bluuebunny/crossref_metadata_2025 huggingface dataset:
Preoperative Significance of Ipsilateral Manual Neck Compression in Patients With Pulsatile Tinnitus Secondary to Sigmoid Sinus Dehiscences and Diverticula
Authors: Lee Seung Jae , Lee Sang-Yeon , Choi Byung Yoon , Koo Ja-Won , Hong Sung Hwa , Song Jae-Jin
Published: March 2022

Venous pulsatile tinnitus (PT) is characterized by an auditory perception of pulse-synchronous sound, suppressed by compression of the ipsilateral internal jugular vein. We sought to determine the preoperative prognostic significance of the effect of ipsilateral neck manual compression on the PT loudness and audiometric changes in patients with sigmoid sinus dehiscences (SS-Deh) and diverticula (SS-Div) by comparing postoperative improvements in ipsilateral low-frequency hearing loss (LFHL) in pure-tone audiogram (PTA) and PT symptoms. Twenty-two subjects with PT originating from SS-Deh/Div were recruited. Air-conduction hearing thresholds were measured using PTA at three time points: twice preoperatively (with neutral neck position and with ipsilateral manual compression of internal jugular vein) and once at 3-months postoperatively with neutral neck position. We defined a positive neck compression effect as a threshold improvement of ≥ 10 dB HL at 250 or 500 Hz after manual neck compression. All but two subjects presented with ipsilateral LFHL in the neutral position. The average hearing threshold in the neutral position markedly improved after manual neck compression, indicating that LFHL originated from the masking effect of venous PT. All subjects had subjective improvements in PT and LFHL after sigmoid sinus surgeries, confirming that LFHL resulted from the masking effect of PT. Additionally, improvement of LFHL after neck compression could be regarded as a positive prognostic indicator after surgery. Collectively, elimination of PT loudness and improvement of LFHL with manual compression over the ipsilateral neck may suggest the venous origin of the PT and predict a favorable outcome following repair of SS-Deh/SS-Div.
The Differential Effects of Tai Chi vs. Brisk Walking on Cognitive Function Among Individuals Aged 60 and Greater
Authors: Yu Ye , Zuo Erfei , Doig Scott
Published: March 2022

Purpose

The aim of this study was to investigate the differential effects of Tai Chi vs. brisk walking on cognitive function among individuals aged 60 and greater.

Patients and Methods

For participant recruitment, a health talk was arranged at two communities in which two different exercise modalities (Tai Chi and brisk walking) were assigned to participants of each community free of charge. The intervention programs lasted 10 weeks, with three 60-min training sessions per week. General cognitive ability and specific cognitive outcomes were measured using the Chinese version of the Montreal Cognitive Assessment (MoCA).

Results

A significant interaction on total scores of the MoCA was observed (F = 11.15, p < 0.05). Post hoc analysis indicated significant improvements on general cognitive performance as measured in performance on the MoCA for both exercise groups at the end of 10 weeks. A significant interaction was only observed on the delayed recall sub-domain (F = 12.93, p < 0.001). Results from post hoc analysis indicate that the Tai Chi group had a significantly better memory performance relative to brisk walking group (p < 0.05). Specifically, significant improvement was observed in Tai Chi group (p < 0.05), but not in the brisk walking group. Both exercise groups demonstrated significant improvements from baseline to Week 10, which emerged in visualspatial ability (p < 0.05) and attention performance (p < 0.001). Lastly, animal naming and orientation significantly benefited from brisk walking (p < 0.05) and Tai Chi training (p < 0.05), respectively.

Conclusion

Tai Chi and brisk walking as the most commonly used, culture-specific mind-body exercise method have been proven to be effective in improving general cognitive performance and specific cognitive domains. Furthermore, differential effects of two different exercise modalities on cognitive domains were observed, which has provided insightful information for customized exercise programs. Finally, aging individuals who are experiencing cognitive decline should either take Tai Chi classes regularly or engage in brisk walking, which could contribute to brain health.
Using Automatic Speech Recognition to Optimize Hearing-Aid Time Constants
Authors: Fontan Lionel , Gonçalves Braz Libio , Pinquier Julien , Stone Michael A. , Füllgrabe Christian
Published: March 2022

Automatic speech recognition (ASR), when combined with hearing-aid (HA) and hearing-loss (HL) simulations, can predict aided speech-identification performances of persons with age-related hearing loss. ASR can thus be used to evaluate different HA configurations, such as combinations of insertion-gain functions and compression thresholds, in order to optimize HA fitting for a given person. The present study investigated whether, after fixing compression thresholds and insertion gains, a random-search algorithm could be used to optimize time constants (i.e., attack and release times) for 12 audiometric profiles. The insertion gains were either those recommended by the CAM2 prescription rule or those optimized using ASR, while compression thresholds were always optimized using ASR. For each audiometric profile, the random-search algorithm was used to vary time constants with the aim to maximize ASR performance. A HA simulator and a HL simulator simulator were used, respectively, to amplify and to degrade speech stimuli according to the input audiogram. The resulting speech signals were fed to an ASR system for recognition. For each audiogram, 1,000 iterations of the random-search algorithm were used to find the time-constant configuration yielding the highest ASR score. To assess the reproducibility of the results, the random search algorithm was run twice. Optimizing the time constants significantly improved the ASR scores when CAM2 insertion gains were used, but not when using ASR-based gains. Repeating the random search yielded similar ASR scores, but different time-constant configurations.
Ultrasound Used for Diagnostic Imaging Facilitates Dendritic Branching of Developing Neurons in the Mouse Cortex
Authors: Papp Tamas , Ferenczi Zsuzsanna , Szilagyi Bernadette , Petro Matyas , Varga Angelika , Kókai Eva , Berenyi Ervin , Olah Gabor , Halmos Gabor , Szucs Peter , Meszar Zoltan
Published: March 2022

Neuronal differentiation and synaptogenesis are regulated by precise orchestration of intrinsic and extrinsic chemical and mechanical factors throughout all developmental steps critical for the assembly of neurons into functional circuits. While ultrasound is known to alter neuronal migration and activity acutely, its chronic effect on neuronal behavior or morphology is not well characterized. Furthermore, higher-frequency (3–5 MHz) ultrasound (HFU) is extensively used in gynecological practice for imaging, and while it has not been shown harmful for the developing brain, it might be associated with mild alterations that may have functional consequences. To shed light on the neurobiological effects of HFU on the developing brain, we examined cortical pyramidal cell morphology in a transgenic mouse model, following a single and short dose of high-frequency ultrasound. Layer V neurons in the retrosplenial cortex of mouse embryos were labeled with green and red fluorescent proteins by in utero electroporation at the time of their appearance (E14.5). At the time of their presumptive arrival to layer V (E18.5), HFU stimulation was performed with parameters matched to those used in human prenatal examinations. On the third postnatal day (P3), basic morphometric analyses were performed on labeled neurons reconstructed with Neurolucida. Low-intensity HFU-treated cells showed significantly increased dendritic branching compared to control (non-stimulated) neurons and showed elevated c-fos immunoreactivity. Labeled neurons were immunopositive for the mechanosensitive receptor TRPC4 at E18.5, suggesting the role of this receptor and the associated signaling pathways in the effects of HFU stimulation.
Development and Testing of SPIDER-NET: An Interactive Tool for Brain Connectogram Visualization, Sub-Network Exploration and Graph Metrics Quantification
Authors: Coluzzi Davide , Pirastru Alice , Pelizzari Laura , Cabinio Monia , Laganà Maria Marcella , Baselli Giuseppe , Baglio Francesca
Published: March 2022

Brain connectomics consists in the modeling of human brain as networks, mathematically represented as numerical connectivity matrices. However, this representation may result in difficult interpretation of the data. To overcome this limitation, graphical representation by connectograms is currently used via open-source tools, which, however, lack user-friendly interfaces and options to explore specific sub-networks. In this context, we developed SPIDER-NET (Software Package Ideal for Deriving Enhanced Representations of brain NETworks), an easy-to-use, flexible, and interactive tool for connectograms generation and sub-network exploration. This study aims to present SPIDER-NET and to test its potential impact on pilot cases. As a working example, structural connectivity (SC) was investigated with SPIDER-NET in a group of 17 healthy controls (HCs) and in two subjects with stroke injury (Case 1 and Case 2, both with a focal lesion affecting part of the right frontal lobe, insular cortex and subcortical structures). 165 parcels were determined from individual structural magnetic resonance imaging data by using the Destrieux atlas, and defined as nodes. SC matrices were derived with Diffusion Tensor Imaging tractography. SC matrices of HCs were averaged to obtain a single group matrix. SC matrices were then used as input for SPIDER-NET. First, SPIDER-NET was used to derive the connectogram of the right hemisphere of Case 1 and Case 2. Then, a sub-network of interest (i.e., including gray matter regions affected by the stroke lesions) was interactively selected and the associated connectograms were derived for Case 1, Case 2 and HCs. Finally, graph-based metrics were derived for whole-brain SC matrices of Case 1, Case 2 and HCs. The software resulted effective in representing the expected (dis) connectivity pattern in the hemisphere affected by the stroke lesion in Cases 1 and 2. Furthermore, SPIDER-NET allowed to test ana priorihypothesis by interactively extracting a sub-network of interest: Case 1 showed a sub-network connectivity pattern different from Case 2, reflecting the different clinical severity. Global and local graph-based metrics derived with SPIDER-NET were different between cases with stroke injury and HCs. The tool proved to be accessible, intuitive, and interactive in brain connectivity investigation and provided both qualitative and quantitative evidence.
PEGASO e-Diary: User Engagement and Dietary Behavior Change of a Mobile Food Record for Adolescents
Authors: Caon Maurizio , Prinelli Federica , Angelini Leonardo , Carrino Stefano , Mugellini Elena , Orte Silvia , Serrano José C. E. , Atkinson Sarah , Martin Anne , Adorni Fulvio
Published: March 2022

Background

Obesity amongst children and adolescents is becoming a major health problem globally and mobile food records can play a crucial role in promoting healthy dietary habits.

Objective

To describe the methodology for the implementation of the e-Diary mobile food record, to assess its capability in promoting healthy eating habits, to evaluate the factors associated with its usage and engagement.

Methods

This is a descriptive study that compared the characteristics of participants engaged in the e-Diary, which was part of the PEGASO project in which an app to provide proactive health promotion was given to 365 students at 4 European sites enrolled during October to December 2016: England (UK), Scotland (UK), Lombardy (Italy), and Catalonia (Spain). The e-Diary tracked the users' dietary habits in terms of food groups, dietary indexes, and 6 dietary target behaviors relating to consumption of: fruit; vegetable; breakfast; sugar-sweetened beverages; fast-food; and snacks. The e-Diary provided also personalized suggestions for the next meal and gamification.

Results

The e-Diary was used for 6 months by 357 adolescents (53.8% females). The study showed that females used the e-Diary much more than males (aOR 3.8, 95% CI 1.6–8.8). Participants aged 14 years were more engaged in the e-Diary than older age groups (aOR 5.1, 95% CI 1.4–18.8) as were those with a very good/excellent self-perceived health status compared to their peers with fair/poor health perception (aOR 4.2, 95% CI 1.3–13.3). Compared to the intervention sites, those living in Catalonia (aOR 13.2 95% CI 2.5–68.8) were more engaged. In terms of behavior change, a significant positive correlation between fruit (p < 0.0001) and vegetables (p = 0.0087) intake was observed in association with increased engagement in the e-Diary. Similarly, adolescents who used the app for more than 2 weeks had significantly higher odds of not skipping breakfast over the study period (aOR 2.5, 95% CI 1.0–6.3).

Conclusions

The users highly engaged with the e-Diary were associated with improved dietary behaviors: increased consumption of fruit and vegetables and reduced skipping of breakfast. Although the overall usage of the e-Diary was high during the first weeks, it declined thereafter. Future applications should foster user engagement, particularly targeting adolescents at high risk.

Clinical Trial Registration

https://www.clinicaltrials.gov/, identifier: NCT02930148.
Development of a Risk Assessment Model for Early Grade ≥ 3 Infection During the First 3 Months in Patients Newly Diagnosed With Multiple Myeloma Based on a Multicenter, Real-World Analysis in China
Authors: Shang Yufeng , Wang Weida , Liang Yuxing , Kaweme Natasha Mupeta , Wang Qian , Liu Minghui , Chen Xiaoqin , Xia Zhongjun , Zhou Fuling
Published: March 2022

Purpose

The study aimed to assess factors associated with early infection and identify patients at high risk of developing infection in multiple myeloma.

Methods

The study retrospectively analyzed patients with MM seen at two medical centers between January 2013 and June 2019. One medical center reported 745 cases, of which 540 of the cases were available for analysis and were further subdivided into training cohort and internal validation cohort. 169 cases from the other medical center served as an external validation cohort. The least absolute shrinkage and selection operator (Lasso) regression model was used for data dimension reduction, feature selection, and model building.

Results

Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In the training cohort, PS≥2, HGB<35g/L of the lower limit of normal range, β2MG≥6.0mg/L, and GLB≥2.1 times the upper limit of normal range were identified as factors associated with early grade ≥ 3 infections by Lasso regression. An infection risk model of MM (IRMM) was established to define high-, moderate- and low-risk groups, which showed significantly different rates of infection in the training cohort (46.5% vs. 22.1% vs. 8.8%, p<0.0001), internal validation cohort (37.9% vs. 24.1% vs. 13.0%, p=0.009) and external validation cohort (40.0% vs. 29.2% vs. 8.5%, p=0.0003). IRMM displayed good calibration (p<0.05) and discrimination with AUC values of 0.76, 0.67 and 0.71 in the three cohorts, respectively. Furthermore, IRMM still showed good classification ability in immunomodulatory (IMiD) based regimens, proteasome-inhibitors (PI) based regimens and combined IMiD and PI regimens.

Conclusion

In this study, we determined risk factors for early grade ≥ 3 infection and established a predictive model to help clinicians identify MM patients with high-risk infection.
Efficacy and Safety of Low-Dose Nab-Paclitaxel Plus Tislelizumab in Elderly Patients With Previously Treated Metastatic Non-Small Cell Lung Cancer
Authors: Zhu Wenyu , Geng Qian , Peng Haoliang , Jin Zhihui , Li Dongqing , Pu Xiaolin , Wang Ge , Jiang Hua
Published: March 2022

The combination of immunotherapy and chemotherapy has a synergic effect in non-small cell lung cancer (NSCLC). However, the elderly are often excluded from clinical trails due to their poor health status and more comorbidities. We sought to assess the efficacy and safety of low-dose nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus tislelizumab (an anti-PD-1 antibody) in elderly patients with advanced NSCLC. In this phase 2 clinical trail, eligible patients were those aged ≥65 years with metastatic NSCLC who had disease progression after treatment with ≥1 line of chemotherapy or targeted therapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) variations were eligible if they demonstrated disease progression after treatment with ≥1 corresponding inhibitor. Primary endpoints were progression-free survival and safety/tolerability. Secondary endpoints included objective response rate and overall survival. Among 29 patients enrolled from May 2019 through August 2020, 21 (72.4%) had adenocarcinoma, 17 (58.6%) had a performance status of 2, 8 (27.6%) had asymptomatic brain metastases, and 13 (44.8%) had EGFR/ALK variations. As of the data cutoff point on April 1, 2021, median progression-free survival and overall survival were 9.5 months and 16.5 months, respectively. Ten patients achieved a partial response (objective response rate of 34.5%). Seventeen (58.6%) patients had ≥1 treatment-related adverse event, with grade 3 events seen in 3 patients (10.3%). The most common adverse events were fatigue (20.7%), fever (17.2%), abnormal liver function (17.2%), and rash (17.2%). These results suggest that low-dose nab-paclitaxel plus tislelizumab is well tolerated and effective in elderly patients with advanced NSCLC, including those with EGFR/ALK variations.
Development and Validation of a Novel Prognostic Model for Overall Survival in Newly Diagnosed Multiple Myeloma Integrating Tumor Burden and Comorbidities
Authors: Jia Shuangshuang , Bi Lei , Chu Yuping , Liu Xiao , Feng Juan , Xu Li , Zhang Tao , Gu Hongtao , Yang Lan , Bai Qingxian , Liang Rong , Tian Biao , Gao Yaya , Tang Hailong , Gao Guangxun
Published: March 2022

Background

Multiple myeloma (MM) is a highly heterogeneous disease with enormously variable outcomes. It remains to be a major challenge to conduct a more precise estimation of the survival of MM patients. The existing stratifications attached less importance to the prognostic significance of comorbidities. In the present study, we aimed to develop and validate a novel and simple prognostic stratification integrating tumor burden and comorbidities measured by HCT-CI.

Method

We retrospectively enrolled 385 consecutive newly diagnosed multiple myeloma (NDMM) patients in Xijing Hospital from January 2013 to December 2020. The cohort between January 2016 and December 2020 was selected as development cohort (N = 233), and the cohort between January 2013 and December 2015 was determined as validation cohort (N = 152). By using LASSO analysis and univariate and multivariable Cox regression analyses, we developed the MM-BHAP model in the way of nomogram composed of β2-MG, HCT-CI, ALB, and PBPC. We internally and externally validated the MM-BHAP model and compared it with ISS stage and R-ISS stage.

Results

The MM-BHAP model was superior to the ISS stage and partially better than the R-ISS stage according to time-dependent AUC, time-dependent C-index, DCA, IDI, and continuous NRI analyses. In predicting OS, only the MM-BHAP stratification clearly divided patients into three groups while both the ISS stage and R-ISS stage had poor classifications in patients with stage I and stage II. Moreover, the MM-BHAP stratification and the R-ISS stage performed well in predicting PFS, but not for the ISS stage. Besides, the MM-BHAP model was also applied to the patients with age ≤65 or age >65 and with or without HRCA and could enhance R-ISS or ISS classifications.

Conclusions

Our study offered a novel simple MM-BHAP stratification containing tumor burden and comorbidities to predict outcomes in the real-world unselected NDMM population.
A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer
Authors: Huang Sheng-Chieh , Lin Chun-Chi , Teng Hao-Wei , Lin Hung-Hsin , Chang Shih-Ching , Lan Yuan-Tzu , Wang Huann-Sheng , Yang Shung-Haur , Chen Wei-Shone , Jiang Jeng-Kai
Published: March 2022

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.
A Fucosylated Glycopeptide as a Candidate Biomarker for Early Diagnosis of NASH Hepatocellular Carcinoma Using a Stepped HCD Method and PRM Evaluation
Authors: Lin Yu , Zhang Jie , Arroyo Ana , Singal Amit G. , Parikh Neehar D. , Lubman David M.
Published: March 2022

Aberrant specific N-glycosylation, especially the increase in fucosylation on specific peptide sites of serum proteins have been investigated as potential markers for diagnosis of nonalcoholic steatohepatitis (NASH)-related HCC. We have combined a workflow involving broad scale marker discovery in serum followed by targeted marker evaluation of these fucosylated glycopeptides. This workflow involved an LC-Stepped HCD-DDA-MS/MS method coupled with offline peptide fractionation for large-scale identification of N-glycopeptides directly from pooled serum samples (each n=10) as well as differential determination of N-glycosylation changes between disease states. We then evaluated the fucosylation level of the glycoprotein ceruloplasmin among 62 patient samples (35 cirrhosis, 27 early-stage NASH HCC) by LC-Stepped HCD-PRM-MS/MS to quantitatively analyze 18 targeted glycopeptides. Of these targets, we found the ratio of fucosylation of a tri-antennary glycopeptide from site N762, involving N762_ HexNAc(5)Hex(6)Fuc(2)NeuAc(3) (P=0.0486), increased significantly from cirrhosis to early HCC. This fucosylation ratio of a tri-antennary glycopeptide in CERU could be a potential biomarker for further validation in a larger sample set and could be a promising candidate for early detection of NASH HCC.
XGboost Prediction Model Based on 3.0T Diffusion Kurtosis Imaging Improves the Diagnostic Accuracy of MRI BiRADS 4 Masses
Authors: Tang Wan , Zhou Han , Quan Tianhong , Chen Xiaoyan , Zhang Huanian , Lin Yan , Wu Renhua
Published: March 2022

Background

The malignant probability of MRI BiRADS 4 breast lesions ranges from 2% to 95%, leading to unnecessary biopsies. The purpose of this study was to construct an optimal XGboost prediction model through a combination of DKI independently or jointly with other MR imaging features and clinical characterization, which was expected to reduce false positive rate of MRI BiRADS 4 masses and improve the diagnosis efficiency of breast cancer.

Methods

120 patients with 158 breast lesions were enrolled. DKI, Diffusion-weighted Imaging (DWI), Proton Magnetic Resonance Spectroscopy (1H-MRS) and Dynamic Contrast-Enhanced MRI (DCE-MRI) were performed on a 3.0-T scanner. Wilcoxon signed-rank test and χ2 test were used to compare patient’s clinical characteristics, mean kurtosis (MK), mean diffusivity (MD), apparent diffusion coefficient (ADC), total choline (tCho) peak, extravascular extracellular volume fraction (Ve), flux rate constant (Kep) and volume transfer constant (Ktrans). ROC curve analysis was used to analyze the diagnostic performances of the imaging parameters. Spearman correlation analysis was performed to evaluate the associations of imaging parameters with prognostic factors and breast cancer molecular subtypes. The Least Absolute Shrinkage and Selectionator operator (lasso) and the area under the curve (AUC) of imaging parameters were used to select discriminative features for differentiating the breast benign lesions from malignant ones. Finally, an XGboost prediction model was constructed based on the discriminative features and its diagnostic efficiency was verified in BiRADS 4 masses.

Results

MK derived from DKI performed better for differentiating between malignant and benign lesions than ADC, MD, tCho, Kep and Ktrans (p < 0.05). Also, MK was shown to be more strongly correlated with histological grade, Ki-67 expression and lymph node status. MD, MK, age, shape and menstrual status were selected to be the optimized feature subsets to construct an XGboost model, which exhibited superior diagnostic ability for breast cancer characterization and an improved evaluation of suspicious breast tumors in MRI BiRADS 4.

Conclusions

DKI is promising for breast cancer diagnosis and prognostic factor assessment. An optimized XGboost model that included DKI, age, shape and menstrual status is effective in improving the diagnostic accuracy of BiRADS 4 masses.
Analgesic Effects of Repetitive Transcranial Magnetic Stimulation in Patients With Advanced Non-Small-Cell Lung Cancer: A Randomized, Sham-Controlled, Pilot Study
Authors: Tang Ying , Chen Han , Zhou Yi , Tan Ming-liang , Xiong Shuang-long , Li Yan , Ji Xiao-hui , Li Yong-sheng
Published: March 2022

Objective

Current pharmacological intervention for the cancer-related pain is still limited. The aim of this study was to explore whether repetitive transcranial magnetic stimulation (rTMS) could be an effective adjuvant therapy to reduce pain in patients with advanced non-small cell lung cancer (NSCLC).

Methods

This was a randomized, sham–controlled study. A total of 41 advanced NSCLC patients with uncontrolled pain (score≥4 on pain intensity assessed with an 11-point numeric rating scale) were randomized to receive active (10 Hz, 2000 stimuli) (n = 20) or sham rTMS (n = 20) for 3 weeks. Pain was the primary outcome and was assessed with the Numeric Rating Scale (NRS). Secondary outcomes were oral morphine equivalent (OME) daily dose, quality of life (WHO Quality of Life-BREF), and psychological distress (the Hospital Depression and Anxiety Scale). All outcomes were measured at baseline, 3 days, 1 week, 2 weeks, and 3 weeks.

Results

The pain intensity in both groups decreased gradually from day 3 and decreased to the lowest at the week 3, with a decrease rate of 41.09% in the rTMS group and 23.23% in the sham group. The NRS score of the rTMS group was significantly lower than that of the sham group on the week 2 (p < 0.001, Cohen’s d =1.135) and week 3 (p=0.017, Cohen’s d = -0.822). The OME daily dose, physiology and psychology domains of WHOQOL-BREF scores, as well as the HAM-A and HAM-D scores all were significantly improved at week 3 in rTMS group.

Conclusion

Advanced NSCL patients with cancer pain treated with rTMS showed better greater pain relief, lower dosage of opioid, and better mood states and quality of life. rTMS is expected to be a new effective adjuvant therapy for cancer pain in advanced NSCLC patients.
Fruquintinib Enhances the Antitumor Immune Responses of Anti-Programmed Death Receptor-1 in Colorectal Cancer
Authors: Li Qingli , Cheng Xiaojiao , Zhou Cong , Tang Yao , Li Fuli , Zhang Baiwen , Huang Tinglei , Wang Jianzheng , Tu Shuiping
Published: March 2022

Background

Programmed death receptor-1 (PD-1) blockade shows little benefit in patients with microsatellite-stable colorectal cancer (MSS-CRC). Fruquintinib is a China-made anti-angiogenic drug which is approved for the third line therapy in mCRC. This study investigates the effect of the combination of fruquintinib and PD-1 blockade on MSS-CRC and its relative mechanisms.

Methods

The mouse allograft tumor models that represent MSS and microsatellite instability (MSI) CRC were established using murine CT26 and MC38 colon cancer cells, respectively, to assess the treatment efficacy. The percentages of immune cells were detected in the peripheral blood, spleen and tumor tissues in the tumor-bearing mice by flow cytometry analysis. Angiogenesis in tumor tissues was detected by immunofluorescence. The safety of drug treatment was evaluated by histopathology analysis in murine main organs. The efficacy of the combination of fruquintinib and sintilimab were verified in the treatment of MSS-CRC patients.

Results

Our results showed that the combination of fruquintinib and sintilimab exhibited the strongest inhibition of tumor growth and achieved the longest survival time in mice bearing MC38 or CT26 xenograft tumors, compared to fruquintinib and sintilimab alone. Mechanistically, the combination of fruquintinib and sintilimab reduced angiogenesis, reprogramed the vascular structure, enhanced the infiltration of CD8+T cells (p<0.05), CD8+TNFα+ (p<0.05) T cells and CD8+IFNγ+ (p<0.05) T cells and reduced the ratios of MDSCs and macrophages in mice. There was no obvious toxicity observed in the main organs of the tumor-bearing mice with the combined treatment. Moreover, the treatment using the combination of fruquintinib and sintilimab achieved effective response in five patients with refractory advanced MSS CRC.

Conclusion

Our results show that the combination of fruquintinib and sintilimab greatly inhibits CRC growth by altering tumor immune microenvironment. This study provides the rational for using the combination of fruquintinib and anti-PD-1 antibody for the treatment of advanced CRC.
iTRAQ-Based Proteomic Analysis Reveals Potential Serum Biomarkers for Pediatric Non-Hodgkin’s Lymphoma
Authors: Yu Runhong , Cheng Linna , Yang Shiwei , Liu Yufeng , Zhu Zunmin
Published: March 2022

Non-Hodgkin’s lymphoma (NHL) is the third most common malignant tumor among children. However, at initial NHL diagnosis, most cases are at an advanced stage because of nonspecific clinical manifestations and currently limited diagnostic methods. This study aimed to screen and verify potential serum biomarkers of pediatric NHL using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis. Serum protein expression profiles from children with B-NHL (n=20) and T-NHL (n=20) and healthy controls (n=20) were detected by utilizing iTRAQ in combination with two-dimensional liquid chromatography-tandem mass spectrometry (2D LC–MS/MS) and analyzed by applying Ingenuity Pathway Analysis (IPA). The candidate biomarkers S100A8 and LRG1 were further validated by using enzyme-linked immunosorbent assays (ELISAs). Receiver operating characteristic (ROC) analysis based on ELISA data was used to evaluate diagnostic efficacy. In total, 534 proteins were identified twice using iTRAQ combined with 2D LC–MS/MS. Further analysis identified 79 and 73 differentially expressed proteins in B-NHL and T-NHL serum, respectively, compared with control serum according to our defined criteria; 34 proteins were overexpressed and 45 proteins underexpressed in B-NHL, whereas 45 proteins were overexpressed and 28 proteins underexpressed in T-NHL (p < 0.05). IPA demonstrated a variety of signaling pathways, including acute phase response signaling and liver X receptor/retinoid X receptor (LXR/RXR) activation, to be strongly associated with pediatric NHL. S100A8 and LRG1 were elevated in NHL patients compared to normal controls according to ELISA (p < 0.05), which was consistent with iTRAQ results. The areas under the ROC curves of S100A8, LRG1, and the combination of S100A8 and LRG1 were 0.873, 0.898 and 0.970, respectively. Our findings indicate that analysis of the serum proteome using iTRAQ combined with 2D LC–MS/MS is a feasible approach for biomarker discovery. Serum S100A8 and LRG1 are promising candidate biomarkers for pediatric NHL, and these differential proteins illustrate a novel pathogenesis and may be clinically helpful for NHL diagnosis in the future.
Antitumoral Effect of Plocabulin in High Grade Serous Ovarian Carcinoma Cell Line Models
Authors: Heredia-Soto Victoria , Escudero Javier , Miguel María , Ruiz Patricia , Gallego Alejandro , Berjón Alberto , Hernández Alicia , Martínez-Díez Marta , Zheng Shuyu , Tang Jing , Hardisson David , Feliu Jaime , Redondo Andrés , Mendiola Marta
Published: March 2022

Ovarian cancer (OC) is a life-threatening tumor and the deadliest among gynecological cancers in developed countries. First line treatment with a carboplatin/paclitaxel regime is initially effective in the majority of patients, but most advanced OC will recur and develop drug resistance. Therefore, the identification of alternative therapies is needed. In this study, we employed a panel of high-grade serous ovarian cancer (HGSOC) cell lines, in monolayer and three-dimensional cell cultures. We evaluated the effects of a novel tubulin-binding agent, plocabulin, on proliferation, cell cycle, migration and invasion. We have also tested combinations of plocabulin with several drugs currently used in OC in clinical practice. Our results show a potent antitumor activity of plocabulin, inhibiting proliferation, disrupting microtubule network, and decreasing their migration and invasion capabilities. We did not observe any synergistic combination of plocabulin with cisplatin, doxorubicin, gemcitabine or trabectedin. In conclusion, plocabulin has a potent antitumoral effect in HGSOC cell lines that warrants further clinical investigation.
Efficacy of Ketogenic Diet for Infantile Spasms in Chinese Patients With or Without Monogenic Etiology
Authors: Wang Jun , Zhang Jie , Yang Ying , Gao Kai , Wu Ye , Zhang Yuehua , Jiang Yuwu
Published: March 2022

Objective

The aim of this study was to evaluate the efficacy of the ketogenic diet (KD) for infantile spasms (IS) in patients with and without different causative genetic mutations.

Methods

We retrospectively evaluated the data of 119 infants with IS who underwent whole-exome sequencing (WES) before KD treatment. The KD efficacy was analyzed at the 16th week after initiation. Patients showing ≥ 50% seizure reduction from baseline and/or the disappeared hypsarrhythmia were considered as the responders. Chi-squared tests or two-sided Fisher's exact tests were performed for categorical data and Mann–Whitney U-tests for non-parametric and continuous data.

Results

The responder rate to KD in 119 patients was 47.90%. Six different causative monogenic mutations were identified in 32 (26.89%) patients with IS, including CDKL5 (n = 8), ALG13 (n = 3), KCNT1 (n = 8), SLC35A2 (n = 5), PCDH19 (n = 4), and STXBP1 (n = 4). Patients with CDKL5 mutations showed a significantly better response to KD (87.50%) than patients without CDKL5 mutations (p = 0.03). Seven of eight patients with CDKL5 mutations were responders, including five mutations located in functional motifs, and two mutations in the catalytic domain.

Conclusion

KD therapy was effective in infants with IS. Patients with CDKL5 mutations might have a better response to KD treatment.
External Evaluation of Risperidone Population Pharmacokinetic Models Using Opportunistic Pediatric Data
Authors: Karatza Eleni , Ganguly Samit , Hornik Chi D. , Muller William J. , Al-Uzri Amira , James Laura , Balevic Stephen J. , Gonzalez Daniel
Published: March 2022

Risperidone is approved to treat schizophrenia in adolescents and autistic disorder and bipolar mania in children and adolescents. It is also used off-label in younger children for various psychiatric disorders. Several population pharmacokinetic models of risperidone and 9-OH-risperidone have been published. The objectives of this study were to assess whether opportunistically collected pediatric data can be used to evaluate risperidone population pharmacokinetic models externally and to identify a robust model for precision dosing in children. A total of 103 concentrations of risperidone and 112 concentrations of 9-OH-risperidone, collected from 62 pediatric patients (0.16–16.8 years of age), were used in the present study. The predictive performance of five published population pharmacokinetic models (four joint parent-metabolite models and one parent only) was assessed for accuracy and precision of the predictions using statistical criteria, goodness of fit plots, prediction-corrected visual predictive checks (pcVPCs), and normalized prediction distribution errors (NPDEs). The tested models produced similarly precise predictions (Root Mean Square Error [RMSE]) ranging from 0.021 to 0.027 nmol/ml for risperidone and 0.053–0.065 nmol/ml for 9-OH-risperidone). However, one of the models (a one-compartment mixture model with clearance estimated for three subpopulations) developed with a rich dataset presented fewer biases (Mean Percent Error [MPE, %] of 1.0% vs. 101.4, 146.9, 260.4, and 292.4%) for risperidone. In contrast, a model developed with fewer data and a more similar population to the one used for the external evaluation presented fewer biases for 9-OH-risperidone (MPE: 17% vs. 69.9, 47.8, and 82.9%). None of the models evaluated seemed to be generalizable to the population used in this analysis. All the models had a modest predictive performance, potentially suggesting that sources of inter-individual variability were not entirely captured and that opportunistic data from a highly heterogeneous population are likely not the most appropriate data to evaluate risperidone models externally.
Targeting Chitinase 1 and Chitinase 3-Like 1 as Novel Therapeutic Strategy of Pulmonary Fibrosis
Authors: Lee Suh-Young , Lee Chang-Min , Ma Bing , Kamle Suchitra , Elias Jack A. , Zhou Yang , Lee Chun Geun
Published: March 2022

Chitinase 1 (CHIT1) and chitinase 3-like-1 (CHI3L1), two representative members of 18-Glycosyl hydrolases family, are significantly implicated in the pathogenesis of various human diseases characterized by inflammation and remodeling. Notably, dysregulated expression of CHIT1 and CHI3L1 was noted in the patients with pulmonary fibrosis and their levels were inversely correlated with clinical outcome of the patients. CHIT1 and CHI3L1, mainly expressed in alveolar macrophages, regulate profibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation, and TGF-β signaling and effector function. Although the mechanism or the pathways that CHIT1 and CHI3L1 use to regulate pulmonary fibrosis have not been fully understood yet, these studies identify CHIT1 and CHI3L1 as significant modulators of fibroproliferative responses leading to persistent and progressive pulmonary fibrosis. These studies suggest a possibility that CHIT1 and CHI3L1 could be reasonable therapeutic targets to intervene or reverse established pulmonary fibrosis. In this review, we will discuss specific roles and regulatory mechanisms of CHIT1 and CHI3L1 in profibrotic cell and tissue responses as novel therapeutic targets of pulmonary fibrosis.
Epigenetic Mechanism of 5-HT/NE/DA Triple Reuptake Inhibitor on Adult Depression Susceptibility in Early Stress Mice
Authors: Meng Ping , Li Chunmei , Duan Sijin , Ji Shengmin , Xu Yangyang , Mao Yutong , Wang Hongbo , Tian Jingwei
Published: March 2022

Major depressive disorder (MDD) is a chronic, remitting and debilitating disease and the etiology of MDD is highly complicated that involves genetic and environmental interactions. Despite many pharmacotherapeutic options, many patients remain poorly treated and the development of effective treatments remains a high priority in the field. LPM570065 is a potent 5-hydroxytryptamine (5-HT), norepinephrine (NE) and dopamine (DA) triple reuptake inhibitor and both preclinical and clinical results demonstrate significant efficacy against MDD. This study extends previous findings to examine the effects and underlying mechanisms of LPM570065 on stress vulnerability using a “two-hit” stress mouse model. The “two-hit” stress model used adult mice that had experienced early life maternal separation (MS) stress for social defeat stress (SDS) and then they were evaluated in three behavioral assays: sucrose preference test, tail suspension test and forced swimming test. For the mechanistic studies, methylation-specific differentially expressed genes in mouse hippocampal tissue and ventral tegmental area (VTA) were analyzed by whole-genome transcriptome analysis along with next-generation bisulfite sequencing analysis, followed by RT-PCR and pyrophosphate sequencing to confirm gene expression and methylation. LPM570065 significantly reversed depressive-like behaviors in the mice in the sucrose preference test, the tail suspension test, and the forced swimming test. Morphologically, LPM570065 increased the density of dendritic spines in hippocampal CA1 neurons. Hypermethylation and downregulation of oxytocin receptor (Oxtr) in the hippocampal tissues along with increased protein expression of Dnmt1 and Dnmt3a in mice that experienced the “two-hit” stress compared to those that only experienced adulthood social defeat stress, and LPM570065 could reverse these changes. Combined, these results suggest that methylation specificity of the gene Oxtr in the hippocampus may play an important role in early life stress-induced susceptibility to depression and that the5-HT/NE/DA triple reuptake inhibitor LPM570065 may reduce depression susceptibility via the reversal of the methylation of the gene Oxtr.
WaSP-ECG: A Wave Segmentation Pretraining Toolkit for Electrocardiogram Analysis
Authors: Brisk Rob , Bond Raymond R. , Finlay Dewar , McLaughlin James A. D. , Piadlo Alicja J. , McEneaney David J.
Published: March 2022

Introduction

Representation learning allows artificial intelligence (AI) models to learn useful features from large, unlabelled datasets. This can reduce the need for labelled data across a range of downstream tasks. It was hypothesised that wave segmentation would be a useful form of electrocardiogram (ECG) representation learning. In addition to reducing labelled data requirements, segmentation masks may provide a mechanism for explainable AI. This study details the development and evaluation of a Wave Segmentation Pretraining (WaSP) application.

Materials and Methods

Pretraining: A non-AI-based ECG signal and image simulator was developed to generate ECGs and wave segmentation masks. U-Net models were trained to segment waves from synthetic ECGs. Dataset: The raw sample files from the PTB-XL dataset were downloaded. Each ECG was also plotted into an image. Fine-tuning and evaluation: A hold-out approach was used with a 60:20:20 training/validation/test set split. The encoder portions of the U-Net models were fine-tuned to classify PTB-XL ECGs for two tasks: sinus rhythm (SR) vs atrial fibrillation (AF), and myocardial infarction (MI) vs normal ECGs. The fine-tuning was repeated without pretraining. Results were compared. Explainable AI: an example pipeline combining AI-derived segmentation masks and a rule-based AF detector was developed and evaluated.

Results

WaSP consistently improved model performance on downstream tasks for both ECG signals and images. The difference between non-pretrained models and models pretrained for wave segmentation was particularly marked for ECG image analysis. A selection of segmentation masks are shown. An AF detection algorithm comprising both AI and rule-based components performed less well than end-to-end AI models but its outputs are proposed to be highly explainable. An example output is shown.

Conclusion

WaSP using synthetic data and labels allows AI models to learn useful features for downstream ECG analysis with real-world data. Segmentation masks provide an intermediate output that may facilitate confidence calibration in the context of end-to-end AI. It is possible to combine AI-derived segmentation masks and rule-based diagnostic classifiers for explainable ECG analysis.
Anabolic-Androgenic Steroids and Exercise Training: Breaking the Myths and Dealing With Better Outcome in Sarcopenia
Authors: Falqueto Hugo , dos Santos Marcelo Rodrigues , Manfredi Leandro H.
Published: March 2022

Sarcopenia is an emerging clinical condition determined by the reduction in physical function and muscle mass, being a health concern since it impairs quality of life and survival. Exercise training is a well-known approach to improve physical capacities and body composition, hence managing sarcopenia progression and worsening. However, it may be an ineffective treatment for many elderly with exercise-intolerant conditions. Thus, the use of anabolic-androgenic steroids (AAS) may be a plausible strategy, since these drugs can increase physical function and muscle mass. The decision to initiate AAS treatment should be guided by an evidence-based patient-centric perspective, once the balance between risks and benefits may change depending on the clinical condition coexisting with sarcopenia. This mini-review points out a critical appraisal of evidence and limitation of exercise training and AAS to treat sarcopenia.
The Sphingolipid Inhibitors Ceranib-2 and SKI-II Reduce Measles Virus Replication in Primary Human Lymphocytes: Effects on mTORC1 Downstream Signaling
Authors: Chithelen Janice , Franke Hannah , Länder Nora , Grafen Anika , Schneider-Schaulies Jürgen
Published: March 2022

The bioactive sphingolipids ceramide and sphingosine-1-phosphate (S1P) are involved in the regulation of cell homeostasis and activity ranging from apoptosis to proliferation. We recently described that the two compounds ceranib-2 (inhibiting acid ceramidase) and SKI-II [inhibiting the sphingosine kinases 1 and − 2 (SphK1/2)] reduce mTORC1 activity and measles virus (MV) replication in human primary peripheral blood lymphocytes (PBL) by about one log step. We now further investigated whether mTORC1 downstream signaling and viral protein expression may be affected by ceranib-2 and/or SKI-II. Western blot analyses showed that in uninfected cells the phosphorylation of the eukaryotic initiation factor 4E (eIF4E) was reduced by both inhibitors. Interestingly, MV infection led to an increase of rpS6 protein levels and phosphorylation of eIF4E. Treatment with both inhibitors reduced the rpS6 protein expression, and in addition, SKI-II reduced rpS6 phosphorylation. The phosphorylation of eIF4E was slightly reduced by both inhibitors. In addition, SKI-II led to reduced levels of IKK in MV-infected cells. Both inhibitors reduced the expression of viral proteins and the titers of newly synthesized MV by approximately one log step. As expected, SKI-II and rapamycin reduced also the virally encoded GFP expression; however, ceranib-2 astonishingly led to increased levels of GFP fluorescence. Our findings suggest that the inhibitors ceranib-2 and SKI-II act via differential mechanisms on MV replication. The observed effects on mTORC1 downstream signaling, predominantly the reduction of rpS6 levels by both inhibitors, may affect the translational capacity of the cells and contribute to the antiviral effect in human primary PBL.