bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanistic Insight Into the Regulation of Immune-Related Genes Expression in Autism Spectrum Disorder
Authors: Sabaie Hani , Dehghani Hossein , Shiva Shadi , Asadi Mohammad Reza , Rezaei Omidvar , Taheri Mohammad , Rezazadeh Maryam
Published: October 2021

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder featuring impairment in verbal and non-verbal interactions, defects in social interactions, stereotypic behaviors as well as restricted interests. In recent times, the incidence of ASD is growing at a rapid pace. In spite of great endeavors devoted to explaining ASD pathophysiology, its precise etiology remains unresolved. ASD pathogenesis is related to different phenomena associated with the immune system; however, the mechanisms behind these immune phenomena as well as the potential contributing genes remain unclear. In the current work, we used a bioinformatics approach to describe the role of long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) in the peripheral blood (PB) samples to figure out the molecular regulatory procedures involved in ASD better. The Gene Expression Omnibus database was used to obtain the PB microarray dataset (GSE89594) from the subjects suffering from ASD and control subjects, containing the data related to both mRNAs and lncRNAs. The list of immune-related genes was obtained from the ImmPort database. In order to determine the immune-related differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs), the limma package of R software was used. A protein-protein interaction network was developed for the immune-related DEmRNAs. By employing the Human MicroRNA Disease Database, DIANA-LncBase, and DIANA-TarBase databases, the RNA interaction pairs were determined. We used the Pearson correlation coefficient to discover the positive correlations between DElncRNAs and DEmRNAs within the ceRNA network. Finally, the lncRNA-associated ceRNA network was created based on DElncRNA-miRNA-DEmRNA interactions and co-expression interactions. In addition, the KEGG enrichment analysis was conducted for immune-related DEmRNAs found within the constructed network. This work found four potential DElncRNA-miRNA-DEmRNA axes in ASD pathogenesis, including, LINC00472/hsa-miR-221-3p/PTPN11, ANP32A-IT1/hsa-miR-182-5p/S100A2, LINC00472/hsa-miR-132-3p/S100A2, and RBM26-AS1/hsa-miR-182-5p/S100A2. According to pathway enrichment analysis, the immune-related DEmRNAs were enriched in the “JAK-STAT signaling pathway” and “Adipocytokine signaling pathway.” An understanding of regulatory mechanisms of ASD-related immune genes would provide novel insights into the molecular mechanisms behind ASD pathogenesis.
Impact of Transcranial Direct Current Stimulation and Cognitive Training on Frontal Lobe Neurotransmitter Concentrations
Authors: Alvarez-Alvarado Stacey , Boutzoukas Emanuel M. , Kraft Jessica N. , O’Shea Andrew , Indahlastari Aprinda , Albizu Alejandro , Nissim Nicole R. , Evangelista Nicole D. , Cohen Ronald , Porges Eric C. , Woods Adam J.
Published: October 2021

Objective: This study examines the impact of transcranial direct current stimulation (tDCS) combined with cognitive training on neurotransmitter concentrations in the prefrontal cortex.

Materials and Methods: Twenty-three older adults were randomized to either active-tDCS or sham-tDCS in combination with cognitive training for 2 weeks. Active-tDCS was delivered over F3 (cathode) and F4 (anode) electrode placements for 20 min at 2 mA intensity. For each training session, 40-min of computerized cognitive training were applied with active or sham stimulation delivered during the first 20-min. Glutamine/glutamate (Glx) and gamma-aminobutyric acid (GABA) concentrations via proton magnetic resonance spectroscopy were evaluated at baseline and at the end of 2-week intervention.

Results: Glx concentrations increased from pre- to post-intervention (p = 0.010) in the active versus sham group after controlling for age, number of intervention days, MoCA scores, and baseline Glx concentration. No difference in GABA concentration was detected between active and sham groups (p = 0.650) after 2-week intervention.

Conclusion: Results provide preliminary evidence suggesting that combining cognitive training and tDCS over the prefrontal cortex elicits sustained increase in excitatory neurotransmitter concentrations. Findings support the combination of tDCS and cognitive training as a potential method for altering neurotransmitter concentrations in the frontal cortices, which may have implications for neuroplasticity in the aging brain.
PEERS — An Open Science “Platform for the Exchange of Experimental Research Standards” in Biomedicine
Authors: Sil Annesha , Bespalov Anton , Dalla Christina , Ferland-Beckham Chantelle , Herremans Arnoud , Karantzalos Konstantinos , Kas Martien J. , Kokras Nikolaos , Parnham Michael J. , Pavlidi Pavlina , Pristouris Kostis , Steckler Thomas , Riedel Gernot , Emmerich Christoph H.
Published: October 2021

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should have been considered a priori. To address this problem, we developed “PEERS” (Platform for the Exchange of Experimental Research Standards), an open-access online platform that is built to aid scientists in determining which experimental factors and variables are most likely to affect the outcome of a specific test, model or assay and therefore ought to be considered during the design, execution and reporting stages. The PEERS database is categorized into in vivo and in vitro experiments and provides lists of factors derived from scientific literature that have been deemed critical for experimentation. The platform is based on a structured and transparent system for rating the strength of evidence related to each identified factor and its relevance for a specific method/model. In this context, the rating procedure will not solely be limited to the PEERS working group but will also allow for a community-based grading of evidence. We here describe a working prototype using the Open Field paradigm in rodents and present the selection of factors specific to each experimental setup and the rating system. PEERS not only offers users the possibility to search for information to facilitate experimental rigor, but also draws on the engagement of the scientific community to actively expand the information contained within the platform. Collectively, by helping scientists search for specific factors relevant to their experiments, and to share experimental knowledge in a standardized manner, PEERS will serve as a collaborative exchange and analysis tool to enhance data validity and robustness as well as the reproducibility of preclinical research. PEERS offers a vetted, independent tool by which to judge the quality of information available on a certain test or model, identifies knowledge gaps and provides guidance on the key methodological considerations that should be prioritized to ensure that preclinical research is conducted to the highest standards and best practice.
Macrophages Are Dispensable for Postnatal Pruning of the Cochlear Ribbon Synapses
Authors: Yu Chaorong , Gao Hui-Ming , Wan Guoqiang
Published: October 2021

Ribbon synapses of cochlear hair cells undergo pruning and maturation before the hearing onset. In the central nervous system (CNS), synaptic pruning was mediated by microglia, the brain-resident macrophages, via activation of the complement system. Whether a similar mechanism regulates ribbon synapse pruning is currently unknown. In this study, we report that the densities of cochlear macrophages surrounding hair cells were highest at around P8, corresponding well to the completion of ribbon synaptic pruning by P8–P9. Surprisingly, using multiple genetic mouse models, we found that postnatal pruning of the ribbon synapses and auditory functions were unaffected by the knockout of the complement receptor 3 (CR3) or by ablations of macrophages expressing either LysM or Cx3cr1. Our results suggest that unlike microglia in the CNS, macrophages in the cochlea do not mediate pruning of the cochlear ribbon synapses.
Simulation and Mitigation of the Wrap-Around Artifact in the MRI Image
Authors: Hu Runze , Yang Rui , Liu Yutao , Li Xiu
Published: October 2021

Magnetic resonance imaging (MRI) is an essential clinical imaging modality for diagnosis and medical research, while various artifacts occur during the acquisition of MRI image, resulting in severe degradation of the perceptual quality and diagnostic efficacy. To tackle such challenges, this study deals with one of the most frequent artifact sources, namely the wrap-around artifact. In particular, given that the MRI data are limited and difficult to access, we first propose a method to simulate the wrap-around artifact on the artifact-free MRI image to increase the quantity of MRI data. Then, an image restoration technique, based on the deep neural networks, is proposed for wrap-around artifact reduction and overall perceptual quality improvement. This study presents a comprehensive analysis regarding both the occurrence of and reduction in the wrap-around artifact, with the aim of facilitating the detection and mitigation of MRI artifacts in clinical situations.
Association Between Cumulative Exposure to Increased Low-Density Lipoprotein Cholesterol and the New Occurrence of Peripheral Artery Disease
Authors: Liu Xinmin , Wang Yu , Wu Jianwei , Wang Anxin , Zhang Xiaoli , Cao Zhentang , Zhao Xingquan
Published: October 2021

Background and Purpose: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis with increased risk of severe cardiovascular and cerebrovascular events. The relationship between one-time measuring of low-density lipoprotein cholesterol (LDL-C) and PAD is inconsistent. Increasing evidence shows that the predictive value of non-high-density lipoprotein cholesterol (non-HDLC) on atherosclerosis disease is superior to LDL-C. We aimed to investigate the relationship between cumulative exposure to increased LDL-C and the risk of newly developed PAD and compare the predictive value of LDL-C with non-HDLC.

Materials and Methods: In the Asymptomatic Polyvascular Abnormalities Community study, we enrolled 2,923 participants with LDL-C and non-HDLC measured every 2 years from 2006 to 2012. Cumulative exposure to increased LDL-C and non-HDLC, defined as LDL-C burden and non-HDLC burden, respectively, was calculated as the weighted sum of the difference between the measured value and the cutoff value. A new occurrence of PAD was identified through ankle brachial index measured in 2010 and 2012. Multivariate models were adopted to analyze the association of LDL-C burden and non-HDLC burden with the newly developed PAD. The receiver operating curve was drawn, and the area under the curve was calculated to compare the predictive performance of LDL-C burden with a single measure of LDL-C in 2006 and non-HDL-C burden adjusted with a model including traditional risk factors.

Results: Of the 2,923 participants, 5.4% (158/2,923) were diagnosed as newly developed PAD. In the univariate analysis, the highest quartile of LDL-C burden was significantly associated with new occurrence of PAD [odds ratio (OR) 1.75, 95% confidence interval (CI) 1.13–2.73]. After adjustment for confounding factors, the same result was obtained (OR 1.59, 95%CI 1.01–2.49). The non-HDLC burden failed to show any statistical significance on the newly developed PAD (OR 1.31, 95% CI 0.84–2.04). Though LDL-C burden had a tendency to show better predictive performance than non-HDLC, it did not reach statistical significance (AUCLDL−C = 0.554 vs. AUCnon−HDLC = 0.544, P = 0.655).

Conclusions: Cumulative exposure to increased LDL-C is an independent risk factor of newly developed PAD. The predictive value of non-HDLC burden was not revealed.
Detraining Effect on Pulmonary and Cardiovascular Autonomic Function and Functional Outcomes in Patients With Parkinson's Disease After Respiratory Muscle Training: An 18-Month Follow-Up Study
Authors: Huang Chih-Cheng , Lai Yun-Ru , Wu Fu-An , Kuo Nai-Ying , Cheng Ben-Chung , Tsai Nai-Wen , Kung Chia-Te , Chiang Yi-Fang , Lu Cheng-Hsien
Published: October 2021

Background: The effect of 3-month respiratory muscle training (RMT) on pulmonary and autonomic function and functional outcomes has been demonstrated in patients with Parkinson's disease (PD); however, there is a paucity of information on the durability of the training effect. In this study, we monitored the pulmonary and cardiovascular autonomic function and clinical severity scales until 18 months after the cessation of RMT to elucidate the detraining effect after RMT.

Methods: All patients with PD receiving RMT were assessed with clinical severity scales as well as pulmonary and autonomic function tests at four different stages (baseline on enrollment, immediately after 3 months of RMT, and 6 and 18 months after cessation of RMT). A control group of PD patients who did not receive RMT was also recruited for comparison. Pulmonary function parameters, including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP), were assessed. Cardiovascular autonomic function was assessed using measures including heart rate response to deep breathing (HRDB), Valsalva ratio, and baroreflex sensitivity. Clinical severity scores were also measured using the Hoehn and Yahr staging and the Unified Parkinson's Disease Rating Scale (UPDRS).

Results: The results showed significant improvements in MIP, MEP, HRDB, and UPDRS immediately after RMT. Despite some decay, the improvements in pulmonary function (MIP and MEP) and functional outcomes (UPDRS) remained significant until 6 months of detraining (9 months after enrollment). However, the improvement in cardiovascular autonomic function (HRDB) was reversed after 6 months of detraining.

Conclusions: Based on these findings, we recommend that RMT may be repeated after at least 6 months after previous session (9 months after enrollment) for patients with PD to maintain optimal therapeutic effects.
Effect of Bilateral Subthalamic Nucleus Deep Brain Stimulation on Pisa Syndrome in Parkinson's Disease
Authors: He Jing , Cui Zhuang , Li Shuhua , Chen Haibo , Su Wen
Published: October 2021

Objective: To observe the efficacy of bilateral subthalamic nucleus deep brain stimulation on Pisa syndrome in patients with Parkinson's disease.

Methods: A total of 52 patients with Parkinson's disease who underwent deep brain stimulation in Beijing Hospital from July 1, 2016 to July 1, 2020 were reviewed. The clinical data were collected for the patients who met the diagnostic criteria of Pisa syndrome on “Medication-Off” state pre-operatively.

Results: Two patients met the diagnostic criteria of Pisa syndrome before operation, with a Pisa angle of 10 and 14°, respectively. The lateral trunk flexion of the two patients improved after operation. In stimulation-on/medication-off state, the Pisa angle decreased from 10 to 2° and from 14 to 6°, respectively.

Conclusion: Bilateral subthalamic nucleus deep brain stimulation might have beneficial effects on lateral trunk flexion in PD patients, but the predictors of curative effect are not clear.
A Retrospective Study on Statins and Post-stroke Patients: What About Functional Outcome and Follow-Up in a Stroke Rehabilitation Cohort?
Authors: Mele Chiara , Maggioni Giorgio , Giordano Andrea , Lunardon Clara , Balsamo Francesca , Mazzone Alessandra , Pistarini Caterina
Published: October 2021

Objective: Statins exert pleiotropic effects by influencing several mechanisms, including synaptogenesis, neurogenesis, cerebral flow regulation, and angiogenesis. Results from in vitro and animal models suggest that statins could have beneficial effect on functional recovery and outcome after stroke events. However, results in human studies are still controversial. The aim of our study was to evaluate the role of statin in influencing functional outcome and subsequent clinical follow-up in a large cohort of post-stroke rehabilitation patients.

Methods: This retrospective study consecutively enrolled 413 adult patients with stroke event, admitted to the division of Neurorehabilitation of the IRCCS ICS Maugeri, Veruno (Italy), for an individual rehabilitation program between 2015 and 2017. Follow-up lasted 3–5 years after discharge. Demographic data, etiology, classification, and anatomical site of stroke lesion, functional assessment, use and duration of statin therapy, and death during hospitalization were collected at baseline and on discharge. Clinical data on subsequent follow-up were also evaluated, considering these as variables: stroke recurrence, bone fractures, cardiovascular complications, and death.

Results: In our cohort, 177 patients (42.9%) were prescribed statin therapy, of whom 50 (28.2%) before the stroke event and 127 (71.8%) at the beginning of the rehabilitation process. The use and type of statin therapy as well as the duration of treatment were not associated with recovery and functional outcome, regardless of confounders including sex, age, etiology, and site of stroke lesion, and initial functional level. For what concern post-discharge clinical follow-up, the use of statin therapy was significantly associated with a lower risk of bone fractures (OR = 0.095, CI 95%: 0.012–0.743, p = 0.01) independently from age, sex, initial and final functional level, and comorbidities.

Conclusions: The use of statins does not seem to influence the functional outcome in post-stroke patients. However, they could exert a protective role against bone fractures during post-discharge follow-up, suggesting further evaluation on this topic.
Emerging Role of microRNAs in Stroke Protection Elicited by Remote Postconditioning
Authors: Pignataro Giuseppe
Published: October 2021

Remote ischemic conditioning (RIC) represents an innovative and attractive neuroprotective approach in brain ischemia. The purpose of this intervention is to activate endogenous tolerance mechanisms by inflicting a subliminal ischemia injury to the limbs, or to another “remote” region, leading to a protective systemic response against ischemic brain injury. Among the multiple candidates that have been proposed as putative mediators of the protective effect generated by the subthreshold peripheral ischemic insult, it has been hypothesized that microRNAs may play a vital role in the infarct-sparing effect of RIC. The effect of miRNAs can be exploited at different levels: (1) as transducers of protective messages to the brain or (2) as effectors of brain protection. The purpose of the present review is to summarize the most recent evidence supporting the involvement of microRNAs in brain protection elicited by remote conditioning, highlighting potential and pitfalls in their exploitation as diagnostic and therapeutic tools. The understanding of these processes could help provide light on the molecular pathways involved in brain protection for the future development of miRNA-based theranostic agents in stroke.
Effects of Piano Training in Unilateral Cerebral Palsy Using Probabilistic and Deterministic Tractography: A Case Report
Authors: Alves-Pinto Ana , Emch Mónica , Lampe Renée
Published: October 2021

Cerebral palsy (CP) is an umbrella term encompassing motor and often additional disabilities, resulting from insult to the developing brain and remaining throughout life. Imaging-detected alterations in white matter microstructure affect not only motor but also sensorimotor pathways. In this context, piano training is believed to promote sensorimotor rehabilitation for the multiplicity of skills and neuronal processes it involves and integrates. However, it remains unknown how this contribution may occur. Here, effects of 1.5 years of piano training in an adolescent with unilateral CP were investigated through tests of manual function and by comparing fractional anisotropy, mean diffusivity, radial and axial diffusivity in neuronal pathways pre- vs. post-training. In the absence of a control condition and of data from a larger cohort, both probabilistic neighborhood and deterministic tractography were employed to reduce bias associated with a single-case analysis and/or with user-input. No changes in manual function were detected with the tests performed. In turn, the two tractography methods yielded similar values for all studied metrics. Furthermore, post-hoc analyses yielded increased fractional anisotropy accompanied by decreases in mean diffusivity in the bilateral dorsal cingulate that were at least as large as and more consistent than in the bilateral corticospinal tract. This suggests contributions of training to the development of non-motor processes. Reduced anisotropy and correspondingly high mean diffusivity were observed for the bilateral corticospinal tract as well as for the right arcuate and the inferior longitudinal fasciculus, two sensory processing-related pathways, confirming the importance of sensorimotor rehabilitation in CP.
Alexithymia and Autistic Traits: Associations With Social and Emotional Challenges Among College Students
Authors: Vaiouli Potheini , Panayiotou Georgia
Published: October 2021

Background: Alexithymia is a multifaceted personality construct defined by marked difficulties in identifying and describing feelings and in externally oriented thinking. Given its intrinsic role in social-emotional processing, alexithymia is now recognized as a trans-diagnostic trait in a range of neurodevelopmental disorders, including autism. Research has pinpointed to the co-occurrence of autism with characteristics typical of alexithymic normative samples, such as social-communication difficulties and decreased emotion regulation abilities. Nonetheless, the role of individual facets of alexithymia in predicting challenges in social communication functioning is still understudied.

Methods: In total, 275 young adults completed the Toronto Alexithymia Scale, the Autism Spectrum Quotient (short form), the Interpersonal Competence Questionnaire, and the Difficulties in Emotion Regulation Scale self-reported questionnaires for assessing alexithymic and autistic traits, social-communication abilities, and emotion regulation difficulties. We used regression models to establish cross-sectional associations between autism, alexithymia, and social-emotional difficulties. Also, we ran a parallel mediation analysis to determine whether the relationship between autistic traits and emotion regulations challenges are mediated by Alexithymia facets.

Results: Analysis showed a significant positive association between autistic traits and alexithymic traits and between autistic traits and emotion regulation difficulties while, as expected, autistic traits were negatively correlated with social skills. A significant relationship was found among the participants’ levels of alexithymia and their interpersonal skills with two of three alexithymic subscales significantly contributing to the model. Similarly, a significant relationship was found among alexithymia subscales and emotion regulation difficulties with all three alexithymia subscales being statistically significant. Finally, analysis on two mediator models indicated a significant effect of autistic traits on social skills mediated by alexithymic traits as well as a significant indirect effect of autistic traits on emotion regulation difficulties mediated by alexithymic traits.

Conclusion: The results of this study provide evidence of the influence of different alexithymic facets on the relationship between autistic traits and social-emotional challenges in young adults. Longitudinal studies may explore further alexithymia and its associations with social-emotional difficulties in autism as well as the potential implications of these findings in intervention and treatment programs.
IE-IQA: Intelligibility Enriched Generalizable No-Reference Image Quality Assessment
Authors: Song Tianshu , Li Leida , Zhu Hancheng , Qian Jiansheng
Published: October 2021

Image quality assessment (IQA) for authentic distortions in the wild is challenging. Though current IQA metrics have achieved decent performance for synthetic distortions, they still cannot be satisfactorily applied to realistic distortions because of the generalization problem. Improving generalization ability is an urgent task to make IQA algorithms serviceable in real-world applications, while relevant research is still rare. Fundamentally, image quality is determined by both distortion degree and intelligibility. However, current IQA metrics mostly focus on the distortion aspect and do not fully investigate the intelligibility, which is crucial for achieving robust quality estimation. Motivated by this, this paper presents a new framework for building highly generalizable image quality model by integrating the intelligibility. We first analyze the relation between intelligibility and image quality. Then we propose a bilateral network to integrate the above two aspects of image quality. During the fusion process, feature selection strategy is further devised to avoid negative transfer. The framework not only catches the conventional distortion features but also integrates intelligibility features properly, based on which a highly generalizable no-reference image quality model is achieved. Extensive experiments are conducted based on five intelligibility tasks, and the results demonstrate that the proposed approach outperforms the state-of-the-art metrics, and the intelligibility task consistently improves metric performance and generalization ability.
Patterns of Unilateral and Bilateral Projections From Layers 5 and 6 of the Auditory Cortex to the Inferior Colliculus in Mouse
Authors: Vaithiyalingam Chandra Sekaran Nathiya , Deshpande Meena S. , Ibrahim Baher A. , Xiao Gang , Shinagawa Yoshitaka , Llano Daniel A.
Published: October 2021

The auditory cortex sends massive projections to the inferior colliculus, but the organization of this pathway is not yet well understood. Previous work has shown that the corticocollicular projection emanates from both layers 5 and 6 of the auditory cortex and that neurons in these layers have different morphological and physiological properties. It is not yet known in the mouse if both layer 5 and layer 6 project bilaterally, nor is it known if the projection patterns differ based on projection location. Using targeted injections of Fluorogold into either the lateral cortex or dorsal cortex of the inferior colliculus, we quantified retrogradely labeled neurons in both the left and right lemniscal regions of the auditory cortex, as delineated using parvalbumin immunostaining. After dorsal cortex injections, we observed that approximately 18–20% of labeled cells were in layer 6 and that this proportion was similar bilaterally. After lateral cortex injections, only ipsilateral cells were observed in the auditory cortex, and they were found in both layer 5 and layer 6. The ratio of layer 5:layer 6 cells after lateral cortex injection was similar to that seen after dorsal cortex injection. Finally, injections of different tracers were made into the two inferior colliculi, and an average of 15–17% of cells in the auditory cortex were double-labeled, and these proportions were similar in layers 5 and 6. These data suggest that (1) only the dorsal cortex of the inferior colliculus receives bilateral projections from the auditory cortex, (2) both the dorsal and lateral cortex of the inferior colliculus receive similar layer 5 and layer 6 auditory cortical input, and (3) a subpopulation of individual neurons in both layers 5 and 6 branch to innervate both dorsal cortices of the inferior colliculus.
Risk of Pneumonitis Associated With Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Network Meta-Analysis
Authors: Sun You-Meng , Li Wei , Chen Zhi-Yu , Wang Ying
Published: October 2021

Background

Immune checkpoint inhibitors (ICIs) have dramatically altered the treatment landscape for patients with melanoma. However, their use also generates unique immune-related adverse effects (irAEs). We performed a systematic review and network meta‐analysis to compare the risk of pneumonitis associated with ICIs for patients with advanced or metastatic melanoma.

Methods

Phase II/III randomized clinical trials (RCTs) with ICIs were identified through comprehensive searches of multiple databases. An NMA was conducted to compare the risk of pneumonitis associated with ICIs and all‐grade (grade 1‐5) and high‐grade (grade 3‐5) immune‐related pneumonitis (IRP) were estimated by odds ratios (ORs).

Results

A total of 10 randomized clinical trials involving 5,335 patients were enrolled in this study. Conventional chemotherapy was associated with a lower risk of grade 1–5 IRP compared with ICIs monotherapy (OR, 0.14, 95% CI, 0.03 to 0.73) and dual ICIs combination (OR, 0.03, 95% CI, 0.00 to 0.19). In addition, dual ICIs combination showed a noticeably higher risk than ICI monotherapy (OR, 4.45, 95% CI, 2.14 to 9.25) of grade 1–5 IRP. No significant difference in grade 1–5 IRP was observed between cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors. As to grade 3‐5 IRP, no statistically significant difference was found among different ICIs-based regimens.

Conclusion

These findings revealed that ICIs could increase the risk of all-grade pneumonitis for patients with advanced melanoma, compared with conventional chemotherapy. Dual ICIs combination could further increase the risk of all-grade pneumonitis than ICIs monotherapy. There was no significant difference in the risk of pneumonia between CTLA-4 and PD-1 inhibitors.
Long Noncoding RNA KLF3-AS1 Acts as an Endogenous RNA of miR-223 to Attenuate Gastric Cancer Progression and Chemoresistance
Authors: Jiang Houxiang , Hu KaiFeng , Xia Yabing , Liang Linhu , Zhu Xiaoli
Published: October 2021

Gastric cancer is a deadly disease, and the low rate of early diagnosis and chemoresistance largely contributed to the poor prognosis of gastric cancer. LncRNAs have been extensively reported for their roles in regulating cancer progression. In this study, we found that KLF3-AS1 was down-regulated in gastric cancer cells. Overexpression of KLF3-AS1 repressed gastric cancer cell proliferation, growth. In addition, KLF3-AS1 overexpression also exerted inhibitory effects on the gastric cancer cell invasion, migration and EMT, but promoted chemosensitivity of gastric cancer cells to cisplatin. The mechanistic studies showed that KLF3-AS1 could act as the “sponge” for miR-223 and to repress miR-223 expression in gastric cancer cells. Overexpression of miR-223 reversed the inhibitory effects of KLF3-AS1 overexpression on gastric cancer cell proliferation, invasion, migration and EMT, and attenuated the enhanced effects of KLF3-AS1 overexpression on gastric cancer cell chemosensitivity to cisplatin. The in vivo studies showed that KLF3-AS1 overexpression suppressed the tumor growth of SGC-7901 in the nude mice. In conclusion, our results for the first time demonstrated that KLF3-AS1 was down-regulated in gastric cancer cells and repressed gastric cancer cell proliferation, invasion, migration and EMT, and enhanced chemosensitivity to cisplatin. Further mechanistic results indicated that KLF3-AS1 exerted its biological function in gastric cancer cells by inhibiting miR-223 expression. Future studies are still required to decipher the detailed molecular mechanisms of KLF3-AS1 in gastric cancer.
A New Prognostic Algorithm Predicting HCC Recurrence in Patients With Barcelona Clinic Liver Cancer Stage B Who Received PA-TACE
Authors: Hu Shuyang , Gan Wei , Qiao Liang , Ye Cheng , Wu Demin , Liao Boyi , Yang Xiaoyu , Jiang Xiaoqing
Published: October 2021

Background

Postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE) is effective in preventing the recurrence of hepatocellular carcinoma (HCC) in patients treated with surgery. However, there is a lack of reports studying the risk factors associated with recurrence in HCC patients who received PA-TACE. In this study, we identified the independent risk factors for recurrence of HCC patients who received PA-TACE. We also developed a novel, effective, and valid nomogram to predict the individual probability of recurrence, 1, 3, and 5 years after PA-TACE.

Methods

A retrospective study was performed to identify the independent risk factors for recurrence of HCC in a group of 502 patients diagnosed in stage B based on the Barcelona Clinic Liver Cancer (BCLC) evaluation system for HCC that underwent curative resections. Then, subgroup analysis was performed for 184 patients who received PA-TACE, who were included in the training cohort. The other 147 HCC patients were included in a validation cohort. A recurrence-free survival (RFS)-predicting nomogram was constructed, and results were assessed using calibration and decision curves and a time-dependent AUC diagram.

Results

PA-TACE was shown to be a significant independent prognostic value for patients with BCLC stage B [p < 0.001, hazard ratio (HR) = 0.508, 95% CI = 0.375–0.689 for OS, p = 0.002; HR = 0.670, 95%CI = 0.517–0.868 for RFS]. Alpha fetoprotein (AFP), tumor number, tumor size, microvascular invasion (MVI), and differentiation were considered as independent risk factors for RFS in the training cohort, and these were further confirmed in the validation cohort. Next, a nomogram was constructed to predict RFS. The C-index for RFS in the nomogram was 0.721 (95% CI = 0.718–0.724), which was higher than SNACOR, HAP, and CHIP scores (0.587, 0.573, and 0.607, respectively). Calibration and decision curve analyses and a time-dependent AUC diagram were used. Our nomogram showed stronger performance than these other nomograms in both the training and validation cohorts.

Conclusions

HCC patients diagnosed as stage B according to BCLC may benefit from PA-TACE after surgery. The RFS nomogram presented here provides an accurate and reliable prognostic model to monitor recurrence. Patients with a high recurrence score based on the nomogram should receive additional high-end imaging exams and shorter timeframes in between follow-up visits.
Radiation Plus Anti-PD-1 Therapy for NSCLC Brain Metastases: A Retrospective Study
Authors: Liao Guixiang , Qian Yuting , Arooj Sumbal , Zhao Zhihong , Yan Maosheng , Li Zihuang , Yang Hongli , Zheng Tao , Li Gang , Li Xianming , Khan Muhammad
Published: October 2021

Background

Radiation therapy (RT) is the mainstay of brain metastases (BMs), and anti-PD-1 blockade has led to intracranial responses in non-small cell lung carcinoma (NSCLC) patients with BMs.

Objective

This study aimed to evaluate the efficacy and safety of adding anti-PD-1 blockade to RT in the management of NSCLC patients with BM in terms of survival outcome.

Materials and Methods

We retrospectively reviewed 70 NSCLC patients with BMs who were treated with whole brain radiation therapy (WBRT) between January 2016 and January 2021. Of the 70 patients, 29 additionally received anti-PD-1 therapy within 30 days of WBRT initiation. Baseline characteristics of the patients and efficacy outcomes such as progression-free survival (PFS) and overall survival (OS) were statistically compared using SPSS v26. Results were obtained using the Chi-square test/Fisher exact test, t-test, Kaplan-Meier, and Cox regression survival analyses.

Results

The median survival for the entire cohort was 24 months (95% CI, 19.5–28.5). The median survival times for WBRT alone and WBRT plus anti-PD-1 therapy cohorts were 20 months (95% CI, 11.6–28.3) and 27 months (95% CI, 19.5–28.5), respectively (p=0.035). There was no statistical difference in PFS for the treatment cohorts (median PFS for WBRT alone: 7 months vs. 12 months for WBRT plus anti-PD-1, p=0.247). In EGFR wild-type subgroup (n=31), both PFS (p=0.037) and OS (p=0.012) were significantly improved. Only the treatment group (WBRT plus anti-PD-1) was a significant predictor of OS on univariate and multivariate analyses (p=0.040). There were no significant differences in adverse events among the treatment groups.

Conclusions

NSCLC patients with BM receiving additional anti-PD-1 therapy may derive better OS than WBRT alone without any increase in adverse events. Prospective well-designed studies are warranted to validate and elucidate the additive effects of the two modalities in this group of patients.
PD-L1, Mismatch Repair Protein, and NTRK Immunohistochemical Expression in Cervical Small Cell Neuroendocrine Carcinoma
Authors: Chen Longyun , Yang Fan , Feng Ting , Wu Shafei , Li Kaimi , Pang Junyi , Shi Xiaohua , Liang Zhiyong
Published: October 2021

Background

Cervical small cell neuroendocrine carcinoma (SCNC) is a rare and aggressive disease that lacks a standard treatment strategy or effective methods of targeted therapy. PD-L1 inhibitors for DNA mismatch repair system-deficient (dMMR) tumors and neurotrophin receptor tyrosine kinase (NTRK) inhibitors offer potential pan-cancer treatments.

Methods

Immunohistochemistry was employed as the main detection method, and any NTRK positive cases, identified by immunohistochemistry, were further submitted for evaluation by fluorescence in situ hybridization (FISH) and real-time polymerase chain reaction (RT-PCR) methods.

Results

Forty-six patients were enrolled. Positive PD-L1 expression was seen in 22 of the 43 patients (51.16%) with an average combined positive score of 6.82. PD-L1-positive patients were more likely to have a higher proliferation rate in the tumor, and they experienced less recurrence and death (p = 0.048 and 0.033, respectively) compared with the patients with negative PD-L1 expression. However, in the multivariate analysis, none of the clinical parameters was associated with the expression of PD-L1. There was no association between PD-L1 expression and disease recurrence or overall survival in the Kaplan-Meier analysis. All cases were found to be MMR-stable and lacked NTRK gene fusion. However, pan-Trk expressed in 14 (32.56%) of the 43 tested cases, but FISH and RT-PCR failed to confirm any positive fusion signals in IHC-positive cases.

Conclusions

PD-L1 may be an effective therapeutic target for cervical SCNC. Cervical SCNC is a MMR-stable tumor and lacks NTRK gene fusion. IHC isn’t a reliable method in the detection of NTRK gene fusion in cervical SCNC.
Which Clinicopathologic Parameters Suggest Primary Resistance to Palbociclib in Combination With Letrozole as the First-Line Treatment for Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer?
Authors: Kim Ji-Yeon , Oh Jung Min , Park Yeon Hee , Ahn Jin Seok , Im Young-Hyuck
Published: October 2021

In this study, we evaluated clinical parameters to predict the primary resistance of palbociclib in combination with endocrine therapy as the first-line treatment in patients with hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer (MBC). We performed a data analysis of patients diagnosed with HR+, HER2-MBC who received palbociclib plus letrozole as the first-line treatment in the metastatic setting from the clinical data warehouse in Samsung Medical Center. In this study, 305 patients were included in the final data analysis. The median follow-up duration was 31 months, and we observed 123 cases of disease progression. The median progression-free survival (PFS) was 28.7 months, and 38 patients (12.5%) had less than a 6-month PFS. The multivariate analysis suggested that primary resistance to adjuvant endocrine therapy (ET) (hazard ratio: 1.91), presence of liver metastasis (hazard ratio: 2.17), initial elevation of serum CA-15-3 (hazard ratio: 1.99), weak positivity of estrogen receptor (ER) (hazard ratio: 2.28), Ki-67 3+ or 4+ (hazard ratios: 2.58 and 10.28), and presence of mutation (hazard ratio: 9.59) were associated with a short PFS duration. A further prediction model was developed with data from 256 patients and 33 cases of disease progression in 6 months. This model included five factors—primary resistance to adjuvant ET (odds ratio, OR: 1.14), liver metastasis (OR: 1.56), initial CA-15-3 elevation (OR: 1.51), weak ER expression (OR: 2.22), and BRCA2 mutation (OR: 2.85)—and the area under the receiver operating characteristic curve was 0.842 (95% CI: 0.775, 0.909; p < 0.001). Finally, we divided them into four risk groups according to the prediction model with the five risk factors. These four groups had different PFS (p < 0.001) and primary resistance of palbociclib with letrozole [OR of group 2 vs. group 1 (ref): 2.18 (p = 0.002), OR of group 3: 3.91 (p < 0.001), and OR of group 4: 4.25 (p < 0.001)]. We developed a prediction model of primary resistance to palbociclib with letrozole as the first-line treatment for HR+, HER2-MBC. Our prediction model might be helpful for considering the first-line treatment strategies. Further well-designed clinical trials would be warranted to validate our prediction model.
Tibetan Medicine for Diabetes Mellitus: Overview of Pharmacological Perspectives
Authors: Yan Li-Shan , Cheng Brian Chi-Yan , Zhang Shuo-Feng , Luo Gan , Zhang Chao , Wang Qing-Gao , Fu Xiu-Qiong , Wang Yi-Wei , Zhang Yi
Published: October 2021

Diabetes mellitus (DM) and its complications pose a major public health threat which is approaching epidemic proportions globally. Current drug options may not provide good efficacy and even cause serious adverse effects. Seeking safe and effective agents for DM treatment has been an area of intensive interest. As a healing system originating in Tibet, Traditional Tibetan Medicine (TTM) has been widely used by Tibetan people for the prevention and treatment of DM and its complications for hundreds of years. Tibetan Materia Medica (TMM) including the flower of Edgeworthia gardneri (Wall.) Meisn., Phyllanthi Fructus, Chebulae Fructus, Huidouba, and Berberidis Cortex are most frequently used and studied. These TMMs possess hypoglycemic, anti-insulin resistant, anti-glycation, lipid lowering, anti-inflammatory, and anti-oxidative effects. The underlying mechanisms of these actions may be related to their α-glucosidase inhibitory, insulin signaling promoting, PPARs-activating, gut microbiota modulation, islet β cell-preserving, and TNF-α signaling suppressive properties. This review presents a comprehensive overview of the mode and mechanisms of action of various active constituents, extracts, preparations, and formulas from TMM. The dynamic beneficial effects of the products prepared from TMM for the management of DM and its complications are summarized. These TMMs are valuable materia medica which have the potential to be developed as safe and effective anti-DM agents.
The Role of Genetic Polymorphisms in High-Dose Methotrexate Toxicity and Response in Hematological Malignancies: A Systematic Review and Meta-Analysis
Authors: Song Zaiwei , Hu Yang , Liu Shuang , Jiang Dan , Yi Zhanmiao , Benjamin Mason M. , Zhao Rongsheng
Published: October 2021

Objective: High-dose methotrexate (HDMTX) is a mainstay therapeutic agent for the treatment of diverse hematological malignancies, and it plays a significant role in interindividual variability regarding the pharmacokinetics and toxicity. The genetic association of HDMTX has been widely investigated, but the conflicting results have complicated the clinical utility. Therefore, this systematic review aims to determine the role of gene variants within the HDMTX pathway and to fill the gap between knowledge and clinical practice.

Methods: Databases including EMBASE, PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and the Clinical Trials.gov were searched from inception to November 2020. We included twelve single-nucleotide polymorphisms (SNPs) within the HDMTX pathway, involving RFC1, SLCO1B1, ABCB1, FPGS, GGH, MTHFR, DHFR, TYMS, and ATIC. Meta-analysis was conducted by using Cochrane Collaboration Review Manager software 5.3. The odds ratios (ORs) or hazard ratios (HRs) with 95% confidence interval (95% CI) were analyzed to evaluate the associations between SNPs and clinical outcomes. This study was performed according to the PRISMA guideline.

Results: In total, 34 studies with 4102 subjects were identified for the association analysis. Nine SNPs involving MTHFR, RFC1, ABCB1, SLCO1B1, TYMS, FPGS, and ATIC genes were investigated, while none of studies reported the polymorphisms of GGH and DHFR yet. Two SNPs were statistically associated with the increased risk of HDMTX toxicity: MTHFR 677C>T and hepatotoxicity (dominant, OR=1.52, 95% CI=1.03-2.23; recessive, OR=1.68, 95% CI=1.10–2.55; allelic, OR=1.41, 95% CI=1.01–1.97), mucositis (dominant, OR=2.11, 95% CI=1.31–3.41; allelic, OR=1.91, 95% CI=1.28–2.85), and renal toxicity (recessive, OR=3.54, 95% CI=1.81–6.90; allelic, OR=1.89, 95% CI=1.18–3.02); ABCB1 3435C>T and hepatotoxicity (dominant, OR=3.80, 95% CI=1.68-8.61), whereas a tendency toward the decreased risk of HDMTX toxicity was present in three SNPs: TYMS 2R>3R and mucositis (dominant, OR=0.66, 95% CI=0.47–0.94); RFC1 80A>G and hepatotoxicity (recessive, OR=0.35, 95% CI=0.16–0.76); and MTHFR 1298A>C and renal toxicity (allelic, OR=0.41, 95% CI=0.18–0.97). Since the data of prognosis outcomes was substantially lacking, current studies were underpowered to investigate the genetic association.

Conclusions: We conclude that genotyping of MTHFR and/or ABCB1 polymorphisms prior to treatment, MTHFR 677C>T particularly, is likely to be potentially useful with the aim of tailoring HDMTX therapy and thus reducing toxicity in patients with hematological malignancies.
Central Nervous System Associated With Light Perception and Physiological Responses of Birds
Authors: Kang Seong W.
Published: October 2021

Environmental light that animal receives (i.e., photoperiod and light intensity) has recently been shown that it affects avian central nervous system for the physiological responses to the environment by up or downregulation of dopamine and serotonin activities, and this, in turn, affects the reproductive function and stress-related behavior of birds. In this study, the author speculated on the intriguing possibility that one of the proposed avian deep-brain photoreceptors (DBPs), i.e., melanopsin (Opn4), may play roles in the dual sensory-neurosecretory cells in the hypothalamus, midbrain, and brain stem for the behavior and physiological responses of birds by light. Specifically, the author has shown that the direct light perception of premammillary nucleus dopamine-melatonin (PMM DA-Mel) neurons is associated with the reproductive activation in birds. Although further research is required to establish the functional role of Opn4 in the ventral tegmental area (VTA), dorsal raphe nucleus, and caudal raphe nucleus in the light perception and physiological responses of birds, it is an exciting prospect because the previous results in birds support this hypothesis that Opn4 in the midbrain DA and serotonin neurons may play significant roles on the light-induced welfare of birds.