bluuebunny/crossref_metadata_2025 huggingface dataset:
The Perspective of Dysregulated LncRNAs in Alzheimer's Disease: A Systematic Scoping Review
Authors: Asadi Mohammad Reza , Hassani Mehdi , Kiani Shiva , Sabaie Hani , Moslehian Marziyeh Sadat , Kazemi Mohammad , Ghafouri-Fard Soudeh , Taheri Mohammad , Rezazadeh Maryam
Published: September 2021

LncRNAs act as part of non-coding RNAs at high levels of complex and stimulatory configurations in basic molecular mechanisms. Their extensive regulatory activity in the CNS continues on a small scale, from the functions of synapses to large-scale neurodevelopment and cognitive functions, aging, and can be seen in both health and disease situations. One of the vast consequences of the pathological role of dysregulated lncRNAs in the CNS due to their role in a network of regulatory pathways can be manifested in Alzheimer's as a neurodegenerative disease. The disease is characterized by two main hallmarks: amyloid plaques due to the accumulation of β-amyloid components and neurofibrillary tangles (NFT) resulting from the accumulation of phosphorylated tau. Numerous studies in humans, animal models, and various cell lines have revealed the role of lncRNAs in the pathogenesis of Alzheimer's disease. This scoping review was performed with a six-step strategy and based on the Prisma guideline by systematically searching the publications of seven databases. Out of 1,591 records, 69 articles were utterly aligned with the specified inclusion criteria and were summarized in the relevant table. Most of the studies were devoted to BACE1-AS, NEAT1, MALAT1, and SNHG1 lncRNAs, respectively, and about one-third of the studies investigated a unique lncRNA. About 56% of the studies reported up-regulation, and 7% reported down-regulation of lncRNAs expressions. Overall, this study was conducted to investigate the association between lncRNAs and Alzheimer's disease to make a reputable source for further studies and find more molecular therapeutic goals for this disease.
Evaluation and Optimization of Methods for Generating High-Resolution Retinotopic Maps Using Visual Cortex Voltage-Sensitive Dye Imaging
Authors: Carmi Ori , Gross Adi , Ivzan Nadav , Franca Lamberto La , Farah Nairouz , Zalevsky Zeev , Mandel Yossi
Published: September 2021

The localization and measurement of neuronal activity magnitude at high spatial and temporal resolution are essential for mapping and better understanding neuronal systems and mechanisms. One such example is the generation of retinotopic maps, which correlates localized retinal stimulation with the corresponding specific visual cortex responses. Here we evaluated and compared seven different methods for extracting and localizing cortical responses from voltage-sensitive dye imaging recordings, elicited by visual stimuli projected directly on the rat retina by a customized projection system. The performance of these methods was evaluated both qualitatively and quantitatively by means of two cluster separation metrics, namely, the (adjusted) Silhouette Index (SI) and the (adjusted) Davies-Bouldin Index (DBI). These metrics were validated using simulated data, which showed that Temporally Structured Component Analysis (TSCA) outperformed all other analysis methods for localizing cortical responses and generating high-resolution retinotopic maps. The analysis methods, as well as the use of cluster separation metrics proposed here, can facilitate future research aiming to localize specific activity at high resolution in the visual cortex or other brain areas.
Widespread White Matter Alterations in Patients With Visual Snow Syndrome
Authors: Michels Lars , Stämpfli Philipp , Aldusary Njoud , Piccirelli Marco , Freund Patrick , Weber Konrad P. , Fierz Fabienne C. , Kollias Spyros , Traber Ghislaine
Published: September 2021

Background: Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant binocular flickering or pixilation of the whole visual field. The underlying neurophysiological and structural alterations remain elusive.

Methods: In this study, we included patients (final n = 14, five dropouts; five females, mean age: 32 years) with visual snow syndrome (VSS) and age- and sex-matched controls (final n = 20, 6 dropouts, 13 females, mean age: 28.2 years). We applied diffusion tensor imaging to examine possible white matter (WM) alterations in patients with VSS.

Results: The patient group demonstrated higher (p-corrected < 0.05, adjusted for age and sex) fractional anisotropy (FA) and lower mean diffusivity (MD) and radial diffusivity (RD) compared to controls. These changes were seen in the prefrontal WM (including the inferior fronto-occipital fascicle), temporal and occipital WM, superior and middle longitudinal fascicle, and sagittal stratum. When additionally corrected for migraine or tinnitus—dominant comorbidities in VSS—similar group differences were seen for FA and RD, but less pronounced.

Conclusions: Our results indicate that patients with VSS present WM alterations in parts of the visual cortex and outside the visual cortex. As parts of the inferior fronto-occipital fascicle and sagittal stratum are associated with visual processing and visual conceptualisation, our results suggest that the WM alterations in these regions may indicate atypical visual processing in patients with VSS. Yet, the frequent presence of migraine and other comorbidities such as tinnitus in VSS makes it difficult to attribute WM disruptions solely to VSS.
Small vs. Large Unruptured Cerebral Aneurysm: Concerns With the Age of Patient
Authors: Zheng Jianfeng , Xu Ru , Sun Xiaochuan , Zhang Xiaodong
Published: September 2021

Objective: The coiling and clipping of unruptured cerebral aneurysms (UCAs) in older patients has increased rapidly, and aneurysm size was a significant factor for decision-making in the treatment of UCAs. The purpose of the study was to investigate the impact of age on the functional outcomes of patients between the small versus large UCAs.

Methods: We conducted a retrospective study for consecutive cases of UCAs admitted from May 2011 to December 2020. According to the maximum diameter of UCA, patients were divided into small UCAs (≤ 5 mm) group and large UCAs (>5 mm) group. Baseline characteristics, clinical complications, and outcomes of patients between the two groups were analyzed.

Results: A total of 564 UCA patients received preventive treatment, including 165 small UCAs and 399 large UCAs. Compared with the small UCA group, the incidence of ischemia event in the large UCA group was significantly higher (7.3 vs. 2.4%; p = 0.029). Multivariable analysis demonstrating age (p = 0.006) and treatment modality (p < 0.001) were independent risk factors associated with poor outcome for patients with large UCAs.

Conclusions: Preventive treatment of small UCAs is safe and effective, but older patients with large UCAs are at high risk of poor outcome, and the operations should be more cautious.
The Effect of Transcranial Direct Current Stimulation and Functional Electrical Stimulation on the Lower Limb Function of Stroke Patients
Authors: Zhang Xiao-Hua , Gu Tao , Liu Xuan-Wei , Han Ping , Lv Hui-Lan , Wang Yu-Long , Xiao Peng
Published: September 2021

Objective:This study aimed to research the effect of transcranial direct current stimulation (tDCS) and functional electrical stimulation (FES) on the lower limb function of post-convalescent stroke patients.

Methods:A total of 122 patients in the stroke recovery stage who suffered from leg dysfunction were randomly divided into two groups: a tDCS group (n= 61) and a FES group (n= 61). All patients received same routine rehabilitation and equal treatment quality, the tDCS group was treated with tDCS, while the FES group received FES. The lower limb Fugl-Meyer assessment (FMA), modified Barthel index (MBI), functional ambulatory category (FAC), and somatosensory evoked potential (SEP) were used to assess the patients at three different stages: prior to treatment, 4 weeks after treatment, and 8 weeks after treatment.

Results:The assessment scores for FMA, MBI, and FAC for the lower extremities after treatment (P> 0.05) were compared with those before treatment. The FMA, MBI, and FAC scores of the tDCS group were significantly higher than those of the FES group in all three stages (P< 0.05). The FMA, MBI, and FAC assessment scores of both groups were significantly higher after 4 weeks of treatment than that before treatment, and the scores after 8 weeks of treatment were significantly higher than those after 4 weeks after treatment (P< 0.05). The P40, N45 latencies decreased and the P40, N45 amplitudes increased, but there was no significant difference before treatment and after treatment (P>0.05), and there was no significant difference of the tDCS and FES groups before treatment and after treatment.

Conclusion:In conclusion, FMA, MBI, and FAC indicate that both tDCS and FES can significantly promote the recovery of a patient’s leg motor function and tDCS is more effective than FES in the stroke recovery stage. The application value of SEP in stroke patients remains to be further studied.
Simulating Local Deformations in the Human Cortex Due to Blood Flow-Induced Changes in Mechanical Tissue Properties: Impact on Functional Magnetic Resonance Imaging
Authors: Zoraghi Mahsa , Scherf Nico , Jaeger Carsten , Sack Ingolf , Hirsch Sebastian , Hetzer Stefan , Weiskopf Nikolaus
Published: September 2021

Investigating human brain tissue is challenging due to the complexity and the manifold interactions between structures across different scales. Increasing evidence suggests that brain function and microstructural features including biomechanical features are related. More importantly, the relationship between tissue mechanics and its influence on brain imaging results remains poorly understood. As an important example, the study of the brain tissue response to blood flow could have important theoretical and experimental consequences for functional magnetic resonance imaging (fMRI) at high spatial resolutions. Computational simulations, using realistic mechanical models can predict and characterize the brain tissue behavior and give us insights into the consequent potential biases or limitations of in vivo, high-resolution fMRI. In this manuscript, we used a two dimensional biomechanical simulation of an exemplary human gyrus to investigate the relationship between mechanical tissue properties and the respective changes induced by focal blood flow changes. The model is based on the changes in the brain’s stiffness and volume due to the vasodilation evoked by neural activity. Modeling an exemplary gyrus from a brain atlas we assessed the influence of different potential mechanisms: (i) a local increase in tissue stiffness (at the level of a single anatomical layer), (ii) an increase in local volume, and (iii) a combination of both effects. Our simulation results showed considerable tissue displacement because of these temporary changes in mechanical properties. We found that the local volume increase causes more deformation and consequently higher displacement of the gyrus. These displacements introduced considerable artifacts in our simulated fMRI measurements. Our results underline the necessity to consider and characterize the tissue displacement which could be responsible for fMRI artifacts.
Aerobic Exercise Attenuates Pain Sensitivity: An Event-Related Potential Study
Authors: Zheng Kangyong , Chen Changcheng , Yang Suyong , Wang Xueqiang
Published: September 2021

In this study, electroencephalography (EEG) was utilized to explore the neurophysiological mechanisms of aerobic exercise-induced hypoalgesia (EIH) and provide a theoretical basis for the application of aerobic exercise in pain assessment and treatment. Forty-five healthy subjects were randomly divided into moderate-intensity aerobic exercise [70% heart rate reserve (HRR)], low-intensity aerobic exercise (50% HRR), or control groups (sitting). Aerobic exercise was performed with cycling. Pressure pain threshold (PPT), heat pain threshold (HPT), event-related potential (ERP) induced by contact heat stimulus and pain scoring were measured before and after the intervention. We found that moderate-intensity aerobic exercise can increase the PPT (rectus femoris: t = −2.71, p = 0.017; tibialis anterior muscle: t = −2.36, p = 0.033) and HPT (tibialis anterior muscle: t = −2.219, p = 0.044) of proximal intervention sites rather than distal sites, and decreased pain scorings of contact heat stimulus. After moderate-intensity aerobic exercise, alpha oscillation power reflecting the central descending inhibitory function was enhanced (t = −2.31, p < 0.05). Low-intensity aerobic exercise mainly reduced the pain unpleasantness rating (Block 1: t = 2.415, p = 0.030; Block 2: t = 3.287, p = 0.005; Block 4: t = 2.646, p = 0.019; Block 5: t = 2.567, p = 0.022). Aerobic exercise had an overall EIH effect. Its hypoalgesic effect was related to exercise intensity and affected by the site and type of pain stimulus. Moderate-intensity aerobic exercise effectively reduced the sensitivity to various painful stimuli, and low-intensity aerobic exercise selectively inhibited the negative emotional pain response. The hypoalgesic mechanism of aerobic exercise involves the enhancement of the central descending inhibitory function.
Metabolites of Procyanidins From Litchi Chinensis Pericarp With Xanthine Oxidase Inhibitory Effect and Antioxidant Activity
Authors: Sui Yong , Shi Jianbin , Cai Sha , Xiong Tian , Xie Bijun , Sun Zhida , Mei Xin
Published: September 2021

Procyanidins from litchi pericarp (LPPC) has been evidenced to possess strong antioxidant activities in vivo that is possibly correlated with their intestinal metabolites. However, the xanthine oxidase inhibitory effect of LPPC and its metabolites was less concerned. In this study, three oligomeric procyanidins and eight metabolic phenolic acids were identified in the urine of rats administrated with LPPC by high performance liquid chromatography and liquid chromatography-mass spectrometry analysis. Data indicated that all the metabolites excreted were significantly increased by the treatment of 300 mg/kg body weight of LPPC (P < 0.05), revealing considerable 1, 1-Diphenyl-2-Picrylhydrazyl (DPPH) and hydroxyl radicals activities of scavenging. Moreover, phenolic metabolites involving epicatechin, A-type dimer, A-type trimer, caffeic acid, and shikimic acid exhibited greater xanthine oxidase inhibition effects compared with other metabolites, with an inhibitory rate higher than 50% at the concentration 200 μg/ml. The IC50 value of these five phenols were 58.43 ± 1.86, 68.37 ± 3.50, 74.87 ± 1.30, 95.67 ± 3.82, and 96.17 ± 1.64 μg/ml, respectively. As a whole, this work suggests that the xanthine oxidase inhibition and antioxidant activity of LPPC-derived metabolites as one of the mechanisms involved in the beneficial effects of LPPC against hyperuricemia or gout.
Irinotecan Plus Doxorubicin Hydrochloride Liposomes for Relapsed or Refractory Wilms Tumor
Authors: Wang Juan , Zhang Lian , Guo Lanying , Que Yi , Zhang Yu , Sun Feifei , Zhu Jia , Lu Suying , Huang Junting , Wu Liuhong , Cai Ruiqing , Zhen Zijun , Zeng Sihui , Zhang Yizhuo , Sun Xiaofei
Published: September 2021

Purpose

The prognosis of relapsed or refractory pediatric Wilms tumor (WT) is dismal, and new salvage therapies are needed. This study aimed to evaluate the efficacy of the combination of irinotecan and a doxorubicin hydrochloride liposome regimen for relapsed or refractory pediatric WT.

Patients and Methods

The present study enrolled relapsed or refractory pediatric WT patients who were treated with the AI regimen (doxorubicin hydrochloride liposomes 40 mg/m2 per day, day 1, and irinotecan 50 mg/m2 per day with 90-min infusion, days 1–5; this regimen was repeated every 3 weeks) at Sun Yat-sen University Cancer Center from July 2018 to September 2020. The response was defined as the best-observed response after at least two cycles according to the Response Evaluation Criteria of Solid Tumors (RECIST 1.1), and toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03).

Results

A total of 16 patients (male:female, 8:8) with a median age of 4.2 years (0.5–11 years) with relapsed or refractory disease were enrolled in this study, including 14 patients with relapsed disease and two patients with refractory disease. These patients received 1–8 courses (median, 3 courses) of the AI regimen. Fourteen patients were assessable for response: two with complete response (CR), five with partial response (PR), two with stable disease (SD), and five with progressive disease (PD). The objective response rate was 50% (two CR, five PR), and the disease control rate was 64% (two CR, five PR, and two SD). Seven out of 14 patients (50%) were alive at the last follow-up, ranging from 2.6 to 32.4 months. The median progression-free survival and median overall survival were 3.5 months (range 0.5–12 months) and 8 months (range 1–28 months), respectively. Sixteen patients were assessable for toxicity, with the most common grade 3 or 4 adverse events being alopecia (62%), leukopenia (40%), abdominal pain (38%), diarrhea (23%), and mucositis (16%), etc. No fatal adverse events have been observed, and modest adverse effects can be administered.

Conclusion

Irinotecan and doxorubicin hydrochloride liposome regimens have positive efficacy on relapsed or refractory pediatric WT with well-tolerated toxicity. A prospective clinical trial is warranted.
Assessment of Intratumor Heterogeneity in Parametric Dynamic Contrast-Enhanced MR Images: A Comparative Study of Novel and Established Methods
Authors: Gaustad Jon-Vidar , Rofstad Einar K.
Published: September 2021

Intratumor heterogeneity is associated with aggressive disease and poor survival rates in several types of cancer. A novel method for assessing intratumor heterogeneity in medical images, named the spatial gradient method, has been developed in our laboratory. In this study, we measure intratumor heterogeneity in Ktrans maps derived by dynamic contrast-enhanced magnetic resonance imaging using the spatial gradient method, and we compare the performance of the novel method with that of histogram analyses and texture analyses using the Haralick method. Ktrans maps of 58 untreated and sunitinib-treated pancreatic ductal adenocaricoma (PDAC) xenografts from two PDAC models were investigated. Intratumor heterogeneity parameters derived by the spatial gradient method were sensitive to tumor line differences as well as sunitinib-induced changes in intratumor heterogeneity. Furthermore, the parameters provided additional information to the median value and were not severely affected by imaging noise. The parameters derived by histogram analyses were insensitive to spatial heterogeneity and were strongly correlated to the median value, and the Haralick features were severely influenced by imaging noise and did not differentiate between untreated and sunitinib-treated tumors. The spatial gradient method was superior to histogram analyses and Haralick features for assessing intratumor heterogeneity in Ktrans maps of untreated and sunitinib-treated PDAC xenografts, and can possibly be used to assess intratumor heterogeneity in other medical images and to evaluate effects of other treatments as well.
A Novel H2O2 Generator for Tumor Chemotherapy-Enhanced CO Gas Therapy
Authors: Li Yang , Liu Zeming , Zeng Weng , Wang Ziqi , Liu Chunping , Zeng Ning , Zhong Keli , Jiang Dazhen , Wu Yiping
Published: September 2021

Carbon monoxide (CO) gas therapy is a promising cancer treatment. However, gas delivery to the tumor site remains problematic. Proper tunable control of CO release in tumors is crucial to increasing the efficiency of CO treatment and reducing the risk of CO poisoning. To overcome such challenges, we designed ZCM, a novel stable nanotechnology delivery system comprising manganese carbonyl (MnCO) combined with anticancer drug camptothecin (CPT) loaded onto a zeolitic imidazole framework-8 (ZIF-8). After intravenous injection, ZCM gradually accumulates in cancerous tissues, decomposing in the acidic tumor microenvironment, releasing CPT and MnCO. CPT acts as a chemotherapy agent destroying tumors and producing copious H2O2. MnCO can react with the H2O2 to generate CO, powerfully damaging the tumor. Both in vitro and in vivo experiments indicate that the ZCM system is both safe and has excellent tumor inhibition properties. ZCM is a novel system for CO controlled release, with significant potential to improve future cancer therapy.
Defining the Role of Immunotherapy in the Curative Treatment of Locoregionally Advanced Head and Neck Cancer: Promises, Challenges, and Opportunities
Authors: Saddawi-Konefka Robert , Simon Aaron B. , Sumner Whitney , Sharabi Andrew , Mell Loren K. , Cohen Ezra E. W.
Published: September 2021

Recent advancements in the development of immunotherapies have raised the hope for patients with locally-advanced HNSCC (LA-HNSCC) to achieve improved oncologic outcomes without the heavy burden of treatment-related morbidity. While there are several ongoing late phase clinical trials that seek to determine whether immunotherapy can be effectively employed in the definitive setting, initial results from concurrent immuno-radiotherapy therapy trials have not shown strong evidence of benefit. Encouragingly, evidence from preclinical studies and early-phase neoadjuvant studies have begun to show potential pathways forward, with therapeutic combinations and sequences that intentionally spare tumor draining lymphatics in order to maximize the synergy between definitive local therapy and immunotherapy. The intent of this review is to summarize the scientific rationale and current clinical evidence for employing immunotherapy for LA-HNSCC as well as the ongoing efforts and challenges to determine how to optimally deliver and sequence immunotherapy alongside traditional therapeutics. In both the preclinical and clinical settings, we will discuss the application of immunotherapies to both surgical and radiotherapeutic management of HNSCC.
Case Report: Multi-Omics Analysis and CAR-T Treatment of a Chronic Myeloid Leukemia Blast Crisis Case 5 Years After the Discontinuation of TKI
Authors: Miao Ya-Ru , Liu Wen , Zhong Zhaodong , You Yong , Tang Yutong , Li Weiming , Zhu Xiaojian , Guo An-Yuan
Published: September 2021

Most relapsed chronic myeloid leukemia (CML) patients after tyrosine kinase inhibitor (TKI) discontinuation are in a chronic phase and could achieve remission through restarting the TKI treatment. Here we reported a case of sudden lymphoid blast crisis after 67 months of TKI discontinuation and depicted the patient by DNA and RNA sequencing to investigate intrinsic molecular features. The mutations of TGFBR2 and PCNT and the dysregulations of TGF-β and other pathways might accelerate the B cell transformation, which may serve as a blast crisis risk indicator of CML. Single-cell transcriptome data revealed that several clusters of immature B cells and late pro-B cells presented clone evolution during the treatment. After failing multiple lines of TKIs, conditioning chemotherapies and chimeric antigen receptor T cells (CAR-T) targeting CD19 and CD22 were performed to achieve remission. In conclusion, we report the first case of a CML patient with sudden lymphoid blast crisis after a long treatment-free remission and additional gene abnormalities other than BCR-ABL1 might participate in the progression, which need to be closely monitored, and CAR-T could be a solution to the chemoresistant progression.
The Clinicopathological Features and Prognosis in Patients With Papillary Renal Cell Carcinoma: A Multicenter Retrospective Study in Chinese Population
Authors: Hong Baoan , Hou Huimin , Chen Lingxiao , Li Zhi , Zhang Zhipeng , Zhao Qiang , Du Xin , Li Yuan , Ye Xiongjun , Xu Wanhai , Liu Ming , Zhang Ning
Published: September 2021

Objective

The purpose of this study was to compare the clinicopathological characteristics of type 1 and type 2 papillary renal cell carcinoma (PRCC) and to explore the prognostic factors of PRCC in the Chinese population.

Methods

A total of 242 patients with PRCC from five Chinese medical centers were retrospectively included. From them, 82 were type 1 PRCC and 160 were type 2 PRCC. Clinicopathological features and oncologic outcomes were reviewed. The Kaplan–Meier analysis and log-rank test were performed to describe the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic factors of PRCC.

Results

Of the 242 patients, the average age at surgery was 55.3 ± 13.1 years. The mean tumor size was 5.1 ± 3.1 cm. Compared with type 1 PRCC patients, type 2 PRCC patients had a larger tumor size and were more likely to undergo radical nephrectomy. Besides, type 2 PRCC patients had higher tumor stage (p < 0.001) and WHO International Society of Urological Pathology (WHO/ISUP) grading (p < 0.001). Furthermore, tumor necrosis was more common in type 2 PRCC than type 1 PRCC (p = 0.030). The Kaplan–Meier survival analysis showed that the PFS and OS of type 1 PRCC patients were significantly better than those of type 2 PRCC patients (p = 0.0032 and p = 0.0385, respectively). Univariate analysis showed that tumor size, surgical procedures, pT stage, WHO/ISUP grading, and microvascular invasion were significant predictors of PFS and OS for type 2 PRCC patients. In the multivariate analysis, only pT stage (p = 0.004) and WHO/ISUP grading (p = 0.010) were the independent risk factors. Among type 2 PRCC patients with pT1 stage, no significant difference was found in PFS and OS between the partial nephrectomy and radical nephrectomy groups (p = 0.159 and p = 0.239, respectively).

Conclusion

This multi-institutional study reveals the significant differences in clinicopathological variables and oncologic outcomes between type 1 and 2 PRCC. For type 2 PRCC in pT1 stage, the prognosis of partial nephrectomy is not inferior to that of radical nephrectomy, and nephron-sparing surgery can be considered.
Combination Immunotherapy Use and Withdrawal in Pediatric Inflammatory Bowel Disease—A Review of the Evidence
Authors: Meredith Joseph , Henderson Paul , Wilson David C. , Russell Richard K.
Published: September 2021

Evidence-based guidelines have been developed outlining the concomitant use of anti-tumor necrosis factor alpha (anti-TNF) agents and immunomodulators including azathioprine (AZA) and methotrexate (MTX) in both adult and pediatric populations. However, there exists a paucity of data guiding evidence-based strategies for their withdrawal in pediatric patients in sustained remission. This narrative review focuses on the available pediatric evidence on this question in the context of what is known from the larger body of evidence available from adult studies. The objective is to provide clarity and practical guidance around who, what, when, and how to step down pediatric patients with inflammatory bowel disease (IBD) from combination immunotherapy. Outcomes following withdrawal of either of the two most commonly used anti-TNF therapies [infliximab (IFX) or adalimumab (ADA)], or immunomodulator therapies, from a combination regimen are examined. Essentially, a judicious approach must be taken to identify a significant minority of patients who would benefit from treatment rationalization. We conclude that step-down to anti-TNF (rather than immunomodulator) monotherapy after at least 6 months of sustained clinical remission is a viable option for a select group of pediatric patients. This group includes those with good indicators of mucosal healing, low or undetectable anti-TNF trough levels, lack of predictors for severe disease, and no prior escalation of anti-TNF therapy. Transmural healing and specific human leukocyte antigen (HLA) typing are some of the emerging targets and tools that may help facilitate improved outcomes in this process. We also propose a simplified evidence-based schema that may assist in this decision-making process. Further pediatric clinical studies are required to develop the evidence base for decision-making in this area.
Lack of Major Involvement of Common CYP2C Gene Polymorphisms in the Risk of Developing Cross-Hypersensitivity to NSAIDs
Authors: Macías Yolanda , García-Menaya Jesús M. , Martí Manuel , Cordobés Concepción , Jurado-Escobar Raquel , Cornejo-García José A. , Torres María J. , Blanca-López Natalia , Canto Gabriela , Blanca Miguel , Laguna José J. , Bartra Joan , Rosado Ana , Fernández Javier , García-Martín Elena , Agúndez José A. G.
Published: September 2021

Cross-hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) is a relatively common, non-allergic, adverse drug event triggered by two or more chemically unrelated NSAIDs. Current evidence point to COX-1 inhibition as one of the main factors in its etiopathogenesis. Evidence also suggests that the risk is dose-dependent. Therefore it could be speculated that individuals with impaired NSAID biodisposition might be at increased risk of developing cross-hypersensitivity to NSAIDs. We analyzed common functional gene variants for CYP2C8, CYP2C9, and CYP2C19 in a large cohort composed of 499 patients with cross-hypersensitivity to NSAIDs and 624 healthy individuals who tolerated NSAIDs. Patients were analyzed as a whole group and subdivided in three groups according to the main enzymes involved in the metabolism of the culprit drugs as follows: CYP2C9, aceclofenac, indomethacin, naproxen, piroxicam, meloxicam, lornoxicam, and celecoxib; CYP2C8 plus CYP2C9, ibuprofen and diclofenac; CYP2C19 plus CYP2C9, metamizole. Genotype calls ranged from 94 to 99%. No statistically significant differences between patients and controls were identified in this study, either for allele frequencies, diplotypes, or inferred phenotypes. After patient stratification according to the enzymes involved in the metabolism of the culprit drugs, or according to the clinical presentation of the hypersensitivity reaction, we identified weak significant associations of a lower frequency (as compared to that of control subjects) of CYP2C8*3/*3 genotypes in patients receiving NSAIDs that are predominantly CYP2C9 substrates, and in patients with NSAIDs-exacerbated cutaneous disease. However, these associations lost significance after False Discovery Rate correction for multiple comparisons. Taking together these findings and the statistical power of this cohort, we conclude that there is no evidence of a major implication of the major functional CYP2C polymorphisms analyzed in this study and the risk of developing cross-hypersensitivity to NSAIDs. This argues against the hypothesis of a dose-dependent COX-1 inhibition as the main underlying mechanism for this adverse drug event and suggests that pre-emptive genotyping aiming at drug selection should have a low practical utility for cross-hypersensitivity to NSAIDs.
Explore the Usefulness of Concurrent Chemotherapy in Stage II Nasopharyngeal Carcinoma: A Retrospective Study
Authors: Li Pei-Jing , Lai Yu-Lin , He Fang , Chen Yuan-Yuan , Gu Zhuo-Sheng , Luo Wei , Zhang Qun
Published: September 2021

Objective: This study aims to compare the treatment outcomes of concurrent chemoradiotherapy (CCRT) versus radiotherapy (RT) alone in stage II nasopharyngeal carcinoma (NPC) patients.

Methods: We retrospectively collected 601 stage II NPC patients treated in two hospitals between June 2003 to June 2016. All patients were divided into the CCRT group (n = 255) and the RT group (n = 346). Overall survival (OS), locoregional failure-free survival (LRFFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) were assessed using the Kaplan-Meier method. The log-rank test was used to compare the differences between the groups. The Cox-regression hazards model was performed to determine potential prognostic factors.

Results: The median follow-up was 99 months. No significant difference was found in locoregional recurrence, distant metastasis, disease progression, and death between the two groups (all p > 0.05). In univariate analysis, the 5-years OS, PFS, LRFFS, and DMFS had no significant differences between the CCRT and RT groups (all p > 0.05). Two-dimensional radiotherapy (2DRT) sub-analysis showed that CCRT remarkably increased DMFS, PFS, and OS rates (all p < 0.05) but not LRFFS (p = 0.258) compared with RT alone. While intensity-modulated radiotherapy (IMRT) sub-analysis showed that the prognosis of the two groups had no significant differences (all p > 0.05). In multivariate analyses, age was significantly and inversely related to OS, PFS, LRFFS, and DMFS. IMRT was an independent favorable factor for improving LRFFS, PFS, and OS. Concurrent chemotherapy was an independent protective factor for DMFS.

Conclusion: In the context of 2DRT, it is definite that concurrent chemotherapy provides survival benefits for patients with stage II NPC. While in the IMRT era, the impact of chemotherapy on survival in patients with stage II NPC is weakened. Prospective randomized controlled studies are required to confirm these results.
An Exploratory Pilot Study of Changes in Global DNA Methylation in Patients Undergoing Major Breast Surgery Under Opioid-Based General Anesthesia
Authors: Caputi Francesca Felicia , Carboni Lucia , Rullo Laura , Alessandrini Irene , Balzani Eleonora , Melotti Rita Maria , Romualdi Patrizia , Candeletti Sanzio , Fanelli Andrea
Published: September 2021

This study aimed to investigate DNA methylation levels in patients undergoing major breast surgery under opioid-based general anesthesia. Blood samples were collected from eleven enrolled patients, before, during and after anesthesia. PBMC were isolated and global DNA methylation levels as well as DNA methyltransferase (DNMT) and cytokine gene expression were assessed. DNA methylation levels significantly declined by 26%, reversing the direction after the end of surgery. Likewise, DNMT1a mRNA expression was significantly reduced at all time points, with lowest level of −68%. DNMT3a and DNMT3b decreased by 65 and 71%, respectively. Inflammatory cytokines IL6 and TNFα mRNA levels showed a trend for increased expression at early time-points to end with a significant decrease at 48 h after surgery. This exploratory study revealed for the first time intraoperative global DNA hypomethylation in patients undergoing major breast surgery under general anesthesia with fentanyl. The alterations of global DNA methylation here observed seem to be in agreement with DNMTs gene expression changes. Furthermore, based on perioperative variations of IL6 and TNFα gene expression, we hypothesize that DNA hypomethylation may occur as a response to surgical stress rather than to opiate exposure.
What Factors Hindered the Access to Essential Anticancer Medicine in Public Hospitals for the Local Population in Hubei Province, China
Authors: Chen Chaoyi , Feng Zhanchun , Ding Yufeng , Yan Ziqi , Wang Jia , Wang Ruoxi , Feng Da
Published: September 2021

Background:Cancer poses a serious threat to one’s health, which caused significant economic burden on the family and society. Poor availability and affordability resulted in some essential medicines failing to meet the basic health needs of this group of patients. The objective of this study was to evaluate the availability, prices and affordability of 32 anticancer essential medicines in Hubei Province, China.

Methods: Data on the availability and price related information of 32 essential anticancer medicines in the capital and five other cities of Hubei Province were collected. A total of 28 hospitals were sampled, which included 13 tertiary hospitals and 15 secondary hospitals. We used the standard methods developed by the World Health Organization and Health Action International to compare the differences in drug price, availability and affordability between secondary hospitals and tertiary hospitals.

Results: Overall, the availability of medicine was higher in tertiary hospitals. The average availability of originator brand (OBs) was 13.70% (tertiary hospitals) VS 6.67% (secondary hospitals), and lowest-priced generic (LPGs) was 62.83% (tertiary hospitals) VS 42.92% (secondary hospitals). The MPR value of most sampled medicines in secondary hospitals were less than 1. In contrast, the MPR of Cytarabine (17.15), Oxaliplatin (12.73) were significantly higher than the international reference price. The top three OBs’ total expenses for 30-days treatment were Irinotecan, Oxaliplatin, Bicalutamide. Further, their affordability was relative low, as the costs for one course using these medicines were much higher than 20% of the minimum family monthly income.

Conclusion: Though the “Zero Mark-Up” and “Centralized procurement policy of anti-tumor drugs” policies have been implemented in China, the availability issue yet to be addressed. High price and low affordability were the major barriers to the access of essential anticancer medicines. Measures should be taken to provide sufficient, available and affordable medicines to patients in need.
Toxicity Evaluation of Long-Term Topical Application of Recombinant Human Keratinocyte Growth Factor-2 Eye Drops on Macaca Fascicularis
Authors: Li Le , Li Lijia , Chen Qi , Yang Xuanxin , Hui Qi , AL-Azzani Hamdi , Huang Yadong , Cai Jianqiu , Wang Xiaojie , Jin Zi
Published: September 2021

Recombinant human keratinocyte growth factor-2 (rhKGF-2), an effective agent for the regeneration of epithelial tissue, was found to have great potential for use in treatments of corneal diseases that involve corneal epithelial defects. Furthermore, the safety of long-term and high-dose external use of KGF-2 eye drops in rabbits has been well established previously. The aim of this study is to determine the safe dose range and target organs for toxicity of rhKGF-2 eye drops in Macaca fascicularis (M. fascicularis). The M. fascicularis animals were administered with different doses of rhKGF-2 eye drops (125, 500, and 2000 μg/ml) for four consecutive weeks, followed by a 2 week recovery period. No significant differences in weight, electrocardiogram characteristics, blood and urine indexes, pathology, and bone marrow cells were detected among the animals in different groups. The corneas of some animals in the middle- and high-dose groups showed fluorescence when stained with sodium fluorescein, and then the staining disappeared on days 28 and 42. Anti-rhKGF-2 antibodies were detected in a small number of animals in the high-dose group, and their level decreased after rhKGF-2 withdrawal. No neutralizing antibodies were detected. The result demonstrated that there was no obvious adverse reaction when topical application of rhKGF-2 eye drops at the dosage of 125 or 500 μg/ml on the M. fascicularis. This study is of great significance for the future clinical transformation of rhKGF-2 eye drops.
Spleen Contraction During Sudden Eupneic Hypoxia Elevates Hemoglobin Concentration
Authors: Pernett Frank , Schagatay Felix , Vildevi Caroline , Schagatay Erika
Published: September 2021

The spleen contracts progressively during moderate normobaric hypoxia exposure of 20 min, which elevates hemoglobin concentration (Hb). However, acute hypoxia exposure could be shorter and more severe when oxygen systems fail during, e.g., high-altitude sky diving, aircraft cabin pressure drop, balloon flights, extreme altitude climbing, and in some maladies. We aimed to evaluate the speed and magnitude of spleen contraction during short exposure to extreme eupneic hypoxia and its subsequent recovery on oxygen. Eight female and seven male volunteers were exposed to normobaric hypoxia (10% oxygen) for 10 min during sitting rest, followed by 10 min on 100% oxygen. Heart rate (HR), arterial oxygen saturation (SpO2), and mean arterial blood pressure (MAP) were measured continuously. The spleen was measured via ultrasonic imaging every minute for volume calculations, and venous blood samples were drawn before and after exposure for hemoglobin concentration (Hb). Mean (SD) spleen volume was 279 (115) mL before exposure, 219 (75) mL (21% reduction; P = 0.005) at 3 min of exposure, and 201 (93) mL after 10 min exposure to hypoxia (28% reduction; P < 0.001). Hb was 138.8 (7.6) g·L−1 before and 142.9 (8.1) g·L−1 after 10 min of exposure (2.9% increase; P < 0.001). SpO2 was 96.4 (1.7)% before exposure and 74.7 (8.4)% during the last minute of exposure (22.5% reduction; P < 0.001). HR increased from 80 (14) to 90 (17) bpm during exposure (12% increase, P < 0.05). MAP remained unchanged. After 10 min recovery on oxygen, values had been restored for spleen volume and Hb, while SpO2 was higher and HR lower compared with before hypoxia exposure. We concluded that acute normobaric hypoxia of only 10 min caused significant spleen volume contraction with Hb increase. This rapid spleen response, evident already after 3 min of exposure, could have a protective effect during sudden exposure to severe hypoxia.
Modulation of Vagal Sensory Neurons via High Mobility Group Box-1 and Receptor for Advanced Glycation End Products: Implications for Respiratory Viral Infections
Authors: Mazzone Stuart B. , Yang Seung-Kwon , Keller Jennifer A. , Simanauskaite Juste , Arikkatt Jaisy , Fogarty Matthew J. , Moe Aung Aung Kywe , Chen Chen , Trewella Matthew W. , Tian Luyi , Ritchie Matthew E. , Chua Brendan Y. , Phipps Simon , Short Kirsty R. , McGovern Alice E.
Published: September 2021

Vagal sensory neurons contribute to the symptoms and pathogenesis of inflammatory pulmonary diseases through processes that involve changes to their morphological and functional characteristics. The alarmin high mobility group box-1 (HMGB1) is an early mediator of pulmonary inflammation and can have actions on neurons in a range of inflammatory settings. We hypothesized that HMGB1 can regulate the growth and function of vagal sensory neurons and we set out to investigate this and the mechanisms involved. Culturing primary vagal sensory neurons from wildtype mice in the presence of HMGB1 significantly increased neurite outgrowth, while acute application of HMGB1 to isolated neurons under patch clamp electrophysiological investigation produced inward currents and enhanced action potential firing. Transcriptional analyses revealed the expression of the cognate HMGB1 receptors, Receptor for Advanced Glycation End products (RAGE) and Toll-like Receptor 4 (TLR4), in subsets of vagal sensory neurons. HMGB1-evoked growth and electrophysiological responses were significantly reduced in primary vagal sensory neurons harvested from RAGE deficient mice and completely absent in neurons from RAGE/TLR4 double deficient mice. Immunohistochemical analysis of vagal sensory neurons collected from mice after intranasal infection with murine pneumovirus or influenza A virus (IAV), or after intratracheal administration with the viral mimetic PolyI:C, revealed a significant increase in nuclear-to-cytoplasm translocation of HMGB1 compared to mock-inoculated mice. Neurons cultured from virus infected wildtype mice displayed a significant increase in neurite outgrowth, which was not observed for neurons from virus infected RAGE or RAGE/TLR4 deficient mice. These data suggest that HMGB1 can enhance vagal sensory neuron growth and excitability, acting primarilyviasensory neuron RAGE. Activation of the HMGB1-RAGE axis in vagal sensory neurons could be an important mechanism leading to vagal hyperinnervation and hypersensitivity in chronic pulmonary disease.
Transcriptomic Profiling Reveals Shared Signalling Networks Between Flower Development and Herbivory-Induced Responses in Tomato
Authors: Ke Lanlan , Wang Yangzi , Schäfer Martin , Städler Thomas , Zeng Rensen , Fabian Jörg , Pulido Hannier , De Moraes Consuelo M. , Song Yuanyuan , Xu Shuqing
Published: September 2021

Most flowering plants must defend themselves against herbivores for survival and attract pollinators for reproduction. Although traits involved in plant defence and pollinator attraction are often localised in leaves and flowers, respectively, they will show a diffuse evolution if they share the same molecular machinery and regulatory networks. We performed RNA-sequencing to characterise and compare transcriptomic changes involved in herbivory-induced defences and flower development, in tomato leaves and flowers, respectively. We found that both the herbivory-induced responses and flower development involved alterations in jasmonic acid signalling, suppression of primary metabolism and reprogramming of secondary metabolism. We identified 411 genes that were involved in both processes, a number significantly higher than expected by chance. Genetic manipulation of key regulators of induced defences also led to the expression changes in the same genes in both leaves and flowers. Targeted metabolomic analysis showed that among closely related tomato species, jasmonic acid and α-tomatine are correlated in flower buds and herbivory-induced leaves. These findings suggest that herbivory-induced responses and flower development share a common molecular machinery and likely have coevolved in nature.
Variables Affecting Shoot Growth and Plantlet Recovery in Tissue Cultures of Drug-Type Cannabis sativa L.
Authors: Holmes Janesse E. , Lung Samantha , Collyer Danielle , Punja Zamir K.
Published: September 2021

Tissue culture approaches are widely used in crop plants for the purposes of micropropagation, regeneration of plants through organogenesis, obtaining pathogen-free plantlets from meristem culture, and developing genetically modified plants. In this research, we evaluated variables that can influence the success of shoot growth and plantlet production in tissue cultures of drug-typeCannabis sativaL. (marijuana). Various sterilization methods were tested to ensure shoot development from nodal explants by limiting the frequency of contaminating endophytes, which otherwise caused the death of explants. Seven commercially grown tetrahydrocannabinol (THC)-containing cannabis genotypes (strains) showed significant differences in response to shoot growth from meristems and nodal explants on Murashige and Skoog (MS) medium containing thidiazuron (1 μM) and naphthaleneacetic acid (0.5 μM) plus 1% activated charcoal. The effect of Driver and Kuniyuki Walnut (DKW) or MS basal salts in media on shoot length and leaf numbers from nodal explants was compared and showed genotype dependency with regard to the growth response. To obtain rooted plantlets, shoots from meristems and nodal explants of genotype Moby Dick were evaluated for rooting, following the addition of sodium metasilicate, silver nitrate, indole-3-butyric acid (IBA), kinetin, or 2,4-D. Sodium metasilicate improved the visual appearance of the foliage and improved the rate of rooting. Silver nitrate also promoted rooting. Following acclimatization, plantlet survival in hydroponic culture, peat plugs, and rockwool substrate was 57, 76, and 83%, respectively. The development of plantlets from meristems is described for the first time inC. sativaand has potential for obtaining pathogen-free plants. The callogenesis response of leaf explants of 11 genotypes on MS medium without activated charcoal was 35% to 100%, depending on the genotype; organogenesis was not observed. The success in recovery of plantlets from meristems and nodal explants is influenced by cannabis genotype, degree of endophytic contamination of the explants, and frequency of rooting. The procedures described here have potential applications for research and commercial utility to obtain plantlets in stage 1 tissue cultures ofC. sativa.