bluuebunny/crossref_metadata_2025 huggingface dataset:
Vectored Immunotherapeutics for Infectious Diseases: Can rAAVs Be The Game Changers for Fighting Transmissible Pathogens?
Authors: Zhan Wei , Muhuri Manish , Tai Phillip W. L. , Gao Guangping
Published: May 2021

Conventional vaccinations and immunotherapies have encountered major roadblocks in preventing infectious diseases like HIV, influenza, and malaria. These challenges are due to the high genomic variation and immunomodulatory mechanisms inherent to these diseases. Passive transfer of broadly neutralizing antibodies may offer partial protection, but these treatments require repeated dosing. Some recombinant viral vectors, such as those based on lentiviruses and adeno-associated viruses (AAVs), can confer long-term transgene expression in the host after a single dose. Particularly, recombinant (r)AAVs have emerged as favorable vectors, given their high in vivo transduction efficiency, proven clinical efficacy, and low immunogenicity profiles. Hence, rAAVs are being explored to deliver recombinant antibodies to confer immunity against infections or to diminish the severity of disease. When used as a vaccination vector for the delivery of antigens, rAAVs enable de novo synthesis of foreign proteins with the conformation and topology that resemble those of natural pathogens. However, technical hurdles like pre-existing immunity to the rAAV capsid and production of anti-drug antibodies can reduce the efficacy of rAAV-vectored immunotherapies. This review summarizes rAAV-based prophylactic and therapeutic strategies developed against infectious diseases that are currently being tested in pre-clinical and clinical studies. Technical challenges and potential solutions will also be discussed.
The Immunology of Hormone Receptor Positive Breast Cancer
Authors: Goldberg Jonathan , Pastorello Ricardo G. , Vallius Tuulia , Davis Janae , Cui Yvonne Xiaoyong , Agudo Judith , Waks Adrienne G. , Keenan Tanya , McAllister Sandra S. , Tolaney Sara M. , Mittendorf Elizabeth A. , Guerriero Jennifer L.
Published: May 2021

Immune checkpoint blockade (ICB) has revolutionized the treatment of cancer patients. The main focus of ICB has been on reinvigorating the adaptive immune response, namely, activating cytotoxic T cells. ICB has demonstrated only modest benefit against advanced breast cancer, as breast tumors typically establish an immune suppressive tumor microenvironment (TME). Triple-negative breast cancer (TNBC) is associated with infiltration of tumor infiltrating lymphocytes (TILs) and patients with TNBC have shown clinical responses to ICB. In contrast, hormone receptor positive (HR+) breast cancer is characterized by low TIL infiltration and minimal response to ICB. Here we review how HR+ breast tumors establish a TME devoid of TILs, have low HLA class I expression, and recruit immune cells, other than T cells, which impact response to therapy. In addition, we review emerging technologies that have been employed to characterize components of the TME to reveal that tumor associated macrophages (TAMs) are abundant in HR+ cancer, are highly immune-suppressive, associated with tumor progression, chemotherapy and ICB-resistance, metastasis and poor survival. We reveal novel therapeutic targets and possible combinations with ICB to enhance anti-tumor immune responses, which may have great potential in HR+ breast cancer.
Composition and Intraspecific Variability in Summer Flounder (Paralichthys dentatus) Diets in a Eutrophic Estuary
Authors: Cernadas-Martín Sara , Rountos Konstantine J. , Nye Janet A. , Frisk Michael G. , Pikitch Ellen K.
Published: May 2021

This study assessed the diet of Summer flounder (SF,Paralichthys dentatus) in Shinnecock Bay, NY. Summer flounder are a recreationally and commercially important marine flatfish species found along the Eastern United States coastline. Despite their importance, few studies have examined the trophodynamics of a broad size spectrum of this species. Diet composition of summer flounder (n= 88) was assessed from 2014 to 2016 throughout Shinnecock Bay, a eutrophic bar-built estuary in New York. Species consumed and diet species richness differed significantly amongst SF size classes, with large [≥375 mm total length (TL)] and medium (>225: <375 mm) summer flounder showing higher levels of piscivory and more diverse diets than small-sized (≤225 mm) conspecifics. As voracious plastic predators, trends in annual and monthly diet variation generally followed prey availability in Shinnecock Bay. One exception to this general pattern occurred for winter flounder (Pseudopleuronectes americanus). Despite their low relative abundance in the bay, winter flounder was highly preferred as prey by summer flounder (Chesson index, α = 0.35) and was their predominant prey item accounting for 12.3% (SD ± 3.9%) of the diet by weight. Other factors that explained the variability of the diet of summer flounder were year, month, dissolved oxygen concentration, bay region and habitat, with a cumulative variance of 10.3%. Interestingly, clear differences in the diet (i.e., species richness and abundance) of summer flounder were found within regions of Shinnecock Bay, with a decrease in teleost biomass and species richness observed in the western region where water quality is more degraded and less seagrass is available compared to the more pristine eastern region. Distinct trophic dynamics in degraded habitats suggests fundamentally different food webs that could have important consequences to ecosystem stability and resilience. As coastal areas continue to experience degradation, diet studies of economically and ecologically important species can aid in the development of effective ecosystem-based management plans.
Repeated ex situ Spawning in Two Highly Disease Susceptible Corals in the Family Meandrinidae
Authors: O’Neil Keri L. , Serafin Rachel M. , Patterson Joshua T. , Craggs Jamie R. K.
Published: May 2021

Members of the family Meandrinidae are highly susceptible to stony coral tissue loss disease, resulting in population reductions up to 88% in both Dendrogyra cylindrus and Meandrina meandrites along the Florida Reef Tract. Reductions in abundance on this scale leave these species susceptible to limitations in sexual reproduction and natural recovery without intervention. In response to the ongoing outbreak of the disease across the Caribbean, a variety of genetic rescue projects have been implemented to bring disease susceptible species into ex situ culture and preserve living genetic diversity. In this study, corals being held in a long-term ex situ genetic bank were maintained using artificial lighting and temperature cues programmed to mimic natural cycles in Key Largo, FL, United States. Synchronized broadcast spawning events in both species were documented in aquaria over two annual spawning cycles in 2019 and 2020. Timing of gamete release relative to the perceived date and sunset was highly synchronized with wild observations. Up to 21 unique D. cylindrus genotypes collected from reef locations spanning over 230 km contributed gametes to the larval pool. The majority of these parental colonies are no longer alive in the wild. Repeatable and predictable ex situ spawning events such as these will become an essential tool for managed breeding and assisted fertilization in species suffering from severe population declines. These annual events have the potential to produce thousands of genetically diverse offspring for restoration efforts and offer future hope for the long-term survival of these threatened species.
Spousal Care and Pain Among the Population Aged 65 Years and Older: A European Analysis
Authors: Barbosa Fátima , Delerue Matos Alice , Voss Gina , Costa Patrício
Published: May 2021

Background: Spousal care is the most important source of informal care in old age. Nevertheless, despite the growing importance of this issue, the association between providing spousal care inside the household and pain remains unexplored in Europe.

Objective and Methods: This study aims to estimate the prevalence of pain reported by spouse caregivers aged 65 plus that provide care inside the household and to investigate the association between providing spousal care and pain. Data from 17 European countries that participated in wave 6 of the Survey of Health, Aging and Retirement in Europe (SHARE) is used. The analyses are based on 26,301 respondents aged 65 years and older who provide informal care inside the household to their spouse/partner exclusively (N = 1,895) or do not provide any informal care (inside or outside the household) (24,406). Descriptive statistics and multilevel logistic regressions (individual-level as level 1, and country as level 2) were performed.

Results: Overall, spouse caregivers report pain more often (63.4%) than their non-caregiver‘s counterparts (50.3%). Important differences in the prevalence of pain among spouse caregivers were found between countries, with Portugal (80.3%), Spain (74.6%), France (73%), Italy (72.4%), and Slovenia (72.1) showing the highest prevalence of pain, and Denmark (36%), Switzerland (41.5) and Sweden (42.3%), the lowest. Results from multilevel logistic regressions show that European individuals aged 65+ who provide spousal care have an increased likelihood of reporting pain (OR 1.30; CI = 1.13–1.48).

Conclusion: Our results suggest that in Europe, spouse caregivers aged 65+ are at greater risk of experiencing pain. Therefore, European policymakers should consider spouse caregivers as a health priority group, and take measures to ensure they receive comprehensive health and socio-economic support.
Computational Biology and Machine Learning Approaches to Understand Mechanistic Microbiome-Host Interactions
Authors: Sudhakar Padhmanand , Machiels Kathleen , Verstockt Bram , Korcsmaros Tamas , Vermeire Séverine
Published: May 2021

The microbiome, by virtue of its interactions with the host, is implicated in various host functions including its influence on nutrition and homeostasis. Many chronic diseases such as diabetes, cancer, inflammatory bowel diseases are characterized by a disruption of microbial communities in at least one biological niche/organ system. Various molecular mechanisms between microbial and host components such as proteins, RNAs, metabolites have recently been identified, thus filling many gaps in our understanding of how the microbiome modulates host processes. Concurrently, high-throughput technologies have enabled the profiling of heterogeneous datasets capturing community level changes in the microbiome as well as the host responses. However, due to limitations in parallel sampling and analytical procedures, big gaps still exist in terms of how the microbiome mechanistically influences host functions at a system and community level. In the past decade, computational biology and machine learning methodologies have been developed with the aim of filling the existing gaps. Due to the agnostic nature of the tools, they have been applied in diverse disease contexts to analyze and infer the interactions between the microbiome and host molecular components. Some of these approaches allow the identification and analysis of affected downstream host processes. Most of the tools statistically or mechanistically integrate different types of -omic and meta -omic datasets followed by functional/biological interpretation. In this review, we provide an overview of the landscape of computational approaches for investigating mechanistic interactions between individual microbes/microbiome and the host and the opportunities for basic and clinical research. These could include but are not limited to the development of activity- and mechanism-based biomarkers, uncovering mechanisms for therapeutic interventions and generating integrated signatures to stratify patients.
Genomic Analysis of Serratia plymuthica MBSA-MJ1: A Plant Growth Promoting Rhizobacteria That Improves Water Stress Tolerance in Greenhouse Ornamentals
Authors: Nordstedt Nathan P. , Jones Michelle L.
Published: May 2021

Water stress decreases the health and quality of horticulture crops by inhibiting photosynthesis, transpiration, and nutrient uptake. Application of plant growth promoting rhizobacteria (PGPR) can increase the growth, stress tolerance, and overall quality of field and greenhouse grown crops subjected to water stress. Here, we evaluatedSerratia plymuthicaMBSA-MJ1 for its ability to increase plant growth and quality ofPetunia×hybrida(petunia),Impatiens walleriana(impatiens), andViola×wittrockiana(pansy) plants recovering from severe water stress. Plants were treated weekly with inoculum of MBSA-MJ1, and plant growth and quality were evaluated 2 weeks after recovery from water stress. Application ofS. plymuthicaMBSA-MJ1 increased the visual quality and shoot biomass of petunia and impatiens and increased the flower number of petunia after recovery from water stress. In addition,in vitrocharacterizations showed that MBSA-MJ1 is a motile bacterium with moderate levels of antibiotic resistance that can withstand osmotic stress. Further, comprehensive genomic analyses identified genes putatively involved in bacterial osmotic and oxidative stress responses and the synthesis of osmoprotectants and vitamins that could potentially be involved in increasing plant water stress tolerance. This work provides a better understanding of potential mechanisms involved in beneficial plant-microbe interactions under abiotic stress using a novelS. plymuthicastrain as a model.
A Survey Using High-Throughput Sequencing Suggests That the Diversity of Cereal and Barley Yellow Dwarf Viruses Is Underestimated
Authors: Sõmera Merike , Massart Sébastien , Tamisier Lucie , Sooväli Pille , Sathees Kanitha , Kvarnheden Anders
Published: May 2021

Worldwide, barley/cereal yellow dwarf viruses (YDVs) are the most widespread and damaging group of cereal viruses. In this study, we applied high-throughput sequencing technologies (HTS) to perform a virus survey on symptomatic plants from 47 cereal fields in Estonia. HTS allowed the assembly of complete genome sequences for 22 isolates of cereal yellow dwarf virus RPS, barley yellow dwarf virus GAV, barley yellow dwarf virus PAS (BYDV-PAS), barley yellow dwarf virus PAV (BYDV-PAV), and barley yellow dwarf virus OYV (BYDV-OYV). We also assembled a near-complete genome of the putative novel species BYDV-OYV from Swedish samples of meadow fescue. Previously, partial sequencing of the central part of the coat protein gene indicated that BYDV-OYV represented a putative new species closely related to BYDV-PAV-CN, which currently is recognized as a subtype of BYDV-PAV. The present study found that whereas the 3′gene block of BYDV-OYV shares the closest relationship with BYDV-PAV-CN, the 5′gene block of BYDV-OYV shows the closest relationships to that of BYDV-PAS. Recombination detection analysis revealed that BYDV-OYV is a parental virus for both. Analysis of complete genome sequence data indicates that both BYDV-OYV and BYDV-PAV-CN meet the species criteria of genus Luteovirus. The study discusses BYDV phylogeny, and through a systematic in silico analysis of published primers for YDV detection, the existing gaps in current diagnostic practices for detection of YDVs, proposing primer pairs based on the most recent genomic information for the detection of different BYDV species. Thanks to the rising number of sequences available in databases, continuous updating of diagnostic primers can improve test specificity, e.g., inclusivity and exclusivity at species levels. This is needed to properly survey the geographical and host distribution of the different species of the YDV complex and their prevalence in cereal/barley yellow dwarf disease epidemics.
Function of Non-coding RNA in Helicobacter pylori-Infected Gastric Cancer
Authors: Wang Chao , Hu Yiyang , Yang Huan , Wang Sumin , Zhou Bo , Bao Yulu , Huang Yu , Luo Qiang , Yang Chuan , Xie Xia , Yang Shiming
Published: May 2021

Gastric cancer is a common malignant tumor of the digestive system. Its occurrence and development are the result of a combination of genetic, environmental, and microbial factors. Helicobacter pylori infection is a chronic infection that is closely related to the occurrence of gastric tumorigenesis. Non-coding RNA has been demonstrated to play a very important role in the organism, exerting a prominent role in the carcinogenesis, proliferation, apoptosis, invasion, metastasis, and chemoresistance of tumor progression. H. pylori infection affects the expression of non-coding RNA at multiple levels such as genetic polymorphisms and signaling pathways, thereby promoting or inhibiting tumor progression or chemoresistance. This paper mainly introduces the relationship between H. pylori-infected gastric cancer and non-coding RNA, providing a new perspective for gastric cancer treatment.
Application of Functional Magnetic Resonance Imaging in the Diagnosis of Parkinson’s Disease: A Histogram Analysis
Authors: Shi Dafa , Zhang Haoran , Wang Siyuan , Wang Guangsong , Ren Ke
Published: May 2021

This study aimed to investigate the value of amplitude of low-frequency fluctuation (ALFF)-based histogram analysis in the diagnosis of Parkinson’s disease (PD) and to investigate the regions of the most important discriminative features and their contribution to classification discrimination. Patients with PD (n = 59) and healthy controls (HCs; n = 41) were identified and divided into a primary set (80 cases, including 48 patients with PD and 32 HCs) and a validation set (20 cases, including 11 patients with PD and nine HCs). The Automated Anatomical Labeling (AAL) 116 atlas was used to extract the histogram features of the regions of interest in the brain. Machine learning methods were used in the primary set for data dimensionality reduction, feature selection, model construction, and model performance evaluation. The model performance was further validated in the validation set. After feature data dimension reduction and feature selection, 23 of a total of 1,276 features were entered in the model. The brain regions of the selected features included the frontal, temporal, parietal, occipital, and limbic lobes, as well as the cerebellum and the thalamus. In the primary set, the area under the curve (AUC) of the model was 0.974, the sensitivity was 93.8%, the specificity was 90.6%, and the accuracy was 93.8%. In the validation set, the AUC, sensitivity, specificity, and accuracy were 0.980, 90.9%, 88.9%, and 90.0%, respectively. ALFF-based histogram analysis can be used to classify patients with PD and HCs and to effectively identify abnormal brain function regions in PD patients.
Reduction of Retinal Thickness Ipsilateral to Hippocampal Sclerosis in Epilepsy
Authors: Xiong Weixi , Lu Lu , Chen Qin , Xiao Yingfeng , An Dongmei , Sander Josemir W. , Zhang Ming , Zhou Dong
Published: May 2021

Objectives: Reductions in the peripapillary retinal nerve fiber layer (pRNFL) have been reported in epilepsy, namely in drug-resistant people. Hippocampal sclerosis (HS) is the most frequent cause of drug-resistant epilepsy in tertiary care centers. We aimed to evaluate the likelihood and characteristic of RNFL loss in individuals with epilepsy having HS.

Methods: Fifty-five adults diagnosed with unilateral HS (mean age of 25 years; 42 female) by magnetic resonance imaging were included in this observational cross-sectional study, 58 age-matched individuals with epilepsy with no detectable structural brain abnormality were included as non-HS, and 55 people without neurological diseases were included as healthy controls. pRNFL of both eyes was measured by optical coherence tomography (OCT). In each individual disease related information was recorded.

Results: Among the 55 individuals with unilateral HS, one (1.82%) and ten (18.18%) had significant or borderline abnormal thinning of the pRNFL of the ipsilateral eye to the HS. The average pRNFL ipsilateral to the side of HS was significantly thinner than people with epilepsy non-HS (p = 0.013) and healthy controls (p = 0.000), especially in the inferior quadrants. Only age was significantly correlated with the average and inferior quadrant pRNFL thickness of the ipsilateral eye to the HS (R = −0.286, p = 0.035; R = −0.353, p = 0.008 respectively).

Conclusion: These preliminary findings suggest that retinal abnormalities associated with HS may have a specific pattern. Further studies need to confirm this finding and to unravel the underlying mechanism.
Differences in Levodopa Response for Progressive and Non-Progressive Micrographia in Parkinson's Disease
Authors: Zham Poonam , Poosapadi Sridhar A. , Kempster Peter , Raghav Sanjay , Nagao Kanae J. , Wong Kitty , Kumar Dinesh
Published: May 2021

Background: Micrographia, one element of the dysgraphia of Parkinson's disease (PD), may be classified according to the presence or absence of a decremental pattern. The decremental form, progressive micrographia, is an expression of the sequence effect seen generally in bradykinesia. Its responsiveness to levodopa has not been evaluated kinematically.

Objectives: Aim of this study is to investigate the difference in levodopa response for progressive and non-progressive micrographia.

Methods: Twenty-four PD patients and 24 age-matched repeatedly wrote the letter e on a computerized digital tablet. PD patients performed the task two times, in a defined off state and again after levodopa. Scripts were classified as progressive micrographia (PDPM) or non-progressive micrographia (PDNPM) depending on whether a 10% decrement was seen between the first and final characters of a line of lettering.

Results: While levodopa produced a similar response on the MDS-UPDRS motor scale for the two groups, the effect on the two types of micrographia was different. While writing speed improved significantly in both groups after levodopa, the responses were over twofold greater for PDNPM. Moreover, the decremental features of PDPM–in size, speed, and pen-pressure—were largely unaltered by a levodopa dose.

Conclusions: Progressive micrographia is less responsive to levodopa. Our findings agree with research showing that the sequence effect of bradykinesia is relatively resistant to medication. Yet we did not find a weaker overall levodopa motor benefit. Caution is needed in the interpretation of such micrographia measurements for estimating drug responses.
Microglial Exosomes in Neurodegenerative Disease
Authors: Guo Min , Hao Yining , Feng Yiwei , Li Haiqing , Mao Yiting , Dong Qiang , Cui Mei
Published: May 2021

Microglia play an important role in neurodegenerative disease [i.e., Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS)]. These diseases share some similar pathological changes and several microglia-associated processes, including immune response, neuroinflammation, phagocytosis, elimination of synapses et al. Microglia in the central nervous system (CNS) has been described as having both destructive and protective effects in neurological disorders. Besides, considerable evidence also indicates that microglia play a significant role in neurogenesis, neuronal cell death, and synaptic interactions. The communication between microglia and neurons is of vital role in regulating complex functions which are key to appropriate the activity of the brain. Accumulating studies have also demonstrated that exosomes with sizes ranging from 40–100 nm, released by microglia, could serve as key mediators in intercellular signaling. These exosomes, identified in terms of cellular origin in many kinds of biological fluids, exert their effects by delivering specific cargos such as proteins, microRNAs (miRNAs), and mRNAs. It was shown that microglial exosomes could transport to and be uptake by neurons, which may either be beneficial or instead, detrimental to CNS diseases. The focus of this review is to summarize the involvement of microglial exosomes in critical pathologies associated with neurodegenerative disease and how they contribute to these disorders, including PD, AD, and ALS. We also review the application of microglia exosomes as potential biomarkers in monitoring disease progression, as well as focusing on their roles as drug delivery vehicles in treating neurodegenerative disorders.
Semaphorins in Adult Nervous System Plasticity and Disease
Authors: Carulli Daniela , de Winter Fred , Verhaagen Joost
Published: May 2021

Semaphorins, originally discovered as guidance cues for developing axons, are involved in many processes that shape the nervous system during development, from neuronal proliferation and migration to neuritogenesis and synapse formation. Interestingly, the expression of many Semaphorins persists after development. For instance, Semaphorin 3A is a component of perineuronal nets, the extracellular matrix structures enwrapping certain types of neurons in the adult CNS, which contribute to the closure of the critical period for plasticity. Semaphorin 3G and 4C play a crucial role in the control of adult hippocampal connectivity and memory processes, and Semaphorin 5A and 7A regulate adult neurogenesis. This evidence points to a role of Semaphorins in the regulation of adult neuronal plasticity. In this review, we address the distribution of Semaphorins in the adult nervous system and we discuss their function in physiological and pathological processes.
Magnetic Resonance Guided Radiation Therapy for Pancreatic Adenocarcinoma, Advantages, Challenges, Current Approaches, and Future Directions
Authors: Hall William A. , Small Christina , Paulson Eric , Koay Eugene J. , Crane Christopher , Intven Martijn , Daamen Lois A. , Meijer Gert J. , Heerkens Hanne D. , Bassetti Michael , Rosenberg Stephen A. , Aitken Katharine , Myrehaug Sten , Dawson Laura A. , Lee Percy , Gani Cihan , Chuong Michael David , Parikh Parag J. , Erickson Beth A.
Published: May 2021

Introduction

Pancreatic adenocarcinoma (PAC) has some of the worst treatment outcomes for any solid tumor. PAC creates substantial difficulty for effective treatment with traditional RT delivery strategies primarily secondary to its location and limited visualization using CT. Several of these challenges are uniquely addressed with MR-guided RT. We sought to summarize and place into context the currently available literature on MR-guided RT specifically for PAC.

Methods

A literature search was conducted to identify manuscript publications since September 2014 that specifically used MR-guided RT for the treatment of PAC. Clinical outcomes of these series are summarized, discussed, and placed into the context of the existing pancreatic literature. Multiple international experts were involved to optimally contextualize these publications.

Results

Over 300 manuscripts were reviewed. A total of 6 clinical outcomes publications were identified that have treated patients with PAC using MR guidance. Successes, challenges, and future directions for this technology are evident in these publications. MR-guided RT holds theoretical promise for the treatment of patients with PAC. As with any new technology, immediate or dramatic clinical improvements associated with its use will take time and experience. There remain no prospective trials, currently publications are limited to small retrospective experiences. The current level of evidence for MR guidance in PAC is low and requires significant expansion. Future directions and ongoing studies that are currently open and accruing are identified and reviewed.

Conclusions

The potential promise of MR-guided RT for PAC is highlighted, the challenges associated with this novel therapeutic intervention are also reviewed. Outcomes are very early, and will require continued and long term follow up. MR-guided RT should not be viewed in the same fashion as a novel chemotherapeutic agent for which dosing, administration, and toxicity has been established in earlier phase studies. Instead, it should be viewed as a novel procedural intervention which must be robustly tested, refined and practiced before definitive conclusions on the potential benefits or detriments can be determined. The future of MR-guided RT for PAC is highly promising and the potential implications on PAC are substantial.
Percutaneous Microwave Ablation Versus Open Surgical Resection for Colorectal Cancer Liver Metastasis
Authors: Zhao Qinxian , Cheng Zhigang , Han Zhiyu , Liu Fangyi , Yu Xiaoling , Tan Xianliang , Han Bin , Dou Jianping , Yu Jie , Liang Ping
Published: May 2021

Purpose

To compare the therapeutic outcomes between open surgical resection (OSR) and percutaneous microwave ablation (PMWA) for colorectal liver metastasis (CRLM) ≤3 cm.

Methods

In this retrospective study, 200 consecutive patients with 306 CRLMs were reviewed. Overall survival (OS), disease-free survival (DFS), local tumour progression (LTP), intrahepatic distant recurrence, and extrahepatic metastasis were analysed to compare the therapeutic efficacy. Cox proportional hazards regression analysis was used to identify the prognostic factors for OS and DFS. Major complications and postoperative hospital stay were also assessed.

Result

The 1-, 3-, and 5-year OS rates were 91.6%, 64.1%, and 46.3%, respectively, in the PMWA group and 89.7%, 62.4% and 44.7%, respectively, in the OSR group (P=0.839). The 1-, 3-, and 5-year DFS rates were 61.9%, 44.8%, and 41.3%, respectively, in the PMWA group and 58.1%, 24.4%, and 18.3%, respectively, in the OSR group (P =0.066). The two groups had comparable 5-year cumulative rates of intrahepatic distant recurrence (P=0.627) and extrahepatic metastasis (P=0.884). The 5-year cumulative LTP rate was lower in the OSR group than in the PMWA group (P=0.023). The rate of major complications was higher in the OSR group than in the PMWA group (P =0.025), and the length of hospital stay after treatment was shorter in the PMWA group (P<0.001).

Conclusion

There were no significant differences in OS or DFS between the two groups. PMWA was associated with increased LTP, fewer postoperative days and fewer major complications.
Targeted Therapy With PI3K and FGFR Inhibitors on Human Papillomavirus Positive and Negative Tonsillar and Base of Tongue Cancer Lines With and Without Corresponding Mutations
Authors: Holzhauser Stefan , Wild Nicole , Zupancic Mark , Ursu Ramona G. , Bersani Cinzia , Näsman Anders , Kostopoulou Ourania N. , Dalianis Tina
Published: May 2021

Objectives

Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC), the major subsites of oropharyngeal squamous cell carcinoma (OPSCC) have favorable outcome, but upon relapse, outcome is poor and new therapies needed. Since, phosphatidyl-inositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and fibroblast-growth-factor-receptor-3 (FGFR3) mutations often occur in such tumors, here, we tested targeted therapy directed to such genes in TSCC/BOTSCC cell lines. We also combined the two types of inhibitors with each other, and cisplatin or docetaxel that are used clinically.

Methods

The HPV+ CU-OP-2, -3, -20, UPCI-SCC-154, and HPV- CU-OP-17 and UT-SCC-60A cell lines were first tested for common PIK3CA/FGFR3 mutations by competitive-allele-specific TaqMan-PCR. They were then treated with the food and drug administration (FDA) approved drugs, alpelisib (BYL719) and erdafitinib (JNJ-42756493) alone and in combination with cisplatin or docetaxel. Viability, proliferation, apoptosis and cytotoxicity responses were thereafter followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System.

Results

HPV+ CU-OP-2 had a pS249C-FGFR3, and like CU-OP-20, a pE545K-PIK3CA mutation, while no other lines had such mutations. Irrespectively, dose dependent responses to all PI3K/FGFR inhibitors were obtained, and upon combining the inhibitors, positive effects were observed. Cisplatin and docetaxel also induced dose dependent responses, and upon combination with the inhibitors, both positive and neutral effects were found.

Conclusions

The data suggest that FDA approved drugs alpelisib and erdafitinib efficiently inhibit TSCC/BOTSCC cell line growth, especially when combined irrespective of presence of corresponding mutations and should be further explored, for use upon recurrent disease.
Positive Crosstalk Between Hedgehog and NF-κB Pathways Is Dependent on KRAS Mutation in Pancreatic Ductal Adenocarcinoma
Authors: Wang Yuqiong , Wang Dan , Dai Yanmiao , Kong Xiangyu , Zhu Xian , Fan Yunxia , Wang Yaodong , Wu Hongyu , Jin Jing , Yao Wenzhu , Gao Jun , Wang Kaixuan , Xu Hongwei
Published: May 2021

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.
Down-Regulating the Expression of miRNA-21 Inhibits the Glucose Metabolism of A549/DDP Cells and Promotes Cell Death Through the PI3K/AKT/mTOR/HIF-1α Pathway
Authors: Sun Ye , Liu Wenjun , Zhao Qiuyu , Zhang Ruiqi , Wang Jianbo , Pan Pengyu , Shang Hai , Liu Chunying , Wang Chun
Published: May 2021

miRNA-21 is a single-stranded non-coding RNA that is highly expressed in a variety of tumor cells. It participates in tumor cell proliferation, metabolism, metastasis, and drug resistance. Here, we tested the potential mechanism of miRNA-21 in cisplatin-resistant non-small cell lung cancer A549/DDP (human lung adenocarcinoma drug-resistant cell line) cells. A549 and A549/DDP RNAs were sequenced to show that miRNA-21 was highly expressed in the latter, and this was verified by qRT-PCR. In addition, we found that miRNA-21 combined with cisplatin can significantly inhibit glycolysis and glycolysis rate-limiting enzyme protein expression in A549/DDP cells. We also found that miRNA-21 combined with cisplatin can promote A549/DDP cell death. Further investigations showed that miRNA-21 combined with cisplatin caused excessive inactivation of the pI3K/AKT/mTOR/HIF-1α signaling pathway in cisplatin-resistant A549/DDP cells. Hence, reduction of the expression of miRNA-21 in combination with cisplatin chemotherapy may effectively improve the therapeutic effect on patients with non-small cell lung cancer, and this may provide a theoretical basis for the treatment of this disease.
Identification of BRCA1:c.5470_5477del as a Founder Mutation in Chinese Ovarian Cancer Patients
Authors: Li Jun , Han Sile , Zhang Cuiyun , Luo Yanlin , Wang Li , Wang Ping , Wang Yi , Xia Qingxin , Wang Xiaoyan , Wei Bing , Ma Jie , Li Hongle , Guo Yongjun
Published: May 2021

Predisposition of germline BRCA1/2 mutations (gBRCAMUT) increases the risk of breast and ovarian cancer in females, but the mutation prevalence and spectrum are highly ethnicity-specific with different recurrent mutations being reported in different populations. Hereby, we performed hybridization-based target sequencing of BRCA1/2 in 530 ovarian cancer patients from Henan, the central region of China, followed by haplotype analysis of six short tandem repeat (STR) markers in the patients with recurrent mutations to determine their founder effect. About 28.3% (150/530) of the OC patients in our cohort harbored gBRCAMUT; of the 151 mutations, 117 in BRCA1 and 34 in BRCA2, identified in this study, BRCA1:c.5470_5477del, c.981_982del, and c.4065_4068del are the top three mutants, recurrently detected in eight, seven, and six independent patients respectively. Haplotype analysis identified a region of 0.6 MB genomic length covering BRCA1 highly conserved across all eight carriers of BRCA1:c.5470_5477del, but not c.981_982del, suggesting a consequence of founder effect. Retrospective analysis in a subgroup of serous ovarian cancer patients revealed gBRCAMUT status was not associated with the progression-free survival (PFS); instead, an expression of Ki-67% ≥50% was associated with a shorter PFS (p = 0.041). In conclusion, patients with pathogenic or likely pathogenic gBRCAMUT account for 28.3% of the OC cases from Henan, and BRCA1:c.5470_5477del, the most frequently detected mutation in Henan patients, is a founder mutation in the population.
A Comparison Between Chemo-Radiotherapy Combined With Immunotherapy and Chemo-Radiotherapy Alone for the Treatment of Newly Diagnosed Glioblastoma: A Systematic Review and Meta-Analysis
Authors: Lara-Velazquez Montserrat , Shireman Jack M. , Lehrer Eric J. , Bowman Kelsey M. , Ruiz-Garcia Henry , Paukner Mitchell J. , Chappell Richard J. , Dey Mahua
Published: May 2021

Background

Immunotherapy for GBM is an emerging field which is increasingly being investigated in combination with standard of care treatment options with variable reported success rates.

Objective

To perform a systematic review of the available data to evaluate the safety and efficacy of combining immunotherapy with standard of care chemo-radiotherapy following surgical resection for the treatment of newly diagnosed GBM.

Methods

A literature search was performed for published clinical trials evaluating immunotherapy for GBM from January 1, 2000, to October 1, 2020, in PubMed and Cochrane using PICOS/PRISMA/MOOSE guidelines. Only clinical trials with two arms (combined therapy vs. control therapy) were included. Outcomes were then pooled using weighted random effects model for meta-analysis and compared using the Wald-type test. Primary outcomes included 1-year overall survival (OS) and progression-free survival (PFS), secondary outcomes included severe adverse events (SAE) grade 3 or higher.

Results

Nine randomized phase II and/or III clinical trials were included in the analysis, totaling 1,239 patients. The meta-analysis revealed no statistically significant differences in group’s 1-year OS [80.6% (95% CI: 68.6%–90.2%) vs. 72.6% (95% CI: 65.7%–78.9%), p = 0.15] or in 1-year PFS [37% (95% CI: 26.4%–48.2%) vs. 30.4% (95% CI: 25.4%–35.6%) p = 0.17] when the immunotherapy in combination with the standard of care group (combined therapy) was compared to the standard of care group alone (control). Severe adverse events grade 3 to 5 were more common in the immunotherapy and standard of care group than in the standard of care group (47.3%, 95% CI: 20.8–74.6%, vs 43.8%, 95% CI: 8.7–83.1, p = 0.81), but this effect also failed to reach statistical significance.

Conclusion

Our results suggests that immunotherapy can be safely combined with standard of care chemo-radiotherapy without significant increase in grade 3 to 5 SAE; however, there is no statistically significant increase in overall survival or progression free survival with the combination therapy.
Ocular Toxicity of Belantamab Mafodotin, an Oncological Perspective of Management in Relapsed and Refractory Multiple Myeloma
Authors: Wahab Ahsan , Rafae Abdul , Mushtaq Kamran , Masood Adeel , Ehsan Hamid , Khakwani Maria , Khan Aqsa
Published: May 2021

Belantamab mafodotin (belamaf), an antibody-drug conjugate approved for the treatment of relapsed and refractory multiple myeloma (RRMM), is an anti B-cell maturation antigen (BCMA) agent. DREAMM-1, a first in-human trial of belamaf, reported several ocular toxicities requiring dose adjustments, dose delays and treatment discontinuations. In DREAMM-1, 53% of patients in part-1 and 63% of patients in part-2 had ocular toxicity. Similarly, 73% of patients in DREAMM-2 had keratopathy (71% in 2.5 mg/kg versus 75% in 3.4 mg/kg) with the most common symptoms being blurred vision and dry eyes. Ocular toxicity of belamaf is attributed to microtubule-disrupting monomethylauristatin-F (MMAF), a cytotoxic payload of the drug that causes an off-target damage to the corneal epithelial cells. Ocular adverse events (AEs) of belamaf are more frequent at higher doses compared with lower doses. Higher belamaf dose, history of dry eyes and soluble BCMA are associated with increased risk of corneal toxicity. Absence of ocular symptoms does not exclude the possibility of belamaf-induced ocular toxicity, so patients need slit lamp and Snellen visual acuity testing to detect microcytic-like epithelial changes and visual decline. Corticosteroid eyes drops for 4-7 days prior to belamaf dose do not prevent ocular AEs and may cause steroid-related AEs instead. Keratopathy and Visual Acuity scale (KVA) is recommended to document the severity of belamaf-induced ocular toxicity and make treatment adjustments. Management of toxicity includes dosage modifications, treatment interruption or discontinuations and preservative-free artificial tears along with close ophthalmology and hematology-oncology follow-ups.
Long-Term Renal Transplant Outcome in Patients With Posterior Urethral Valves. Prognostic Factors Related to Bladder Dysfunction Management
Authors: Amesty María Virginia , García-Vaz Claudia , Espinosa Laura , Martínez-Urrutia María José , López-Pereira Pedro
Published: May 2021

Introduction: To obtain a successful renal transplant (RT) outcome in patients with posterior urethral valves (PUV), it is necessary to accomplish an adequate bladder dysfunction treatment. Our aim was to determine prognostic factors related to bladder dysfunction management in long-term RT outcome in patients with PUV.

Methods: A retrospective review of patients with PUV who received a first RT after 1985 in our institution with at least 5 years of follow-up was performed. Variables analyzed included prenatal diagnosis, age of diagnosis, initial presentation and management, bladder dysfunction treatment, other surgical treatments, pre-transplant dialysis, age of transplantation, type of donor, immunosuppression regimen, vascular and urological complications, rejections episodes, and graft survival.

Results: Fifty-one patients were included in the analysis. Prenatal diagnosis was done in 37.3%. Median age of diagnosis was 0.30 (0–88) months. Initial presentation was vesicoureteral reflux (VUR) in 78% and obstructive ureterohydronefrosis in 35.3%. Initial management was valve ablation (29.4%), pyelo-ureterostomy (64.7%), and vesicostomy (5.9%). In 33.3%, a type of bladder dysfunction treatment was performed: 21.6% bladder augmentation (BA), 15.7% Mitrofanoff procedure, 17.6% anticholinergic drugs, and 27.5% clean intermittent catheterization (CIC). Pre-transplant dialysis was received by 66.7%. Transplantation was performed at 6.28 ± 5.12 years, 62.7% were cadaveric and 37.3% living-donor grafts. Acute rejection episodes were found in 23.6%. Urological complications included recurrent urinary tract infections (UTIs) (31.4%); native kidneys VUR (31.4%); graft VUR (45.1%); and ureteral obstruction (2%). Vascular complications occurred in 3.9%. Mean graft survival was 11.1 ± 6.9 years. Analyzing the prognostic factor that influenced graft survival, patients with had CIC or a Mitrofanoff procedure had a significant better long-term graft survival after 10 years of follow-up (p < 0.05), despite of the existence of more recurrent UTIs in them. A better graft survival was also found in living-donor transplants (p < 0.05). No significant differences were observed in long-term graft survival regarding native kidneys or graft VUR, BA, immunosuppression regimen, or post-transplant UTIs.

Conclusion: Optimal bladder dysfunction treatment, including CIC with or without a Mitrofanoff procedure, might result in better long-term graft survival in patients with PUV. These procedures were not related to a worse RT outcome in spite of being associated with more frequent UTIs.
Cinnamomum Species: Bridging Phytochemistry Knowledge, Pharmacological Properties and Toxicological Safety for Health Benefits
Authors: Sharifi-Rad Javad , Dey Abhijit , Koirala Niranjan , Shaheen Shabnum , El Omari Nasreddine , Salehi Bahare , Goloshvili Tamar , Cirone Silva Nathália Cristina , Bouyahya Abdelhakim , Vitalini Sara , Varoni Elena M. , Martorell Miquel , Abdolshahi Anna , Docea Anca Oana , Iriti Marcello , Calina Daniela , Les Francisco , López Víctor , Caruntu Constantin
Published: May 2021

The genusCinnamomumincludes a number of plant species largely used as food, food additives and spices for a long time. Different traditional healing systems have used these plants as herbal remedies to cure diverse ailments. The aim of this comprehensive and updated review is to summarize the biodiversity of the genusCinnamomum, its bioactive compounds, the mechanisms that underlie the pharmacological activities and molecular targets and toxicological safety. All the data in this review have been collected from databases and recent scientific literature including Web of Science, PubMed, ScienceDirect etc. The results showed that the bioactive compounds ofCinnamomumspecies possess antimicrobial, antidiabetic, antioxidant, anti-inflammatory, anticancer and neuroprotective effects. The preclinical (in vitro/in vivo) studies provided the possible molecular mechanisms of these action. As a novelty, recent clinical studies and toxicological data described in this paper support and confirm the pharmacological importance of the genusCinnamomum.In conclusion, the obtained results from preclinical studies and clinical trials, as well as reduced side effects provide insights into future research of new drugs based on extracts and bioactive compounds fromCinnamomumplants.