bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting potential receptor molecules in non-small cell lung cancer (NSCLC) using in silico approaches
Authors: Kirubhanand C. , Merciline Leonora J. , Anitha S. , Sangeetha R. , Nachammai K. T. , Langeswaran K. , Gowtham Kumar S.
Published: February 2023

Introduction: Non-Small Cell Lung Cancer is the most prevalent type of cancer in lung cancer. Chemotherapy, radiation therapy, and other conventional cancer treatments have a low success rate. Thus, creating new medications is essential to halt the spread of lung cancer.

Methods: In this study bioactive nature of lochnericine against Non-Small Cell Lung Cancer (NSCLC) was analyzed using various computational approaches such as quantum chemical calculations, molecular docking, and molecular dynamic simulation. Furthermore, the MTT assay shows the anti-proliferation activity of lochnericine.

Results and Discussion: Using Frontier Molecular Orbital (FMO), the calculated band gap energy value associated with bioactive compounds and the molecule’s potential bioactivity is confirmed. The H38 hydrogen atom and O1 oxygen atom in the molecule are effectively electrophilic, and potential nucleophilic attack sites were confirmed through analysis of the Molecular electrostatic potential surface. Furthermore, the electrons within the molecule were delocalized, which confers bioactivity on the title molecule and was authorized through Mulliken atomic charge distribution analysis. A molecular docking study revealed that lochnericine inhibits non-small cell lung cancer-associated targeted protein. The lead molecule and targeted protein complex were stable during molecular dynamics simulation studies till the simulation period. Further, lochnericine demonstrated remarkable anti-proliferative and apoptotic features against A549 lung cancer cells. The current investigation powerfully suggests that lochnericine is a potential candidate for lung cancer.
Visual-spatial processing impairment in the occipital-frontal connectivity network at early stages of Alzheimer’s disease
Authors: Plaza-Rosales Iván , Brunetti Enzo , Montefusco-Siegmund Rodrigo , Madariaga Samuel , Hafelin Rodrigo , Ponce Daniela P. , Behrens María Isabel , Maldonado Pedro E. , Paula-Lima Andrea
Published: February 2023

Introduction

Alzheimer’s disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists. In the present cross-sectional study, our objective was to evaluate the manifestations and mechanisms underlying visual-spatial deficits at the early stages of AD.

Methods

We combined behavioral, electroencephalography (EEG), and eye movement recordings during the performance of a spatial navigation task (a virtual version of the Morris Water Maze adapted to humans). Participants (69–88 years old) with amnesic mild cognitive impairment–Clinical Dementia Rating scale (aMCI–CDR 0.5) were selected as probable early AD (eAD) by a neurologist specialized in dementia. All patients included in this study were evaluated at the CDR 0.5 stage but progressed to probable AD during clinical follow-up. An equal number of matching healthy controls (HCs) were evaluated while performing the navigation task. Data were collected at the Department of Neurology of the Clinical Hospital of the Universidad de Chile and the Department of Neuroscience of the Faculty of Universidad de Chile.

Results

Participants with aMCI preceding AD (eAD) showed impaired spatial learning and their visual exploration differed from the control group. eAD group did not clearly prefer regions of interest that could guide solving the task, while controls did. The eAD group showed decreased visual occipital evoked potentials associated with eye fixations, recorded at occipital electrodes. They also showed an alteration of the spatial spread of activity to parietal and frontal regions at the end of the task. The control group presented marked occipital activity in the beta band (15–20 Hz) at early visual processing time. The eAD group showed a reduction in beta band functional connectivity in the prefrontal cortices reflecting poor planning of navigation strategies.

Discussion

We found that EEG signals combined with visual-spatial navigation analysis, yielded early and specific features that may underlie the basis for understanding the loss of functional connectivity in AD. Still, our results are clinically promising for early diagnosis required to improve quality of life and decrease healthcare costs.
Profiles of circumscribed interests in autistic youth
Authors: Spackman Emily , Smillie Luke D. , Frazier Thomas W. , Hardan Antonio Y. , Alvares Gail A. , Whitehouse Andrew , Uljarević Mirko
Published: February 2023

Circumscribed interests (CI) encompass a range of different interests and related behaviors that can be characterized by either a high intensity but otherwise usual topic [referred to as restricted interests (RI)] or by a focus on topics that are not salient outside of autism [referred to as unusual interests (UI)]. Previous research has suggested that there is pronounced variability across individuals in terms of the endorsement of different interests, however, this variability has not been quantified using formal subtyping approaches. Therefore, using Latent Profile Analysis in a sample of 1,892 autistic youth (Mage = 10.82, SDage = 4.14; 420 females), this study aimed to identify subgroups based on the RU and UI profiles. Three profiles of autistic individuals were identified. They were characterized as Low CI, Predominantly RI, and Predominantly UI. Importantly, profiles differed on several key demographic and clinical variables, including age, sex composition, IQ, language level, social and communication abilities, anxiety, and obsessive-compulsive behaviors. Although replication across other samples is needed, the profiles identified in this study are potentially promising for future research given their distinct profiles of RI and UI and unique patterns of associations with key cognitive and clinical variables. Therefore, this study represents an important initial step towards more individualized assessment and support for diverse presentations of CI in autistic youth.
Systematic review of probiotics as an adjuvant treatment for psychiatric disorders
Authors: Forth Evan , Buehner Benjamin , Storer Ana , Sgarbossa Cassandra , Milev Roumen , Chinna Meyyappan Arthi
Published: February 2023

Introduction

Many psychiatric illnesses have been linked to the gut microbiome, with supplements such as probiotics showing some efficacy in alleviating the symptoms of some psychiatric illnesses. The aim of this review is to evaluate the current literature investigating the effects of adjuvant probiotic or synbiotic administration in combination with first-line treatments for psychiatric illnesses.

Method

A systematic search of four databases was conducted using key terms related to treatments for psychiatric illnesses, the gut microbiome, and probiotics. All results were then evaluated based on specific eligibility criteria.

Results

Eight studies met eligibility criteria and were analyzed for reported changes in outcome measures used to assess the symptoms of psychiatric illness and the tolerability of treatment. All Major Depressive Disorder (MDD) (n = 5) and Generalized Anxiety Disorder (GAD) (n = 1) studies found adjuvant probiotic or synbiotic treatment to be more efficacious in improving the symptoms of psychiatric illness than the first-line treatment alone or with placebo. The schizophrenia studies (n = 2) found adjuvant probiotic treatment to have no significant difference in clinical outcomes, but it was found to improve the tolerability of first-line antipsychotics.

Discussion and conclusion

The findings of the studies included in this review suggest the use of adjuvant probiotic treatment with selective serotonin reuptake inhibitors (SSRIs) for MDD and GAD to be superior to SSRI treatment alone. Probiotic adjuvant treatment with antipsychotics could be beneficial for improving the tolerability of the antipsychotics, but these findings do not suggest that adjuvant probiotic treatment would result in improved clinical outcomes for symptoms of schizophrenia.
DualFlow: Generating imperceptible adversarial examples by flow field and normalize flow-based model
Authors: Liu Renyang , Jin Xin , Hu Dongting , Zhang Jinhong , Wang Yuanyu , Zhang Jin , Zhou Wei
Published: February 2023

Recent adversarial attack research reveals the vulnerability of learning-based deep learning models (DNN) against well-designed perturbations. However, most existing attack methods have inherent limitations in image quality as they rely on a relatively loose noise budget, i.e., limit the perturbations byLp-norm. Resulting that the perturbations generated by these methods can be easily detected by defense mechanisms and are easily perceptible to the human visual system (HVS). To circumvent the former problem, we propose a novel framework, calledDualFlow, to craft adversarial examples by disturbing the image's latent representations with spatial transform techniques. In this way, we are able to fool classifiers with human imperceptible adversarial examples and step forward in exploring the existing DNN's fragility. For imperceptibility, we introduce the flow-based model and spatial transform strategy to ensure the calculated adversarial examples are perceptually distinguishable from the original clean images. Extensive experiments on three computer vision benchmark datasets (CIFAR-10, CIFAR-100 and ImageNet) indicate that our method can yield superior attack performance in most situations. Additionally, the visualization results and quantitative performance (in terms of six different metrics) show that the proposed method can generate more imperceptible adversarial examples than the existing imperceptible attack methods.
Impaired muscarinic modulation of the rat prelimbic cortex in neuropathic pain is sexually dimorphic and associated with cold allodynia
Authors: Jefferson Taylor , Kim Haram R. , Martina Marco
Published: February 2023

Cholinergic modulation of the brain cortex is critical for cognitive processes, and altered cholinergic modulation of the prefrontal cortex is emerging as an important mechanism of neuropathic pain. Sex differences in pain prevalence and perception are well known, yet the precise nature of the mechanisms responsible for sexual dimorphism in chronic neuropathic pain are poorly understood. Here we investigated potential sex differences in cholinergic modulation of layer five commissural pyramidal neurons of the rat prelimbic cortex in control conditions and in the SNI model of neuropathic pain. We discovered that cholinergic modulation is stronger in cells from male compared with female rats, and that in neuropathic pain rats, cholinergic excitation of pyramidal neurons was more severely impaired in males than in females. Finally, we found that selective pharmacological blockade of the muscarinic M1 subunit in the prefrontal cortex induces cold sensitivity (but not mechanical allodynia) in naïve animals of both sexes.
Efficacy of electroacupuncture in the treatment of peripheral neuropathy caused by Utidelone: Study protocol for a randomized controlled trial
Authors: Lu Chao , Li Guangliang , Deng Dehou , Li Rongrong , Li Xiaoyu , Feng Xukang , Wu Taoping , Shao Xiying , Chen Weiji
Published: February 2023

Introduction

Utidelone (UTD1) is a new chemotherapeutic drug for recurrent or metastatic breast cancer. However, it usually leads to severe peripheral neuropathy (PN) and causes numbness of the hands and feet and significant pain in patients' life. Electroacupuncture (EA) is considered beneficial in improving PN and relieving numbness of the hands and feet. This trial aims to evaluate the therapeutic effect of EA on PN caused by UTD1 in patients with advanced breast cancer.

Methods and analysis

This study is a prospective randomized controlled trial. A total of 70 patients with PN caused by UTD1 will be randomly assigned to the EA treatment group and the control group in a ratio of 1:1. The patients in the EA treatment group will receive 2 Hz EA three times a week for 4 weeks. The patients in the control group will take mecobalamin (MeCbl) tablets orally, one tablet each, three times a day for 4 weeks. The main outcome measures will be the evaluation scale of peripheral neurotoxicity of chemotherapeutic drugs according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item (EORTC QLQ-CIPN20) and the peripheral neurotoxicity assessment rating according to NCI CTCAE version 5.0. Secondary outcomes will be the quality of life scale according to the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). The results will be evaluated at baseline, post-treatment phase, and follow-up. All major analyses will be based on the intention-to-treat principle.

Ethics and dissemination

This protocol was approved by the Medical Ethics Committee of Zhejiang Cancer Hospital on 26 July 2022. The license number is IRB-2022-425. This study will provide clinical efficacy data on EA in the treatment of PN caused by UTD1 and will help to prove whether EA is an effective and safe therapy. The study results will be shared with healthcare professionals through the publication of manuscripts and conference reports.

Trial registration number

ChiCTR2200062741.
Imaging and neuropathological findings in patients with Post COVID-19 Neurological Syndrome—A review
Authors: Okrzeja Jakub , Garkowski Adam , Kubas Bożena , Moniuszko-Malinowska Anna
Published: February 2023

Post COVID-19 syndrome is determined as signs and symptoms that appear during or after an infection consistent with SARS-CoV-2 disease, persist for more than 12 weeks and are not explained by an alternative diagnosis. This review presents the neuropathological findings and imaging findings in Post COVID-19 Neurological Syndrome: the focal point is on the manifestations of involvement evident on brain and spine imaging.
A fast and intuitive method for calculating dynamic network reconfiguration and node flexibility
Authors: Chinichian Narges , Kruschwitz Johann D. , Reinhardt Pablo , Palm Maximilian , Wellan Sarah A. , Erk Susanne , Heinz Andreas , Walter Henrik , Veer Ilya M.
Published: February 2023

Dynamic interactions between brain regions, either during rest or performance of cognitive tasks, have been studied extensively using a wide variance of methods. Although some of these methods allow elegant mathematical interpretations of the data, they can easily become computationally expensive or difficult to interpret and compare between subjects or groups. Here, we propose an intuitive and computationally efficient method to measure dynamic reconfiguration of brain regions, also termed flexibility. Our flexibility measure is defined in relation to an a-priori set of biologically plausible brain modules (or networks) and does not rely on a stochastic data-driven module estimation, which, in turn, minimizes computational burden. The change of affiliation of brain regions over time with respect to these a-priori template modules is used as an indicator of brain network flexibility. We demonstrate that our proposed method yields highly similar patterns of whole-brain network reconfiguration (i.e., flexibility) during a working memory task as compared to a previous study that uses a data-driven, but computationally more expensive method. This result illustrates that the use of a fixed modular framework allows for valid, yet more efficient estimation of whole-brain flexibility, while the method additionally supports more fine-grained (e.g. node and group of nodes scale) flexibility analyses restricted to biologically plausible brain networks.
Effect of percutaneous electrical stimulation with high-frequency alternating currents at 30 kHz on the sensory-motor system
Authors: Álvarez David Martín-Caro , Serrano-Muñoz Diego , Fernández-Pérez Juan José , Gómez-Soriano Julio , Avendaño-Coy Juan
Published: February 2023

Background

Unmodulated high-frequency alternating currents (HFAC) are employed for producing peripheral nerves block. HFAC have been applied in humans with frequencies up to 20 kHz, whether transcutaneously, percutaneously, or via surgically-implanted electrodes. The aim of this study was to assess the effect of percutaneous HFAC, applied with ultrasound-guided needles at 30 kHz, on the sensory-motor nerve conduction of healthy volunteers.

Methods

A parallel, double-blind, randomized clinical trial with a placebo control was conducted. Percutaneous HFAC at 30 kHz or sham stimulation was applied via ultrasound-guided needles in 48 healthy volunteers (n = 24 in each group) for 20 min. The assessed outcome variables were pressure pain threshold (PPT), mechanical detection threshold (MDT), maximal finger flexion strength (MFFS), antidromic sensory nerve action potential (SNAP), hand temperature, and subjective sensations by the participants. The measurements were recorded pre-intervention, during the stimulation (at 15 min), immediately post-intervention (at 20 min), and 15 min after the end of treatment.

Results

The PPT increased in the active group compared with sham stimulation, both during the intervention [14.7%; 95% confidence interval (CI): 4.4–25.0], immediately post-intervention (16.9%; 95% CI: −7.2–26.5), and 15 min after the end of the stimulation (14.3%; 95% CI: 4.4–24.3) (p < 0.01). The proportion of participants who reported feelings of numbness and heaviness was significantly higher in the active group (46 and 50%, respectively) than in the sham group (8 and 18%, respectively) (p < 0.05). No intergroup differences were observed in the remaining outcome variables. No unexpected adverse effects derived from the electrical stimulation were reported.

Conclusion

Percutaneous stimulation with HFAC at 30 kHz applied to the median nerve increased the PPT and subjective perception of numbness and heaviness. Future research should evaluate its potential therapeutic effect in people with pain.

Clinical trial registration

https://clinicaltrials.gov/ct2/show/NCT04884932, identifier NCT04884932.
What made us “hunter-gatherers of words”
Authors: Boeckx Cedric
Published: February 2023

This paper makes three interconnected claims: (i) the “human condition” cannot be captured by evolutionary narratives that reduce it to a recent ‘cognitive modernity', nor by narratives that eliminates all cognitive differences between us and out closest extinct relatives, (ii) signals from paleogenomics, especially coming from deserts of introgression but also from signatures of positive selection, point to the importance of mutations that impact neurodevelopment, plausibly leading to temperamental differences, which may impact cultural evolutionary trajectories in specific ways, and (iii) these trajectories are expected to affect the language phenotypes, modifying what is being learned and how it is put to use. In particular, I hypothesize that these different trajectories influence the development of symbolic systems, the flexible ways in which symbols combine, and the size and configurations of the communities in which these systems are put to use.
Branched-chain amino acids and risk of stroke: A Mendelian randomization study
Authors: Zhang Yang , Duan Yunxia , Jiang Miaowen , He Xiaoduo , Xu Shuaili , Guo Jiaqi , Li Ming , Zhou Chen , Wu Di , Liu Guiyou , Ji Xunming
Published: February 2023

Background

The causality between plasma branched-chain amino acids (BCAAs) levels and stroke remains uncertain and the stratified research on the association between BCAAs levels and subtypes of stroke is not well studied. Therefore, the association of genetically proxied circulating BCAA levels with the risks of stroke and its subtypes was explored by Mendelian randomization (MR) in this study.

Methods

Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. Data for plasma BCAA levels (n = 16,596) were obtained from a meta-analysis of GWAS. The MEGASTROKE consortium provided data for ischemic stroke (n = 440,328) and its subtypes and data for hemorrhagic stroke were available from 2 meta-analyses of GWAS of European-ancestry groups (intracerebral hemorrhage, n = 3,026; subarachnoid hemorrhage, n = 77,074). The inverse variance weighted (IVW) method was selected as the primary MR analysis. Supplementary analysis used included the weighted median, MR-Egger regression, Cochran’s Q statistic, MR Pleiotropy Residual Sum and Outlier global test, and leave-one-out analysis method.

Results

According to IVW analysis, 1-SD increment in genetically determined circulating isoleucine was associated with increased risks of cardioembolic stroke (CES) (OR: 1.56, 95% CI: 1.21–2.20, P = 0.0007), but not with risks of other stroke subtypes. We could not discover any proof that leucine and valine levels could increase risk of any stroke subtype. All heterogeneity tests produced stable findings, and there was no concrete evidence to indicate the perturbation of horizontal multiplicity.

Conclusion

Increasing plasma isoleucine level had a causal effect on the risk of CES but not on the risk of other stroke subtypes. Further research is needed to identify the mechanisms of the causal associations between BCAAs and stroke subtypes.
Investigation of the effects of bovine collagen peptides and mixed berries on rheological properties and biological activity of egg white-based beverage via central composite design
Authors: Varga-Tóth Adrienn , Németh Csaba , Dalmadi István , Csurka Tamás , Csorba Renáta , Elayan Majd , Enkhbold Munkhnasan , Hidas Karina , Friedrich László Ferenc
Published: February 2023

Modern consumer expectations have become highly diversified: they want more opportunities to meet diverse family needs (diversity of family members in age, gender, physical activity, etc. ,) and individual health goals with a huge variety of sensorial preferences. Our research is aimed to develop a protein-dense, highly bioactive, lactose- and whey protein-free beverage applying a central composite rotational design (CCRD) with 2 factors. For this purpose, an egg white-based beverage was flavored with mixed berries (factor A) and enriched with bovine collagen peptides (factor B). After suitable sample preparation, the rheological properties were investigated by an Anton Paar MCR 92 rheometer (with CC 27 system, and flow behavior was analyzed with a Herschel-Bulkley (H-B) model). The antioxidant capacity of samples was investigated by Ferric Reducing Antioxidant Power (FRAP) method, the total anthocyanin content was estimated based on a spectrophotometric method, and the total phenolic content was determined by the Folin Ciocalteu method. Our results are figured on response surfaces demonstrating that both factors and their interactions show a positive correlation with the examined parameters. Based on the CCRD, all investigated parameters are significantly influenced by at least one aspect and can be adequately estimated for further product development.
Quality assessment of maize tortillas produced from landraces and high yield hybrids and varieties
Authors: Acosta-Estrada Beatriz A. , Serna-Saldívar Sergio O. , Chuck-Hernández Cristina
Published: February 2023

Introduction

Different analyses of the profiles of tortillas have been made using the traditional method, whether from landraces or hybrids versus those made with dry masa flour in which significant variability (p < 0.05) is reported in favor or against each type of tortilla which may be due to various factors such as the type of maize or the processing methods.

Methods

Twenty-two samples including hybrids, hybrid mixtures, varieties, landraces and dry masa flours were processed to masa and tortilla under similar and controlled conditions and tortilla quality evaluated. In total, 70 characteristics were analyzed as physicochemical properties of the maize (e.g., hectoliter weight and dimensions), processability characteristics, masa characteristics [e.g. viscoamylographic parameters (RVA)], and quality parameters of tortillas (e.g., sensory performance, color and texture).

Results and discussión

The studied materials presented variability among genotypes, especially within landraces. The physical and chemical properties of corn affected the processability and quality characteristics of tortillas (sensory and composition), and it was found that high producing hybrids and varieties (p < 0.05) were better and more consistent in all stages of processing. Forty percent of the landraces yielded masa with poor machinability.

Conclusion

Landraces averaged 1.27 percentage points more protein (p < 0.05) than other analyzed samples and they comparatively yielded tortillas with lower extensibility (12.34%) compared to counterparts produced from hybrids and varieties. This work provides valuable information on how the chemical and physical characteristics of different types of maize genotypes affect the nixtamalization process and the quality of tortillas to provide more elements in the selection of the most appropriate genotypes for tortilla production.
The role of Gamma Knife radiosurgery in the management of skull base chordoma
Authors: Wang Kuanyu , Gao Dezhi , Pan Jian , Bao Enmeng , Sun Shibin
Published: February 2023

Objective

Chordoma is a slow-growing and locally aggressive cancer, which arises from the remnants of the primitive notochord. The first line treatment for the skull base chordoma is neurosurgery. Gamma Knife radiosurgery (GKS) is often be chosen especially in the setting of residual or recurrent chordomas. The purpose of this study is to evaluate the prognosis of patients with skull base chordoma who underwent GKS.

Methods

The present study was a retrospective analysis of 53 patients with skull base chordomas who underwent GKS. Univariate Cox and Kaplan-Meier survival analysis were performed to analyze the relationship between the tumor control time and the clinical characteristics.

Results

The 1-, 2-, 3-, and 5-year progression free survival (PFS) rates were 87, 71, 51, and 18%, respectively. After performing the univariate analysis, the clinical characteristics were not found to be significantly associated with the time of PFS; however, surgical history, peripheral dose, and tumor volume did have tendencies to predict the prognosis.

Conclusion

GKS provided a safe and relatively effective treatment for residual or recurrent chordomas after surgical resection. A higher tumor control rate depends on two approaches, an appropriate dose of radiation for the tumor and the accurate identification of the tumor margins.
Case report: Responses to the combination of gemcitabine with sirolimus in two patients with TSC-mutated sarcomas
Authors: Nassif Elise F. , Joseph Cissimol P. , Lazcano Rossana , Joseph Jocelyn T. , Thirasastr Prapassorn , Lazar Alexander J. , Somaiah Neeta
Published: February 2023

TSC-mutated sarcomas are rare molecular and histologic types of sarcoma. Due to the presence of their specific oncogenic driver mutation, these sarcomas are particularly sensitive to mTOR inhibitors. Recently, nab-sirolimus, an albumin-bound mTOR inhibitor, was approved by the Food and Drug Administration (FDA) for PEComas, which harbor a TSC mutation, and this drug remains the only FDA-approved systemic treatment for these tumors. We report on two cases of patients with TSC-mutated sarcomas who experienced significant responses to the combination of gemcitabine and sirolimus, after progression on prior gemcitabine-based chemotherapy and single agent mTOR inhibition with nab-sirolimus. Preclinical and clinical data support rationale for a synergistic effect of the combination. This combination may represent a valid therapeutic option after failure of nab-sirolimus in these patients, with no standard-of-care treatment options.
Dynamic changes in PSA levels predict prognostic outcomes in prostate cancer patients undergoing androgen -deprivation therapy: A multicenter retrospective analysis
Authors: Hu Mingqiu , Mao Yifeng , Guan Chao , Tang Zhizhong , Bao Zhihang , Li Yingbang , Liang Guowu
Published: February 2023

Background

Androgen-deprivation therapy (ADT) is used for the treatment of prostate cancer. However, the specific risk factors for the development of castration-resistant disease are still unclear. The present study sought to identify predictors of patient prognostic outcomes through analyses of clinical findings in large numbers of prostate cancer patients following ADT treatment.

Methods

Data pertaining to 163 prostate cancer patients treated at the Second Affiliated Hospital of Bengbu Medical University and Maoming People’s Hospital from January 1, 2015, to December 30, 2020, were retrospectively analyzed. Dynamic changes in prostate-specific antigen (PSA) levels were regularly assessed, including both time to nadir (TTN) and nadir PSA (nPSA). Univariate and multivariate analyses were performed with Cox risk proportional regression models, while differences in biochemical progression-free survival (bPFS) were compared among groups with Kaplan-Meier curves and log-rank tests.

Results

The bPFS values over the median 43.5-month follow-up period differed significantly between patients with nPSA levels < 0.2 ng/mL and ≥ 0.2 ng/mL, being 27.6 months and 13.5 months, respectively (log-rank P < 0.001). A significant difference in median bPFS was also observed when comparing patients with a TTN ≥ 9 months (27.8 months) to those with a TTN < 9 months (13.5 months) (log-rank P < 0.001).

Conclusions

TTN and nPSA are valuable predictors of prognosis in prostate cancer patients after ADT treatment, with better outcomes evident in patients with nPSA < 0.2 ng/mL and TTN > 9 months.
Targeted O-glycoproteomics for the development of diagnostic markers for advanced colorectal cancer
Authors: Takakura Daisuke , Ohashi Shoko , Kobayashi Noritoshi , Tokuhisa Motohiko , Ichikawa Yasushi , Kawasaki Nana
Published: February 2023

Aberrant glycosylation is a prominent feature of cancer, that can be used as targets to improve the existing cancer biomarkers, and help to assess metastasis risks, and therapeutic effects. We developed a targeted O-glycoproteomics method using serum specimens, and evaluated its utility in identifying advanced colorectal cancer (CRC) markers. To this end, we combined consecutive lectin affinity purification using Maclura pomifera lectin (MPL), jacalin, and Sambucus nigra lectin, which have affinities for the following O-glycans, that have received attention as cancer-related antigens, Tn (GalNAc-Ser/Thr), Sialyl Tn (Siaα2-6GalNAc-Ser/Thr), T (Galβ1-3GalNAc-Ser/Thr), Sialyl T (Siaα2-3Galβ1-GalNAc-Ser/Thr), and di-Sialyl T (Siaα2-3Galβ1-3[Siaα2-6] GalNAc-Ser/Thr), with a unique O-glycoproteomics approach. A total of 2,068 O-glycoforms derived from 265 proteins were identified in healthy individuals and patients with advanced CRC, of which 44 CRC-specific O-glycoforms were extracted. Particularly, five glycoproteins with T, Sialyl T, and di-Sialyl T antigens in specific peptide regions were evaluated quantitatively and statistically. We found that fibulin-2 (FBLN2) (aa330-349)/T antigen (area under the curve [AUC] = 0.92); macrophage colony-stimulating factor 1 (CSF1) (aa370-395)/(T + di-Sialyl T) (AUC = 0.94); macrophage mannose receptor 1 (MRC1) (aa1083-1101 and aa1215-1229)/T (AUC = 0.96 and 0.99); fibrinogen alpha chain (FGA) (aa354-367, aa511-527 and aa559-573)/Sialyl T (AUC = 0.98, 0.90 and 0.94); and complement component C7 (C7) (aa692-701)/di-Sialyl T (AUC = 1.00), can have high diagnostic efficacy to strategically predict advanced CRC groups. Hence, they could be promising markers for detection of advanced CRC, and provide new clinical test indicators along with lectins, such as MPL and jacalin. Our O-glycoproteomics platform provides a novel tool and resource, for researchers and clinicians seeking to better understand and treat advanced CRC.
A phase Ib study of interleukin-2 plus pembrolizumab for patients with advanced melanoma
Authors: Silk Ann W. , Curti Brendan , Bryan Jennifer , Saunders Tracie , Shih Weichung , Kane Michael P. , Hannon Phoebe , Fountain Christopher , Felcher Jessica , Zloza Andrew , Kaufman Howard L. , Mehnert Janice M. , McDermott David F.
Published: February 2023

Introduction

High-dose interleukin-2 (HD IL-2) and pembrolizumab are each approved as single agents by the U.S. F.D.A. for the treatment of metastatic melanoma. There is limited data using the agents concurrently. The objectives of this study were to characterize the safety profile of IL-2 in combination with pembrolizumab in patients with unresectable or metastatic melanoma.

Methods

In this Phase Ib study, patients received pembrolizumab (200 mg IV every 3 weeks) and escalating doses of IL-2 (6,000 or 60,000 or 600,000 IU/kg IV bolus every 8 hours up to 14 doses per cycle) in cohorts of 3 patients. Prior treatment with a PD-1 blocking antibody was allowed. The primary endpoint was the maximum tolerated dose (MTD) of IL-2 when co-administered with pembrolizumab.

Results

Ten participants were enrolled, and 9 participants were evaluable for safety and efficacy. The majority of the evaluable participants (8/9) had been treated with PD-1 blocking antibody prior to enrollment. Patients received a median of 42, 22, and 9 doses of IL-2 in the low, intermediate, and high dose cohorts, respectively. Adverse events were more frequent with increasing doses of IL-2. No dose limiting toxicities were observed. The MTD of IL-2 was not reached. One partial response occurred in 9 patients (11%). The responding patient, who had received treatment with an anti-PD-1 prior to study entry, was treated in the HD IL-2 cohort.

Discussion

Although the sample size was small, HD IL-2 therapy in combination with pembrolizumab appears feasible and tolerable.

Clinical trial registration

ClinicalTrials.gov, identifier NCT02748564.
Mitochondrial gene expression signature predicts prognosis of pediatric acute myeloid leukemia patients
Authors: Chaudhary Shilpi , Ganguly Shuvadeep , Palanichamy Jayanth Kumar , Singh Archna , Pradhan Dibyabhaba , Bakhshi Radhika , Chopra Anita , Bakhshi Sameer
Published: February 2023

Introduction

Gene expression profile of mitochondrial-related genes is not well deciphered in pediatric acute myeloid leukaemia (AML). We aimed to identify mitochondria-related differentially expressed genes (DEGs) in pediatric AML with their prognostic significance.

Methods

Children with de novo AML were included prospectively between July 2016-December 2019. Transcriptomic profiling was done for a subset of samples, stratified by mtDNA copy number. Top mitochondria-related DEGs were identified and validated by real-time PCR. A prognostic gene signature risk score was formulated using DEGs independently predictive of overall survival (OS) in multivariable analysis. Predictive ability of the risk score was estimated along with external validation in The Tumor Genome Atlas (TCGA) AML dataset.

Results

In 143 children with AML, twenty mitochondria-related DEGs were selected for validation, of which 16 were found to be significantly dysregulated. Upregulation of SDHC (p<0.001), CLIC1 (p=0.013) and downregulation of SLC25A29 (p<0.001) were independently predictive of inferior OS, and included for developing prognostic risk score. The risk score model was independently predictive of survival over and above ELN risk categorization (Harrell’s c-index: 0.675). High-risk patients (risk score above median) had significantly inferior OS (p<0.001) and event free survival (p<0.001); they were associated with poor-risk cytogenetics (p=0.021), ELN intermediate/poor risk group (p=0.016), absence of RUNX1-RUNX1T1 (p=0.027), and not attaining remission (p=0.016). On external validation, the risk score also predicted OS (p=0.019) in TCGA dataset.

Discussion

We identified and validated mitochondria-related DEGs with prognostic impact in pediatric AML and also developed a novel 3-gene based externally validated gene signature predictive of survival.
Construction and validation of a novel nomogram to predict cancer-specific survival in patients with gastric adenocarcinoma
Authors: Nie Guole , Zhang Honglong , Yan Jun , Xie Danna , Zhang Haijun , Li Xun
Published: February 2023

Background and aims

Adenocarcinoma is one of the most common pathological types of gastric cancer. The aims of this study were to develop and validate prognostic nomograms that could predict the probability of cancer-specific survival (CSS) for gastric adenocarcinoma (GAC) patients at 1, 3, and 5 years.

Methods

In total, 7747 patients with GAC diagnosed between 2010 and 2015, and 4591 patients diagnosed between 2004 and 2009 from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. The 7747 patients were used as a prognostic cohort to explore GAC-related prognostic risk factors. Moreover, the 4591 patients were used for external validation. The prognostic cohort was also divided into a training and internal validation sets for construction and internal validation of the nomogram. CSS predictors were screened using least absolute shrinkage and selection operator regression analysis. A prognostic model was built using Cox hazard regression analysis and provided as static and dynamic network-based nomograms.

Results

The primary site, tumor grade, surgery of the primary site, T stage, N stage, and M stage were determined to be independent prognostic factors for CSS and were subsequently included in construction of the nomogram. CSS was accurately estimated using the nomogram at 1, 3, and 5 years. The areas under the curve (AUCs) for the training group at 1, 3, and 5 years were 0.816, 0.853, and 0.863, respectively. Following internal validation, these values were 0.817, 0.851, and 0.861. Further, the AUC of the nomogram was much greater than that of American Joint Committee on Cancer (AJCC) or SEER staging. Moreover, the anticipated and actual CSS values were in good agreement based on decision curves and time-calibrated plots. Then, patients from the two subgroups were divided into high- and low-risk groups based on this nomogram. The survival rate of high-risk patients was considerably lower than that of low-risk patients, according to Kaplan–Meier (K-M) curves (p<0.0001).

Conclusions

A reliable and convenient nomogram in the form of a static nomogram or an online calculator was constructed and validated to assist physicians in quantifying the probability of CSS in GAC patients.
Common statistical concepts in the supervised Machine Learning arena
Authors: Rashidi Hooman H. , Albahra Samer , Robertson Scott , Tran Nam K. , Hu Bo
Published: February 2023

One of the core elements of Machine Learning (ML) is statistics and its embedded foundational rules and without its appropriate integration, ML as we know would not exist. Various aspects of ML platforms are based on statistical rules and most notably the end results of the ML model performance cannot be objectively assessed without appropriate statistical measurements. The scope of statistics within the ML realm is rather broad and cannot be adequately covered in a single review article. Therefore, here we will mainly focus on the common statistical concepts that pertain to supervised ML (i.e. classification and regression) along with their interdependencies and certain limitations.
GPX3 expression was down-regulated but positively correlated with poor outcome in human cancers
Authors: Hu Qingyi , Chen Jiaoshun , Yang Wen , Xu Ming , Zhou Jun , Tan Jie , Huang Tao
Published: February 2023

Introduction

Cancer is a crucial public health problem and one of the leading causes of death worldwide. Previous studies have suggested that GPX3 may be involved in cancer metastasis and chemotherapy resistance. However, how GPX3 affects cancer patients’ outcomes and the underlying mechanism remains unclear.

Methods

Sequencing data and clinical data from TCGA, GTEx, HPA, and CPTAC were used to explore the relationship between GPX3 expression and clinical features. Immunoinfiltration scores were used to assess the relationship between GPX3 and the tumor immune microenvironment. Functional enrichment analysis was used to predict the role of GPX3 in tumors. Gene mutation frequency, methylation level, and histone modification were used to predict the GPX3 expression regulation method. Breast, ovarian, colon, and gastric cancer cells were used to investigate the relationship between GPX3 expression and cancer cell metastasis, proliferation, and chemotherapy sensitivity.

Results

GPX3 is down-regulated in various tumor tissues, and GPX3 expression level can be used as a marker for cancer diagnosis. However, GPX3 expression is associated with higher stage and lymph node metastasis, as well as poorer prognosis. GPX3 is closely related to thyroid function and antioxidant function, and its expression may be regulated by epigenetic inheritance such as methylation modification or histone modification. In vitro experiments, GPX3 expression is associated with cancer cell sensitivity to oxidant and platinum-based chemotherapy and is involved in tumor metastasis in oxidative environments.

Discussion

We explored the relationship between GPX3 and clinical features, immune infiltration characteristics, migration and metastasis, and chemotherapy sensitivities of human cancers. We further investigated the potential genetic and epigenetic regulation of GPX3 in cancer. Our results suggested that GPX3 plays a complicated role in the tumor microenvironment, simultaneously promoting metastasis and chemotherapy resistance in human cancers.
Coexistence of anomalous muscle, persistent median artery, bifid median nerve causing carpal tunnel syndrome: A case report and literature review
Authors: Qin Jun , Tan Xia-xian , Xue Ming-qiang , Wang Jing-wei , Zhao Jin-min , Sha Ke
Published: February 2023

Carpal tunnel syndrome (CTS) is an upper extremity median nerve entrapment disorder that is rare in children and adolescents. Anatomical variations of the wrist, such as anomalous muscles, persistent median artery (PMA), and bifid median nerves (BMN), are rare etiology of CTS. Coexistence of all three variants combined with CTS in adolescents has been rarely reported. Case description: A 16-year-old right-hand dominant male presented to our clinic with several years of bilateral thenar muscle atrophy and weakness but no paresthesia or pain in his both hands. Ultrasonography showed that the right median nerve become significantly thinner, and the left median nerve was split into two branches by PMA. Magnetic resonance imaging (MRI) revealed that anomalous muscles in the bilateral wrist extending to the carpal tunnel, causing compression of the median nerve. Considering the possibility of CTS clinically, the patient underwent bilateral open carpal tunnel release without resection of anomalous muscles and PMA. The patient has no discomfort after 2 years. This suggests that anatomical variations of the carpal tunnel may contribute to CTS, which can be confirmed by preoperative ultrasonography and MRI, and the possibility of carpal tunnel anatomical variations should be considered when CTS occurs in adolescents. Open carpal tunnel release is an effective treatment for juvenile CTS without the need to resect abnormal muscle and PMA during the operation.
Seroprevalence of Epstein–Barr virus infection in children during the COVID-19 pandemic in Zhejiang, China
Authors: Cai Fengqing , Gao Hui , Ye Qing
Published: February 2023

Aim

We aimed to investigate the seroprevalence of Epstein–Barr virus (EBV) infection in children before and during the COVID-19 pandemic.

Methods

All children admitted to the Children's Hospital Affiliated to Zhejiang University from January 2019 to December 2021 with suspected EBV-associated disease and EBV antibodies were detected by a two-step indirect method of chemiluminescence technology. A total of 44,943 children were enrolled in this study. The seroprevalence of EBV infections was compared from January 2019 to December 2021.

Results

The total seropositive rate of EBV infections was 61.02% between January 2019 and December 2021, and the seropositive trend decreased year by year. The total number of seropositive EBV infections in 2020 was reduced by 30% compared to that in 2019. In particular, nearly 30% and 50% reductions in the number of acute EBV infections and EBV reactivations or late primary infections from 2019 to 2020 were found, respectively. The number of acute EBV infections in children aged 1–3 years and EBV reactivation or late primary infection in children aged 6–9 years in 2020 sharply dropped by approximately 40% and 64% compared to that in 2019.

Conclusions

Our study further demonstrated that the prevention and control measures for COVID-19 in China had a certain effect on containing acute EBV infections and EBV reactivations or late primary infections.
How to use COVID-19 antiviral drugs in patients with chronic kidney disease
Authors: Kale Ajinath , Shelke Vishwadeep , Dagar Neha , Anders Hans-Joachim , Gaikwad Anil Bhanudas
Published: February 2023

Antiviral drugs such as Remdesivir (Veklury), Nirmatrelvir with Ritonavir (Paxlovid), Azvudine, and Molnupiravir (Lagevrio) can reduce the risk for severe and fatal Coronavirus Disease (COVID)-19. Although chronic kidney disease is a highly prevalent risk factor for severe and fatal COVID-19, most clinical trials with these drugs excluded patients with impaired kidney function. Advanced CKD is associated with a state of secondary immunodeficiency (SIDKD), which increases the susceptibility to severe COVID-19, COVID-19 complications, and the risk of hospitalization and mortality among COVID-19 patients. The risk to develop COVID-19 related acute kidney injury is higher in patients with precedent CKD. Selecting appropriate therapies for COVID-19 patients with impaired kidney function is a challenge for healthcare professionals. Here, we discuss the pharmacokinetics and pharmacodynamics of COVID-19-related antiviral drugs with a focus on their potential use and dosing in COVID-19 patients with different stages of CKD. Additionally, we describe the adverse effects and precautions to be taken into account when using these antivirals in COVID-19 patients with CKD. Lastly, we also discuss about the use of monoclonal antibodies in COVID-19 patients with kidney disease and related complications.
Identification of linderalactone as a natural inhibitor of SHP2 to ameliorate CCl4-induced liver fibrosis
Authors: Zhang Yi , Cai Binhao , Li Yingying , Xu Ying , Wang Yuhan , Zheng Lulu , Zheng Xiaochun , Yin Lina , Chen Gaozhi , Wang Yunxiang , Liang Guang , Chen Lingfeng
Published: February 2023

Liver fibrosis is characterised by the activation of hepatic stellate cells (HSCs) and matrix deposition. Accumulating evidence has revealed that the oncogenic protein tyrosine phosphatase Src homology 2 domain-containing phosphatase 2 (SHP2) acts as a therapeutic target of fibrosis. Although several SHP2 inhibitors have reached early clinical trials, there are currently no FDA-approved drugs that target SHP2. In this study, we aimed to identify novel SHP2 inhibitors from an in-house natural product library to treat liver fibrosis. Out of the screened 800 compounds, a furanogermacrane sesquiterpene, linderalactone (LIN), significantly inhibited SHP2 dephosphorylation activity in vitro. Cross-validated enzymatic assays, bio-layer interferometry (BLI) assays, and site-directed mutagenesis were used to confirm that LIN directly binds to the catalytic PTP domain of SHP2. In vivo administration of LIN significantly ameliorated carbon tetrachloride (CCl4)-induced HSC activation and liver fibrosis by inhibiting the TGFβ/Smad3 pathway. Thus, LIN or its derivatives could be considered potential therapeutic agents against SHP2-related diseases, such as liver fibrosis or NASH.