an intrinsically immunosuppressed GBM population. Special consideration was given to TTFields' use in elderly patients and in combination with radiotherapy regimens. Finally, the panel discussed the need to better capture data on COVID-19–positive brain tumor patients to analyze longitudinal outcomes and changes in treatment decision-making during the pandemic.

Expert Opinion

TTFields is a portable home-use device which can be managed via telemedicine and safely used in GBM patients during the COVID-19 pandemic. TTFields has no known immunosuppressive effects which is important during a crisis where other treatment methods might be limited, especially for elderly patients with multiple co-morbidities. It is too early to estimate the full impact of COVID-19 on the global healthcare system and on patient outcomes and the panel strongly recommended collaboration with existing cancer COVID-19 registries to follow CNS tumor patients.
Current Status of Newborn Screening in Southeastern Europe
Authors: Koracin Vanesa , Mlinaric Matej , Baric Ivo , Brincat Ian , Djordjevic Maja , Drole Torkar Ana , Fumic Ksenija , Kocova Mirjana , Milenkovic Tatjana , Moldovanu Florentina , Mulliqi Kotori Vjosa , Nanu Michaela Iuliana , Remec Ziga Iztok , Repic Lampret Barbka , Platis Dimitrios , Savov Alexey , Samardzic Mira , Suzic Biljana , Szatmari Ildiko , Toromanovic Alma , Zerjav Tansek Mojca , Battelino Tadej , Groselj Urh
Published: May 2021

Significant part of Southeastern Europe (with a population of 76 million) has newborn screening (NBS) programs non-harmonized with developed European countries. Initial survey was conducted in 2013/2014 among 11 countries from the region (Albania, Bulgaria, Bosnia and Herzegovina (BIH), Croatia, Kosovo, Macedonia, Moldova, Montenegro, Romania, Serbia, and Slovenia) to assess the main characteristics of their NBS programs and their future plans. Their cumulative population at that time was ~52,5 million. At that time, none of the countries had an expanded NBS program, while phenylketonuria screening was not introduced in four and congenital hypothyroidism in three of 11 countries. We repeated the survey in 2020 inviting the same 11 countries, adding Cyprus, Greece, Hungary, and Malta (due to their geographical position in the wider region). The aims were to assess the current state, to evaluate the change in the period, and to identify the main obstacles impacting the implementation of expanded NBS and/or reaching a wider population. Responses were collected from 12 countries (BIH—Federation of BIH, BIH—Republic of Srpska, Bulgaria, Croatia, Greece, Hungary, Kosovo, North Macedonia, Malta, Montenegro, Romania, Serbia, Slovenia) with a population of 68.5 million. The results of the survey showed that the regional situation regarding NBS only modestly improved in this period. All of the surveyed countries except Kosovo screened for at least congenital hypothyroidism, while phenylketonuria was not screened in four of 12 countries. Croatia and Slovenia implemented an expanded NBS program using tandem mass spectrometry from the time of last survey. In conclusion, the current status of NBS programs in Southeastern Europe is very variable and is still underdeveloped (or even non-existent) in some of the countries. We suggest establishing an international task-force to assist with implementation and harmonization of basic NBS services where needed.
MicroRNA-223 Regulates the Development of Cardiovascular Lesions in LCWE-Induced Murine Kawasaki Disease Vasculitis by Repressing the NLRP3 Inflammasome
Authors: Maruyama Daisuke , Kocatürk Begüm , Lee Youngho , Abe Masanori , Lane Malcolm , Moreira Debbie , Chen Shuang , Fishbein Michael C. , Porritt Rebecca A. , Noval Rivas Magali , Arditi Moshe
Published: May 2021

Kawasaki disease (KD), an acute febrile childhood illness and systemic vasculitis of unknown etiology, is the leading cause of acquired heart disease among children. Experimental data from murine models of KD vasculitis and transcriptomics data generated from whole blood of KD patients indicate the involvement of the NLRP3 inflammasome and interleukin-1 (IL-1) signaling in KD pathogenesis. MicroRNA-223 (miR-223) is a negative regulator of NLRP3 activity and IL-1β production, and its expression has been reported to be upregulated during acute human KD; however, the specific role of miR-223 during KD vasculitis remains unknown. Here, using the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, we demonstrate increased miR-223 expression in LCWE-induced cardiovascular lesions. Compared with control WT mice, LCWE-injected miR-223-deficient mice (miR223−/y) developed more severe coronary arteritis and aortitis, as well as more pronounced abdominal aorta aneurysms and dilations. The enhanced cardiovascular lesions and KD vasculitis observed in LCWE-injected miR223−/y mice correlated with increased NLRP3 inflammasome activity and elevated IL-1β production, indicating that miR-223 limits cardiovascular lesion development by downmodulating NLRP3 inflammasome activity. Collectively, our data reveal a previously unappreciated role of miR-223 in regulating innate immune responses and in limiting KD vasculitis and its cardiovascular lesions by constraining the NLRP3 inflammasome and the IL-1β pathway. These data also suggest that miR-223 expression may be used as a marker for KD vasculitis pathogenesis and provide a novel therapeutic target.
Anti-Inflammatory Effects of Dimethyl Fumarate in Microglia via an Autophagy Dependent Pathway
Authors: Lee Young-Sun , Gupta Deepak Prasad , Park Sung Hee , Yang Hyun-Jeong , Song Gyun Jee
Published: May 2021

Dimethyl fumarate (DMF), which has been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis, is considered to exert anti-inflammatory and antioxidant effects. Microglia maintain homeostasis in the central nervous system and play a key role in neuroinflammation, while autophagy controls numerous fundamental biological processes, including pathogen removal, cytokine production, and clearance of toxic aggregates. However, the role of DMF in autophagy induction and the relationship of this effect with its anti-inflammatory functions in microglia are not well known. In the present study, we investigated whether DMF inhibited neuroinflammation and induced autophagy in microglia. First, we confirmed the anti-neuroinflammatory effect of DMF in mice with streptozotocin-induced diabetic neuropathy. Next, we used in vitro models including microglial cell lines and primary microglial cells to examine the anti-inflammatory and neuroprotective effects of DMF. We found that DMF significantly inhibited nitric oxide and proinflammatory cytokine production in lipopolysaccharide-stimulated microglia and induced the switch of microglia to the M2 state. In addition, DMF treatment increased the expression levels of autophagy markers including microtubule-associated protein light chain 3 (LC3) and autophagy-related protein 7 (ATG7) and the formation of LC3 puncta in microglia. The anti-inflammatory effect of DMF in microglia was significantly reduced by pretreatment with autophagy inhibitors. These data suggest that DMF leads to the induction of autophagy in microglia and that its anti-inflammatory effects are partially mediated through an autophagy-dependent pathway.
The Genus Eriosema (Fabaceae): From the Ethnopharmacology to an Evidence-Based Phytotherapeutic Perspective?
Authors: Ateba Sylvin Benjamin , Njamen Dieudonné , Krenn Liselotte
Published: May 2021

The genusEriosema(Fabaceae) includes approximately 150 species widely distributed across tropical and subtropical regions of the world (Africa, Neotropics, Asia and Australia). Throughout these regions, several species are used since centuries in different traditional medicinal systems, while others are used as food or food supplement. The present review attempts to critically summarize current information concerning the uses, phytochemistry and pharmacology of theEriosemagenus and to evaluate the therapeutic potential. The information published in English and French (up to September 2020) on ethnopharmacology or traditional uses, chemistry, pharmacology and toxicology ofEriosemagenus was collected from electronic databases [SciFinder, PubMed, Google, Google Scholar, Scopus, Web of Science, Prelude Medicinal Plants—http://www.ethnopharmacologia.org/recherche-dans-prelude/?plant, The Plant List (http://www.theplantlist.org/), POWO (http://powo.science.kew.org/) and IUCN Red List Categories (https://www.iucnredlist.org/)], conference proceedings, books, M.Sc. and Ph.D. dissertations. The information retrieved on the ethnomedicinal indications ofEriosemagenus allowed to list 25 species (∼16.6% of the genus). The majority of uses is recorded from Africa. Phytochemical analyses of 8 species led to the identification and/or isolation of 107 compounds, with flavonoids (69.2%), chromones (7.5%) and benzoic acid derivatives (3.7%) as the main chemical classes. Pharmacological investigations with crude extracts and isolated compounds showed a broad range of activities including aphrodisiac, estrogenic, anti-osteoporosis, hypolipidemic, anti-diabetic, anti-diarrheal, anti-microbial, anti-oxidant, anthelmintic, anti-cancer, and acetylcholinesterase inhibitory activities. Despite the low number ofEriosemaspecies tested, there is convincing evidence invitroandin vivostudies validating some traditional and ethnobotanical uses. However, the utility of several of the described uses has not yet been confirmed in pharmacological studies. Reviewed data could serve as a reference tool and preliminary information for advanced research onEriosemaspecies.
Clinical Efficacy of Cortex Daphnes (Zushima) Patch in Patients With Symptomatic Knee Osteoarthritis: A Multicenter Non-Inferiority Randomized Controlled Clinical Trial
Authors: Li Yan-Ting , Jiao Juan , Zhang Yi , Huang Ci-Bo , Wang Hai-Dong , Wang Bei , Su Xiao , Song Hui , Zhao Mian-Song , Jiang De-Xun , Wang Jia-Qiang , Jiang Quan
Published: May 2021

Background: Osteoarthritis (OA) is imposing substantial burdens on individuals and society with the aging population. Cortex Daphnes patch is widely used for symptomatic knee OA in China with a satisfying clinical efficacy; however, there is scant clinical evidence supporting its use. To evaluate its efficacy, we conducted a multicenter, non-inferiority, randomized, parallel-group study comparing Cortex Daphnes patch with topical nonsteroidal anti-inflammatory drugs in patients with knee OA (NCT02770950).

Methods: A total of 264 symptomatic knee OA patients were treated with Cortex Daphnes or indomethacin cataplasms applied to affected sites once daily for 2 weeks. The primary outcome was improvement in knee pain on walking as assessed using a visual analog scale (VAS). The non-inferiority margin based on the full analysis population was set as –5 mm on the pain VAS. The secondary outcomes were changes of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, WOMAC scores for pain, function and stiffness, the 36-item Short Form Health Survey (SF-36), and global assessment of knees by the patients. Responder rates for pain VAS, WOMAC total score, and WOMAC pain were also included in the secondary outcomes.

Results: The Cortex Daphnes patch was non-inferior to indomethacin cataplasms for the primary outcome with a group difference (Cortex Daphnes patch–indomethacin cataplasm) of 2.1 mm (95% confidence interval: 2.1–6.4); similar results were found in the per-protocol population. For all other outcomes, no significant differences were found in the full analysis set or in the per-protocol analysis set, except the responder rates for WOMAC pain was higher in the Cortex Daphnes patch group than in the indomethacin cataplasm group (78.4 vs. 64.7%, p = 0.022) in the per-protocol analysis set. Overall, 28.8% patients in the Cortex Daphnes patch group and 9.8% in the indomethacin cataplasm group reported treatment-related adverse events, the vast majority of which were mild-to-moderate skin irritation, resulting in only 3.8 and 0.8% of patients dropping out, respectively.

Conclusion: The Cortex Daphnes patch, which provides satisfactory analgesic efficacy and enhances the physical function of the knee, as well as improving quality of life, may be a promising alternative to knee OA.
Pemetrexed-Platinum With or Without Bevacizumab for Chinese Chemo-Naive Advanced Lung Adenocarcinoma Patients: A Real-World Study
Authors: Li Xin , Huang Jie , Qiu Yao , Zhang Qianyun , Yang Shaoyu , Wu Kan , Wang Jiaoli , Wang Limin , Ye Jian , Ma Shenglin , Xia Bing , Chen Xueqin
Published: May 2021

Despite recent advances in the treatment of advanced non–small-cell lung cancer (NSCLC), bevacizumab plus platinum–based doublet chemotherapy remains a commonly used first-line regimen. This study was conducted to compare the efficacy and safety of pemetrexed–platinum with or without bevacizumab in Chinese chemo-naive advanced lung adenocarcinoma patients in a real-world setting. We retrospectively collected 100 patients who received pemetrexed–platinum with or without bevacizumab (PP, n = 46; Bev+PP, n = 54) until disease progression or unacceptable toxicity. Clinical characteristics of patients were balanced, except for the proportion of stage IV b+c (Bev+PP and PP: 67.4 vs. 37.0%, p = 0.0066). Bev+PP significantly improved the objective response rate (ORR, 65 vs. 30%, p = 0.0004) and progression-free survival (PFS, 7.4 vs. 6.8 months, p = 0.009), but not overall survival (OS, 17.5 vs. 15.0 months, p = 0.553) compared with PP. Treatment (p = 0.001), gender (p = 0.008), adrenal metastasis (p = 0.001), and liver metastasis (p = 0.013) were independent risk factors for PFS. Patients with adrenal metastasis tended to be at the highest risk of not benefiting from bevacizumab addition (HR [95% CI]: 2.244 [0.6495–7.753]). The safety profile was acceptable, and grade ≥3 toxicity occurred similarly. This study showed that pemetrexed–platinum plus bevacizumab was effective compared to chemotherapy alone in Chinese patients with advanced NSCLC.
Integrated Pharmacological Analysis on the Mechanism of Fuyou Formula in Treating Precocious Puberty
Authors: Guo Chunyan , Sun Ning , Hu Kaili , Bai Guoliang , Zhang Meng , Wang Qian , Ding Qian , Liu Jing , Wang Xiaoling , Zhao Libo
Published: May 2021

Fu-you formula (FY), a Traditional Chinese Medicine (TCM) formula composed of 12 herbs, as an in-hospital preparation, has been used treat to precocious puberty (PP) for decades. However, the lack of phytochemical characterization and mechanism of FY remains the main limitation for its spreading. In this study, we analyze the components and mechanisms of FY in PP, based on the integrated pharmacology. Investigated main constituents, targets, pathways of FY by using an integrative pharmacology, and recognized main constituents by HPLC-MS/MS. Then, observed the levels of Follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen (E2) in danazol-induced PP in Sprague–Dawley (SD) rats. Lastly, retrospective study analyzed the clinical data of 575 patients who were diagnosed PP, treated by the FY, and followed-up in our hospital from 2014–2020. The result that total of 116 important candidate targets were selected based on pharmacological analysis. Selected the top 10 values key targets such as the estrogen receptor alpha (ESR1) and insulin-like growth factor 1 (IGF1), were localized and the related gene functions were determined. Gene functions were associated with biological regulation, a cellular process, or signaling pathway, such as the Estrogen signaling pathway, MAPK signaling pathway and PI3K-Akt signaling pathway. By recognizing the five compounds related to the ESR1 and IGF1, which are Quercetin, kaempferol, Luteolin, Apigenin, and Emodin. The results of the molecular docking study further showed that the flavonoids had a strong binding affinity for ESR1 and IGF1 after docking into the crystal structure. The results showed that the FY could effectively reduce E2, LH, and FSH levels in SD rats. Furthermore, the results of the retrospective analysis of medical records showed that the FY could remarkably reduce E2 levels in girls with PP.
Integrated Isogenic Human Induced Pluripotent Stem Cell–Based Liver and Heart Microphysiological Systems Predict Unsafe Drug–Drug Interaction
Authors: Lee-Montiel Felipe T. , Laemmle Alexander , Charwat Verena , Dumont Laure , Lee Caleb S. , Huebsch Nathaniel , Okochi Hideaki , Hancock Matthew J. , Siemons Brian , Boggess Steven C. , Goswami Ishan , Miller Evan W. , Willenbring Holger , Healy Kevin E.
Published: May 2021

Three-dimensional (3D) microphysiological systems (MPSs) mimicking human organ function in vitro are an emerging alternative to conventional monolayer cell culture and animal models for drug development. Human induced pluripotent stem cells (hiPSCs) have the potential to capture the diversity of human genetics and provide an unlimited supply of cells. Combining hiPSCs with microfluidics technology in MPSs offers new perspectives for drug development. Here, the integration of a newly developed liver MPS with a cardiac MPS—both created with the same hiPSC line—to study drug–drug interaction (DDI) is reported. As a prominent example of clinically relevant DDI, the interaction of the arrhythmogenic gastroprokinetic cisapride with the fungicide ketoconazole was investigated. As seen in patients, metabolic conversion of cisapride to non-arrhythmogenic norcisapride in the liver MPS by the cytochrome P450 enzyme CYP3A4 was inhibited by ketoconazole, leading to arrhythmia in the cardiac MPS. These results establish integration of hiPSC-based liver and cardiac MPSs to facilitate screening for DDI, and thus drug efficacy and toxicity, isogenic in the same genetic background.
Curcumin as a Potential Treatment for COVID-19
Authors: Rattis Bruna A. C. , Ramos Simone G. , Celes Mara R. N.
Published: May 2021

Coronavirus disease 2019 (COVID-19) is an infectious disease that rapidly spread throughout the world leading to high mortality rates. Despite the knowledge of previous diseases caused by viruses of the same family, such as MERS and SARS-CoV, management and treatment of patients with COVID-19 is a challenge. One of the best strategies around the world to help combat the COVID-19 has been directed to drug repositioning; however, these drugs are not specific to this new virus. Additionally, the pathophysiology of COVID-19 is highly heterogeneous, and the way of SARS-CoV-2 modulates the different systems in the host remains unidentified, despite recent discoveries. This complex and multifactorial response requires a comprehensive therapeutic approach, enabling the integration and refinement of therapeutic responses of a given single compound that has several action potentials. In this context, natural compounds, such as Curcumin, have shown beneficial effects on the progression of inflammatory diseases due to its numerous action mechanisms: antiviral, anti-inflammatory, anticoagulant, antiplatelet, and cytoprotective. These and many other effects of curcumin make it a promising target in the adjuvant treatment of COVID-19. Hence, the purpose of this review is to specifically point out how curcumin could interfere at different times/points during the infection caused by SARS-CoV-2, providing a substantial contribution of curcumin as a new adjuvant therapy for the treatment of COVID-19.