bluuebunny/crossref_metadata_2025 huggingface dataset:
vol2Brain: A New Online Pipeline for Whole Brain MRI Analysis
Authors: Manjón José V. , Romero José E. , Vivo-Hernando Roberto , Rubio Gregorio , Aparici Fernando , de la Iglesia-Vaya Mariam , Coupé Pierrick
Published: May 2022

Automatic and reliable quantitative tools for MR brain image analysis are a very valuable resource for both clinical and research environments. In the past few years, this field has experienced many advances with successful techniques based on label fusion and more recently deep learning. However, few of them have been specifically designed to provide a dense anatomical labeling at the multiscale level and to deal with brain anatomical alterations such as white matter lesions (WML). In this work, we present a fully automatic pipeline (vol2Brain) for whole brain segmentation and analysis, which densely labels (N > 100) the brain while being robust to the presence of WML. This new pipeline is an evolution of our previous volBrain pipeline that extends significantly the number of regions that can be analyzed. Our proposed method is based on a fast and multiscale multi-atlas label fusion technology with systematic error correction able to provide accurate volumetric information in a few minutes. We have deployed our new pipeline within our platform volBrain (www.volbrain.upv.es), which has been already demonstrated to be an efficient and effective way to share our technology with the users worldwide.
The Impact of Probiotic Supplementation on Cognitive, Pathological and Metabolic Markers in a Transgenic Mouse Model of Alzheimer’s Disease
Authors: Webberley Thomas S. , Masetti Giulia , Bevan Ryan J. , Kerry-Smith Joshua , Jack Alison A. , Michael Daryn R. , Thomas Sophie , Glymenaki Maria , Li Jia , McDonald Julie A. K. , John Daniel , Morgan James E. , Marchesi Julian R. , Good Mark A. , Plummer Sue F. , Hughes Timothy R.
Published: May 2022

Brain degenerative disorders such as Alzheimer’s disease (AD) can be exacerbated by aberrant metabolism. Supplementation with probiotic bacteria is emerging as a promising preventative strategy for both neurodegeneration and metabolic syndrome. In this study, we assess the impact of the Lab4b probiotic consortium on (i) cognitive and pathological markers of AD progression and (ii) metabolic status in 3xTg-AD mice subjected to metabolic challenge with a high fat diet. The group receiving the probiotic performed better in the novel object recognition test and displayed higher hippocampal neuronal spine density than the control group at the end of the 12 weeks intervention period. These changes were accompanied by differences in localised (brain) and systemic anti-inflammatory responses that favoured the Probiotic group together with the prevention of diet induced weight gain and hypercholesterolaemia and the modulation of liver function. Compositional differences between the faecal microbiotas of the study groups included a lower Firmicutes:Bacteroidetes ratio and less numbers of viable yeast in the Probiotic group compared to the Control. The results illustrate the potential of the Lab4b probiotic as a neuroprotective agent and encourage further studies with human participants.
Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities
Authors: Liu Sophie S. , Yang Rong
Published: May 2022

Most therapies for treating sensorineural hearing loss are challenged by the delivery across multiple tissue barriers to the hard-to-access anatomical location of the inner ear. In this review, we will provide a recent update on various pharmacotherapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for the treatment of sensorineural hearing loss and approaches taken to overcome the drug delivery barriers in the ear. Small-molecule drugs for pharmacotherapy can be delivered via systemic or local delivery, where the blood-labyrinth barrier hinders the former and tissue barriers including the tympanic membrane, the round window membrane, and/or the oval window hinder the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved via intra-cochlear or intra-labyrinthine injection. To improve the stability of the biomacromolecules during treatment, e.g., RNAs, DNAs, proteins, additional packing vehicles are often required. To address the diverse range of biological barriers involved in inner ear drug delivery, each class of therapy and the intended therapeutic cargoes will be discussed in this review, in the context of delivery routes commonly used, delivery vehicles if required (e.g., viral and non-viral nanocarriers), and other strategies to improve drug permeation and sustained release (e.g., hydrogel, nanocarriers, permeation enhancers, and microfluidic systems). Overall, this review aims to capture the important advancements and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prophylaxis of sensorineural hearing loss.
PET Imaging in Animal Models of Alzheimer’s Disease
Authors: Chen Baosheng , Marquez-Nostra Bernadette , Belitzky Erika , Toyonaga Takuya , Tong Jie , Huang Yiyun , Cai Zhengxin
Published: May 2022

The successful development and translation of PET imaging agents targeting β-amyloid plaques and hyperphosphorylated tau tangles have allowed for in vivo detection of these hallmarks of Alzheimer’s disease (AD) antemortem. Amyloid and tau PET have been incorporated into the A/T/N scheme for AD characterization and have become an integral part of ongoing clinical trials to screen patients for enrollment, prove drug action mechanisms, and monitor therapeutic effects. Meanwhile, preclinical PET imaging in animal models of AD can provide supportive information for mechanistic studies. With the recent advancement of gene editing technologies and AD animal model development, preclinical PET imaging in AD models will further facilitate our understanding of AD pathogenesis/progression and the development of novel treatments. In this study, we review the current state-of-the-art in preclinical PET imaging using animal models of AD and suggest future research directions.
A Prebiotic Diet Alters the Fecal Microbiome and Improves Sleep in Response to Sleep Disruption in Rats
Authors: Bowers Samuel J. , Summa Keith C. , Thompson Robert S. , González Antonio , Vargas Fernando , Olker Christopher , Jiang Peng , Lowry Christopher A. , Dorrestein Pieter C. , Knight Rob , Wright Kenneth P. , Fleshner Monika , Turek Fred W. , Vitaterna Martha H.
Published: May 2022

Sleep disruption is a challenging and exceedingly common physiological state that contributes to a wide range of biochemical and molecular perturbations and has been linked to numerous adverse health outcomes. Modern society exerts significant pressure on the sleep/wake cycle via myriad factors, including exposure to electric light, psychological stressors, technological interconnection, jet travel, shift work, and widespread use of sleep-affecting compounds. Interestingly, recent research has identified a link between the microbiome and the regulation of sleep, suggesting that interventions targeting the microbiome may offer unique therapeutic approaches to challenges posed by sleep disruption. In this study, we test the hypothesis that administration of a prebiotic diet containing galactooligosaccharides (GOS) and polydextrose (PDX) in adult male rats improves sleep in response to repeated sleep disruption and during recovery sleep. We found that animals fed the GOS/PDX prebiotic diet for 4 weeks exhibit increased non-rapid eye movement (NREM) and rapid eye movement (REM) sleep during 5 days of sleep disruption and increased total sleep time during 24 h of recovery from sleep disruption compared to animals fed a control diet, despite similar baseline sleep characteristics. Further, the GOS/PDX prebiotic diet led to significant changes in the fecal microbiome. Consistent with previous reports, the prebiotic diet increased the relative abundance of the species Parabacteroides distasonis, which positively correlated with sleep parameters during recovery sleep. Taken together, these findings suggest that the GOS/PDX prebiotic diet may offer an approach to improve resilience to the physiologic challenge of sleep disruption, in part through impacts on the microbiome.
Case Report: Stroke Chameleon: Acute Large Vessel Occlusion in the Posterior Circulation With Paroxysmal Sympathetic Hyperactivity as the First Manifestation
Authors: Yin Juntao , Wang Wan , Wang Yu , Li Guofeng , Kong Yongmei , Li Xiaoqiang , Xu Yingdong , Wei Yuqing
Published: May 2022

Paroxysmal sympathetic hyperactivity (PSH) is a neurological emergency mostly secondary to traumatic brain injury (TBI). Acute large vessel occlusion (LVO) in the posterior circulation with PSH as the initial manifestation is uncommon. It may lead to catastrophic consequences for patients if not detected and treated timely. Here, we present three patients with acute LVO in the posterior circulation with PSH as the initial symptom. All patients were male and averaged 63 years old. The PSH Assessment Measure (PSH-AM) scores of all cases were > 17. Brain imaging showed that multiple lesions in posterior circulation were involved in three patients. Although the prognosis of all patients was poor, PSH symptoms disappeared in all patients after endovascular treatment. These cases suggests that acute posterior circulation-related ischemic stroke should be considered with PSH occurring as the first symptom. Extensive disconnection due to multiple lesions in posterior circulation may play an important role in the occurrence and development of PSH. Endovascular treatment may be effective for PSH caused by acute posterior circulation-related ischemic stroke. This is worthy of further study in the future.
Connectivity Mapping Using a Novel sv2a Loss-of-Function Zebrafish Epilepsy Model as a Powerful Strategy for Anti-epileptic Drug Discovery
Authors: Zhang Yifan , Heylen Lise , Partoens Michèle , Mills James D. , Kaminski Rafal M. , Godard Patrice , Gillard Michel , de Witte Peter A. M. , Siekierska Aleksandra
Published: May 2022

Synaptic vesicle glycoprotein 2A (SV2A) regulates action potential-dependent neurotransmitter release and is commonly known as the primary binding site of an approved anti-epileptic drug, levetiracetam. Although several rodent knockout models have demonstrated the importance of SV2A for functional neurotransmission, its precise physiological function and role in epilepsy pathophysiology remains to be elucidated. Here, we present a novel sv2a knockout model in zebrafish, a vertebrate with complementary advantages to rodents. We demonstrated that 6 days post fertilization homozygous sv2a–/– mutant zebrafish larvae, but not sv2a+/– and sv2a+/+ larvae, displayed locomotor hyperactivity and spontaneous epileptiform discharges, however, no major brain malformations could be observed. A partial rescue of this epileptiform brain activity could be observed after treatment with two commonly used anti-epileptic drugs, valproic acid and, surprisingly, levetiracetam. This observation indicated that additional targets, besides Sv2a, maybe are involved in the protective effects of levetiracetam against epileptic seizures. Furthermore, a transcriptome analysis provided insights into the neuropathological processes underlying the observed epileptic phenotype. While gene expression profiling revealed only one differentially expressed gene (DEG) between wildtype and sv2a+/– larvae, there were 4386 and 3535 DEGs between wildtype and sv2a–/–, and sv2a+/– and sv2a–/– larvae, respectively. Pathway and gene ontology (GO) enrichment analysis between wildtype and sv2a–/– larvae revealed several pathways and GO terms enriched amongst up- and down-regulated genes, including MAPK signaling, synaptic vesicle cycle, and extracellular matrix organization, all known to be involved in epileptogenesis and epilepsy. Importantly, we used the Connectivity map database to identify compounds with opposing gene signatures compared to the one observed in sv2a–/– larvae, to finally rescue the epileptic phenotype. Two out of three selected compounds rescued electrographic discharges in sv2a–/– larvae, while negative controls did not. Taken together, our results demonstrate that sv2a deficiency leads to increased seizure vulnerability and provide valuable insight into the functional importance of sv2a in the brain in general. Furthermore, we provided evidence that the concept of connectivity mapping represents an attractive and powerful approach in the discovery of novel compounds against epilepsy.
Probiotic Therapy With VSL#3® in Patients With NAFLD: A Randomized Clinical Trial
Authors: Derosa Giuseppe , Guasti Luigina , D’Angelo Angela , Martinotti Chiara , Valentino Maria Chiara , Di Matteo Sergio , Bruno Giacomo M. , Maresca Andrea M. , Gaudio Giovanni V. , Maffioli Pamela
Published: May 2022

Aim

To evaluate if VSL#3® [a high-concentration multi-strain probiotic mix containing one strain of Streptococcus thermophilus BT01, three strains of Bifidobacteria (B. breve BB02; B. animalis subspecies [subsp.] lactis BL03, previously identified as B. longum BL03; and B. animalis subsp. lactis BI04, previously identified as B. infantis BI04), and four strains of Lactobacilli (L. acidophilus BA05, L. plantarum BP06, L. paracasei BP07, and L. helveticus BD08, previously identified as L. delbrueckii subsp. bulgaricus BD08)] therapy could improve hepatic parameters.

Methods

We enrolled 60 Caucasian patients aged ≥ 18 years of either sex with the diagnosis of non-alcoholic fatty liver disease (NAFLD), according to practice guidance, in a double-blind, placebo-controlled study. Patients were randomized to take placebo or VSL#3®, 2 sachets/day in the morning for 3 months. VSL#3® and placebo were self-administered.

Results

We did not observe any change in body mass index (BMI), circumferences, fasting plasma glucose (FPG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), and adiponectin (ADN) with neither treatment. A statistically significant triglycerides (Tg) decrease (p < 0.05 vs. baseline, and p < 0.05 vs. placebo, respectively) and high-sensitivity C-reactive protein (Hs-CRP) decrease (p < 0.05 vs. baseline) was observed in the group of patients being treated with VSL#3® compared with placebo. Transaminases and gamma-glutamyltransferase (γ-GT) were significantly reduced in VSL#3® group (p < 0.05 vs. baseline and placebo, respectively) compared with the placebo group. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and hepatic steatosis index (HSI) were significantly lower than the VSL#3® group (p < 0.05 vs. baseline and placebo, respectively) compared with the placebo group. All patients reported an improvement or the disappearance of hepatic steatosis.

Conclusion

Probiotic therapy with VSL#3® ameliorates hepatic parameters and echography grading, while reducing Tg and the inflammatory status, without any difference between men and women.
Impact of Extensively Hydrolyzed Infant Formula on Circulating Lipids During Early Life
Authors: Lamichhane Santosh , Siljander Heli , Salonen Marja , Ruohtula Terhi , Virtanen Suvi M. , Ilonen Jorma , Hyötyläinen Tuulia , Knip Mikael , Orešič Matej
Published: May 2022

Background

Current evidence suggests that the composition of infant formula (IF) affects the gut microbiome, intestinal function, and immune responses during infancy. However, the impact of IF on circulating lipid profiles in infants is still poorly understood. The objectives of this study were to (1) investigate how extensively hydrolyzed IF impacts serum lipidome compared to conventional formula and (2) to associate changes in circulatory lipids with gastrointestinal biomarkers including intestinal permeability.

Methods

In a randomized, double-blind controlled nutritional intervention study (n = 73), we applied mass spectrometry-based lipidomics to analyze serum lipids in infants who were fed extensively hydrolyzed formula (HF) or conventional, regular formula (RF). Serum samples were collected at 3, 9, and 12 months of age. Child’s growth (weight and length) and intestinal functional markers, including lactulose mannitol (LM) ratio, fecal calprotectin, and fecal beta-defensin, were also measured at given time points. At 3 months of age, stool samples were analyzed by shotgun metagenomics.

Results

Concentrations of sphingomyelins were higher in the HF group as compared to the RF group. Triacylglycerols (TGs) containing saturated and monounsaturated fatty acyl chains were found in higher levels in the HF group at 3 months, but downregulated at 9 and 12 months of age. LM ratio was lower in the HF group at 9 months of age. In the RF group, the LM ratio was positively associated with ether-linked lipids. Such an association was, however, not observed in the HF group.

Conclusion

Our study suggests that HF intervention changes the circulating lipidome, including those lipids previously found to be associated with progression to islet autoimmunity or overt T1D.

Clinical Trial Registration

[Clinicaltrials.gov], identifier [NCT01735123].
Effects of Soy Isoflavones and Green Tea Extract on Simvastatin Pharmacokinetics and Influence of the SLCO1B1 521T > C Polymorphism
Authors: Zeng Weiwei , Hu Miao , Lee Hon Kit , Wat Elaine , Lau Clara Bik San , Ho Chung Shun , Wong Chun Kwok , Tomlinson Brian
Published: May 2022

Objectives

Green tea and soy products are extensively consumed by many people and they may influence the activity of drug metabolizing enzymes and drug transporters to result in drug interactions. This study was performed to evaluate the effect of green tea and soy isoflavone extracts on the pharmacokinetics of simvastatin in healthy subjects and to clarify the role of polymorphisms in the SLCO1B1 drug transporter in this effect.

Methods

This was an open-label, three-phase randomized crossover pharmacokinetic study. A single dose of simvastatin 20 mg was taken on three occasions (without herbs, with green tea, and with soy isoflavones) by healthy male Chinese subjects. The green tea and soy isoflavone extracts were given at a dose containing EGCG 800 mg once daily or soy isoflavones about 80 mg once daily for 14 days before simvastatin dosing with at least 4-weeks washout period between phases.

Results

All the 18 subjects completed the study. Intake of soy isoflavones was associated with reduced systemic exposure to simvastatin acid [geometric mean (% coefficient of variation) AUC0–24h from 16.1 (44.2) h⋅μg/L to 12.1 (54.6) h⋅μg/L, P < 0.05) but not the lactone. Further analysis showed that the interaction between simvastatin and the soy isoflavones only resulted in a significant reduction of AUC in subjects with the SLCO1B1 521TT genotype and not in those with the 521C variant allele. There was no overall effect of the green tea extract on simvastatin pharmacokinetics but the group with the SLCO1B1 521TT genotype showed reduced AUC values for simvastatin acid.

Conclusion

This study showed repeated administration of soy isoflavones reduced the systemic bioavailability of simvastatin in healthy volunteers that was dependent on the SLCO1B1 genotype which suggested that soy isoflavones-simvastatin interaction is impacted by genotype-related function of this liver uptake transporter.
Natural Mineral Waters and Metabolic Syndrome: Insights From Obese Male and Female C57BL/6 Mice on Caloric Restriction
Authors: Narciso Laura , Martinelli Andrea , Torriani Flavio , Frassanito Paolo , Bernardini Roberta , Chiarotti Flavia , Marianelli Cinzia
Published: May 2022

Metabolic syndrome (MetS) represents one of the greatest challenges to public health given its serious consequences on cardiovascular diseases and type 2 diabetes. A carbohydrate-restricted, low-fat diet is the current therapy for MetS. Natural mineral waters (NMWs) are known to exert beneficial effects on human health. Our primary objective was to shed light on the potential therapeutic properties of NMWs in MetS. A total of 125 C57BL/6 male and female mice were included in the study. Of these, 10 were left untreated. They were fed a standard diet with tap water throughout the study period, and stayed healthy. The remaining 115 mice were initially fed a high-calorie diet (HCD) consisting of a high-fat feed (60% of energy from fat) with 10% fructose in tap water, served ad libitum over a period of 4 months to induce MetS (the MetS induction phase). Mice were then randomly divided into six treatment groups and a control group, all of which received a low-calorie diet (LCD), but with a different kind of drinking water, for 2 months (the treatment phase). Five groups were each treated with a different kind of NMW, one group by alternating the five NMWs, and one group – the control group – was given tap water. Body weight and blood biochemistry were monitored over the 6-month trial. After 4 months, male and female mice on HCD developed obesity, hypercholesterolaemia and hyperglycaemia, although gains in body weight, total cholesterol, and blood glucose in males were greater than those observed in females (P < 0.0001). When combined with an LCD, the NMWs rich in sulphate, magnesium and bicarbonate, and the minimally mineralised one were the most effective in reducing the blood levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and glucose. Sex differences emerged during both the MetS induction phase and the treatment phase. These results suggest that NMWs rich in specific macronutrients, such as bicarbonate, sulphate and magnesium, and minimally mineralised water, in combination with an LCD, may contribute to controlling blood lipid and glucose levels in subjects with MetS. Further studies are needed to confirm these results and to extend them to humans.
The Effect of Glycosylated Soy Protein Isolate on the Stability of Lutein and Their Interaction Characteristics
Authors: Wang Xia , Wang Shaojia , Xu Duoxia , Peng Jingwei , Gao Wei , Cao Yanping
Published: May 2022

Lutein is a natural fat-soluble carotenoid with various physiological functions. However, its poor water solubility and stability restrict its application in functional foods. The present study sought to analyze the stability and interaction mechanism of the complex glycosylated soy protein isolate (SPI) prepared using SPI and inulin-type fructans and lutein. The results showed that glycosylation reduced the fluorescence intensity and surface hydrophobicity of SPI but improved the emulsification process and solubility. Fluorescence intensity and ultraviolet–visible (UV–Vis) absorption spectroscopy results showed that the fluorescence quenching of the glycosylated soybean protein isolate by lutein was static. Through thermodynamic parameter analysis, it was found that lutein and glycosylated SPI were bound spontaneously through hydrophobic interaction, and the binding stoichiometry was 1:1. The X-ray diffraction analysis results showed that lutein existed in the glycosylated soybean protein isolate in an amorphous form. The Fourier transform infrared spectroscopy analysis results revealed that lutein had no effect on the secondary structure of glycosylated soy protein isolate. Meanwhile, the combination of lutein and glycosylated SPI improved the water solubility of lutein and the stability of light and heat.
Discrimination of Geographical Origin of Agricultural Products From Small-Scale Districts by Widely Targeted Metabolomics With a Case Study on Pinggu Peach
Authors: Zhao Jie , Li An , Jin Xinxin , Liang Gang , Pan Ligang
Published: May 2022

Geographical indications of agricultural products are characterized by high quality and regional attributes, while they are more likely to be counterfeited by similar products from nearby regions. Accurate discrimination of origin on small geographical scales is extremely important for geographical indications of agricultural products to avoid food fraud. In this study, a widely targeted metabolomics based on ultra-high-performance liquid chromatography–tandem mass spectrometry combined with multivariate statistical analysis was used to distinguish the geographical origin of Pinggu Peach of Beijing and its two surrounding areas in Heibei province (China). Orthogonal partial least squares-discriminant analysis (OPLS-DA) based on 159 identified metabolites showed significant separation from Pinggu and the other adjacent regions. The number of the most important discriminant variables (VIP value >1) was up to 62, which contributed to the differentiation model. The results demonstrated that the metabolic fingerprinting combined with OPLS-DA could be successfully implemented to differentiate the geographical origin of peach from small-scale origins, thus providing technical support to further ensure the authenticity of geographical indication products. The greenness of the developed method was assessed using the Analytical GREEnness Metric Approach and Software (ARGEE) tool. It was a relatively green analytical method with room for improvement.
Real-World Implementation of Neurosurgical Enhanced Recovery After Surgery Protocol for Gliomas in Patients Undergoing Elective Craniotomy
Authors: Wang Yuan , Xue Ya-Fei , Zhao Bin-Fang , Guo Shao-Chun , Ji Pei-Gang , Liu Jing-Hui , Wang Na , Chen Fan , Zhai Yu-Long , Wang Yue , Xue Yan-Rong , Gao Guo-Dong , Qu Yan , Wang Liang
Published: May 2022

Objective

To design a multidisciplinary enhanced recovery after surgery (ERAS) protocol for glioma patients undergoing elective craniotomy and evaluate its clinical efficacy and safety after implementation in a tertiary neurosurgical center in China.

Methods

ERAS protocol for glioma patients was developed and modified based on the best available evidence. Patients undergoing elective craniotomy for treatment of glioma between September 2019 to May 2021 were enrolled in a randomized clinical trial comparing a conventional neurosurgical perioperative care (control group) to an ERAS protocol (ERAS group). The primary outcome was postoperative hospital length of stay (LOS). Secondary outcomes were 30-day readmission rate, postoperative complications, duration of the drainage tube, time to first oral fluid intake, time to ambulation and functional recovery status.

Results

A total of 151 patients were enrolled (ERAS group: n = 80; control group: n = 71). Compared with the control group, postoperative LOS was significantly shorter in the ERAS group (median: 5 days vs. 7 days, p<0.0001). No 30-day readmission or reoperation occurred in either group. The time of first oral intake, urinary catheter removal within 24 h and early ambulation on postoperative day (POD) 1 were earlier and shorter in the ERAS group compared with the control group (p<0.001). No statistical difference was observed between the two groups in terms of surgical- and nonsurgical-related complications. Functional recovery in terms of Karnofsky Performance Status (KPS) scores both at discharge and 30-day follow-up was similar in the two groups. Moreover, no significant difference was found between the two groups in the Hospital Anxiety and Depression Scale (HADS) scores.

Conclusion

The implementation of the ERAS protocol for glioma patients offers significant benefits over conventional neurosurgical perioperative management, as it is associated with enhancing postoperative recovery, without additional perioperative complications and risks.

Clinical Trial Registration

Chinese Clinical Trial Registry (http://www.chictr.org.cn/showproj.aspx?proj=42016), identifier ChiCTR1900025108
The Treatment Status of Patients in NSCLC With RET Fusion Under the Prelude of Selective RET-TKI Application in China: A Multicenter Retrospective Research
Authors: Meng Yan , Yang Yilin , Fang Yujia , Lin Xinqing , Xie Xiaohong , Deng Haiyi , Wu Jianhui , Zhou Maolin , Sun Ni , Xie Zhanhong , Liu Ming , Ouyang Ming , Qin Yinyin , Su Chunxia , Zhou Chengzhi
Published: May 2022

Background

Rearranged during transfection (RET) fusion is a kind of uncommon mutation (about 1%) in non-small cell lung cancer (NSCLC). Although selective tyrosine kinase inhibitors (TKI) (selpercatinib and pralsetinib) have been available, there are no real-world data about the difference in the efficacy between RET-TKI and other regimens in China.

Methods

We conducted a multicenter retrospective analysis of 49 patients with RET-fusion-positive NSCLC. The characteristics and the clinical outcomes with RET-TKI, multi-kinase inhibitor (MKI), systematic chemotherapy, and immune-checkpoint inhibitor (ICI)-based regimens were evaluated.

Results

Of the 92 treatments in patients included, RET-TKI was administered 24 times (26.1%), systematic chemotherapy was 35 times (38.0%), ICI-based regimens was 26 times (28.3%), and MKI was 7 times (7.6%). RET-TKI had a higher objective response rate than the chemotherapy and ICI-based regimens (63.6% vs. 14.3% vs. 21.0%, p < 0.001). The median progress-free survival (mPFS) of RET-TKI, chemotherapy, immunotherapy, and MKI was 16.9 (95% CI: 1.8–32.0) months, 11.9 (95% CI: 7.7–16.1) months, 6.7 (95% CI: 2.9–10.5) months, and 2.8 (95% CI: 1.1–4.4) months, respectively. The mPFS of RET-TKI was longer than MKI and immunotherapy (p < 0.001), while without difference with chemotherapy (p = 0.096). Moreover, chemotherapy had longer mPFS than MKI (p < 0.001). In subgroup analysis, patients with brain metastases in RET-TKI treatment had worse mPFS than the one of patients without brain metastases (6.1 (95% CI: 0.0–13.9) months and 8.5 (95% CI: 6.3–10.6) months, p = 0.012). For patients having chemotherapy with or without angiogenesis inhibitors, the mPFS was 12.0 (95% CI: 11.05–13.02) months and 9.1 (95% CI: 8.31–9.89) months (p = 0.468). In the group of ICI-based regimens, the expression level of PD-L1 did not affect the mPFS of ICI [PD-L1 (+) vs. PD-L1 (–): 4.7 (95% CI: 1.8–9.0) months vs. 7.6 (95% CI: 1.1–14.0) months, p = 0.910]. For overall patients, ECOG PS score, therapy lines, and therapeutic regimens were the independent factors affecting the prognosis.

Conclusions

In RET-fusion-positive NSCLC, RET-TKI is the best choice for a better response rate and PFS. In addition, chemotherapy which may bring a good PFS, is still a good choice for this group of patients.
Stereotactic Body Radiation Therapy for the Treatment of Locally Recurrent and Oligoprogressive Non-Small Cell Lung Cancer: A Single Institution Experience
Authors: Katz Leah M. , Ng Victor , Wu S. Peter , Yan Sherry , Grew David , Shin Samuel , Colangelo Nicholas W. , McCarthy Allison , Pass Harvey I. , Chachoua Abraham , Schiff Peter B.
Published: May 2022

Objectives

To investigate the efficacy and safety of lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) including oligorecurrent and oligoprogressive disease.

Methods

Single-institution retrospective analysis of 60 NSCLC patients with 62 discrete lesions treated with SBRT between 2008 and 2017. Patients were stratified into three groups, including early stage, locally recurrent, and oligoprogressive disease. Group 1 included early stage local disease with no prior local therapy. Group 2 included locally recurrent disease after local treatment of a primary lesion, and group 3 included regional or well-controlled distant metastatic disease receiving SBRT for a treatment naive lung lesion (oligoprogressive disease). Patient/tumor characteristics and adverse effects were recorded. Local failure free survival (LFFS), progression free survival (PFS), and overall survival (OS) were estimated using the Kaplan Meier method.

Results

At median follow-up of 34 months, 67% of the study population remained alive. The estimated 3-year LFFS for group 1, group 2, and group 3 patients was 95% (95% CI: 86%-100%), 82%(62% - 100%), and 83% (58-100%), respectively. The estimated 3-year PFS was 59% (42-83%), 40% (21%-78%), and 33% (12%-95%), and the estimated 3-year OS was 58% (41-82%), 60% (37-96%), and 58% (31-100%)), respectively for each group. When adjusted for age and size of lesion, no significant difference in OS, LFFS, and PFS emerged between groups (p > 0.05). No patients experienced grade 3 to 5 toxicity. Eighteen patients (29%) experienced grade 1 to 2 toxicity. The most common toxicities reported were cough and fatigue.

Conclusions

Our data demonstrates control rates in group 1 patients comparable to historical controls. Our study also reveals comparable clinical results for SBRT in the treatment of NSCLC by demonstrating similar rates of LFFS and OS in group 2 and group 3 patients with locally recurrent and treatment naïve lung lesion with well-controlled distant metastatic disease.
An Extensive Review on Preclinical and Clinical Trials of Oncolytic Viruses Therapy for Pancreatic Cancer
Authors: Nisar Maryum , Paracha Rehan Zafar , Adil Sidra , Qureshi Sumair Naseem , Janjua Hussnain Ahmed
Published: May 2022

Chemotherapy resistance and peculiar tumor microenvironment, which diminish or mitigate the effects of therapies, make pancreatic cancer one of the deadliest malignancies to manage and treat. Advanced immunotherapies are under consideration intending to ameliorate the overall patient survival rate in pancreatic cancer. Oncolytic viruses therapy is a new type of immunotherapy in which a virus after infecting and lysis the cancer cell induces/activates patients’ immune response by releasing tumor antigen in the blood. The current review covers the pathways and molecular ablation that take place in pancreatic cancer cells. It also unfolds the extensive preclinical and clinical trial studies of oncolytic viruses performed and/or undergoing to design an efficacious therapy against pancreatic cancer.
Current Researches on Nanodrug Delivery Systems in Bladder Cancer Intravesical Chemotherapy
Authors: Lu Yilei , Wang Siqi , Wang Yuhang , Li Mingshan , Liu Yili , Xue Dongwei
Published: May 2022

Bladder cancer is one of the most common malignant tumors in urinary system. Intravesical chemotherapy is a common adjuvant therapy after transurethral resection of bladder tumors. However, it has several disadvantages such as low drug penetration rate, short residence time, unsustainable action and inability to release slowly, thus new drug delivery and new modalities in delivery carriers need to be continuously explored. Nano-drug delivery system is a novel way in treatment for bladder cancer that can increase the absorption rate and prolong the duration of drug, as well as sustain the action by controlling drug release. Currently, nano-drug delivery carriers mainly included liposomes, polymers, and inorganic materials. In this paper, we reveal current researches in nano-drug delivery system in bladder cancer intravesical chemotherapy by describing the applications and defects of liposomes, polymers and inorganic material nanocarriers, and provide a basis for the improvement of intravesical chemotherapy drugs in bladder cancer.
Combined Use of Shear Wave Elastography, Microvascular Doppler Ultrasound Technique, and BI-RADS for the Differentiation of Benign and Malignant Breast Masses
Authors: Wang Bin , Chen Yu-Yuan , Yang Si , Chen Zhen-Wen , Luo Jia , Cui Xin-Wu , Dietrich Christoph F. , Yi Ai-jiao
Published: May 2022

Objective

To evaluate the value of the combined use of Breast Imaging Reporting and Data System (BI-RADS), qualitative shear wave elastography (SWE), and AngioPLUS microvascular Doppler ultrasound technique (AP) for distinguishing benign and malignant breast masses.

Materials and Methods

A total of 210 pathologically confirmed breast lesions in 210 patients were reviewed using BI-RADS, qualitative SWE, and AP. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), accuracy, and area under the receiver operating characteristic curve (AUC) of BI-RADS and the combination of qualitative SWE and/or AP with BI-RADS were compared, respectively.

Results

Compared with using BI-RADS alone, the use of combined qualitative SWE and/or AP with BI-RADS had higher AUC values (P < 0.001). Besides this, the combination of qualitative SWE and AP with BI-RADS had the best diagnostic performance for differentiating between benign and malignant masses. When AP and SWE were combined with BI-RADS, 49/76 benign masses were downgraded from BI-RADS category 4a into BI-RADS category 3, while no benign masses were upgraded from BI-RADS category 3 into BI-RADS category 4a. Three sub-centimeter malignant masses were downgraded from BI-RADS category 4a into BI-RADS category 3, while three malignant masses remain in BI-RADS category 3 due to a benign manifestation in both AP and qualitative SWE. Moreover, 5/6 of them were sub-centimeter masses, and 4/6 of them were intraductal carcinoma. The sensitivity, specificity, PPV, NPV, accuracy, and AUC were 91.0%, 81.1%, 69.3%, 95.1%, 84.3%, and 0.861 (95% confidence interval, 0.806–0.916; P < 0.001), respectively. Compared with BI-RADS alone, the sensitivity slightly decreased, while the specificity, PPV, NPV, and accuracy were significantly improved.

Conclusion

Combination of qualitative SWE and AP with BI-RADS improved the diagnostic performance in differentiating benign from malignant breast lesions, which is helpful for avoiding unnecessary biopsies. However, we should be careful about the downgrading of sub-centimeter BI-RADS 4a category lesions.
Next-Generation Sequencing Reveals Novel Homozygous Missense Variant c.934T > C in POLR1C Gene Causing Leukodystrophy and Hypomyelinating Disease
Authors: Naseer Muhammad Imran , Abdulkareem Angham Abdulrahman , Pushparaj Peter Natesan , Saharti Samah , Muthaffar Osama Y.
Published: May 2022

Leukodystrophies are a diverse group of genetically established disorders categorized by unusual white matter changes on brain imaging. Hypomyelinating leukodystrophies (HLDs) are a group of neurodevelopmental disorders that affect myelin sheath development in the brain. These disorders are categorized as developmental delay, spasticity, hypotonia, and intellectual disabilities. We describe a patient with developmental delay, cerebellar ataxia, spasticity, hypotonia, and intellectual disability from a healthy family member. Whole exome sequencing (WES) was performed to identify causative variants, which were further analyzed by bioinformatic analysis. WES was performed, and Sanger sequencing-based segregation analysis confirmed the presence of the homozygous missense variants of NM_203290.3 c.934T > C p.Ser312Pro of RNA polymerase I and III subunit C (POLR1C) gene in this patient and heterozygous variant in the unaffected carrier father and mother, supporting the pathogenicity and inheritance pattern of this variant. Furthermore, the variant identified by WES was validated in healthy controls (n = 100) using Sanger sequencing analysis. Finally, our study explained the important use of WES in disease diagnosis and provided further evidence that the variant in the POLR1C gene may play an important role in the development of hypomyelinating leukodystrophy in Saudi families.
Traditional Uses, Phytochemistry and Biological Activities of Alocasia Species: A Systematic Review
Authors: Arbain Dayar , Sinaga Lorenskia Maria Regina , Taher Muhammad , Susanti Deny , Zakaria Zainul Amiruddin , Khotib Junaidi
Published: May 2022

The genus Alocasia (Schott) G. Don consists of 113 species distributed across Asia, Southeast Asia, and Australia. Alocasia plants grow in tropical and subtropical forests with humid lowlands. Featuring their large green heart-shaped or arrow-shaped ear leaves and occasionally red-orange fruit, they are very popular ornamental plants and are widely used as traditional medicines to treat various diseases such as jaundice, snake bite, boils, and diabetes. This manuscript critically analysed the distribution, traditional uses, and phytochemical contents of 96 species of Alocasia. The numerous biological activities of Alocasia species were also presented, which include anti-cancer, antidiabetic and antihyperglycaemic, antioxidant, antidiarrhoea, antimicrobial and antifungal, antiparasitic (antiprotozoal and anthelminthic), antinociceptive and anti-inflammatory, brine shrimp lethality, hepatoprotective, anti-hemagglutinin, anti-constipation and diuretic, and radioprotective activities as well as acute toxicity studies. Research articles were acquired by the accessing three scientific databases comprising PubMed, Scopus, and Google Scholar. For this review, specific information was obtained using the general search term “Alocasia”, followed by the “plant species names” and “phytochemical” or “bioactivity” or “pharmacological activity”. The accepted authority of the plant species was referred from theplantlist.org. Scientific studies have revealed that the genus is mainly scattered throughout Asia. It has broad traditional benefits, which have been associated with various biological properties such as cytotoxic, antihyperglycaemic, antimicrobial, and anti-inflammatory. Alocasia species exhibit diverse biological activities that are very useful for medical treatment. The genus Alocasia was reported to be able to produce a strong and high-quality anti-cancer compound, namely alocasgenoside B, although information on this compound is currently limited. Therefore, it is strongly recommended to further explore the relevant use of natural compounds present in the genus Alocasia, particularly as an anti-cancer agent. With only a few Alocasia species that have been scientifically studied so far, more attention and effort is required to establish the link between traditional uses, active compounds, and pharmacological activities of various species of this genus.
Effect of Medium on Fundamental Interactions in Gravity and Condensed Matter
Authors: Zhuk Alexander , Shulga Valerii
Published: May 2022

Recently, it was shown that the gravitational field undergoes exponential cutoff at large cosmological scales due to the presence of background matter. In this article, we demonstrate that there is a close mathematical analogy between this effect and the behavior of the magnetic field induced by a solenoid placed in a superconductor.
Effect of Surgical Mask use on Peak Physical Performance During Exercise Treadmill Testing-A Real World, Crossover Study
Authors: Dalakoti Mayank , Long Cheryl , Bains Arshia , Djohan Andie , Ahmad Isabel , Chan Siew Pang , Kua Jieli , Chan Po Fun , Yeo Tee Joo
Published: May 2022

Background: Mask wearing is an essential strategy to combat the spread of SARS-CoV-2. Some individuals may wear masks during physical activity to reduce disease transmission. This study aimed to investigate the real-world effect of wearing a surgical face mask on physiological parameters at peak exercise in healthy individuals.

Methods: In this crossover design study, participants underwent maximal treadmill electrocardiogram exercise tests using the Bruce protocol on two separate occasions, once with a standard 3-ply surgical face mask and once without. Heart rate, oxygen saturation, blood pressure, rate pressure product, metabolic equivalents (METS) and total exercise time were measured. Subjective rate of perceived exertion was also assessed using the modified Borg Scale.

Results: 50 adults (mean age = 31.7 ± 6.5 years; 27 males) completed both treadmill tests. Mask wearing resulted in a significant reduction in peak METS by 1.5 units, maximum speed by 0.5 km/h, exercise time by 68.4 s with a significantly lower peak heart rate by 4.4 bpm, and lower percentage of age-predicted maximum heart rate by 2.5% (p < 0.001 for all parameters). During each corresponding stage of the Bruce protocol, the average modified Borg score was found to be significantly higher in subjects exercising with mask after adjusting for age, gender and body mass index (p < 0.03).

Conclusion: In a cohort of healthy individuals, wearing of a surgical face mask during maximal treadmill exercise lead to reduced physical performance and increased rate of perceived exertion. Individuals exercising with surgical masks need to be mindful of these limitations while undergoing physical training in order to differentiate these physiological responses from symptoms of early respiratory illness.
Lightweight-Convolutional Neural Network for Apple Leaf Disease Identification
Authors: Fu Lili , Li Shijun , Sun Yu , Mu Ye , Hu Tianli , Gong He
Published: May 2022

As a widely consumed fruit worldwide, it is extremely important to prevent and control disease in apple trees. In this research, we designed convolutional neural networks (CNNs) for five diseases that affect apple tree leaves based on the AlexNet model. First, the coarse-grained features of the disease are extracted in the model using dilated convolution, which helps to maintain a large receptive field while reducing the number of parameters. The parallel convolution module is added to extract leaf disease features at multiple scales. Subsequently, the series 3 × 3 convolutions shortcut connection allows the model to deal with additional nonlinearities. Further, the attention mechanism is added to all aggregated output modules to better fit channel features and reduce the impact of a complex background on the model performance. Finally, the two fully connected layers are replaced by global pooling to reduce the number of model parameters, to ensure that the features are not lost. The final recognition accuracy of the model is 97.36%, and the size of the model is 5.87 MB. In comparison with five other models, our model design is reasonable and has good robustness; further, the results show that the proposed model is lightweight and can identify apple leaf diseases with high accuracy.
Inheritance of Yield Components and Morphological Traits in Avocado cv. Hass From “Criollo” “Elite Trees” via Half-Sib Seedling Rootstocks
Authors: Cañas-Gutiérrez Gloria Patricia , Sepulveda-Ortega Stella , López-Hernández Felipe , Navas-Arboleda Alejandro A. , Cortés Andrés J.
Published: May 2022

Grafting induces precocity and maintains clonal integrity in fruit tree crops. However, the complex rootstock × scion interaction often precludes understanding how the tree phenotype is shaped, limiting the potential to select optimum rootstocks. Therefore, it is necessary to assess (1) how seedling progenies inherit trait variation from elite ‘plus trees’, and (2) whether such family superiority may be transferred after grafting to the clonal scion. To bridge this gap, we quantified additive genetic parameters (i.e., narrow sense heritability—h2, and genetic-estimated breeding values—GEBVs) across landraces, “criollo”, “plus trees” of the super-food fruit tree crop avocado (Persea americanaMill.), and their open-pollinated (OP) half-sib seedling families. Specifically, we used a genomic best linear unbiased prediction (G-BLUP) model to merge phenotypic characterization of 17 morpho-agronomic traits with genetic screening of 13 highly polymorphic SSR markers in a diverse panel of 104 avocado “criollo” “plus trees.” Estimated additive genetic parameters were validated at a 5-year-old common garden trial (i.e., provenance test), in which 22 OP half-sib seedlings from 82 elite “plus trees” served as rootstocks for the cv. Hass clone. Heritability (h2) scores in the “criollo” “plus trees” ranged from 0.28 to 0.51. The highesth2values were observed for ribbed petiole and adaxial veins with 0.47 (CI 95%0.2–0.8) and 0.51 (CI 0.2–0.8), respectively. Theh2scores for the agronomic traits ranged from 0.34 (CI 0.2–0.6) to 0.39 (CI 0.2–0.6) for seed weight, fruit weight, and total volume, respectively. When inspecting yield variation across 5-year-old grafted avocado cv. Hass trees with elite OP half-sib seedling rootstocks, the traits total number of fruits and fruits’ weight, respectively, exhibitedh2scores of 0.36 (± 0.23) and 0.11 (± 0.09). Our results indicate that elite “criollo” “plus trees” may serve as promissory donors of seedling rootstocks for avocado cv. Hass orchards due to the inheritance of their outstanding trait values. This reinforces the feasibility to leverage natural variation from “plus trees”viaOP half-sib seedling rootstock families. By jointly estimating half-sib family effects and rootstock-mediated heritability, this study promises boosting seedling rootstock breeding programs, while better discerning the consequences of grafting in fruit tree crops.