bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Composition, Larvicidal and Repellent Activities of Wild Plant Essential Oils against Aedes aegypti
Authors: Abbas Muhammad Ghazanfar , Haris Abdullah , Binyameen Muhammad , Nazir Abdul , Mozūratis Raimondas , Azeem Muhammad
Published: December 2022

Bio-degradable and eco-friendly essential oils (EOs) extracted from Mentha longifolia, Salsola imbricata, Erigeron bonariensis, E. canadensis, Ailanthus altissima, and Zanthoxylum armatum were investigated for their repellent and larvicidal potential against Aedes aegypti mosquitoes. The EOs of M. longifolia, S. imbricata, E. bonariensis, E. canadensis, A. altissima, and Z. armatum exhibited 99.0%, 96.8%, 40.2%, 41.7%, 29.1%, and 13.2% repellency against mosquitoes at a tested dose of 33.3 μg/cm2, respectively. In time span bioassays, the EOs of M. longifolia, S. imbricata, E. bonariensis, and E. canadensis showed more than 40% repellency for 60 min at a tested dose of 330 μg/cm2. Larvicidal bioassays revealed that larvae of Ae. aegypti were the most susceptible to M. longifolia (LC50, 39.3 mg/L), E. bonariensis (LC50, 26.0 mg/L), E. canadensis (LC50, 35.7 mg/L), and Z. armatum (LC50, 35.9 mg/L) EOs upon 48 h exposure. The most abundant constituents in the EOs of M. longifolia, S. imbricata, E. bonariensis, E. canadensis and A. altissima were piperitone oxide (45.5%), carvone (39.9%), matricaria ester (43.1%), (31.7%) and eugenol (24.4%), respectively. Our study demonstrates that EOs of M. longifolia, S. imbricata, E. bonariensis, and E. canadensis might be used to control Ae. aegypti mosquitoes without harming humans or the environment.
Genome-Wide Identification and Expression Pattern of the GRAS Gene Family in Pitaya (Selenicereus undatus L.)
Authors: Zaman Qamar U , Hussain Muhammad Azhar , Khan Latif Ullah , Cui Jian-Peng , Hui Liu , Khan Darya , Lv Wei , Wang Hua-Feng
Published: December 2022

The GRAS gene family is one of the most important families of transcriptional factors that have diverse functions in plant growth and developmental processes including axillary meristem patterning, signal-transduction, cell maintenance, phytohormone and light signaling. Despite their importance, the function of GRAS genes in pitaya fruit (Selenicereus undatus L.) remains unknown. Here, 45 members of the HuGRAS gene family were identified in the pitaya genome, which was distributed on 11 chromosomes. All 45 members of HuGRAS were grouped into nine subfamilies using phylogenetic analysis with six other species: maize, rice, soybeans, tomatoes, Medicago truncatula and Arabidopsis. Among the 45 genes, 12 genes were selected from RNA-Seq data due to their higher expression in different plant tissues of pitaya. In order to verify the RNA-Seq data, these 12 HuGRAS genes were subjected for qRT-PCR validation. Nine HuGRAS genes exhibited higher relative expression in different tissues of the plant. These nine genes which were categorized into six subfamilies inlcuding DELLA (HuGRAS-1), SCL-3 (HuGRAS-7), PAT1 (HuGRAS-34, HuGRAS-35, HuGRAS-41), HAM (HuGRAS-37), SCR (HuGRAS-12) and LISCL (HuGRAS-18, HuGRAS-25) might regulate growth and development in the pitaya plant. The results of the present study provide valuable information to improve tropical pitaya through a molecular and conventional breeding program.
The ‘Reverse FDUF’ Mechanism of Atrial Excitation–Contraction Coupling Sustains Calcium Alternans—A Hypothesis
Authors: Banach Kathrin , Blatter Lothar A.
Published: December 2022

Cardiac calcium alternans is defined as beat-to-beat alternations of Ca transient (CaT) amplitude and has been linked to cardiac arrhythmia, including atrial fibrillation. We investigated the mechanism of atrial alternans in isolated rabbit atrial myocytes using high-resolution line scan confocal Ca imaging. Alternans was induced by increasing the pacing frequency until stable alternans was observed (1.6–2.5 Hz at room temperature). In atrial myocytes, action potential-induced Ca release is initiated in the cell periphery and subsequently propagates towards the cell center by Ca-induced Ca release (CICR) in a Ca wave-like fashion, driven by the newly identified ‘fire-diffuse-uptake-fire’ (FDUF) mechanism. The development of CaT alternans was accompanied by characteristic changes of the spatio-temporal organization of the CaT. During the later phase of the CaT, central [Ca]i exceeded peripheral [Ca]i that was indicative of a reversal of the subcellular [Ca]i gradient from centripetal to centrifugal. This gradient reversal resulted in a reversal of CICR propagation, causing a secondary Ca release during the large-amplitude alternans CaT, thereby prolonging the CaT, enhancing Ca-release refractoriness and reducing Ca release on the subsequent beat, thus enhancing the degree of CaT alternans. Here, we propose the ‘reverse FDUF’ mechanism as a novel cellular mechanism of atrial CaT alternans, which explains how the uncoupling of central from peripheral Ca release leads to the reversal of propagating CICR and to alternans.
A Novel Frameshift CHD4 Variant Leading to Sifrim-Hitz-Weiss Syndrome in a Proband with a Subclinical Familial t(17;19) and a Large dup(2)(q14.3q21.1)
Authors: Da Silva Jorge Diogo , Oliva-Teles Natália , Tkachenko Nataliya , Fino Joana , Marques Mariana , Fortuna Ana Maria , David Dezso
Published: December 2022

The genetic complexity of neurodevelopmental disorders (NDD), combined with a heterogeneous clinical presentation, makes accurate assessment of their molecular bases and pathogenic mechanisms challenging. Our purpose is to reveal the pathogenic variant underlying a complex NDD through identification of the “full” spectrum of structural genomic and genetic variants. Therefore, clinical phenotyping and identification of variants by genome and exome sequencing, together with comprehensive assessment of these and affected candidate genes, were carried out. A maternally-inherited familial translocation [t(17;19)(p13.1;p13.3)mat] disrupting the GSG1 like 2 gene (GSG1L2), a 3.2 Mb dup(2)(q14.3q21.1) encompassing the autosomal dominant OMIM phenotype-associated PROC and HS6ST1 gene, and a novel frameshift c.4442del, p.(Gly1481Valfs*21) variant within exon 30 of the Chromodomain helicase DNA binding protein 4 (CHD4) have been identified. Considering the pathogenic potential of each variant and the proband’s phenotype, we conclude that this case basically fits the Sifrim–Hitz–Weiss syndrome or CHD4-associated neurodevelopmental phenotype. Finally, our data highlight the need for identification of the “full” spectrum of structural genomic and genetic variants and of reverse comparative phenotyping, including unrelated patients with variants in same genes, for improved genomic healthcare of patients with NDD.
Non-Coding RNAs in Health and Disease: Editorial
Authors: Catanzaro Giuseppina
Published: December 2022

Non-coding RNAs (ncRNAs) represent the largest part of the transcriptional production of the human genome and play key roles in health and disease processes [...]
The Overlap Syndrome of Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease: A Systematic Review
Authors: Czerwaty Katarzyna , Dżaman Karolina , Sobczyk Krystyna Maria , Sikorska Katarzyna Irmina
Published: December 2022

Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are common diseases that strongly impact the quality and length of life. Their coexistence is determined by overlap syndrome (OS). This systematic review aims to define the significance of these comorbidities according to the current state of knowledge. For this systematic review, we searched PubMed, Scopus, and Cochrane for studies published between 2018 and 26 October 2022, to find original, observational, human studies published in English, where the diagnosis of COPD was according to the Global Initiative for Obstructive Lung Disease guidelines and the diagnosis of OSA was based on polysomnography. The quality of studies was assessed using the Newcastle–Ottawa quality assessment tool for cohort and case–control studies, as well as its modification for cross-sectional studies. Of the 1548 records identified, 38 were eligible and included in this systematic review. The included studies covered a total population of 27,064 participants. This paper summarizes the most important, up-to-date information regarding OS, including the prevalence, meaning of age/gender/body mass index, polysomnography findings, pulmonary function, comorbidities, predicting OSA among COPD patients, and treatment of this syndrome.
Comprehensive Profiling of Early Neoplastic Gastric Microenvironment Modifications and Biodynamics in Impaired BMP-Signaling FoxL1+-Telocytes
Authors: Alfonso Alain B. , Pomerleau Véronique , Nicolás Vilcy Reyes , Raisch Jennifer , Jurkovic Carla-Marie , Boisvert François-Michel , Perreault Nathalie
Published: December 2022

FoxL1+telocytes (TCFoxL1+) are novel gastrointestinal subepithelial cells that form a communication axis between the mesenchyme and epithelium. TCFoxL1+ are strategically positioned to be key contributors to the microenvironment through production and secretion of growth factors and extracellular matrix (ECM) proteins. In recent years, the alteration of the bone morphogenetic protein (BMP) signaling in TCFoxL1+ was demonstrated to trigger a toxic microenvironment with ECM remodeling that leads to the development of pre-neoplastic gastric lesions. However, a comprehensive analysis of variations in the ECM composition and its associated proteins in gastric neoplasia linked to TCFoxL1+ dysregulation has never been performed. This study provides a better understanding of how TCFoxL1+ defective BMP signaling participates in the gastric pre-neoplastic microenvironment. Using a proteomic approach, we determined the changes in the complete matrisome of BmpR1a△FoxL1+ and control mice, both in total antrum as well as in isolated mesenchyme-enriched antrum fractions. Comparative proteomic analysis revealed that the deconstruction of the gastric antrum led to a more comprehensive analysis of the ECM fraction of gastric tissues microenvironment. These results show that TCFoxL1+ are key members of the mesenchymal cell population and actively participate in the establishment of the matrisomic fraction of the microenvironment, thus influencing epithelial cell behavior.
The Effect of Mirror Visual Feedback on Spatial Neglect for Patients after Stroke: A Preliminary Randomized Controlled Trial
Authors: Fong Kenneth N. K. , Ting K. H. , Zhang Xinfei , Yau Christina S. F. , Li Leonard S. W.
Published: December 2022

We investigated the effects of mirror visual feedback (MVF), with reference to using a glass wall or a covered mirror, on the reduction of spatial neglect for patients with stroke. A total of 21 subacute patients with left spatial neglect after right-hemispheric stroke were randomly assigned to 3 groups: MVF, sham 1 (viewing the hemiparetic arm through the transparent glass during bilateral arm movement) and sham 2 (using a covered mirror). The 3-week treatment program for all groups consisted of 12 sessions of movement tasks for the hemiparetic arm graded according to the severity of arm impairments. Blinded assessments were administered at pre/post and a three-week follow-up. The results showed that there was no significant advantage for MVF than sham 1; however, MVF was more beneficial than sham 2, as shown by the line crossing (p = 0.022). Improvement in discriminating the left-gap figures on the left and right side of the page in the Gap Detection Test was greater in MVF than using the covered mirror (p = 0.013; p = 0.010), showing a slight advantage of MVF in alleviating allocentric symptoms. Our study confirms that MVF was superior to using a covered mirror as a method for reducing spatial neglect and in alleviating its allocentric symptoms, but no significant advantage over bilateral arm movement through transparent glass was found. Further research in comparing their therapeutic effects is warranted.
A Holistic Analysis of Individual Brain Activity Revealed the Relationship of Brain Areal Activity with the Entire Brain’s Activity
Authors: Huang Jie
Published: December 2022

The relationship between brain areal activity and the entire brain’s activity is unknown, and understanding this relationship is imperative for understanding the neural mechanisms of human brain function at systems level. The complex activity of human brains varies from area to area and from time to time across the whole brain. BOLD-fMRI measures this spatiotemporal activity at a large-scale systems level. The BOLD time signal of an area reflects a collective neuronal activity of over one million neurons under that area, and the temporal correlation of this time signal with that of every point in the brain yields a full spatial map that characterizes the entire brain’s functional co-activity (FC) relative to that area’s activity. Here we show a quantitative relationship between brain areal activity and the activity of the entire brain. The temporal correlation coefficient r of the signal time courses of two areas quantifies the degree of co-activity between the two areas, and the spatial correlation coefficient R of their corresponding two FC maps quantifies the co-activity between these two maps. We found that a modified sigmoid function quantified this R with r, i.e., Rr=1+ra−1−ra1+ra+1−ra, revealing a relationship between the activity of brain areas and that of the entire brain. The parameter a in this equation was found to be associated with the mean degree of the temporal co-activity among all brain areas, and its value was brain functional state dependent too. Our study demonstrated a novel approach for analyzing fMRI data to holistically characterize the entire brain’s activity quantitatively for any brain functional state in individual humans.
Effects of Physiological Signal Removal on Resting-State Functional MRI Metrics
Authors: Choi Uk-Su , Sung Yul-Wan , Ogawa Seiji
Published: December 2022

Resting-state fMRIs (rs-fMRIs) have been widely used for investigation of diverse brain functions, including brain cognition. The rs-fMRI has easily elucidated rs-fMRI metrics, such as the fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), voxel-mirrored homotopic connectivity (VMHC), and degree centrality (DC). To increase the applicability of these metrics, higher reliability is required by reducing confounders that are not related to the functional connectivity signal. Many previous studies already demonstrated the effects of physiological artifact removal from rs-fMRI data, but few have evaluated the effect on rs-fMRI metrics. In this study, we examined the effect of physiological noise correction on the most common rs-fMRI metrics. We calculated the intraclass correlation coefficient of repeated measurements on parcellated brain areas by applying physiological noise correction based on the RETROICOR method. Then, we evaluated the correction effect for five rs-fMRI metrics for the whole brain: FC, fALFF, ReHo, VMHC, and DC. The correction effect depended not only on the brain region, but also on the metric. Among the five metrics, the reliability in terms of the mean value of all ROIs was significantly improved for FC, but it deteriorated for fALFF, with no significant differences for ReHo, VMHC, and DC. Therefore, the decision on whether to perform the physiological correction should be based on the type of metric used.
Perceived Control and Work-Related Stress Mediate the Effects of Grit on Depression among Employees
Authors: Jung Sra , Shin Young Chul , Oh Kang-Seob , Shin Dong-Won , Kim Eun Soo , Lee Mi Yeon , Cho Sung Joon , Jeon Sang-Won
Published: December 2022

We developed and evaluated an interpersonal model of depression in employees, where passion and perseverance affect occupational stress and perceived control, which in turn affect risk of depression. The participants were employees of 18 private companies and local government organizations in Korea aged 19 to 65 years. A total of 11,422 participants completed questionnaires including the Korean version of the Grit scale, the occupational stress scale, the perceived control subscale in the perceived stress scale, and the Center for Epidemiologic Studies Depression Scale. Mediation analysis was performed to determine relationships among trait-level passion and perseverance, work-related stress, perceived control, and depression. Passion and perseverance preceded depression in employees. Higher occupational stress and lower perceived control mediated the association between passion and depression, and between perseverance and depression. Passion and perseverance exert preventive effects on depression by decreasing workplace stress and elevating perceived control. Future studies should investigate the effects of psychological characteristics on the development of depression in employees.
Clinical and Neurophysiological Follow-Up of Chronic Inflammatory Demyelinating Polyneuropathy Patients Treated with Subcutaneous Immunoglobulins: A Real-Life Single Center Study
Authors: Alonge Paolo , Di Stefano Vincenzo , Lupica Antonino , Gangitano Massimo , Torrente Angelo , Pignolo Antonia , Maggio Bruna , Iacono Salvatore , Gentile Francesca , Brighina Filippo
Published: December 2022

Background: chronic idiopathic demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated neuropathy characterized by weakness, sensory symptoms and significant reduction or loss of deep tendon reflexes evolving over 2 months at least, associated with electrophysiological evidence of peripheral nerve demyelination. Recently, subcutaneous immunoglobulins (SCIg) have been introduced in clinical practice as a maintenance therapy for CIDP; nevertheless, electrophysiological and efficacy data are limited. Methods: to evaluate SCIg treatment efficacy, we retrospectively reviewed data from 15 CIDP patients referring to our clinic, receiving SCIg treatment and who performed electrophysiological studies (NCS) and clinical scores (MRC sumscore, INCAT disability score and ISS) before starting the treatment and at least one year after. Results: NCS showed no significant changes before and during treatment for all the nerves explored. Clinical scores did not significantly change between evaluations. Correlation analysis evidenced a positive correlation of cMAPs distal amplitude with MRC sumscore and a trend of negative correlation with the INCAT disability score. Conclusions: SCIg maintenance therapy preserves nerve function in CIDP with a good efficacy and safety. Treatment effectiveness can be assessed with ENG, which represents a useful instrument in the follow-up and prognostic assessment of CIDP.
Axial Attention Convolutional Neural Network for Brain Tumor Segmentation with Multi-Modality MRI Scans
Authors: Tian Weiwei , Li Dengwang , Lv Mengyu , Huang Pu
Published: December 2022

Accurately identifying tumors from MRI scans is of the utmost importance for clinical diagnostics and when making plans regarding brain tumor treatment. However, manual segmentation is a challenging and time-consuming process in practice and exhibits a high degree of variability between doctors. Therefore, an axial attention brain tumor segmentation network was established in this paper, automatically segmenting tumor subregions from multi-modality MRIs. The axial attention mechanism was employed to capture richer semantic information, which makes it easier for models to provide local–global contextual information by incorporating local and global feature representations while simplifying the computational complexity. The deep supervision mechanism is employed to avoid vanishing gradients and guide the AABTS-Net to generate better feature representations. The hybrid loss is employed in the model to handle the class imbalance of the dataset. Furthermore, we conduct comprehensive experiments on the BraTS 2019 and 2020 datasets. The proposed AABTS-Net shows greater robustness and accuracy, which signifies that the model can be employed in clinical practice and provides a new avenue for medical image segmentation systems.
The Power of Images and the Logics of Discovery in Psychiatric Care
Authors: Stanghellini Giovanni
Published: December 2022

This paper, aligned with contemporary thinking in terms of patient-centered care and co-creation of patient care, highlights the limitations of the reductionist approaches to psychiatry, offering an alternative, “emergent” perspective and approach. Assuming that psychopathological phenomena are essentially relational, what kind of epistemological framework and ‘logic of discovery’ should be adopted? I review two standard methods I call ‘ticking boxes’ and ‘drafting arrows’. Within the ticking boxes framework, the clinician’s main goal is to discover whether a patient showing psychopathological phenomena meets pre-given diagnostic criteria. The process of discovery can be compared to two people assembling a puzzle where the patient has the pieces and the interviewer has the image of the completed design. Drafting arrows consists in constructing pathogenetic diagrams that display linear causative relationships between variables connected by an arrow to other nodes. These explanatory narratives include psychodynamic (motivational) and biological (causal) diagrams. I argue for a third approach called ‘linking dots’, a method of discovery based on the emergent properties of psychopathological phenomena. I build on and develop the approach to images and discovery devised by art historian Aby Warburg in his atlas of images Bilderatlas Mnemosyne. The visual constellations created by Warburg in the panels of the Bilderatlas can be understood as a method to reveal the layers of memory and the web of relationships manifested in them, inviting the viewer to participate in the production of meanings, forging ever new connections between the images. It is the viewer’s acts of perception that draw relationships between singularities. I suggest that this method is of enormous significance in the context of today’s socio-cultural transformation processes and related forms of psychopathological conditions, which can no longer be comprehended using the categories of existing knowledge systems.
Retrospective Clinical Analysis of Epilepsy Treatment for Children with Drug-Resistant Epilepsy (A Single-Center Experience)
Authors: Liu Changqing , Hu Yue , Zhou Jian , Guan Yuguang , Wang Mengyang , Qi Xueling , Wang Xiongfei , Zhang Huawei , Adilijiang Aihemaitiniyazi , Li Tiemin , Luan Guoming
Published: December 2022

Objectives: This retrospective cohort study investigated the clinical characteristics and seizure outcomes of patients aged 1–14 years with drug-resistant epilepsy (DRE) who were treated by different typologies of therapy. Methods: Four hundred and eighteen children with DRE were recruited from Sanbo Brain Hospital of Capital Medical University from April 2008 to February 2015. The patients were divided into three groups: medication (n = 134, 32.06%), resection surgery (n = 185, 44.26%), and palliative surgery (n = 99, 23.68%) groups. Demographic characteristics were attained from medical records. All patients were followed up for at least 5 years, with seizure outcomes classified according to International League Against Epilepsy criteria. The psychological outcome was evaluated with the development quotient and Wechsler Intelligence Quotient Scale for children (Chinese version). Results: The most frequent seizure type was generalized tonic seizure in 53.83% of patients. Age at seizure onset in 54.55% of patients was <3 years. The most frequent etiologies were focal cortical dysplasia (FCD). West syndrome was the most common epilepsy syndrome. Favorable seizure outcomes at the 5-year follow-up in the medication, resection surgery, and palliative surgery groups were 5.22%, 77.30%, and 14.14%, respectively. The patients showed varying degrees of improvement in terms of developmental and intellectual outcomes post-treatment. Conclusions: Pediatric patients with DRE were characterized by frequent seizures, a variety of seizure types, and complex etiology. Recurrent seizures severely affected the cognitive function and development of children. Early surgical intervention would be beneficial for seizure control and prevention of mental retardation. Palliative surgery was also a reasonable option for patients who were not suitable candidates for resection surgery.
White Matter Correlates of Domain-Specific Working Memory
Authors: Horne Autumn , Ding Junhua , Schnur Tatiana , Martin Randi
Published: December 2022

Prior evidence suggests domain-specific working memory (WM) buffers for maintaining phonological (i.e., speech sound) and semantic (i.e., meaning) information. The phonological WM buffer’s proposed location is in the left supramarginal gyrus (SMG), whereas semantic WM has been related to the left inferior frontal gyrus (IFG), the middle frontal gyrus (MFG), and the angular gyrus (AG). However, less is known about the white matter correlates of phonological and semantic WM. We tested 45 individuals with left hemisphere brain damage on single word processing, phonological WM, and semantic WM tasks and obtained T1 and diffusion weighted neuroimaging. Virtual dissections were performed for each participants’ arcuate fasciculus (AF), inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), middle longitudinal fasciculus (MLF), and uncinate fasciculus (UF), which connect the proposed domain-specific WM buffers with perceptual or processing regions. The results showed that the left IFOF and the posterior segment of the AF were related to semantic WM performance. Phonological WM was related to both the left ILF and the whole AF. This work informs our understanding of the white matter correlates of WM, especially semantic WM, which has not previously been investigated. In addition, this work helps to adjudicate between theories of verbal WM, providing some evidence for separate pathways supporting phonological and semantic WM.
Effective Motion Sensors and Deep Learning Techniques for Unmanned Ground Vehicle (UGV)-Based Automated Pavement Layer Change Detection in Road Construction
Authors: Patel Tirth , Guo Brian H. W. , van der Walt Jacobus Daniel , Zou Yang
Published: December 2022

As-built progress of the constructed pavement should be monitored effectively to provide prompt project control. However, current pavement construction progress monitoring practices (e.g., data collection, processing, and analysis) are typically manual, time-consuming, tedious, and error-prone. To address this, this study proposes sensors mounted using a UGV-based methodology to develop a pavement layer change classifier measuring pavement construction progress automatically. Initially, data were collected using the UGV equipped with a laser ToF (time-of-flight) distance sensor, accelerometer, gyroscope, and GPS sensor in a controlled environment by constructing various scenarios of pavement layer change. Subsequently, four Long Short-Term Memory network variants (LSTMs) (LSTM, BiLSTM, CNN-LSTM, and ConvLSTM) were implemented on collected sensor data combinations for developing pavement layer change classifiers. The authors conducted the experiment to select the best sensor combinations for feature detection of the layer change classifier model. Subsequently, individual performance measures of each class with learning curves and confusion matrices were generated using sensor combination data to find out the best algorithm among all implemented algorithms. The experimental result demonstrates the (az + gx + D) sensor combination as the best feature detector with high-performance measures (accuracy, precision, recall, and F1 score). The result also confirms the ConvLSTM as the best algorithm with the highest overall accuracy of 97.88% with (az + gx + D) sensor combination data. The high-performance measures with the proposed approach confirm the feasibility of detecting pavement layer changes in real pavement construction projects. This proposed approach can potentially improve the efficiency of road construction progress measurement. This research study is a stepping stone for automated road construction progress monitoring.
Pathologic Response of Associated Ductal Carcinoma In Situ to Neoadjuvant Systemic Therapy: A Systematic Review
Authors: Wazir Umar , Patani Neill , Balalaa Nahed , Mokbel Kefah
Published: December 2022

Contrary to traditional assumptions, recent evidence suggests that neoadjuvant systemic therapy (NST) given for invasive breast cancer may eradicate co-existent ductal carcinoma in-situ (DCIS), which may facilitate de-escalation of breast resections. The aim of this systematic review was to assess the eradication rate of DCIS by NST given for invasive breast cancer. Searches were performed in MEDLINE using appropriate search terms. Six studies (N = 659) in which pathological data were available regarding the presence of DCIS prior to neoadjuvant chemotherapy (NACT) were identified. Only one study investigating the impact of neoadjuvant endocrine therapy (NET) met the search criteria. After pooled analysis, post-NACT pathology showed no residual DCIS in 40.5% of patients (267/659; 95% CI: 36.8–44.3). There was no significant difference in DCIS eradication rate between triple negative breast cancer (TNBC) and HER2-positive disease (45% vs. 46% respectively). NET achieved eradication of DCIS in 15% of patients (9/59). Importantly, residual widespread micro-calcifications after NST did not necessarily indicate residual disease. In view of the results of the pooled analysis, the presence of extensive DCIS prior to NST should not mandate mastectomy and de-escalation to breast conserving surgery (BCS) should be considered in patients identified by contrast enhanced magnetic resonance imaging (CE-MRI).
Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience
Authors: Diehl Christian D. , Pigorsch Steffi U. , Gempt Jens , Krieg Sandro M. , Reitz Silvia , Waltenberger Maria , Barz Melanie , Meyer Hanno S. , Wagner Arthur , Wilkens Jan , Wiestler Benedikt , Zimmer Claus , Meyer Bernhard , Combs Stephanie E.
Published: December 2022

Background: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. Method: Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16–30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan–Meyer analysis were applied. Results: The mean follow-up time was 10.8 months (range, 0–39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3–100%), 71.4% (95%-CI 50.2–92.6%) and 58.0% (95%-CI 34.1–81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. Conclusion: In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis.
Clinical Practice Evolvement for Post-Operative Prostate Cancer Radiotherapy—Part 1: Consistent Organs at Risk Management with Advanced Image Guidance
Authors: Laughlin Brady S. , Lo Stephanie , Vargas Carlos E. , DeWees Todd A. , Van der Walt Charles , Tinnon Katie , Beckett Mason , Hobbis Dean , Schild Steven E. , Wong William W. , Keole Sameer R. , Rwigema Jean-Claude M. , Yu Nathan Y. , Clouser Edward , Rong Yi
Published: December 2022

Purpose: Post-operative prostate cancer patients are treated with full bladder instruction and the use of an endorectal balloon (ERB). We reassessed the efficacy of this practice based on daily image guidance and dose delivery using high-quality iterative reconstructed cone-beam CT (iCBCT). Methods: Fractional dose delivery was calculated on daily iCBCT for 314 fractions from 14 post-operative prostate patients (8 with and 6 without ERB) treated with volumetric modulated radiotherapy (VMAT). All patients were positioned using novel iCBCT during image guidance. The bladder, rectal wall, femoral heads, and prostate bed clinical tumor volume (CTV) were contoured and verified on daily iCBCT. The dose-volume parameters of the contoured organs at risk (OAR) and CTV coverage were assessed for the clinical impact of daily bladder volume variations and the use of ERB. Minimum bladder volume was studied, and a straightforward bladder instruction was explored for easy clinical adoption. Results: A “minimum bladder” contour, the overlap between the original bladder contour and a 15 mm anterior and superior expansion from prostate bed PTV, was confirmed to be effective in identifying cases that might fail a bladder constraint of V65% <60%. The average difference between the maximum and minimum bladder volumes for each patient was 277.1 mL. The daily bladder volumes varied from 62.4 to 590.7 mL and ranged from 29 to 286% of the corresponding planning bladder volume. The bladder constraint of V65% <60% was met in almost all fractions (98%). CTVs (D90%, D95%, and D98%) remained well-covered regardless of the absolute bladder volume daily variation or the presence of the endorectal balloon. Patients with an endorectal balloon showed smaller variation but a higher average maximum rectal wall dose (D0.03mL: 104.3% of the prescription) compared to patients without (103.3%). Conclusions: A “minimum bladder” contour was determined that can be easily generated and followed to ensure sufficient bladder sparing. Further analysis and validation are needed to confirm the utility of the minimal bladder contour. Accurate dose delivery can be achieved for prostate bed target coverage and OAR sparing with or without the use of ERB.
Evolutionary Analysis of TCGA Data Using Over- and Under- Mutated Genes Identify Key Molecular Pathways and Cellular Functions in Lung Cancer Subtypes
Authors: Freischel Audrey R. , Teer Jamie K. , Luddy Kimberly , Cunningham Jessica , Artzy-Randrup Yael , Epstein Tamir , Tsai Kenneth Y. , Berglund Anders , Cleveland John L. , Gillies Robert J. , Brown Joel S. , Gatenby Robert A.
Published: December 2022

We identify critical conserved and mutated genes through a theoretical model linking a gene’s fitness contribution to its observed mutational frequency in a clinical cohort. “Passenger” gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected. Non-synonymous mutations in essential genes reduce fitness and are eliminated by natural selection resulting in lower prevalence than expected. We apply this “evolutionary triage” principle to TCGA data from EGFR-mutant, KRAS-mutant, and NEK (non-EGFR/KRAS) lung adenocarcinomas. We find frequent overlap of evolutionarily selected non-synonymous gene mutations among the subtypes suggesting enrichment for adaptations to common local tissue selection forces. Overlap of conserved genes in the LUAD subtypes is rare suggesting negative evolutionary selection is strongly dependent on initiating mutational events during carcinogenesis. Highly expressed genes are more likely to be conserved and significant changes in expression (>20% increased/decreased) are common in genes with evolutionarily selected mutations but not in conserved genes. EGFR-mut cancers have fewer average mutations (89) than KRAS-mut (228) and NEK (313). Subtype-specific variation in conserved and mutated genes identify critical molecular components in cell signaling, extracellular matrix remodeling, and membrane transporters. These findings demonstrate subtype-specific patterns of co-adaptations between the defining driver mutation and somatically conserved genes as well as novel insights into epigenetic versus genetic contributions to cancer evolution.
Neuroblastoma Tumor-Associated Mesenchymal Stromal Cells Regulate the Cytolytic Functions of NK Cells
Authors: Di Matteo Sabina , Avanzini Maria Antonietta , Pelizzo Gloria , Calcaterra Valeria , Croce Stefania , Spaggiari Grazia Maria , Theuer Charles , Zuccotti Gianvincenzo , Moretta Lorenzo , Pelosi Andrea , Azzarone Bruno
Published: December 2022

Neuroblastoma tumor-associated mesenchymal stromal cells (NB-TA-MSC) have been extensively characterized for their pro-tumorigenic properties, while their immunosuppressive potential, especially against NK cells, has not been thoroughly investigated. Herein, we study the immune-regulatory potential of six primary young and senescent NB-TA-MSC on NK cell function. Young cells display a phenotype (CD105+/CD90+/CD73+/CD29+/CD146+) typical of MSC cells and, in addition, express high levels of immunomodulatory molecules (MHC-I, PDL-1 and PDL-2 and transcriptional-co-activator WWTR1), able to hinder NK cell activity. Notably, four of them express the neuroblastoma marker GD2, the most common target for NB immunotherapy. From a functional point of view, young NB-TA-MSC, contrary to the senescent ones, are resistant to activated NK cell-mediated lysis, but this behavior is overcome using anti-CD105 antibody TRC105 that activates antibody-dependent cell-mediated cytotoxicity. In addition, proliferating NB-TA-MSC, but not the senescent ones, after six days of co-culture, inhibit proliferation, expression of activating receptors and cytolytic activity of freshly isolated NK. Inhibitors of the soluble immunosuppressive factors L-kynurenine and prostaglandin E2 efficiently counteract this latter effect. Our data highlight the presence of phenotypically heterogeneous NB-TA-MSC displaying potent immunoregulatory properties towards NK cells, whose inhibition could be mandatory to improve the antitumor efficacy of targeted immunotherapy.
The Ginsenoside Compound K Suppresses Stem-Cell-like Properties and Colorectal Cancer Metastasis by Targeting Hypoxia-Driven Nur77-Akt Feed-Forward Signaling
Authors: Zhang Minda , Shi Zeyu , Zhang Shuaishuai , Li Xudan , To Sally Kit Yan , Peng Yijia , Liu Jie , Chen Siming , Hu Hongyu , Wong Alice Sze Tsai , Zeng Jin-Zhang
Published: December 2022

Hypoxia reprograms cancer stem cells. Nur77, an orphan nuclear receptor, highly expresses and facilitates colorectal cancer (CRC) stemness and metastasis under a hypoxic microenvironment. However, safe and effective small molecules that target Nur77 for CSC depletion remain unexplored. Here, we report our identification of the ginsenoside compound K (CK) as a new ligand of Nur77. CK strongly inhibits hypoxia-induced CRC sphere formation and CSC phenotypes in a Nur77-dependent manner. Hypoxia induces an intriguing Nur77-Akt feed-forward loop, resulting in reinforced PI3K/Akt signaling that is druggable by targeting Nur77. CK directly binds and modulates Nur77 phosphorylation to block the Nur77-Akt activation loop by disassociating Nur77 from the p63-bound Dicer promoter. The transcription of Dicer that is silenced under a hypoxia microenvironment is thus reactivated by CK. Consequently, the expression and processing capability of microRNA let-7i-5p are significantly increased, which targets PIK3CA mRNA for decay. The in vivo results showed that CK suppresses cancer stemness and metastasis without causing significant adverse effects. Given that the majority of FDA-approved and currently clinically tested PI3K/Akt inhibitors are reversible ATP-competitive kinase antagonists, targeting Nur77 for PI3K/Akt inactivation may provide an alternative strategy to overcoming concerns about drug selectivity and safety. The mechanistic target identification provides a basis for exploring CK as a promising nutraceutical against CRC.
On the Therapeutic Potential of ERK4 in Triple-Negative Breast Cancer
Authors: Boudghene-Stambouli Fadia , Soulez Mathilde , Ronkina Natalia , Dörrie Anneke , Kotlyarov Alexey , Seternes Ole-Morten , Gaestel Matthias , Meloche Sylvain
Published: December 2022

ERK3 and ERK4 define a distinct and understudied subfamily of mitogen-activated protein kinases (MAPKs). Little is known about the physiological roles of these atypical MAPKs and their association with human diseases. Interestingly, accumulating evidence points towards a role for ERK3 and ERK4 signaling in the initiation and progression of various types of cancer. Notably, a recent study reported that ERK4 is expressed in a subset of triple-negative breast cancer (TNBC) cell lines and that this expression is critical for AKT activation and for sustaining TNBC cell proliferation in vitro and tumor growth in mice. The authors also showed that depletion of ERK4 sensitizes TNBC cells to phosphatidylinositol-3-kinase (PI3K) inhibitors. They concluded that ERK4 is a promising therapeutic target for TNBC and has potential for combination therapy with PI3K inhibitors. Here, we raise concerns about the cellular models and experimental approaches used in this study, which compromise the conclusions on the oncogenic role of ERK4 in TNBC.
Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy
Authors: Li Lingjiao , Wang Shengmei , Zhou Wenhu
Published: December 2022

Chemotherapy is a standard treatment modality in clinic that exerts an antitumor effect via the activation of the caspase-3 pathway, inducing cell death. While a number of chemotherapeutic drugs have been developed to combat various types of tumors, severe side effects have been their common limitation, due to the nonspecific drug biodistribution, bringing significant pain to cancer patients. Recently, scientists found that, besides apoptosis, chemotherapy could also cause cell pyroptosis, both of which have great influence on the therapeutic index. For example, cell apoptosis is, generally, regarded as the main mechanism of killing tumor cells, while cell pyroptosis in tumors promotes treatment efficacy, but in normal tissue results in toxicity. Therefore, significant research efforts have been paid to exploring the rational modulation mode of cell death induced by chemotherapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. We first reviewed the mechanisms of chemotherapy-induced cell apoptosis and pyroptosis, in which the activated caspase-3 is the key signaling molecule for regulating both types of cell deaths. Then, we systematically discussed the rationale and methods of switching apoptosis to pyroptosis for enhanced antitumor efficacy, as well as the blockage of pyroptosis to decrease side effects. To balance cell pyroptosis in tumor and normal tissues, the level of GSDME expression and tumor-targeting drug delivery are two important factors. Finally, we proposed potential future research directions, which may provide guidance for researchers in the field.
Syntaxin-6, a Reliable Biomarker for Predicting the Prognosis of Patients with Cancer and the Effectiveness of Immunotherapy
Authors: Li Wenchao , Li Kuan , Wei Hongfa , Sun Yu , Liao Yangjing , Zou Yuan , Chen Xiancong , Deng Cuncan , Chen Songyao , He Yulong , Huo Mingyu , Zhang Changhua
Published: December 2022

Syntaxin-6 (STX6), a vesicular transport protein, is a direct target of the tumor suppressor gene P53, supporting cancer growth dependent on P53. However, STX6’s function in the tumor microenvironment has yet to be reported. In this research, we comprehensively explored the role of the oncogene STX6 in pan-cancer by combining data from several databases, including the Cancer Genome Atlas, CPTAC, cBioPortal, and TIMER. Then, we verified the carcinogenic effect of STX6 in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) through a series of experiments in vitro and in vivo. Bioinformatics analysis demonstrated that STX6 is an oncogene for several cancers and is mainly involved in the cell cycle, epithelial–mesenchymal transition, oxidative phosphorylation, and tumor immune modulation, especially for tumor-associated fibroblasts (CAFs) and NKT cells. Additionally, a high level of STX6 could indicate patients’ resistance to immunotherapy. Our own data indicated that the STX6 level was upregulated in HCC and CRC. Knockdown of the STX6 levels could arrest the cell cycle and restrain cell proliferation, migration, and invasion. RNA-seq indicated that STX6 was significantly involved in pathways for cancer, such as the MAPK signal pathway. In a mouse model, knockdown of STX6 inhibited tumor growth and potentiated anti-PD-1 efficacy. In light of the essential roles STX6 plays in carcinogenesis and cancer immunology, it has the potential to be a predictive biomarker and a target for cancer immunotherapy.
3T-MRI Artificial Intelligence in Patients with Invasive Breast Cancer to Predict Distant Metastasis Status: A Pilot Study
Authors: Calabrese Alessandro , Santucci Domiziana , Gravina Michela , Faiella Eliodoro , Cordelli Ermanno , Soda Paolo , Iannello Giulio , Sansone Carlo , Zobel Bruno Beomonte , Catalano Carlo , de Felice Carlo
Published: December 2022

Background: The incidence of breast cancer metastasis has decreased over the years. However, 20–30% of patients with early breast cancer still die from metastases. The purpose of this study is to evaluate the performance of a Deep Learning Convolutional Neural Networks (CNN) model to predict the risk of distant metastasis using 3T-MRI DCE sequences (Dynamic Contrast-Enhanced). Methods: A total of 157 breast cancer patients who underwent staging 3T-MRI examinations from January 2011 to July 2022 were retrospectively examined. Patient data, tumor histological and MRI characteristics, and clinical and imaging follow-up examinations of up to 7 years were collected. Of the 157 MRI examinations, 39/157 patients (40 lesions) had distant metastases, while 118/157 patients (120 lesions) were negative for distant metastases (control group). We analyzed the role of the Deep Learning technique using a single variable size bounding box (SVB) option and employed a Voxel Based (VB) NET CNN model. The CNN performance was evaluated in terms of accuracy, sensitivity, specificity, and area under the ROC curve (AUC). Results: The VB-NET model obtained a sensitivity, specificity, accuracy, and AUC of 52.50%, 80.51%, 73.42%, and 68.56%, respectively. A significant correlation was found between the risk of distant metastasis and tumor size, and the expression of PgR and HER2. Conclusions: We demonstrated a currently insufficient ability of the Deep Learning approach in predicting a distant metastasis status in patients with BC using CNNs.