bluuebunny/crossref_metadata_2025 huggingface dataset:
Location-Specific Radiomics Score: Novel Imaging Marker for Predicting Poor Outcome of Deep and Lobar Spontaneous Intracerebral Hemorrhage
Authors: Zhou Zhiming , Zhou Hongli , Song Zuhua , Chen Yuanyuan , Guo Dajing , Cai Jinhua
Published: December 2021

Objective: To derive and validate a location-specific radiomics score (Rad-score) based on noncontrast computed tomography for predicting poor deep and lobar spontaneous intracerebral hemorrhage (SICH) outcome.

Methods: In total, 494 SICH patients from multiple centers were retrospectively reviewed. Poor outcome was considered mRS 3–6 at 6 months. The Rad-score was derived using optimal radiomics features. The optimal location-specific Rad-score cut-offs for poor deep and lobar SICH outcomes were identified using receiver operating characteristic curve analysis. Univariable and multivariable analyses were used to determine independent poor outcome predictors. The combined models for deep and lobar SICH were constructed using independent predictors of poor outcomes, including dichotomized Rad-score in the derivation cohort, which was validated in the validation cohort.

Results: Of 494 SICH patients, 392 (79%) had deep SICH, and 373 (76%) had poor outcomes. The Glasgow Coma Scale score, haematoma enlargement, haematoma location, haematoma volume and Rad-score were independent predictors of poor outcomes (all P < 0.05). Cut-offs of Rad-score, 82.90 (AUC = 0.794) in deep SICH and 80.77 (AUC = 0.823) in lobar SICH, were identified for predicting poor outcomes. For deep SICH, the AUCs of the combined model were 0.856 and 0.831 in the derivation and validation cohorts, respectively. For lobar SICH, the combined model AUCs were 0.866 and 0.843 in the derivation and validation cohorts, respectively.

Conclusion: Location-specific Rad-scores and combined models can identify subjects at high risk of poor deep and lobar SICH outcomes, which could improve clinical trial design by screening target patients.
The Transcriptional Complex Sp1/KMT2A by Up-Regulating Restrictive Element 1 Silencing Transcription Factor Accelerates Methylmercury-Induced Cell Death in Motor Neuron-Like NSC34 Cells Overexpressing SOD1-G93A
Authors: Guida Natascia , Sanguigno Luca , Mascolo Luigi , Calabrese Lucrezia , Serani Angelo , Molinaro Pasquale , Lau C. Geoffrey , Annunziato Lucio , Formisano Luigi
Published: December 2021

Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu2+/Zn2+superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression.
Effect of Pulse Duration and Direction on Plasticity Induced by 5 Hz Repetitive Transcranial Magnetic Stimulation in Correlation With Neuronal Depolarization
Authors: Halawa Islam , Reichert Katharina , Aberra Aman S. , Sommer Martin , Peterchev Angel V. , Paulus Walter
Published: December 2021

Introduction: High frequency repetitive transcranial magnetic stimulation applied to the motor cortex causes an increase in the amplitude of motor evoked potentials (MEPs) that persists after stimulation. Here, we focus on the aftereffects generated by high frequency controllable pulse TMS (cTMS) with different directions, intensities, and pulse durations.

Objectives: To investigate the influence of pulse duration, direction, and amplitude in correlation to induced depolarization on the excitatory plastic aftereffects of 5 Hz repetitive transcranial magnetic stimulation (rTMS) using bidirectional cTMS pulses.

Methods: We stimulated the hand motor cortex with 5 Hz rTMS applying 1,200 bidirectional pulses with the main component durations of 80, 100, and 120 μs using a controllable pulse stimulator TMS (cTMS). Fourteen healthy subjects were investigated in nine sessions with 80% resting motor threshold (RMT) for posterior-anterior (PA) and 80 and 90% RMT anterior-posterior (AP) induced current direction. We used a model approximating neuronal membranes as a linear first order low-pass filter to estimate the strength–duration time constant and to simulate the membrane polarization produced by each waveform.

Results: PA and AP 5 Hz rTMS at 80% RMT produced no significant excitation. An exploratory analysis indicated that 90% RMT AP stimulation with 100 and 120 μs pulses but not 80 μs pulses led to significant excitation. We found a positive correlation between the plastic outcome of each session and the simulated peak neural membrane depolarization for time constants >100 μs. This correlation was strongest for neural elements that are depolarized by the main phase of the AP pulse, suggesting the effects were dependent on pulse direction.

Conclusions: Among the tested conditions, only 5 Hz rTMS with higher intensity and wider pulses appeared to produce excitatory aftereffects. This correlated with the greater depolarization of neural elements with time constants slower than the directly activated neural elements responsible for producing the motor output (e.g., somatic or dendritic membrane).

Significance: Higher intensities and wider pulses seem to be more efficient in inducing excitation. If confirmed, this observation could lead to better results in future clinical studies performed with wider pulses.
Bilateral Globus Pallidus Interna Combined With Subthalamic Nucleus Variable Frequency Deep Brain Stimulation in the Treatment of Young-Onset Parkinson's Disease With Refractory Dyskinesia: A Case Report
Authors: Chang Bowen , Mei Jiaming , Xiong Chi , Chen Peng , Jiang Manli , Niu Chaoshi
Published: December 2021

Background: Main motor characteristics in Parkinson's disease (PD) include bradykinesia, rigidity, and tremors. With the development of neuromodulation techniques, it has become possible to use deep brain stimulation (DBS) to control the symptoms of PD. However, since the subthalamic nucleus(STN) and globus pallidus interna (GPi) DBS have their own advantages and disadvantages, it is difficult to control symptoms of the patients. It is essential to find new stimulation methods.

Case Presentation: A 33-year-old male PD patient with onset at the age of 12 years. The onset of the disease is presented with bradykinesia and progressively developed severe choreic dyskinesia with the use of medications. We then performed a thorough evaluation of the patient and decided to perform bilateral globus pallidus interna combined with subthalamic nucleus variable frequency DBS (bSGC-DBS) implantation, and after 2 years of follow-up the patient's bradykinesia and dyskinesia symptoms and quality of life improved significantly.

Conclusions: This is the first case of bSCG-DBS in a PD patient with refractory dyskinesia, and the first report of encouraging results from this clinical condition. This important finding explores multi-electrode and multi-target stimulation for the treatment of dystonia disorders.
Do Hippocampal Neurons Really Count for Comorbid Depression in Patients With Mesial Temporal Lobe Epilepsy and Hippocampal Sclerosis? A Histopathological Study
Authors: Visoná de Figueiredo Nathália Stela , Jardim Anaclara Prada , Mazetto Lenon , Corso Duarte Jeana Torres , Comper Sandra Mara , Alonso Neide Barreira , da Silva Noffs Maria Helena , Scorza Carla Alessandra , Cavalheiro Esper Abrão , Centeno Ricardo Silva , de Araújo Filho Gerardo Maria , Yacubian Elza Márcia Targas
Published: December 2021

Depression is the most frequent psychiatric comorbidity seen in mesial temporal lobe epilepsy (MTLE) patients with hippocampal sclerosis (HS). Moreover, the HS is the most frequent pathological hallmark in MTLE-HS. Although there is a well-documented hippocampal volumetric reduction in imaging studies of patients with major depressive disorder, in epilepsy with comorbid depression, the true role of the hippocampus is not entirely understood. This study aimed to verify if patients with unilateral MTLE-HS and the co-occurrence of depression have differences in neuronal density of the hippocampal sectors CA1–CA4. For this purpose, we used a histopathological approach. This was a pioneering study with patients having both clinical disorders. However, we found no difference in hippocampal neuronal density when depression co-occurs in patients with epilepsy. In this series, CA1 had the lowest counting in both groups, and HS ILAE Type 1 was the most prevalent. More studies using histological assessments are needed to clarify the physiopathology of depression in MTLE-HS.
Criticality Creates a Functional Platform for Network Transitions Between Internal and External Processing Modes in the Human Brain
Authors: Kim Minkyung , Kim Hyoungkyu , Huang Zirui , Mashour George A. , Jordan Denis , Ilg Rüdiger , Lee UnCheol
Published: December 2021

Continuous switching between internal and external modes in the brain appears important for generating models of the self and the world. However, how the brain transitions between these two modes remains unknown. We propose that a large synchronization fluctuation of brain networks, emerging only near criticality (i.e., a balanced state between order and disorder), spontaneously creates temporal windows with distinct preferences for integrating the network’s internal information or for processing external stimuli. Using a computational model, electroencephalography (EEG) analysis, and functional magnetic resonance imaging (fMRI) analysis during alterations of consciousness in humans, we report that synchronized and incoherent networks, respectively, bias toward internal and external information with specific network configurations. In the brain network model and EEG-based network, the network preferences are the most prominent at criticality and in conscious states associated with the bandwidth 4−12 Hz, with alternating functional network configurations. However, these network configurations are selectively disrupted in different states of consciousness such as general anesthesia, psychedelic states, minimally conscious states, and unresponsive wakefulness syndrome. The network preference for internal information integration is only significant in conscious states and psychedelic states, but not in other unconscious states, suggesting the importance of internal information integration in maintaining consciousness. The fMRI co-activation pattern analysis shows that functional networks that are sensitive to external stimuli–such as default mode, dorsal attentional, and frontoparietal networks–are activated in incoherent states, while insensitive networks, such as global activation and deactivation networks, are dominated in highly synchronized states. We suggest that criticality produces a functional platform for the brain’s capability for continuous switching between two modes, which is crucial for the emergence of consciousness.
Inhibitory Effect of Ascorbic Acid on in vitro Enzymatic Digestion of Raw and Cooked Starches
Authors: Guo Jiayue , Gutierrez Alyssa , Tan Libo , Kong Lingyan
Published: December 2021

Ascorbic acid, also known as vitamin C, was previously reported to inhibit the activity of pancreatic α-amylase, the primary digestive enzyme for starch. A major implication of such inhibition is a slowed rate of starch digestion into glucose, which thereby reduces postprandial hyperglycemia. The aim of this study was to explore the inhibitory effects of ascorbic acid at various concentrations on the in vitro digestion of high amylose maize starch (HAMS) and potato starch (PS) in both raw and cooked conditions. Resistant starch (RS) content, defined as the starch that remained after 4 h of simulated in vitro enzymatic digestion, was measured for the starch samples. Upon the addition of ascorbic acid, the RS contents increased in both raw and cooked starches. Cooking significantly reduced the RS contents as compared to raw starches, and less increase in RS was observed with the addition of ascorbic acid. The inhibitory effect of ascorbic acid on the digestion of raw starches showed a dose-dependent trend until it reached the maximum extent of inhibition. At the concentrations of 12.5 and 18.75 mg/mL, ascorbic acid exhibited the most potent inhibitory effect on the in vitro starch digestion in raw and cooked conditions, respectively. Overall, our results strongly indicate that ascorbic acid may function as a glycemic modulatory agent beyond other important functions, and its effects persist upon cooking with certain concentrations applied.
Negative Impacts of COVID-19 Induced Lockdown on Changes in Eating Behavior, Physical Activity, and Mental Health as Modified by Digital Healthy Diet Literacy and eHealth Literacy
Authors: Nguyen Tham T. , Nguyen Minh H. , Pham Thu T. M. , Le Vinh-Tuyen T. , Nguyen Tan T. , Luong Thuc C. , Do Binh N. , Dao Hung K. , Nguyen Huu C. , Ha Tung H. , Pham Linh V. , Nguyen Phuoc B. , Nguyen Hoai T. T. , Do Thinh V. , Nguyen Hung Q. , Trinh Manh V. , Le Thuy T. , Tra Anh L. , Nguyen Thao T. P. , Nguyen Kien T. , Phan Dung T. , Pham Khue M. , Bai Chyi-Huey , Duong Tuyen Van
Published: December 2021

Background: The COVID-19-induced lockdown has been implemented in many countries, which may cause unfavorable changes in lifestyles and psychological health. People's health literacy, healthy diet, and lifestyles play important roles in mitigating the negative impacts of the pandemic. Therefore, we aimed to examine associations of COVID-19 lockdown with changes in eating behavior, physical activity, and mental health; and the modification effects by digital healthy diet literacy (DDL) and eHealth literacy (eHEALS) on the associations.

Methods: We conducted an observational study on 4,348 outpatients from 7th April to 31st May 2020. Data from 11 hospitals in Vietnam included demographic characteristics, DDL, eHEALS, eating behavior, physical activity, and mental health changes. Multiple logistic regression and interaction models were performed to examine associations.

Results: Patients under lockdown had a lower likelihood of having “unchanged or healthier” eating behavior (odds ratio, OR, 0.38; 95% confidence interval, 95%CI, 0.29 to 0.51; p < 0.001), “unchanged or more” physical activity (OR, 0.79; 95% CI, 0.69 to 0.90; p < 0.001), and “stable or better” mental health (OR, 0.77; 95% CI, 0.67 to 0.89; p < 0.001), as compared to those after lockdown. In interaction models, as compared to patients after lockdown and with the lowest DDL score, those under lockdown and with a one-score increment of DDL had a higher likelihood of having “unchanged or healthier” eating behavior (OR, 1.05; 95% CI, 1.02 to 1.07; p < 0.001), and “stable or better” mental health (OR, 1.02; 95% CI, 1.01 to 1.04; p < 0.001). Similarly, as compared to patients after lockdown and with the lowest eHEALS score, those under lockdown and with a one-score increment of eHEALS had a higher likelihood of having an “unchanged or more” physical activity (OR, 1.03; 95% CI, 1.01 to 1.05; p < 0.001).

Conclusion: The COVID-19 lockdown measure could negatively affect eating behavior, physical activity, and mental health among outpatients. Better DDL and eHEALS were found to mitigate the negative impacts of the lockdown, which may empower outpatients to maintain healthy lifestyles and protect mental health. However, this study holds several limitations that may undermine the certainty of reported findings.
Chemometric-Guided Approaches for Profiling and Authenticating Botanical Materials
Authors: Abraham Evelyn J. , Kellogg Joshua J.
Published: December 2021

Botanical supplements with broad traditional and medicinal uses represent an area of growing importance for American health management; 25% of U.S. adults use dietary supplements daily and collectively spent over $9. 5 billion in 2019 in herbal and botanical supplements alone. To understand how natural products benefit human health and determine potential safety concerns, careful in vitro, in vivo, and clinical studies are required. However, botanicals are innately complex systems, with complicated compositions that defy many standard analytical approaches and fluctuate based upon a plethora of factors, including genetics, growth conditions, and harvesting/processing procedures. Robust studies rely upon accurate identification of the plant material, and botanicals' increasing economic and health importance demand reproducible sourcing, as well as assessment of contamination or adulteration. These quality control needs for botanical products remain a significant problem plaguing researchers in academia as well as the supplement industry, thus posing a risk to consumers and possibly rendering clinical data irreproducible and/or irrelevant. Chemometric approaches that analyze the small molecule composition of materials provide a reliable and high-throughput avenue for botanical authentication. This review emphasizes the need for consistent material and provides insight into the roles of various modern chemometric analyses in evaluating and authenticating botanicals, focusing on advanced methodologies, including targeted and untargeted metabolite analysis, as well as the role of multivariate statistical modeling and machine learning in phytochemical characterization. Furthermore, we will discuss how chemometric approaches can be integrated with orthogonal techniques to provide a more robust approach to authentication, and provide directions for future research.
A Review on Polymer and Lipid-Based Nanocarriers and Its Application to Nano-Pharmaceutical and Food-Based Systems
Authors: Lu Hongyun , Zhang Shengliang , Wang Jinling , Chen Qihe
Published: December 2021

Recently, owing to well-controlled release, enhanced distribution and increased permeability, nanocarriers used for alternative drug and food-delivery strategies have received increasingly attentions. Nanocarriers have attracted a large amount of interest as potential carriers of various bioactive molecules for multiple applications. Drug and food-based delivery via polymeric-based nanocarriers and lipid-based nanocarriers has been widely investigated. Nanocarriers, especially liposomes, are more and more widely used in the area of novel nano-pharmaceutical or food-based design. Herein, we aimed to discuss the recent advancement of different surface-engineered nanocarriers type, along with cutting-edge applications for food and nanomedicine and highlight the alternative of phytochemical as nanocarrier. Additionally, safety concern of nanocarriers was also highlighted.
A Starvation-Based 9-mRNA Signature Correlates With Prognosis in Patients With Hepatocellular Carcinoma
Authors: Lei Dengliang , Chen Yue , Zhou Yang , Hu Gangli , Luo Fang
Published: December 2021

Background

Hepatocellular carcinoma (HCC) is one of the world’s most prevalent and lethal cancers. Notably, the microenvironment of tumor starvation is closely related to cancer malignancy. Our study constructed a signature of starvation-related genes to predict the prognosis of liver cancer patients.

Methods

The mRNA expression matrix and corresponding clinical information of HCC patients were obtained from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GSEA) was used to distinguish different genes in the hunger metabolism gene in liver cancer and adjacent tissues. Gene Set Enrichment Analysis (GSEA) was used to identify biological differences between high- and low-risk samples. Univariate and multivariate analyses were used to construct prognostic models for hunger-related genes. Kaplan-Meier (KM) and receiver-operating characteristic (ROC) were used to assess the model accuracy. The model and relevant clinical information were used to construct a nomogram, protein expression was detected by western blot (WB), and transwell assay was used to evaluate the invasive and metastatic ability of cells.

Results

First, we used univariate analysis to identify 35 prognostic genes, which were further demonstrated to be associated with starvation metabolism through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). We then used multivariate analysis to build a model with nine genes. Finally, we divided the sample into low- and high-risk groups according to the median of the risk score. KM can be used to conclude that the prognosis of high- and low-risk samples is significantly different, and the prognosis of high-risk samples is worse. The prognostic accuracy of the 9-mRNA signature was also tested in the validation data set. GSEA was used to identify typical pathways and biological processes related to 9-mRNA, cell cycle, hypoxia, p53 pathway, and PI3K/AKT/mTOR pathway, as well as biological processes related to the model. As evidenced by WB, EIF2S1 expression was increased after starvation. Overall, EIF2S1 plays an important role in the invasion and metastasis of liver cancer.

Conclusions

The 9-mRNA model can serve as an accurate signature to predict the prognosis of liver cancer patients. However, its mechanism of action warrants further investigation.
Alphataxin, a Small-Molecule Drug That Elevates Tumor-Infiltrating CD4+ T Cells, in Combination With Anti-PD-1 Therapy, Suppresses Murine Renal Cancer and Metastasis
Authors: Bristow Cynthia L. , Reeves Mary Ann B. , Winston Ronald
Published: December 2021

By promoting the cytotoxic function of CD8+T cells, immune checkpoint inhibitor therapy,e.g.programmed cell death protein-1 (PD-1), effectively inhibits tumor growth in renal cell carcinoma. Yet, as many as 87% of cancer patients do not respond to immune checkpoint therapy. Importantly, cytotoxic CD8+T cell function crucially relies on CD4+T helper cell cytokines, in particular, tumor necrosis factor beta (TNFβ) and its CD8+T cell receptor (TNFR2) in the opposing manner as immune checkpoints and their receptors. Remarkably, despite advances in immunotherapy, there are no pharmaceutical treatments that increase circulating CD4+T cell counts. Nor has there been much attention given to tumor-infiltrating CD4+T cells. Using data from a clinical trial (NCT01731691), we discovered that the protein alpha-1 proteinase inhibitor (α1PI, alpha-1 antitrypsin) regulates the number of circulating CD4+T cells. The orally available small-molecule drug Alphataxin acts as a surrogate for α1PI in this pathway. We aimed to examine how Alphataxin affected tumor growth in a murine model of renal cell carcinoma. Alphataxin, in combination with anti-PD-1 antibody, significantly elevated the ratio of circulating and tumor-infiltrating CD4+T cells. In one study, following orthotopic implantation of syngeneic renal adenocarcinoma cells, combination treatment resulted in 100% regression of tumor growth. Moreover, in mice implanted orthotopically with one log more tumor cells, doubling Alphataxin dose in combination treatment led to 100% regression in one-third of mice and 81% suppression of tumor growth in the remaining two-thirds of mice. Lung metastasis was present in monotherapy, but significantly reduced in combination-treated mice. Orally available Alphataxin, the first and only drug developed to increase CD4+T cells, in combination with anti-PD-1, is a powerful therapeutic method that provides long-term remission in renal cell carcinoma and potentially other T cell-responsive cancers by increasing the number of CD4+tumor-infiltrating T cells.
Early T-Cell Precursor Acute Lymphoblastic Leukemia: Diagnosis, Updates in Molecular Pathogenesis, Management, and Novel Therapies
Authors: Sin Chun-fung , Man Pui-hei Marcus
Published: December 2021

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T lymphoblastic leukemia (T-ALL) identified in 2009, due to its unique immunophenotypic and genomic profile. The outcome of patients was poor in earlier studies, and they were prone to have induction failure, with more frequent relapse/refractory disease. Recent advances had been made in discoveries of genetic aberrations and molecular pathogenesis of ETP-ALL. However, the diagnosis and management of ETP-ALL is still challenging. There are limited choices of novel therapies so far. In this review article, it highlighted the diagnostic issue of ETP-ALL, pitfall in diagnosis, and strategy of accurate diagnosis. The review also summarized current understanding of molecular mechanism of leukemogenesis. The emerging role of risk-adapted therapy and allogenic stem cell transplant in optimizing the outcome of patients with ETP-ALL was discussed. Finally, some potential novel therapies were proposed based on the current understanding of molecular pathogenesis.
Identification of a Novel Stem Cell Subtype for Clear Cell Renal Cell Carcinoma Based on Stem Cell Gene Profiling
Authors: Wang Hongzhi , Xu Hanjiang , Cheng Quan , Liang Chaozhao
Published: December 2021

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer and is characterized by high rates of metastasis. Cancer stem cell is a vital cause of renal cancer metastasis and recurrence. However, little is known regarding the change and the roles of stem cells during the development of renal cancer. To clarify this problem, we developed a novel stem cell clustering strategy. Based on The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) genomic datasets, we used 19 stem cell gene sets to classify each dataset. A machine learning method was used to perform the classification. We classified ccRCC into three subtypes—stem cell activated (SC-A), stem cell dormant (SC-D), and stem cell excluded (SC-E)—based on the expressions of stem cell-related genes. Compared with the other subtypes, C2(SC-A) had the highest degree of cancer stem cell concentration, the highest level of immune cell infiltration, a distinct mutation landscape, and the worst prognosis. Moreover, drug sensitivity analysis revealed that subgroup C2(SC-A) had the highest sensitivity to immunotherapy CTLA-4 blockade and the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib. The identification of ccRCC subtypes based on cancer stem cell gene sets demonstrated the heterogeneity of ccRCC and provided a new strategy for its treatment.
Malignant Melanoma With Neuroendocrine Differentiation: A Case Report and Literature Review
Authors: Cham Jason , Shavit Ayal , Ebrahimi Aren , Viray Miguel , Gibbs Paul , Bhangoo Munveer S.
Published: December 2021

Background

Melanoma has a wide range of histologic variants and cytomorphologic features that make its diagnosis challenging. Melanoma can also rarely have neuroendocrine markers adding further diagnostic uncertainty particularly given that unrelated tumor types, such as prostate cancer, can also display focal neuroendocrine differentiations.

Case presentation

Our patient is a 74-year-old Caucasian man found to have a lung mass. Initial biopsy revealed typical microscopic morphology and neuroendocrine differentiation consistent with small cell carcinoma. Despite standard chemoradiation treatment, the patient continued to progress with new metastasis in the brain, liver and bone. Subsequent chest wall biopsy revealed golden-brown pigment associated with melanin. Further tumor immunohistochemistry revealed extensive neuroendocrine differentiation with CD56, synaptophysin, and INSM1, as well as strong immunoreactivity for melanocyte markers including SOX10, S100, PRAME, and MITF, consistent with metastatic melanoma with neuroendocrine differentiation. Genomic testing revealed increased tumor mutational burden and alterations in NF1, BRAF, CDKN2A/B, TERT. The patient was transitioned to checkpoint inhibitor therapy with nivolumab and ipilimumab and had resolution of his intracranial mass and decrease in size of other metastatic lesions.

Conclusion

Often the combination of anatomic findings such as a lung mass, typical microscopic morphology, and confirmation of neuroendocrine differentiation correctly identifies a patient with small cell carcinoma. However, in a patient who fails to respond to treatment, a broader immunohistochemical workup along with molecular testing with additional tissue may be warranted.
Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
Authors: Gerson-Gurwitz Adina , Young Nathan P. , Goel Vikas K. , Eam Boreth , Stumpf Craig R. , Chen Joan , Fish Sarah , Barrera Maria , Sung Eric , Staunton Jocelyn , Chiang Gary G. , Webster Kevin R. , Thompson Peggy A.
Published: December 2021

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5’-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.
Preliminary Efficacy and Safety of Camrelizumab in Combination With XELOX Plus Bevacizumab or Regorafenib in Patients With Metastatic Colorectal Cancer: A Retrospective Study
Authors: Zhou Hong , Wang Yuehui , Lin Yanfang , Cai Wenjie , Li Xiaofeng , He Xiaomeng
Published: December 2021

Background

For a majority of patients with metastatic colorectal cancer (mCRC) with MS stable (MSS) or mismatch repair proficient (pMMR), the role of immunotherapy is undetermined. This study investigated the efficacy and safety of camrelizumab when added to XELOX chemotherapy plus bevacizumab or regorafenib as first-line therapy for mCRC.

Materials and Methods

Medical records of mCRC patients who received camrelizumab and XELOX plus bevacizumab or regorafenib at the First Hospital of Quanzhou Affiliated to Fujian Medical University between June 1, 2019, and April 30, 2021, were retrospectively collected. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed.

Results

Twenty-five eligible patients received combination therapy, including bevacizumab in 19 patients and regorafenib in 6. Twenty-one patients had pMMR/MSS and one MSI-H. Of the 25 patients who could be evaluated for efficacy, 18 (72%) achieved PR, 6 (24%) achieved SD, and 1 (4%) achieved PD. The ORR and DCR were 72% (18/25) and 96% (24/25), respectively. The median progression-free survival (PFS) was 11.2 months (95% CI 8.9–13.9), and OS had not yet been reached. The combination regimen of regorafenib in six (24%) patients was unassociated with treatment outcomes. Most AEs were either grade 1 or 2, and treatment-related grade 3 toxicities were observed in 8/25 (32%) patients.

Conclusion

Camrelizumab combined with XELOX plus bevacizumab or regorafenib was feasible, producing high rates of responses as first-line therapy in unselected Chinese patients with MSS mCRC. The toxicities were generally tolerable and manageable. Prospective randomized trials with large sample sizes are needed to evaluate these findings.
Duration of Perioperative Chemotherapy in Locally Advanced Gastric Cancer: A “Less Is More” Question When ypN0 Is Achieved
Authors: Liu Zining , Wang Yinkui , Shan Fei , Ying Xiangji , Zhang Yan , Li Shuangxi , Jia Yongning , Miao Rulin , Xue Kan , Li Zhemin , Li Ziyu , Ji Jiafu
Published: December 2021

Backgrounds

Perioperative chemotherapy (PEC) and neoadjuvant chemotherapy (NAC) have become a vital part of locally advanced gastric cancer (LAGC) treatment, but the optimal duration of PEC has not been studied. The aim of this study was to demonstrate the possibility of duration reduction in PEC in the adjuvant chemotherapy (AC) phase for ypN0 patients.

Methods

We included LAGC patients who achieved ypN0 after NAC in our institution from 2005 to 2018. The risk/benefit of AC and other covariates were majorly measured by overall survival (OS) and progression-free survival (PFS). We developed a survival-tree-based model to determine the optimal PEC duration for ypN0 patients in different classes.

Results

A total of 267 R0 resection patients were included. There were 55 patients who did not receive AC. The 5-year OS was 74.34% in the non-AC group and 83.64% in the AC group with a significant difference (p = 0.012). Multivariate Cox regression revealed that both AC (AC vs. non-AC: HR, 0.49; 95%CI, 0.27–0.88; p = 0.018) and ypT stages (ypT3-4 vs. ypT0-2: HR, 2.00; 95%CI, 1.11–3.59; p = 0.021) were significant protective/risk factors on patients OS and PFS. A decision tree model for OS indicated an optimal four to six cycles of PEC, which was recommended for ypT0-2N0 patients, while a minimum of five PEC cycles was recommended for ypT3-4N0 patients.

Conclusion

AC treatment is still necessary for ypN0. The duration reduction could be applied for the ypT0-2N0 stage patients but may not be suitable for higher ypT stages and beyond. A multicenter-based study is required.
Refined Temporal-to-Frontal Horn Shunt for Treatment of Trapped Temporal Horn After Surgery of Peri- or Intraventricular Tumor: A Case Series Study
Authors: Ren Xiaohui , Cui Yong , Yang Chuanwei , Jiang Zhongli , Lin Song , Lin Zhiqin
Published: December 2021

Background

Trapped temporal horn (TTH) is a localized hydrocephalus that can be treated with cerebrospinal fluid diversion. Refined temporal-to-frontal horn shunt (RTFHS) through the parieto-occipital approach is rarely reported in the literature and its effectiveness remains unclear. The aim of the present study is to investigate the efficacy and outcome of RTFHS for treatment of TTH.

Materials and Methods

We consecutively enrolled 10 patients who underwent RTFHS for TTH after surgical resection of peri- or intraventricular tumors from February 2018 to March 2021. Clinical, radiological, and follow-up data were collected and analyzed. The most common underlying pathology was meningioma (n=4), followed by central neurocytoma (n=3), thalamic glioblastoma (n=2), and anaplastic ependymoma (n=1).

Results

The mean Karnofsky performance scale (KPS) score and TTH volume at onset were 54.0 ± 15.1 (range 40-80) and 71.3 ± 33.2cm3 (range 31.7-118.6cm3), respectively. All patients (10/10, 100.0%) presented with periventricular brain edema (PVBE), while midline shift was observed in 9 patients (9/10, 90.0%). RTFHSs were implanted using valveless shunting catheters. No patients developed acute intracranial hemorrhage or new neurological deficit postoperatively. During the follow-up of 17.2 ± 13.7 months (range 3-39 months), all patients showed clinical and radiological improvement. The mean KPS score at the last follow-up was significantly increased to 88.0 ± 10.3 (range 70-100, p<0.0001). RTFHS resulted in significant complete remission in PVBE and midline shift in 8 (80.0%, p=0.0007) and 9 (100.0%, p=0.0001) patients, respectively. As the postoperative follow-up duration prolonged, the mean TTH volume decreased in a consistent, linear trend (p<0.0001). At last follow-up, the mean TTH volume was significantly reduced to 15.4 ± 11.5 cm3 (range 5.6-44.1 cm3, p=0.0003), resulting in a mean relative reduction of 77.2 ± 13.1% compared with the volume of TTH at onset. Over drainage was not observed during the follow-up. No patient suffered from proximal or distal shunt obstruction or shunt related infection, and the revision rate was 0%.

Conclusion

RTFHS seems to be safe and effective for the treatment of TTH with favorable outcomes. Advantages of this technique could be technically less complex and invasive, cost-effective, avoidance of various intraperitoneal complications, and maintaining a near-physiological CSF pathway.
Modified Gap Arthroplasty for Temporomandibular Joint Ankylosis Following Radiotherapy for Rhabdomyosarcoma: Report of an Unusual Case and Brief Literature Review
Authors: Zhang Jianfei , Dai Liyan , Abdelrehem Ahmed , Wu Jinyang , Li Xiaobo , Shen Steve Guofang
Published: December 2021

Radiotherapy at the temporomandibular joint (TMJ) area often results in trismus, however, post radiation ankylosis is extremely rare and has not been previously reported in literature. Radiation is known to impact the vasculature of bony structures leading to bone necrosis with certain risk factors including surgical intervention, even teeth extraction, that could lead to osteoradionecrosis. Accordingly, gap arthroplasty for such case seemed rather challenging. In this report, we introduce for the first time, a rare case of temporomandibular joint ankylosis post radiotherapy for management of rhabdomyosarcoma in a 12 years-old boy. A modified gap arthroplasty technique combined simultaneously with pterygo-masseteric muscle flap was applied to lower the risk of osteoradionecrosis due surgical trauma at irradiated area. Computed tomographic scan on the head indicated that the TMJ architecture was completely replaced by bone, with fusion of the condyle, sigmoid notch, and coronoid process to the zygomatic arch and glenoid fossa. The patient’s problem was totally solved with no osteoradionecrosis or relapse of ankylosis observed at follow up visits. Herein, the modified gap arthroplasty combined with pterygo-masseteric muscle flap could be recommended to be applied on other cases of ankylosis especially after receiving radiotherapy.
Biological Rationale and Clinical Evidence of Carbon Ion Radiation Therapy for Adenoid Cystic Carcinoma: A Narrative Review
Authors: Loap Pierre , Vischioni Barbara , Bonora Maria , Ingargiola Rossana , Ronchi Sara , Vitolo Viviana , Barcellini Amelia , Goanta Lucia , De Marzi Ludovic , Dendale Remi , Pacelli Roberto , Locati Laura , Calugaru Valentin , Mammar Hamid , Cavalieri Stefano , Kirova Youlia , Orlandi Ester
Published: December 2021

Adenoid cystic carcinoma (ACC) is a rare, basaloid, epithelial tumor, arising mostly from salivary glands. Radiation therapy can be employed as a single modality for unresectable tumors, in an adjuvant setting after uncomplete resection, in case of high-risk pathological features, or for recurrent tumors. Due to ACC intrinsic radioresistance, high linear energy transfer (LET) radiotherapy techniques have been evaluated for ACC irradiation: while fast neutron therapy has now been abandoned due to toxicity concerns, charged particle beams such as protons and carbon ions are at present the beams used for hadron therapy. Carbon ion radiation therapy (CIRT) is currently increasingly used for ACC irradiation. The aim of this review is to describe the immunological, molecular and clinicopathological bases that support ACC treatment with CIRT, as well as to expose the current clinical evidence that reveal the advantages of using CIRT for treating ACC.
Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients
Authors: Wang Ping , Shu Jianbo , Gu Chunyu , Yu Xiaoli , Zheng Jie , Zhang Chunhua , Cai Chunquan
Published: December 2021

Introduction: Combined malonic and methylmalonic aciduria (CMAMMA) is a rare metabolic disease caused by biallelic variants in ACSF3 gene. The clinical phenotype is highly heterogeneous in this disorder, ranging from asymptomatic to severe symptoms. No cases with CMAMMA were reported in China.

Materials and Methods: In this study, three Chinese pediatric patients were diagnosed with CMAMMA unexpectedly while being treated for other ailments. To better characterize CMAMMA in a Chinese population, we made a multidimensional analysis with detailed clinical phenotype, semi-quantitative detection of urine organic acid, and analysis of ACSF3 gene variants.

Results: The clinical presentation of these patients is quite different; their main complaints were anemia, jaundice, or abnormal urine test, respectively. They showed no symptoms of the classic methylmalonic academia, but urine organic acid analysis showed elevated malonic acid and methylmalonic acid in all the patients repeatedly. Variants were found at four sites in ACSF3 gene. Patient 1 carried the compound heterogeneous variant c.689G> A (p.Trp230*)/c.1456G> A (p.Ala486Thr). A compound heterozygous variant c.473C> T (p.Pro158Leu)/c.1456G> A (p.Ala486Thr) was identified in patient 2. Patient 3 harbored a novel homozygous variant c.1447A> G (p.Lys483Glu).

Conclusions: Three Chinese patients were diagnosed with CMAMMA caused by ACSF3 variants. Their clinical course revealed that CMAMMA can be a benign condition that does not affect individual growth and development, but severe clinical phenotype may appear when other triggers exist. This study systematically elaborates CMAMMA in a Chinese population for the first time, broadens the spectrum of gene variant, and provides a strong basis for the etiological study of this disorder.
Traditional Uses, Pharmacological Effects, and Molecular Mechanisms of Licorice in Potential Therapy of COVID-19
Authors: Zhang Qian-hui , Huang Hao-zhou , Qiu Min , Wu Zhen-feng , Xin Zhan-chang , Cai Xin-fu , Shang Qiang , Lin Jun-zhi , Zhang Ding-kun , Han Li
Published: December 2021

The current Coronavirus disease 2019 (COVID-19) pandemic has become a global challenge, and although vaccines have been developed, it is expected that mild to moderate patients will control their symptoms, especially in developing countries. Licorice, not only a food additive, but also a common traditional Chinese herbal medicine, which has several pharmacological effects, such as anti-inflammation, detoxification, antibacterial, antitussive, and immunomodulatory effects, especially in respiratory diseases. Since the outbreak of COVID-19, glycyrrhizin, glycyrrhizin diamine and glycyrrhizin extract have been widely studied and used in COVID-19 clinical trials. Therefore, it is a very interesting topic to explore the material basis, pharmacological characteristics and molecular mechanism of licorice in adjuvant treatment of COVID-19. In this paper, the material basis of licorice for the prevention and treatment of COVID-19 is deeply analyzed, and there are significant differences among different components in different pharmacological mechanisms. Glycyrrhizin and glycyrrhetinic acid inhibit the synthesis of inflammatory factors and inflammatory mediators by blocking the binding of ACE 2 to virus spike protein, and exert antiviral and antibacterial effects. Immune cells are stimulated by multiple targets and pathways to interfere with the pathogenesis of COVID-19. Liquiritin can prevent and cure COVID-19 by simulating type I interferon. It is suggested that licorice can exert its therapeutic advantage through multi-components and multi-targets. To sum up, licorice has the potential to adjuvant prevent and treat COVID-19. It not only plays a significant role in anti-inflammation and anti-ACE-2, but also significantly improves the clinical symptoms of fever, dry cough and shortness of breath, suggesting that licorice is expected to be a candidate drug for adjuvant treatment of patients with early / mild COVID-19.
Polypharmacy Management in the Older Adults: A Scoping Review of Available Interventions
Authors: Kurczewska-Michalak M. , Lewek P. , Jankowska-Polańska B. , Giardini A. , Granata N. , Maffoni M. , Costa E. , Midão L. , Kardas P.
Published: December 2021

Background: Polypharmacy paves the way for non-adherence, adverse drug reactions, negative health outcomes, increased use of healthcare services and rising costs. Since it is most prevalent in the older adults, there is an urgent need for introducing effective strategies to prevent and manage the problem in this age group.

Purpose: To perform a scoping review critically analysing the available literature referring to the issue of polypharmacy management in the older adults and provide narrative summary.

Data sources: Articles published between January 2010–March 2018 indexed in CINHAL, EMBASE and PubMed addressing polypharmacy management in the older adults.

Results: Our search identified 49 papers. Among the identified interventions, the most often recommended ones involved various types of drug reviews based on either implicit or explicit criteria. Implicit criteria-based approaches are used infrequently due to their subjectivity, and limited implementability. Most of the publications advocate the use of explicit criteria, such as e.g. STOPP/START, Beers and Medication Appropriateness Index (MAI). However, their applicability is also limited due to long lists of potentially inappropriate medications covered. To overcome this obstacle, such instruments are often embedded in computerised clinical decision support systems.

Conclusion: Multiple approaches towards polypharmacy management are advised in current literature. They vary in terms of their complexity, applicability and usability, and no “gold standard” is identifiable. For practical reasons, explicit criteria-based drug reviews seem to be advisable. Having in mind that in general, polypharmacy management in the older adults is underused, both individual stakeholders, as well as policymakers should strengthen their efforts to promote these activities more strongly.