bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuberculous Meningitis in Children: A Forgotten Public Health Emergency
Authors: du Preez Karen , Jenkins Helen E. , Donald Peter R. , Solomons Regan S. , Graham Stephen M. , Schaaf H. Simon , Starke Jeffrey R. , Hesseling Anneke C. , Seddon James A.
Published: March 2022

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally.
Development and Content Validity of the Bilateral Vestibulopathy Questionnaire
Authors: van Stiphout Lisa , Hossein Israt , Kimman Merel , Whitney Susan L. , Ayiotis Andrianna , Strupp Michael , Guinand Nils , Pérez Fornos Angélica , Widdershoven Josine , Ramos-Macías Ángel , Van Rompaey Vincent , van de Berg Raymond
Published: March 2022

Background

To date, the burden and severity of the full spectrum of bilateral vestibulopathy (BVP) symptoms has not yet been measured in a standardized manner. Since therapeutic interventions aiming to improve BVP symptoms are emerging, the need for a new standardized assessment tool that encompasses the specific aspects of BVP arises. Therefore, the aim of this study was to develop a multi-item Patient Reported Outcome Measure (PROM) that captures the clinically important symptoms of BVP and assesses its impact on daily life.

Methods

The development of the Bilateral Vestibulopathy Questionnaire (BVQ) consisted of two phases: (I) initial item generation and (II) face and content validity testing. Items were derived from a literature review and individual semi-structured interviews focusing on the full spectrum of reported BVP symptoms (I). Subsequently (IIa), individual patient interviews were conducted using “thinking aloud” and concurrent verbal probing techniques to assess the comprehensibility of the instructions, questions and response options, and the relevance, missing domains, or missing items. Interviews continued until saturation of input was reached. Finally, international experts with experience in the field of the physical, emotional, and cognitive symptoms of BVP participated in an online focus group to assess the relevance and comprehensiveness of the BVQ (IIb).

Results

The BVQ consisted of two sections. The first section included 50 items scored on a six-point Likert scale arranged into seven constructs (i.e., imbalance, oscillopsia, other physical symptoms, cognitive symptoms, emotional symptoms, limitations and behavioral changes and social life). The second section consisted of four items, scored on a visual analog scale from 0 to 100, to inquire about limitations in daily life, perceived health and expectations regarding future recovery. Interviews with BVP patients [n= 8, 50% female, mean age 56 years (range 24–88 years)] and the expert meeting confirmed face and content validity of the developed BVQ.

Conclusion

The BVQ, which was developed to assess the spectrum of BVP symptoms and its impact on daily life, proved to have good face and content validity. It can be used to characterize current self-reported symptoms and disability and to evaluate symptom burden before and after therapeutic interventions in future research and clinical practice.
Neuroplasticity in Motor Learning Under Variable and Constant Practice Conditions—Protocol of Randomized Controlled Trial
Authors: Czyż Stanisław H. , Marusiak Jarosław , Klobušiaková Patrícia , Sajdlová Zuzana , Rektorová Irena
Published: March 2022

Background

There is numerous literature on mechanisms underlying variability of practice advantages. Literature includes both behavioral and neuroimaging studies. Unfortunately, no studies are focusing on practice in constant conditions to the best of our knowledge. Hence it is essential to assess possible differences in mechanisms of neuroplasticity between constant vs. variable practice conditions. The primary objectives of the study described in this protocol will be: (1) to determine the brain’s structural and functional changes following constant and variable practice conditions in motor learning (structural and functional magnetic resonance imaging, MRI); (2) to determine the EEG activation and connectivity between cognitive, sensory, and motor cerebral cortex areas (central, temporal, parietal, occipital) in constant and variable practice conditions and as a function of practice time.

Methods

The study will follow the interventional (experimental) design with two arms (parallel groups). Fifty participants will be randomly assigned to two groups practicing in constant (CG) and variable conditions (VG). CG will be practicing only one pattern of step isometric contractions during unimanual index finger abduction, i.e., 90 trials in all training sessions, whereas VG will practice three different patterns. Each will be practiced 30 times per session in variable conditions. Resting-state fMRI, EEG (cortical networking), and motor task proficiency will be examined before (pre-) and after practice (post- and retentions tests).

Discussion

Findings will enhance our understanding of structural and functional neural changes following practice in constant and variable conditions. Therefore, the study can be considered pure (basic) research (clinical research in healthy individuals).

Clinical Trial Registration

Study registered at clinicaltrials.gov (ID# NCT04921072) on 9 June 2021. Last version update: 21 December 2021.

The protocol has been prepared according to the complete SPIRIT checklist (http://www.spirit-statement.org/), although the item order has been modified in order to comply with the manuscript structure.
The Effectiveness of Repetitive Transcranial Magnetic Stimulation for Post-stroke Dysphagia: A Systematic Review and Meta-Analysis
Authors: Wen Xin , Liu Zicai , Zhong Lida , Peng Yang , Wang Jing , Liu Huiyu , Gong Xiaoqian
Published: March 2022

Background

Repetitive transcranial magnetic stimulation (rTMS) applied to the mylohyoid cortical region has positive clinical effects on post-stroke. Therefore, we conducted a meta-analysis to investigate the efficacy of rTMS for patients with post-stroke dysphagia.

Methods

According to PRISMA guidelines, we searched the databases of MEDLINE (PubMed), Cochrane Library, Embase, Web of Science, CNKI, Wangfang. We searched for studies of randomized controlled trials (RCTs) of rTMS to treat dysphagia after stroke and screened by inclusion and exclusion criteria. Features of RCTs were extracted. The heterogeneity of the trials was measured by I2 statistic.

Results

In total, 11 RCTs with 463 dysphagia patients fulfilled our inclusion criteria. In our analysis, rTMS demonstrated a great beneficial effect for post-stroke dysphagia when combined with traditional swallowing exercises. Moreover, a greatly significant difference (P = 0.008) was noted based on stimulation frequency (high frequency vs. low frequency). Additionally, no significant difference (P = 0.53) was observed based on stimulation site (affected vs. unaffected hemisphere).

Conclusions

Overall, rTMS can effectively accelerate the improvement of swallowing function in patients with post-stroke swallowing disorders.
Measuring Speech Intelligibility and Hearing-Aid Benefit Using Everyday Conversational Sentences in Real-World Environments
Authors: Miles Kelly , Beechey Timothy , Best Virginia , Buchholz Jörg
Published: March 2022

Laboratory and clinical-based assessments of speech intelligibility must evolve to better predict real-world speech intelligibility. One way of approaching this goal is to develop speech intelligibility tasks that are more representative of everyday speech communication outside the laboratory. Here, we evaluate speech intelligibility using both a standard sentence recall task based on clear, read speech (BKB sentences), and a sentence recall task consisting of spontaneously produced speech excised from conversations which took place in realistic background noises (ECO-SiN sentences). The sentences were embedded at natural speaking levels in six realistic background noises that differed in their overall level, which resulted in a range of fixed signal-to-noise ratios. Ten young, normal hearing participants took part in the study, along with 20 older participants with a range of levels of hearing loss who were tested with and without hearing-aid amplification. We found that scores were driven by hearing loss and the characteristics of the background noise, as expected, but also strongly by the speech materials. Scores obtained with the more realistic sentences were generally lower than those obtained with the standard sentences, which reduced ceiling effects for the majority of environments/listeners (but introduced floor effects in some cases). Because ceiling and floor effects limit the potential for observing changes in performance, benefits of amplification were highly dependent on the speech materials for a given background noise and participant group. Overall, the more realistic speech task offered a better dynamic range for capturing individual performance and hearing-aid benefit across the range of real-world environments we examined.
The Use of Sonification for the Analysis and Teaching of Interpretive Auditory Nuances
Authors: Kathleen Riley
Published: March 2022

The integrative powers of human auditory perception in masterful performing artists can create nuances of sound from the interpretation of notes on a written page that often seem beyond one’s grasp as a listener. It is important to consider what type of feedback can provide a clearer understanding of nuances in sound to guide motor learning for the acquisition of new skills for expression. Master pianists’ performance has been used as a model for imitation. However, to ensure the accuracy of imitation and clear understanding, sonification was examined for its effectiveness in providing a more immediate understanding of individual interpretations in terms of inter-onset timing and velocity of the notes. Three master concert pianists volunteered to record a performance of the Chopin Nocturne Opus 15 No. 1 on a Yamaha Disklavier Pro MIDI (music instrument digital interface) grand piano. Logic software was used to analyze and compare MIDI data from each performance from the perspective of phrase-by-phrase, note onset timings, and corresponding data from the other pianists. The study objectives were to examine commonalities and differences in timing and dynamics among the performances using MIDI measurements; to probe whether listening to comparative performance data assisted with feedback from sonification would enhance music students’ understanding of the interpretive nuances through imitation; and to determine whether auditory-assisted sonification feedback could be used as a tool to expand students’ interpretive choices and enhance performance. Participants imitated selected phrases of each of the master pianists, first with only music listening, and then with feedback from the sonified, comparative performance data. Results showed limited success in attempts to imitate the model with auditory feedback alone. Auditory-assisted sonification feedback significantly enhanced the participants’ abilities to imitate the model faster and with greater accuracy in the final imitation experiments. The data gathered by the study provide insights on this kind of sonification as an effective feedback tool for heightening participants’ auditory understanding of nuances in sound, as well as providing an effective teaching tool for imitation exercises.
Whole Exome Sequencing Study in Isolated South-Eastern Moravia (Czechia) Population Indicates Heterogenous Genetic Background for Parkinsonism Development
Authors: Kolarikova Kristyna , Vodicka Radek , Vrtel Radek , Stellmachova Julia , Prochazka Martin , Mensikova Katerina , Kanovsky Petr
Published: March 2022

Parkinsonism belongs to the most common neurodegenerative disease. Genetic predisposition could be one of the significant risk factor for disease development. It has been described higher prevalence of parkinsonism in large pedigree from southeastern Moravia region. The study aims were to select accessible subfamily trios from the pedigree suitable for segregation genetic analyses to perform whole exome sequencing (WES) in trio individuals and further to evaluate genetic variants in the each trio. We used IonTorrent platform for WES for five subfamily trios (1–5). Each trio included two affected and one healthy person (as control). Found variants were filtered with respect to MAF < 1% (minor allele frequency), variants effect (based on prediction tools) and disease filter (Parkinsonism responsible genes). Finally, the variants from each trio were assessed with respect to the presence in the patients. There were found no one founder mutation in the subfamilies from the pedigree. Trio 1 shares two variants with trio 2:MC1R:c.322G > A (p.A108T) and MTCL1:c.1445C > T (p.A482V), trio 3 shares two variants with trio 5: DNAJC6:c.1817A > C (p.H606P) and HIVEP3:c.3856C > A (p.R1286W). In trios 4 and 5, there were found two variants in gene CSMD1:c.3335A > G (p.E1112G) and c.4071C > G (p.I1357M) respectively. As the most potentially damaging, we evaluated the non-shared variant SLC18A2:c.583G > A (p.G195S). The variant could affect dopamine transport in dopaminergic neurons. The study of the parkinsonism genetic background in isolated Moravian population suggested that there could be significant accumulation of many risk genetic factors. For verification of the variants influence, it would be appropriate to perform a more extensive population study and suitable functional analysis.
Lactobacillus paracasei BD5115-Derived 2-Hydroxy-3-Methylbutyric Acid Promotes Intestinal Epithelial Cells Proliferation by Upregulating the MYC Signaling Pathway
Authors: Qiao Zhenyi , Wang Xiaohua , Wang Chaoyue , Han Jin , Qi Weiwei , Zhang Huanchang , Liu Zhenmin , You Chunping
Published: March 2022

Metabolites of probiotics that are beneficial to human health have been isolated from the intestinal tract and natural dairy products. However, many studies on probiotics and prebiotics are limited to the observation of human cohorts and animal phenotypes. The molecular mechanisms by which metabolites of probiotics regulate health are still need further exploration. In this work, we isolated a strain of Lactobacillus Paracasei from human milk samples. We numbered it as Lactobacillus Paracasei BD5115. The mouse model of high-fat diet confirmed that the metabolites of this strain also promotes intestinal epithelial cells (IECs) proliferation. Single-cell sequencing showed that a bZIP transcription factor MAFF was specifically expressed in some IECs. We found that MAFF interacted with MBP1 to regulate the expression of MYC. Analysis of the active components in BD5115 metabolites confirmed that 2-hydroxy-3-methylbutyric acid promotes the expression of the MYC gene. This promotes the proliferation of IECs. Our findings indicate that 2-hydroxy-3-methylbutyric acid regulate MYC gene expression mediated by MAFF/MBP1 interaction. This study not only screened a strain with promoted IECs proliferation, but also discovered a new signal pathway that regulates MYC gene expression.
Microbes: A Hidden Treasure of Polyunsaturated Fatty Acids
Authors: Shah Aabid Manzoor , Yang Wu , Mohamed Hassan , Zhang Yingtong , Song Yuanda
Published: March 2022

Microbes have gained a lot of attention for their potential in producing polyunsaturated fatty acids (PUFAs). PUFAs are gaining scientific interest due to their important health-promoting effects on higher organisms including humans. The current sources of PUFAs (animal and plant) have associated limitations that have led to increased interest in microbial PUFAs as most reliable alternative source. The focus is on increasing the product value of existing oleaginous microbes or discovering new microbes by implementing new biotechnological strategies in order to compete with other sources. The multidisciplinary approaches, including metabolic engineering, high-throughput screening, tapping new microbial sources, genome-mining as well as co-culturing and elicitation for the production of PUFAs, have been considered and discussed in this review. The usage of agro-industrial wastes as alternative low-cost substrates in fermentation for high-value single-cell oil production has also been discussed. Multidisciplinary approaches combined with new technologies may help to uncover new microbial PUFA sources that may have nutraceutical and biotechnological importance.
Combined Application of Malic Acid and Lycopene Maintains Content of Phenols, Antioxidant Activity, and Membrane Integrity to Delay the Pericarp Browning of Litchi Fruit During Storage
Authors: Huang Hua , Wang Ling , Bi Fangcheng , Xiang Xu
Published: March 2022

Litchi fruit contains abundant polyphenols and is susceptible to browning after harvest. Herein the combined treatments of malic acid (MA) and lycopene (LYC) to delay the development of browning in litchi fruit stored at room temperature (25°C) and low temperature (4°C) was investigated. The results showed that the pericarp browning could be alleviated, and the increase of malondialdehyde (MDA) content and relative leakage rate was retarded by the combined MA and LYC during storage. As compared to control, the content of pericarp anthocyanins, flavonoids, and the total phenols maintained higher levels; and the decrease of antioxidant activity of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging capacity and reducing power were slowed down in treated fruit. The enzyme activity of polyphenol oxidase (PPO) and peroxidase (POD) related to oxidation of polyphenols were depressed by the combined treatments. Furthermore, correlation analysis revealed that the content of phenols in the pericarp negatively affected the changes in the browning index, and was positively related to the DPPH radical scavenging capacity. Taken together, the combined treatments of MA and LYC exhibited potential effects in delaying the pericarp browning of litchi fruit by maintaining the content of polyphenols, antioxidant activity, and membrane integrity.
Higher Coffee Consumption Is Associated With Reduced Cerebral Gray Matter Volume: A Mendelian Randomization Study
Authors: Zheng Bing-Kun , Niu Peng-Peng
Published: March 2022

Background

Recently published two-sample Mendelian randomization (MR) studies showed that genetically predicted coffee consumption may be associated with increased risk of Alzheimer’s disease and intracerebral hemorrhage but associated with a decreased risk of small vessel ischemic stroke. We aimed to investigate the effects of genetically predicted coffee consumption on magnetic resonance imaging (MRI) markers of cerebral small vessel disease and brain volume using the two-sample MR method.

Methods

Twelve single nucleotide polymorphisms (SNPs) in up to 375,833 individuals were used as genetic instruments for cups consumed per day of coffee. Another four SNPs from an independent sample were used to perform the replication analysis. Three SNPs in up to 45,821 individuals were used as genetic instruments for high coffee consumption vs. low/no coffee consumption.

Results

Mendelian randomization analysis showed that coffee consumption (cups/day) was inversely associated with gray matter volume (beta = −0.371, 95% CI = −0.596 to −0.147, p = 0.001). Replication analysis and multivariable analyses after adjusting for other risk factors confirmed the effect. High coffee consumption was also suggestively associated with decreased gray matter volume (beta = −0.061, 95% CI = −0.109 to −0.013, p = 0.013) compared with low/no coffee consumption. All analyses did not find an effect of coffee consumption on other outcomes including white matter hyperintensity volume, mean diffusivity, fractional anisotropy, brain microbleed, total brain volume, white matter volume, and hippocampus volume.

Conclusion

This two-sample MR study showed that genetically predicted higher coffee consumption is causally associated with reduced gray matter volume of the brain.
Modulation of ERCC1-XPF Heterodimerization Inhibition via Structural Modification of Small Molecule Inhibitor Side-Chains
Authors: Weilbeer Claudia , Jay David , Donnelly James C. , Gentile Francesco , Karimi-Busheri Feridoun , Yang Xiaoyan , Mani Rajam S. , Yu Yaping , Elmenoufy Ahmed H. , Barakat Khaled H. , Tuszynski Jack A. , Weinfeld Michael , West Frederick G.
Published: March 2022

Inhibition of DNA repair enzymes is an attractive target for increasing the efficacy of DNA damaging chemotherapies. The ERCC1-XPF heterodimer is a key endonuclease in numerous single and double strand break repair processes, and inhibition of the heterodimerization has previously been shown to sensitize cancer cells to DNA damage. In this work, the previously reported ERCC1-XPF inhibitor 4 was used as the starting point for an in silico study of further modifications of the piperazine side-chain. A selection of the best scoring hits from the in silico screen were synthesized using a late stage functionalization strategy which should allow for further iterations of this class of inhibitors to be readily synthesized. Of the synthesized compounds, compound 6 performed the best in the in vitro fluorescence based endonuclease assay. The success of compound 6 in inhibiting ERCC1-XPF endonuclease activity in vitro translated well to cell-based assays investigating the inhibition of nucleotide excision repair and disruption of heterodimerization. Subsequently compound 6 was shown to sensitize HCT-116 cancer cells to treatment with UVC, cyclophosphamide, and ionizing radiation. This work serves as an important step towards the synergistic use of DNA repair inhibitors with chemotherapeutic drugs.
Physicians’ Perceptions of Clinical Utility of a Digital Health Tool for Electronic Patient-Reported Outcome Monitoring in Real-Life Hematology Practice. Evidence From the GIMEMA-ALLIANCE Platform
Authors: Efficace Fabio , Patriarca Andrea , Luppi Mario , Potenza Leonardo , Caocci Giovanni , Tafuri Agostino , Fazio Francesca , Cartoni Claudio , Petrucci Maria Teresa , Carmosino Ida , Moia Riccardo , Margiotta Casaluci Gloria , Boggione Paola , Colaci Elisabetta , Giusti Davide , Pioli Valeria , Sparano Francesco , Cottone Francesco , De Fabritiis Paolo , Ardu Nicolina Rita , Niscola Pasquale , Capodanno Isabella , Leporace Anna Paola , Pelliccia Sabrina , Lugli Elisabetta , La Sala Edoardo , Rigacci Luigi , Santopietro Michelina , Fozza Claudio , Siragusa Sergio , Breccia Massimo , Fazi Paola , Vignetti Marco
Published: March 2022

Digital health tools are increasingly being used in cancer care and may include electronic patient-reported outcome (ePRO) monitoring systems. We examined physicians’ perceptions of usability and clinical utility of a digital health tool (GIMEMA-ALLIANCE platform) for ePRO monitoring in the real-life practice of patients with hematologic malignancies. This tool allows for the collection and assessment of ePROs with real-time graphical presentation of results to medical staff. Based on a predefined algorithm, automated alerts are sent to medical staff. Participating hematologists completed an online survey on their experience with the platform. Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) agreed to enter the platform and had a median age of 57 years. Twenty-three hematologists with a median age of 42 years and an average of 17 years of experience in clinical practice were surveyed. All hematologists agreed or strongly agreed that the platform was easy to use, and 87%, agreed or strongly agreed that ePROs data were useful to enhance communication with their patients. The majority of physicians (78%) accessed the platform at least once per month to consult the symptom and health status profile of their patients. The frequency of access was independent of physician sex (p=0.393) and years of experience in clinical practice (p=0.404). In conclusion, our preliminary results support the clinical utility, from the perspective of the treating hematologist, of integrating ePROs into the routine cancer care of patients with hematologic malignancies.
Senecavirus A as an Oncolytic Virus: Prospects, Challenges and Development Directions
Authors: Luo Dankun , Wang Haiwei , Wang Qiang , Liang Wenping , Liu Bo , Xue Dongbo , Yang Yang , Ma Biao
Published: March 2022

Oncolytic viruses have the capacity to selectively kill infected tumor cells and trigger protective immunity. As such, oncolytic virotherapy has become a promising immunotherapy strategy against cancer. A variety of viruses from different families have been proven to have oncolytic potential. Senecavirus A (SVA) was the first picornavirus to be tested in humans for its oncolytic potential and was shown to penetrate solid tumors through the vascular system. SVA displays several properties that make it a suitable model, such as its inability to integrate into human genome DNA and the absence of any viral-encoded oncogenes. In addition, genetic engineering of SVA based on the manipulation of infectious clones facilitates the development of recombinant viruses with improved therapeutic indexes to satisfy the criteria of safety and efficacy regulations. This review summarizes the current knowledge and strategies of genetic engineering for SVA, and addresses the current challenges and future directions of SVA as an oncolytic agent.
Clinical Outcomes of MRI-Guided Adaptive Brachytherapy for Each Fraction in Locally Advanced Cervical Cancer: A Single Institution Experience
Authors: Chi Yunbo , Pan Ying , Zhang Ning , Han Dongmei , Guo Xin , Mao Zhuang , Cheng Guanghui
Published: March 2022

Purpose

This study aims to evaluate clinical outcomes of MRI-guided adaptive brachytherapy (MR-IGABT) for each brachytherapy fraction in patients with locally advanced cervical cancer (LACC).

Methods and Materials

A retrospective analysis was performed on 97 consecutive patients with LACC treated with 44.0–50.4 Gy external beam radiotherapy (EBRT) ± concurrent platinum-containing chemotherapy followed by 4 × 7 Gy MR-IGABT between September 2014 and April 2019. Intracavitary (IC)/interstitial (IS)/hybrid intracavitary and interstitial (IC/IS) brachytherapy was used in MR-IGABT. Brachytherapy planning and dose reporting followed the GEC-ESTRO recommendations. Clinical outcomes including overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), local control (LC), and treatment-related toxicity evaluated by the RTOG criteria were analyzed. Kaplan–Meier and univariable and multivariable Cox regression analyses were used to analyze the prognostic factor.

Results

Median follow-up was 21.1 months. Median dose to 90% (D90) of the high-risk clinical target volume (HR-CTV) was 91.7 Gy (range 76.7~107.2 Gy). Two-year OS, CSS, PFS, and LC were 83.5%, 84.1%, 71.1%, and 94.8%, respectively. Four patients (4.1%) suffered from grade 3 late gastrointestinal radiation toxicity, and no other grade 3 or greater radiation toxicity occurred. Initial HR-CTV was an independent factor of OS (p = 0.001, HR = 1.018/cm3), PFS (p = 0.012, HR = 1.012/cm3), and LC (p = 0.011, HR = 1.028/cm3). The HR-CTV D90 (p = 0.044, HR = 0.923/Gy) was an independent factor of PFS. Age was an independent factor of LC (p = 0.010, HR = 1.111/year).

Conclusion

For patients with LACC, MR-IGABT was effective and safe. It showed favorable LC, OS, and minimal toxicity. Moreover, initial HR-CTV, HR-CTV D90, and age were significant prognostic factors.
Long-Term Outcomes of an International Cooperative Study of Intraoperative Radiotherapy Upfront Boost With Low Energy X-Rays in Breast Cancer
Authors: Sarria Gustavo R. , Ramos Maria L. , Palacios Amalia , Del Castillo Ruben , Castro Felipe , Calvo Angel , Cotrina Jose M. , Heredia Adela , Galarreta Jose A. , Fuentes-Rivera Paola , Avalos Alicia , Martinez David A. , Colqui Kevin , Ziegler Gonzalo , Schmeel Leonard Christopher , Pinillos Luis V. , Wenz Frederik , Giordano Frank A. , Sarria Gustavo J. , Sperk Elena
Published: March 2022

Purpose

The purpose of this study was to assess the effectivity of upfront kilovoltage intraoperative radiotherapy (IORT) as a boost in high-risk early-stage breast cancer patients from an international pooled cohort.

Materials/Methods

Patients from four centers in three different countries were retrospectively screened. Those with a minimum 1-year follow-up were included. Cumulative local (LR), regional (RR), and distant metastasis rates (DM) were analyzed. Additionally, the estimated overall survival (OS) was assessed. The Cox regression analysis was performed to identify failure predicting factors.

Results

A total of 653 patients from centers in Peru, Spain, and Germany were included. The median follow-up was 55 (12–180) months, and age was 58 (27–86) years. Clinical tumor (T) staging was T1 65.85%, T2 30.17%, and T3 3.98%. Positive margins were found in 7.9% and in-situ component in 20.06%. The median IORT dose was 20 (6–20). The median time from IORT to EBRT was 74.5 (13-364) days. An overall 3.4% (n = 22) of patients developed local recurrence at some point during follow-up. The 12-, 60-, and 120-month cumulative LR were 0.3%, 2.3%, and 7.9%, respectively. After multivariate analysis, only age <50 remained to be a significant prognostic factor for local recurrence (HR 0.19, 95% CI 0.08–0.47; p < 0.05). The 10-year estimated OS was 81.2%.

Conclusion

Upfront boost with IORT yields similar local control outcomes to those EBRT-based reports. Results from prospective trials, regarding toxicity, cosmesis, and effectivity are awaited to confirm these findings.
Application of Organoids in Carcinogenesis Modeling and Tumor Vaccination
Authors: Wang Zeyu , Zhao Shasha , Lin Xiaolin , Chen Guanglong , Kang Jiawei , Ma Zhongping , Wang Yiming , Li Zhi , Xiao Xiuying , He Aina , Xiang Dongxi
Published: March 2022

Organoids well recapitulate organ-specific functions from their tissue of origin and remain fundamental aspects of organogenesis. Organoids are widely applied in biomedical research, drug discovery, and regenerative medicine. There are various cultivated organoid systems induced by adult stem cells and pluripotent stem cells, or directly derived from primary tissues. Researchers have drawn inspiration by combination of organoid technology and tissue engineering to produce organoids with more physiological relevance and suitable for translational medicine. This review describes the value of applying organoids for tumorigenesis modeling and tumor vaccination. We summarize the application of organoids in tumor precision medicine. Extant challenges that need to be conquered to make this technology be more feasible and precise are discussed.
Development and Validation of Novel Nomograms to Predict the Overall Survival and Cancer-Specific Survival of Cervical Cancer Patients With Lymph Node Metastasis
Authors: Yi Jianying , Liu Zhili , Wang Lu , Zhang Xingxin , Pi Lili , Zhou Chunlei , Mu Hong
Published: March 2022

Objective

The objective of this study was to establish and validate novel individualized nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) in cervical cancer patients with lymph node metastasis.

Methods

A total of 2,956 cervical cancer patients diagnosed with lymph node metastasis (American Joint Committee on Cancer, AJCC N stage=N1) between 2000 and 2018 were included in this study. Univariate and multivariate Cox regression models were applied to identify independent prognostic predictors, and the nomograms were established to predict the OS and CSS. The concordance index (C-index), calibration curves, and receiver operating characteristic (ROC) curves were applied to estimate the precision and discriminability of the nomograms. Decision-curve analysis (DCA) was used to assess the clinical utility of the nomograms.

Results

Tumor size, log odds of positive lymph nodes (LODDS), radiotherapy, surgery, T stage, histology, and grade resulted as significant independent predictors both for OS and CSS. The C-index value of the prognostic nomogram for predicting OS was 0.788 (95% CI, 0.762–0.814) and 0.777 (95% CI, 0.758–0.796) in the training and validation cohorts, respectively. Meanwhile, the C-index value of the prognostic nomogram for predicting CSS was 0.792 (95% CI, 0.767–0.817) and 0.781 (95% CI, 0.764–0.798) in the training and validation cohorts, respectively. The calibration curves for the nomograms revealed gratifying consistency between predictions and actual observations for both 3- and 5-year OS and CSS. The 3- and 5-year area under the curves (AUCs) for the nomogram of OS and CSS ranged from 0.781 to 0.828. Finally, the DCA curves emerged as robust positive net benefits across a wide scale of threshold probabilities.

Conclusion

We have successfully constructed nomograms that could predict 3- and 5-year OS and CSS of cervical cancer patients with lymph node metastasis and may assist clinicians in decision-making and personalized treatment planning.
Bioenergetic and Metabolic Adaptation in Tumor Progression and Metastasis
Authors: Herst Patries M. , Carson Georgia M. , Eccles David A. , Berridge Michael V.
Published: March 2022

The ability of cancer cells to adjust their metabolism in response to environmental changes is a well-recognized hallmark of cancer. Diverse cancer and non-cancer cells within tumors compete for metabolic resources. Metabolic demands change frequently during tumor initiation, progression and metastasis, challenging our quest to better understand tumor biology and develop novel therapeutics. Vascularization, physical constraints, immune responses and genetic instability promote tumor evolution resulting in immune evasion, opportunities to breach basement membrane barriers and spread through the circulation and lymphatics. In addition, the unfolded protein response linked to the ubiquitin proteasome system is a key player in addressing stoichiometric imbalances between nuclear and mitochondrially-encoded protein subunits of respiratory complexes, and nuclear-encoded mitochondrial ribosomal protein subunits. While progressive genetic changes, some of which affect metabolic adaptability, contribute to tumorigenesis and metastasis through clonal expansion, epigenetic changes are also important and more dynamic in nature. Understanding the role of stromal and immune cells in the tumor microenvironment in remodeling cancer cell energy metabolism has become an increasingly important area of research. In this perspective, we discuss the adaptations made by cancer cells to balance mitochondrial and glycolytic energy metabolism. We discuss how hypoxia and nutrient limitations affect reductive and oxidative stress through changes in mitochondrial electron transport activity. We propose that integrated responses to cellular stress in cancer cells are central to metabolic flexibility in general and bioenergetic adaptability in particular and are paramount in tumor progression and metastasis.
Sevoflurane Induces Ferroptosis of Glioma Cells Through Activating the ATF4-CHAC1 Pathway
Authors: Xu Yingyi , Zhang Na , Chen Cheng , Xu Xinke , Luo Ailing , Yan Yaping , Lu Yanhua , Liu Jianhua , Ou Xinxu , Tan Yonghong , Liang Yufeng , Chen Lihe , Song Xingrong , Liu Xiaoping
Published: March 2022

Objective

To clarify the function and mechanisms of sevoflurane (Sev) on ferroptosis in glioma cells.

Methods

Different concentrations of Sev were used to treat glioma cells U87 and U251. Ferroptosis inducer Erastin was used to incubate glioma cells combined with Sev and ATF4 siRNA transfection treatment. CCK-8 assay and colorimetric assay were performed to analyze cell viability and Fe+ concentration, respectively. The releases of reactive oxygen species (ROS) were determined by flow cytometry analysis. Transcriptional sequencing was used to screen the differential genes affected by Sev in U251 cells. The mRNA and protein expression of ferroptosis-associated genes was detected by qRT-PCR and Western blotting.

Results

Sev could suppress cell viability, increase ROS levels and Fe+ concentration, downregulate the protein expression levels of GPX4, and upregulate transferrin, ferritin, and Beclin-1 in a dose-dependent manner in U87 and U251 cells. The expression of ferroptosis and mitophagy-related gene activating transcription factor 4 (ATF4) was identified to be enhanced by Sev analyzed by transcriptional sequencing. ChaC glutathione-specific gamma-glutamylcyclotransferase 1 (CHAC1), which is involved in ferroptosis, is a downstream gene of ATF4. Inhibition of ATF4 could interrupt the expression of CHAC1 induced by Sev in U87 and U251 cells. Ferroptosis inducer Erastin treatment obviously inhibited the cell viability, elevated the Fe2+ concentration, and promoted ROS generation in U87 and U251 cells. The protein level of ATF4 and CHAC1 was increased in Erastin-treated U87 and U251 cells. Moreover, the interruption of Sev-induced ferroptosis and CHAC1 activating induced by ATF4 suppression could be reversed by Erastin.

Conclusions

In summary, this study suggested that Sev exposure-induced ferroptosis by the ATF4-CHAC1 pathway in glioma cells.
NTRK Fusion in Non-Small Cell Lung Cancer: Diagnosis, Therapy, and TRK Inhibitor Resistance
Authors: Liu Fangfang , Wei Yuxuan , Zhang Huan , Jiang Jizong , Zhang Peng , Chu Qian
Published: March 2022

Neurotrophic tropomyosin receptor kinase (NTRK) gene fusion has been identified as an oncogenic driver of various solid tumors, and it is rare in non-smalll cell lung cancer (NSCLC) with a frequency of approximately less than 1%. Next-generation sequencing (NGS) is of priority for detecting NTRK fusions, especially RNA-based NGS. Currently, the tropomyosin receptor kinase (TRK) inhibitors have shown promising efficacy and well tolerance in patients with NTRK fusion-positive solid tumors, regardless of tumor histology. The first-generation TRK inhibitors (larotrectinib and entrectinib) are recommended as the first-line treatment for locally advanced or metastatic NSCLC patients with positive NTRK fusion. However, TRK inhibitor resistance can eventually occur due to on-target or off-target mechanisms. Further studies are under investigation to overcome resistance and improve survival. Interestingly, NTRK fusion might be the mechanism of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in NSCLC patients with EGFR mutation. Regarding immunotherapy, the efficacy of immune checkpoint inhibitors in NSCLC patients harboring NTRK fusion has yet to be well described. In this review, we elucidate the function of NTRK genes, summarize the diagnostic techniques for NTRK fusions, and present clinical data for TRK inhibitors; we also discuss potential mechanisms of resistance to TRK inhibitors.
HGF/c-Met: A Key Promoter in Liver Regeneration
Authors: Zhao Yang , Ye Wenling , Wang Yan-Dong , Chen Wei-Dong
Published: March 2022

Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.
Number 2 Feibi Recipe Inhibits H2O2-Mediated Oxidative Stress Damage of Alveolar Epithelial Cells by Regulating the Balance of Mitophagy/Apoptosis
Authors: Gu Xiaofeng , Long Qi , Wei Wan , Tong Jiahuan , Li Zhipeng , Zhang Zhengju , Jiao Yang
Published: March 2022

Reactive oxygen species (ROS)-mediated alveolar epithelial cell (AEC) injury and apoptosis are considered to be the initiating link of idiopathic pulmonary fibrosis (IPF), and protecting AECs can alleviate IPF. This study aimed to explore the protective effect of number 2 Feibi recipe (FBR-2) medicated serum on H2O2-mediated oxidative stress injury in AECs and further explore its mechanism. We found that FBR-2 can regulate downstream antioxidant enzymes expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2), reducing the level of intracellular ROS, protecting mitochondrial function and improving cell survival. FBR-2 can also activate mitophagy through the PINK1/Parkin pathway. Moreover, FBR-2 can inhibit apoptosis by blocking the mitochondrial apoptosis mechanism. In summary, these data indicate that FBR-2 medicated serum can inhibit H2O2-mediated oxidative stress damage in AECs by regulating the balance of mitophagy/apoptosis. This study provides new evidence for the antifibrotic effect of FBR-2 and provides new drug candidates for the clinical treatment of IPF.
Analysis of Gene-Environment Interactions Related to Developmental Disorders
Authors: Nishimura Yuhei , Kurosawa Kenji
Published: March 2022

Various genetic and environmental factors are associated with developmental disorders (DDs). It has been suggested that interaction between genetic and environmental factors (G × E) is involved in the etiology of DDs. There are two major approaches to analyze the interaction: genome-wide and candidate gene-based approaches. In this mini-review, we demonstrate how these approaches can be applied to reveal the G × E related to DDs focusing on zebrafish and mouse models. We also discuss novel approaches to analyze the G × E associated with DDs.
Maternal Prepregnancy 5-Hydroxytryptamine Exposure Affects the Early Development of the Fetus
Authors: Han Yu , Zhang Meng , Duan Jiahui , Li Leyi , Du Jinge , Cheng Hui , Zhang Sheng , Zhai Yanhui , An Xinglan , Li Qi , Zhang Xueming , Li Ziyi , Tang Bo
Published: March 2022

In recent decades, the increasing incidence of depression has contributed to an increase in the use of serotonergic drugs, such as antidepressants, which predisposes humans to serotonin syndrome. Serotonin syndrome is caused by elevated serotonin levels in the central and peripheral nervous systems. It has been well documented that the development of offspring can be affected by maternal exposure to environmental challenges, such as stress, diseases, or an unhealthy diet during pregnancy. Serotonin, also called 5-hydroxytryptamine (5-HT), is widely expressed in the female reproductive system and plays an important role in the development of follicles and embryos. However, whether the suffering of the mother from serotonin syndrome before pregnancy affects fetal development is still uncertain. In the present study, to explore the effect of maternal prepregnancy 5-HT exposure on the fetus, intraperitoneal injection of 5-HT was used to change maternal prepregnancy 5-HT levels. It was found that maternal prepregnancy 5-HT exposure significantly reduced the body weight and liver weight and the levels of estrogen and progesterone in female mice. Although there was no significant difference in the cleavage rate and blastocyst rate between the 5-HT and control groups, maternal prepregnancy 5-HT exposure increased the percentage of embryo resorption, decreased placental weight, and led to placental inflammation at E13.5. Notably, 5-HT exposure caused weight loss in the offspring at 2 weeks. These results suggested that maternal prepregnancy 5-HT exposure could affect the development of the offspring, which was partly caused by reduced hormonal secretion and placental inflammation.
Effect of Six-Week Resistance and Sensorimotor Training on Trunk Strength and Stability in Elite Adolescent Athletes: A Randomized Controlled Pilot Trial
Authors: Mueller Steffen , Mueller Juliane , Stoll Josefine , Mayer Frank
Published: March 2022

Intervention in the form of core-specific stability exercises is evident to improve trunk stability. The purpose was to assess the effect of an additional 6 weeks sensorimotor or resistance training on maximum isokinetic trunk strength and response to sudden dynamic trunk loading (STL) in highly trained adolescent athletes. The study was conducted as a single-blind, 3-armed randomized controlled trial. Twenty-four adolescent athletes (14f/10 m, 16 ± 1 yrs.;178 ± 10 cm; 67 ± 11 kg; training sessions/week 15 ± 5; training h/week 22 ± 8) were randomized into resistance training (RT; n = 7), sensorimotor training (SMT; n = 10), and control group (CG; n = 7). Athletes were instructed to perform standardized, center-based training for 6 weeks, two times per week, with a duration of 1 h each session. SMT consisted of four different core-specific sensorimotor exercises using instable surfaces. RT consisted of four trunk strength exercises using strength training machines, as well as an isokinetic dynamometer. All participants in the CG received an unspecific heart frequency controlled, ergometer-based endurance training (50 min at max. heart frequency of 130HF). For each athlete, each training session was documented in an individual training diary (e.g., level of SMT exercise; 1RM for strength exercise, pain). At baseline (M1) and after 6 weeks of intervention (M2), participants’ maximum strength in trunk rotation (ROM:63°) and flexion/extension (ROM:55°) was tested on an isokinetic dynamometer (concentric/eccentric 30°/s). STL was assessed in eccentric (30°/s) mode with additional dynamometer-induced perturbation as a marker of core stability. Peak torque [Nm] was calculated as the main outcome. The primary outcome measurements (trunk rotation/extension peak torque: con, ecc, STL) were statistically analyzed by means of the two-factor repeated measures analysis of variance (α = 0.05). Out of 12 possible sessions, athletes participated between 8 and 9 sessions (SMT: 9 ± 3; RT: 8 ± 3; CG: 8 ± 4). Regarding main outcomes of trunk performance, experimental groups showed no significant pre–post difference for maximum trunk strength testing as well as for perturbation compensation (p > 0.05). It is concluded, that future interventions should exceed 6 weeks duration with at least 2 sessions per week to induce enhanced trunk strength or compensatory response to sudden, high-intensity trunk loading in already highly trained adolescent athletes, regardless of training regime.