bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell Fate Reprogramming in the Era of Cancer Immunotherapy
Authors: Zimmermannova Olga , Caiado Inês , Ferreira Alexandra G. , Pereira Carlos-Filipe
Published: July 2021

Advances in understanding how cancer cells interact with the immune system allowed the development of immunotherapeutic strategies, harnessing patients’ immune system to fight cancer. Dendritic cell-based vaccines are being explored to reactivate anti-tumor adaptive immunity. Immune checkpoint inhibitors and chimeric antigen receptor T-cells (CAR T) were however the main approaches that catapulted the therapeutic success of immunotherapy. Despite their success across a broad range of human cancers, many challenges remain for basic understanding and clinical progress as only a minority of patients benefit from immunotherapy. In addition, cellular immunotherapies face important limitations imposed by the availability and quality of immune cells isolated from donors. Cell fate reprogramming is offering interesting alternatives to meet these challenges. Induced pluripotent stem cell (iPSC) technology not only enables studying immune cell specification but also serves as a platform for the differentiation of a myriad of clinically useful immune cells including T-cells, NK cells, or monocytes at scale. Moreover, the utilization of iPSCs allows introduction of genetic modifications and generation of T/NK cells with enhanced anti-tumor properties. Immune cells, such as macrophages and dendritic cells, can also be generated by direct cellular reprogramming employing lineage-specific master regulators bypassing the pluripotent stage. Thus, the cellular reprogramming toolbox is now providing the means to address the potential of patient-tailored immune cell types for cancer immunotherapy. In parallel, development of viral vectors for gene delivery has opened the door for in vivo reprogramming in regenerative medicine, an elegant strategy circumventing the current limitations of in vitro cell manipulation. An analogous paradigm has been recently developed in cancer immunotherapy by the generation of CAR T-cells in vivo. These new ideas on endogenous reprogramming, cross-fertilized from the fields of regenerative medicine and gene therapy, are opening exciting avenues for direct modulation of immune or tumor cells in situ, widening our strategies to remove cancer immunotherapy roadblocks. Here, we review current strategies for cancer immunotherapy, summarize technologies for generation of immune cells by cell fate reprogramming as well as highlight the future potential of inducing these unique cell identities in vivo, providing new and exciting tools for the fast-paced field of cancer immunotherapy.
Roles of Inflammasome in Cigarette Smoke-Related Diseases and Physiopathological Disorders: Mechanisms and Therapeutic Opportunities
Authors: Ma Yiming , Long Yingjiao , Chen Yan
Published: July 2021

Cigarette smoke damages a wide range of immunological functions, including innate and adaptive immune responses. Emerging literature demonstrates that inflammasome constitutes an essential component in innate immune response. In this review, we focus on the cumulative mechanisms of inflammasome in cigarette smoke-related diseases and physiopathological disorders, and summarize potential therapeutic opportunities targeting inflammasome. This review suggests that inflammasomes (NLRP3, NLRP6, NLRP12 and AIM2) are involved in the pathogenesis of several cigarette smoke-related diseases (including COPD, ALI, atherosclerosis, kidney injury, bladder dysfunction, and oral leukoplakia) and physiopathological disorders (macrophage dysfunction, endothelial barrier dysfunction, podocyte injury, and ubiquitin-mediated proteasomal processing). MyD88/NF-κB, HMGB1, production of ROS, endoplasmic reticulum stress and mitochondrial dysfunction, and Ca2+ influx are potentially involved in cigarette smoke induced-inflammasome activation. Strategies targeting ROS/NLRP3 inflammasome axis are most widely investigated and show potential therapeutic effects.
Dietary Shifts and Risks of Artifact Ingestion for Argentine Shortfin Squid Illex argentinus in the Southwest Atlantic
Authors: Chang Ssu-Wei , Chen Ruei-Gu , Liu Tsung-Han , Lee Yao-Chang , Chen Chih-Shin , Chiu Tai-Sheng , Ko Chia-Ying
Published: July 2021

Cephalopods play an important role in both ecology and fisheries. Variations in the dietary compositions of squids with large populations further promote interactions between different trophic levels in marine ecosystems. Moreover, due to marine pollution, squids are also at risks of artifact ingestion, and there is limited understanding about the influence of artifacts on the feeding behavior of squids. We examined 296 stomachs of the Argentine shortfin squid Illex argentinus collected through commercial catches across the Southwest Atlantic from February to April of 2018 and 2019 to establish the monthly dietary compositions and risks of artifact ingestion. The results supported typical observations that the Argentine shortfin squids switched from a diet dominated by crustaceans at small sizes to consuming larger prey, predominantly fishes and/or cephalopods, at large sizes during their growth and southward migration. Significantly higher consumption of fishes was observed in recent years compared with that observed in other studies since 1992. The ingested artifacts examined were composed of plastic and non-plastic materials. Artifacts were observed in 19.9% of the total number of stomachs, with 20.5% of the empty stomachs containing artifact remains. The results indicate that although the main dietary compositions of the Argentine shortfin squid maintain the taxonomic groups of prey compositions, the dietary structure, i.e., composition percentage, is varying. The detection of artifacts suggests that environmental monitoring is needed in this region in order to manage and conserve the squid and safeguard aquatic food safety.
Interspecies RNA Interactome of Pathogen and Host in a Heritable Defensive Strategy
Authors: Legüe Marcela , Aguila Blanca , Calixto Andrea
Published: July 2021

Communication with bacteria deeply impacts the life history traits of their hosts. Through specific molecules and metabolites, bacteria can promote short- and long-term phenotypic and behavioral changes in the nematode Caenorhabditis elegans. The chronic exposure of C. elegans to pathogens promotes the adaptive behavior in the host’s progeny called pathogen-induced diapause formation (PIDF). PIDF is a pathogen avoidance strategy induced in the second generation of animals infected and can be recalled transgenerationally. This behavior requires the RNA interference machinery and specific nematode and bacteria small RNAs (sRNAs). In this work, we assume that RNAs from both species co-exist and can interact with each other. Under this principle, we explore the potential interspecies RNA interactions during PIDF-triggering conditions, using transcriptomic data from the holobiont. We study two transcriptomics datasets: first, the dual sRNA expression of Pseudomonas aeruginosa PAO1 and C. elegans in a transgenerational paradigm for six generations and second, the simultaneous expression of sRNAs and mRNA in intergenerational PIDF. We focus on those bacterial sRNAs that are systematically overexpressed in the intestines of animals compared with sRNAs expressed in host-naïve bacteria. We selected diverse in silico methods that represent putative mechanisms of RNA-mediated interspecies interaction. These interactions are as follows: heterologous perfect and incomplete pairing between bacterial RNA and host mRNA; sRNAs of similar sequence expressed in both species that could mimic each other; and known or predicted eukaryotic motifs present in bacterial transcripts. We conclude that a broad spectrum of tools can be applied for the identification of potential sRNA and mRNA targets of the interspecies RNA interaction that can be subsequently tested experimentally.
Clostridium cellulovorans Proteomic Responses to Butanol Stress
Authors: Costa Paolo , Usai Giulia , Re Angela , Manfredi Marcello , Mannino Giuseppe , Bertea Cinzia Margherita , Pessione Enrica , Mazzoli Roberto
Published: July 2021

Combination of butanol-hyperproducing and hypertolerant phenotypes is essential for developing microbial strains suitable for industrial production of bio-butanol, one of the most promising liquid biofuels. Clostridium cellulovorans is among the microbial strains with the highest potential for direct production of n-butanol from lignocellulosic wastes, a process that would significantly reduce the cost of bio-butanol. However, butanol exhibits higher toxicity compared to ethanol and C. cellulovorans tolerance to this solvent is low. In the present investigation, comparative gel-free proteomics was used to study the response of C. cellulovorans to butanol challenge and understand the tolerance mechanisms activated in this condition. Sequential Window Acquisition of all Theoretical fragment ion spectra Mass Spectrometry (SWATH-MS) analysis allowed identification and quantification of differentially expressed soluble proteins. The study data are available via ProteomeXchange with the identifier PXD024183. The most important response concerned modulation of protein biosynthesis, folding and degradation. Coherent with previous studies on other bacteria, several heat shock proteins (HSPs), involved in protein quality control, were up-regulated such as the chaperones GroES (Cpn10), Hsp90, and DnaJ. Globally, our data indicate that protein biosynthesis is reduced, likely not to overload HSPs. Several additional metabolic adaptations were triggered by butanol exposure such as the up-regulation of V- and F-type ATPases (involved in ATP synthesis/generation of proton motive force), enzymes involved in amino acid (e.g., arginine, lysine, methionine, and branched chain amino acids) biosynthesis and proteins involved in cell envelope re-arrangement (e.g., the products of Clocel_4136, Clocel_4137, Clocel_4144, Clocel_4162 and Clocel_4352, involved in the biosynthesis of saturated fatty acids) and a redistribution of carbon flux through fermentative pathways (acetate and formate yields were increased and decreased, respectively). Based on these experimental findings, several potential gene targets for metabolic engineering strategies aimed at improving butanol tolerance in C. cellulovorans are suggested. This includes overexpression of HSPs (e.g., GroES, Hsp90, DnaJ, ClpC), RNA chaperone Hfq, V- and F-type ATPases and a number of genes whose function in C. cellulovorans is currently unknown.
An Ensemble Matrix Completion Model for Predicting Potential Drugs Against SARS-CoV-2
Authors: Li Wen , Wang Shulin , Xu Junlin
Published: July 2021

Because of the catastrophic outbreak of global coronavirus disease 2019 (COVID-19) and its strong infectivity and possible persistence, computational repurposing of existing approved drugs will be a promising strategy that facilitates rapid clinical treatment decisions and provides reasonable justification for subsequent clinical trials and regulatory reviews. Since the effects of a small number of conditionally marketed vaccines need further clinical observation, there is still an urgent need to quickly and effectively repurpose potentially available drugs before the next disease peak. In this work, we have manually collected a set of experimentally confirmed virus-drug associations through the publicly published database and literature, consisting of 175 drugs and 95 viruses, as well as 933 virus-drug associations. Then, because the samples are extremely sparse and unbalanced, negative samples cannot be easily obtained. We have developed an ensemble model, EMC-Voting, based on matrix completion and weighted soft voting, a semi-supervised machine learning model for computational drug repurposing. Finally, we have evaluated the prediction performance of EMC-Voting by fivefold crossing-validation and compared it with other baseline classifiers and prediction models. The case study for the virus SARS-COV-2 included in the dataset demonstrates that our model achieves the outperforming AUPR value of 0.934 in virus-drug association’s prediction.
Complete Genome Sequences of Two Novel KPC-2-Producing IncU Multidrug-Resistant Plasmids From International High-Risk Clones of Escherichia coli in China
Authors: Wu Wenhao , Lu Lingling , Fan Wenjia , Chen Chun , Jin Dazhi , Pan Hongying , Li Xi
Published: July 2021

The rapidly increasing prevalence of Klebsiella pneumoniae carbapenemase 2 (KPC-2)-producing bacteria has become a serious challenge to public health. Currently, the blaKPC–2 gene is mainly disseminated through plasmids of different sizes and replicon types. However, the plasmids carrying the blaKPC–2 gene have not been fully characterized. In this study, we report the complete genome sequences of two novel blaKPC–2-harboring incompatibility group U (IncU) plasmids, pEC2341-KPC and pEC2547-KPC, from international high-risk clones of Escherichia coli isolated from Zhejiang, China. Two KPC-2-producing E. coli isolates (EC2341 and EC2547) were collected from clinical samples. Whole-genome sequencing (WGS) analysis indicated that EC2341 and EC2547 belonged to the ST410 and ST131 clones, respectively. S1-nuclease pulsed-field gel electrophoresis (S1-PFGE), Southern blot and conjugation experiments confirmed the presence of the blaKPC–2 gene on the pEC2341-KPC plasmid and that this was a conjugative plasmid, while the blaKPC–2 gene on the pEC2547-KPC plasmid was a non-conjugative plasmid. In addition, plasmid analysis further revealed that the two blaKPC–2-harboring plasmids have a close evolutionary relationship. To the best of our knowledge, this is the first report of E. coli strains carrying the blaKPC–2 gene on IncU plasmids. The emergence of the IncU-type blaKPC–2-positive plasmid highlights further dissemination of blaKPC–2 in Enterobacteriaceae. Therefore, effective measures should be taken immediately to prevent the spread of these blaKPC–2–positive plasmids.
The Selective Advantage of the lac Operon for Escherichia coli Is Conditional on Diet and Microbiota Composition
Authors: Pinto Catarina , Melo-Miranda Rita , Gordo Isabel , Sousa Ana
Published: July 2021

The lac operon is one of the best known gene regulatory circuits and constitutes a landmark example of how bacteria tune their metabolism to nutritional conditions. It is nearly ubiquitous in Escherichia coli strains justifying the use of its phenotype, the ability to consume lactose, for species identification. Lactose is the primary sugar found in milk, which is abundant in mammals during the first weeks of life. However, lactose is virtually non-existent after the weaning period, with humans being an exception as many consume dairy products throughout their lives. The absence of lactose during adulthood in most mammals and the rarity of lactose in the environment, means that the selective pressure for maintaining the lac operon could be weak for long periods of time. Despite the ability to metabolize lactose being a hallmark of E. coli’s success when colonizing its primary habitat, the mammalian intestine, the selective value of this trait remains unknown in this ecosystem during adulthood. Here we determine the competitive advantage conferred by the lac operon to a commensal strain of E. coli when colonizing the mouse gut. We find that its benefit, which can be as high as 11%, is contingent on the presence of lactose in the diet and on the presence of other microbiota members in the gut, but the operon is never deleterious. These results help explaining the pervasiveness of the lac operon in E. coli, but also its polymorphism, as lac-negative E. coli strains albeit rare can naturally occur in the gut.
Murine GRXCR1 Has a Different Function Than GRXCR2 in the Morphogenesis of Stereocilia
Authors: Liu Chang , Zhao Bo
Published: July 2021

Mutations in human glutaredoxin domain-containing cysteine-rich protein 1 (GRXCR1) and its paralog GRXCR2 have been linked to hearing loss in humans. Although both GRXCR1 and GRXCR2 are required for the morphogenesis of stereocilia in cochlear hair cells, a fundamental question that remains unclear is whether GRXCR1 and GRXCR2 have similar functions in hair cells. Previously, we found that GRXCR2 is critical for the stereocilia morphogenesis by regulating taperin localization at the base of stereocilia. Reducing taperin expression level rescues the morphological defects of stereocilia and hearing loss in Grxcr2-deficient mice. So far, functions of GRXCR1 in mammalian hair cells are still unclear. Grxcr1-deficient hair cells have very thin stereocilia with less F-actin content inside, which is different from Grxcr2-deficient hair cells. In contrast to GRXCR2, which is concentrated at the base of stereocilia, GRXCR1 is diffusely distributed throughout the stereocilia. Notably, GRXCR1 interacts with GRXCR2. In Grxcr1-deficient hair cells, the expression level of GRXCR2 and taperin is reduced. Remarkably, different from that in Grxcr2-deficient mice, reducing taperin expression level does not rescue the morphological defects of stereocilia or hearing loss in Grxcr1-deficient mice. Thus, our findings suggest that GRXCR1 has different functions than GRXCR2 during the morphogenesis of stereocilia.
Persistent Activity During Working Memory From Front to Back
Authors: Curtis Clayton E. , Sprague Thomas C.
Published: July 2021

Working memory (WM) extends the duration over which information is available for processing. Given its importance in supporting a wide-array of high level cognitive abilities, uncovering the neural mechanisms that underlie WM has been a primary goal of neuroscience research over the past century. Here, we critically review what we consider the two major “arcs” of inquiry, with a specific focus on findings that were theoretically transformative. For the first arc, we briefly review classic studies that led to the canonical WM theory that cast the prefrontal cortex (PFC) as a central player utilizing persistent activity of neurons as a mechanism for memory storage. We then consider recent challenges to the theory regarding the role of persistent neural activity. The second arc, which evolved over the last decade, stemmed from sophisticated computational neuroimaging approaches enabling researchers to decode the contents of WM from the patterns of neural activity in many parts of the brain including early visual cortex. We summarize key findings from these studies, their implications for WM theory, and finally the challenges these findings pose. Our goal in doing so is to identify barriers to developing a comprehensive theory of WM that will require a unification of these two “arcs” of research.
Circuit Organization Underlying Optic Flow Processing in Zebrafish
Authors: Matsuda Koji , Kubo Fumi
Published: July 2021

Animals’ self-motion generates a drifting movement of the visual scene in the entire field of view called optic flow. Animals use the sensation of optic flow to estimate their own movements and accordingly adjust their body posture and position and stabilize the direction of gaze. In zebrafish and other vertebrates, optic flow typically drives the optokinetic response (OKR) and optomotor response (OMR). Recent functional imaging studies in larval zebrafish have identified the pretectum as a primary center for optic flow processing. In contrast to the view that the pretectum acts as a relay station of direction-selective retinal inputs, pretectal neurons respond to much more complex visual features relevant to behavior, such as spatially and temporally integrated optic flow information. Furthermore, optic flow signals, as well as motor signals, are represented in the cerebellum in a region-specific manner. Here we review recent findings on the circuit organization that underlies the optic flow processing driving OKR and OMR.
In Patients With Parkinson’s Disease in an OFF-Medication State, Does Bilateral Electrostimulation of Tibialis Anterior Improve Anticipatory Postural Adjustments During Gait Initiation?
Authors: Delafontaine Arnaud , Fourcade Paul , Zemouri Ahmed , Diakhaté D. G. , Saiydoun Gabriel , Yiou Eric
Published: July 2021

A complete lack of bilateral activation of tibialis anterior (TA) during gait initiation (GI), along with bradykinetic anticipatory postural adjustments (APAs), often occurs in patients with Parkinson’s disease (PD) in their OFF-medication state. Functional electrical stimulation (FES) is a non-pharmacological method frequently used in neurorehabilitation to optimize the effect of L-DOPA on locomotor function in this population. The present study tested the potential of bilateral application of FES on TA to improve GI in PD patients. Fourteen PD patients (OFF-medication state, Hoehn and Yahr state 2-3) participated in this study. They performed series of 10 GI trials on a force-plate under the following experimental conditions: (1) GI without FES (control group), (2) GI with 2Hz-FES (considered as a very low FES frequency condition without biomechanical effect; placebo group) and (3) GI with 40Hz-FES (test group). In (2) and (3), FES was applied bilaterally to the TA during APAs (300 mA intensity/300 μs pulse width). Main results showed that the peak of anticipatory backward center of pressure shift, the forward center of mass (COM) velocity and shift at foot off were significantly larger in the 40 Hz FES condition than in the control condition, while the duration of step execution was significantly shorter. In contrast, the capacity of participants to brake the fall of their COM remained unchanged across conditions. Globally taken, these results suggest that acute application of 40-Hz FES to the TA may improve the capacity of PD patients to generate APAs during GI, without altering their balance capacity. Future studies are required before considering that TA FES application might be a valuable tool to improve GI in PD patients and be relevant to optimize the effects of L-DOPA medication on locomotor function.
Auditory Attention Detection via Cross-Modal Attention
Authors: Cai Siqi , Li Peiwen , Su Enze , Xie Longhan
Published: July 2021

Humans show a remarkable perceptual ability to select the speech stream of interest among multiple competing speakers. Previous studies demonstrated that auditory attention detection (AAD) can infer which speaker is attended by analyzing a listener's electroencephalography (EEG) activities. However, previous AAD approaches perform poorly on short signal segments, more advanced decoding strategies are needed to realize robust real-time AAD. In this study, we propose a novel approach, i.e., cross-modal attention-based AAD (CMAA), to exploit the discriminative features and the correlation between audio and EEG signals. With this mechanism, we hope to dynamically adapt the interactions and fuse cross-modal information by directly attending to audio and EEG features, thereby detecting the auditory attention activities manifested in brain signals. We also validate the CMAA model through data visualization and comprehensive experiments on a publicly available database. Experiments show that the CMAA achieves accuracy values of 82.8, 86.4, and 87.6% for 1-, 2-, and 5-s decision windows under anechoic conditions, respectively; for a 2-s decision window, it achieves an average of 84.1% under real-world reverberant conditions. The proposed CMAA network not only achieves better performance than the conventional linear model, but also outperforms the state-of-the-art non-linear approaches. These results and data visualization suggest that the CMAA model can dynamically adapt the interactions and fuse cross-modal information by directly attending to audio and EEG features in order to improve the AAD performance.
Chinese and Western Musical Training Impacts the Circuit in Auditory and Reward Systems
Authors: Guo Sijia , Peng Ke , Ding Rui , Zhou Junchen , Liu Yan , He Yao , Liu Yuhong , Li Ke , Liu Pei , Luo Cheng , Lu Jing , Yao Dezhong
Published: July 2021

Previous studies have provided evidence about the brain plasticity effects of musical training, however, the issue of how expertise in music styles induced by Chinese or Western musical training affects neuroplasticity and reward responses has been less considered, especially for subjects of Chinese origin. In this work, 16 musicians who trained in the Western music style (Western-trained musicians) and 18 musicians who trained in the Chinese music style (Chinese-trained musicians) were recruited as the musician group for the experiment, while 15 non-musicians were recruited as the control group. Using a paradigm that consisted of listening to Chinese and Western music and measurements using functional magnetic resonance imaging (fMRI) technology, we found that Chinese-trained musicians activated the bilateral superior temporal gyrus (STG) when listening to music, while Western-trained musicians activated the left STG. In addition, under the condition of listening to music with Chinese style, Chinese-trained musicians have a stronger functional connection in the circuit of the auditory and reward system than Western-trained musicians. The finding is opposite under the condition of listening to music with Western style. Interestingly, it seems that the circuit of Chinese-trained musicians is partial to the right STG, while Western-trained musicians show the opposite, i.e., a tendency toward the left STG. The influence of different music styles on experienced musicians is reflected by the functional activities and connections between the auditory system and the reward system. This outcome indicates that training in Chinese music style or Western music style affects the strategies of musicians when listening to music. Musical characteristics such as rhythm, melody and cultural attributes play an important role in this process. These findings, which provide evidence for functional neuroplasticity based on musical training, can enrich our insights into the musical brain.
Presence of Vessel Wall Hyperintensity in Unruptured Arteriovenous Malformations on Vessel Wall Magnetic Resonance Imaging: Pilot Study of AVM Vessel Wall “Enhancement”
Authors: Eisenmenger Laura B. , Junn Jacqueline C. , Cooke Daniel , Hetts Steven , Zhu Chengcheng , Johnson Kevin M. , Manunga Jesse M. , Saloner David , Hess Christopher , Kim Helen
Published: July 2021

Purpose: High-resolution vessel wall magnetic resonance imaging (VW-MRI) could provide a way to identify high risk arteriovenous malformation (AVM) features. We present the first pilot study of clinically unruptured AVMs evaluated by high-resolution VW-MRI.

Methods: A retrospective review of clinically unruptured AVMs with VW-MRI between January 1, 2016 and December 31, 2018 was performed documenting the presence or absence of vessel wall “hyperintensity,” or enhancement, within the nidus as well as perivascular enhancement and evidence of old hemorrhage (EOOH). The extent of nidal vessel wall “hyperintensity” was approximated into five groups: 0, 1–25, 26–50, 51–75, and 76–100%.

Results: Of the nine cases, eight demonstrated at least some degree of vessel wall nidus “hyperintensity.” Of those eight cases, four demonstrated greater than 50% of the nidus with hyperintensity at the vessel wall, and three cases had perivascular enhancement adjacent to nidal vessels. Although none of the subjects had prior clinical hemorrhage/AVM rupture, of the six patients with available susceptibility weighted imaging to assess for remote hemorrhage, only two had subtle siderosis to suggest prior sub-clinical bleeds.

Conclusion: Vessel wall “enhancement” occurs in AVMs with no prior clinical rupture. Additional studies are needed to further investigate the implication of these findings.
Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients
Authors: García-Trejo José J. , Ortega Raquel , Zarco-Zavala Mariel
Published: July 2021

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.
The Role of Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis
Authors: Wang Haowei , Zhou Fei , Qiao Meng , Li Xuefei , Zhao Chao , Cheng Lei , Chen Xiaoxia , Zhou Caicun
Published: July 2021

Background

The use of circulating tumor DNA (ctDNA) to reflect clinical benefits of advanced non-small cell lung cancer (NSCLC) patients during immune checkpoint inhibitor (ICI) therapy remains controversial. This study aimed to determine the association of pre-treatment and early dynamic changes of ctDNA with clinical outcomes in advanced NSCLC patients treated with ICIs.

Methods

Electronic databases (PubMed, Embase, Web of Science, and Cochrane) were systematically searched to include relevant studies published in English up to November 2020. The primary outcomes were overall survival (OS) and progression-free survival (PFS) and the secondary outcome was objective response rate (ORR) with RECIST criteria.

Results

A total of 1017 patients from 10 studies were identified. The baseline ctDNA levels (detected versus not detected) showed no significant association with clinical outcomes regarding OS (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.93-1.51), PFS (HR, 0.98; 95% CI, 0.80-1.21), and ORR (odds ratio [OR], 0.89; 95% CI, 0.54-1.46). Interestingly, when taken early longitudinal assessment of ctDNA into consideration, the early reduction of the concentration of ctDNA was associated with significant improvements of OS (HR, 0.19; 95% CI, 0.10-0.35), PFS (HR, 0.30; 95% CI, 0.22-0.41) and ORR (OR, 0.07; 95% CI, 0.03-0.18). Further subgroup analyses revealed that the reduction magnitude did not significantly impact the association between ctDNA and clinical outcomes, suggesting that both patients with decreased ctDNA or a ≥50% reduction of ctDNA was associated with improved OS, PFS and ORR.

Conclusion

Early reduction of ctDNA was associated with improved OS, PFS and ORR in advanced NSCLC patients treated with ICIs.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO, CRD42021226255.
Abiraterone In Vitro Is Superior to Enzalutamide in Response to Ionizing Radiation
Authors: Wright Timothy C. , Dunne Victoria L. , Alshehri Ali H. D. , Redmond Kelly M. , Cole Aidan J. , Prise Kevin M.
Published: July 2021

Abiraterone acetate and Enzalutamide are novel anti-androgens that are key treatments to improve both progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. In this study, we aimed to determine whether combinations of AR inhibitors with radiation are additive or synergistic, and investigated the underlying mechanisms governing this. This study also aimed to compare and investigate a biological rationale for the selection of Abiraterone versus Enzalutamide in combination with radiotherapy as currently selection is based on consideration of side effect profiles and clinical experience. We report that AR suppression with Enzalutamide produces a synergistic effect only in AR-sensitive prostate models. In contrast, Abiraterone displays synergistic effects in combination with radiation regardless of AR status, alluding to potential alternative mechanisms of action. The underlying mechanisms governing this AR-based synergy are based on the reduction of key AR linked DNA repair pathways such as NHEJ and HR, with changes in HR potentially the result of changes in cell cycle distribution, with these reductions ultimately resulting in increased cell death. These changes were also shown to be conserved in combination with radiation, with AR suppression 24 hours before radiation leading to the most significant differences. Comparison between Abiraterone and Enzalutamide highlighted Abiraterone from a mechanistic standpoint as being superior to Abiraterone for all endpoints measured. Therefore, this provides a potential rationale for the selection of Abiraterone over Enzalutamide.
Cardiovascular Toxicity Induced by Chronic Vincristine Treatment
Authors: Herradón Esperanza , González Cristina , González Antonio , Uranga Jose Antonio , López-Miranda Visitación
Published: July 2021

Vincristine is an effective anticancer agent for treating leukemias, lymphomas, and other solid tumors. Vincristine’s better-known severe side effects include bone marrow depression, hyponatremia, peripheral neuropathy, and gastrointestinal distress. In recent years, cardiovascular damage also has been described during vincristine treatments. However, the vascular toxicity induced by vincristine is little studied. The aim of the present is to evaluate whether these alterations remain after the suspension of chemotherapy treatment (sequelae) and the possible mechanisms involved in this vascular damage. Adult male Wistar rats were used. The animals were divided into four treatment groups: two groups of saline (0.9% NaCl; saline, sequelae saline) and two groups of vincristine (100 μg/kg; vincristine, sequelae vincristine). Saline or vincristine was administered intraperitoneally in two cycles of 5 days each, leaving a rest period between cycles of 2 days. The final cumulative vincristine dose administered was 1 mg/kg. Sequelae groups correspond to 2 weeks after stopping treatment with the antitumor agent. At the end of the different experimental protocols, cardiac and vascular functions were analyzed. Alterations in the expression of different proteins in the cardiovascular tissues were also investigated. Chronic treatment with vincristine did not produce significant changes in basal cardiac function but provoked significant endothelial dysfunction in the aorta and a significant decrease in the mesenteric contractile function. These cardiovascular functional alterations disappeared 2 weeks after the suspension of chemotherapy treatment. Vincristine treatment caused a significant increase in the expression of tumor necrosis factor-alpha (TNFα), endothelial and inducible nitric oxide synthases (eNOS and iNOS), and connexin 43 in cardiac tissue. In the aorta, the chronic treatment with vincristine caused a slight non-significant increase in TNFα expression, a significant increase in eNOS and iNOS, and a significant decrease in connexin 43. After 2 weeks of vincristine treatment (sequelae group), the expression of TNFα increased and eNOS and iNOS expressions disappeared, but a significant decrease in the expression of connexin 43 was still observed in the aorta. In mesenteric arteries, similar data to those found in the aorta were observed. In conclusion, chronic treatment with vincristine causes functional alterations in the vascular function of both conductance and resistance vessels and changes in the expressions of TNFα, eNOS, iNOS, and connexin 43 in cardiovascular tissues, implicating direct toxicity during its treatment. These functional alterations are transitory and disappear after the suspension of its treatment.
Brimonidine is Neuroprotective in Animal Paradigm of Retinal Ganglion Cell Damage
Authors: Conti Federica , Romano Giovanni Luca , Eandi Chiara Maria , Toro Mario Damiano , Rejdak Robert , Di Benedetto Giulia , Lazzara Francesca , Bernardini Renato , Drago Filippo , Cantarella Giuseppina , Bucolo Claudio
Published: July 2021

To investigate the neuroprotective effect of brimonidine after retinal ischemia damage on mouse eye. Glaucoma is an optic neuropathy characterized by retinal ganglion cells (RGCs) death, irreversible peripheral and central visual field loss, and high intraocular pressure. Ischemia reperfusion (I/R) injury model was used in C57BL/6J mice to mimic conditions of glaucomatous neurodegeneration. Mouse eyes were treated topically with brimonidine and pattern electroretinogram were used to assess the retinal ganglion cells (RGCs) function. A wide range of inflammatory markers, as well as anti-inflammatory and neurotrophic molecules, were investigated to figure out the potential protective effects of brimonidine in mouse retina. In particular, brain-derived neurotrophic factor (BDNF), IL-6, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor DR-5, TNF-α, GFAP, Iba-1, NOS, IL-1β and IL-10 were assessed in mouse retina that underwent to I/R insult with or without brimonidine treatment. Brimonidine provided remarkable RGCs protection in our paradigm. PERG amplitude values were significantly (p < 0.05) higher in brimonidine-treated eyes in comparison to I/R retinas. Retinal BDNF mRNA levels in the I/R group dropped significantly (p < 0.05) compared to the control group (normal mice); brimonidine treatment counteracted the downregulation of retinal BDNF mRNA in I/R eyes. Retinal inflammatory markers increased significantly (p < 0.05) in the I/R group and brimonidine treatment was able to revert that. The anti-inflammatory IL-10 decreased significantly (p < 0.05) after retinal I/R insult and increased significantly (p < 0.05) in the group treated with brimonidine. In conclusion, brimonidine was effective in preventing loss of function of RGCs and in regulating inflammatory biomarkers elicited by retinal I/R injury.
Exploring Phytochemicals for Combating Antibiotic Resistance in Microbial Pathogens
Authors: Khare Tushar , Anand Uttpal , Dey Abhijit , Assaraf Yehuda G. , Chen Zhe-Sheng , Liu Zhijun , Kumar Vinay
Published: July 2021

Antibiotic resistance or microbial drug resistance is emerging as a serious threat to human healthcare globally, and the multidrug-resistant (MDR) strains are imposing major hurdles to the progression of drug discovery programs. Newer antibiotic-resistance mechanisms in microbes contribute to the inefficacy of the existing drugs along with the prolonged illness and escalating expenditures. The injudicious usage of the conventional and commonly available antibiotics in human health, hygiene, veterinary and agricultural practices is proving to be a major driver for evolution, persistence and spread of antibiotic-resistance at a frightening rate. The drying pipeline of new and potent antibiotics is adding to the severity. Therefore, novel and effective new drugs and innovative therapies to treat MDR infections are urgently needed. Apart from the different natural and synthetic drugs being tested, plant secondary metabolites or phytochemicals are proving efficient in combating the drug-resistant strains. Various phytochemicals from classes including alkaloids, phenols, coumarins, terpenes have been successfully demonstrated their inhibitory potential against the drug-resistant pathogens. Several phytochemicals have proved effective against the molecular determinants responsible for attaining the drug resistance in pathogens like membrane proteins, biofilms, efflux pumps and bacterial cell communications. However, translational success rate needs to be improved, but the trends are encouraging. This review highlights current knowledge and developments associated challenges and future prospects for the successful application of phytochemicals in combating antibiotic resistance and the resistant microbial pathogens.
The Role of Macrophage Migration Inhibitory Factor in Adipose-Derived Stem Cells Under Hypoxia
Authors: Hofmann Elena , Soppert Josefin , Ruhl Tim , Gousopoulos Epameinondas , Gerra Simona , Storti Gabriele , Tian Yuan , Brandhofer Markus , Schweizer Riccardo , Song Seung-Yong , Lindenblatt Nicole , Pallua Norbert , Bernhagen Jürgen , Kim Bong-Sung
Published: July 2021

Background: Adipose-derived stem cells (ASCs) are multipotent mesenchymal stem cells characterized by their strong regenerative potential and low oxygen consumption. Macrophage migration inhibitory factor (MIF) is a multifunctional chemokine-like cytokine that is involved in tissue hypoxia. MIF is not only a major immunomodulator but also is highly expressed in adipose tissue such as subcutaneous adipose tissue of chronic non-healing wounds. In the present study, we investigated the effect of hypoxia on MIF in ASCs isolated from healthy versus inflamed adipose tissue.

Methods: Human ASCs were harvested from 17 patients (11 healthy adipose tissue samples, six specimens from chronic non-healing wounds). ASCs were treated in a hypoxia chamber at <1% oxygen. ASC viability, MIF secretion as well as expression levels of MIF, its receptor CD74, hypoxia-inducible transcription factor-1α (HIF-1α) and activation of the AKT and ERK signaling pathways were analyzed. The effect of recombinant MIF on the viability of ASCs was determined. Finally, the effect of MIF on the viability and production capacity of ASCs to produce the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β was determined upon treatment with recombinant MIF and/or a blocking MIF antibody.

Results: Hypoxic treatment inhibited proliferation of ASCs derived from healthy or chronic non-healing wounds. ASCs from healthy adipose tissue samples were characterized by a low degree of MIF secretion during hypoxic challenge. In contrast, in ASCs from adipose tissue samples of chronic non-healing wounds, secretion and expression of MIF and CD74 expression were significantly elevated under hypoxia. This was accompanied by enhanced ERK signaling, while AKT signaling was not altered. Recombinant MIF did stimulate HIF-1α expression under hypoxia as well as AKT and ERK phosphorylation, while no effect on ASC viability was observed. Recombinant MIF significantly reduced the secretion of IL-1β under hypoxia and normoxia, and neutralizing MIF-antibodies diminished TNF-α and IL-1β release in hypoxic ASCs.

Conclusions: Collectively, MIF did not affect the viability of ASCs from neither healthy donor site nor chronic wounds. Our results, however, suggest that MIF has an impact on the wound environment by modulating inflammatory factors such as IL-1β.
Impaired Cerebrovascular Reactivity in Huntington’s Disease
Authors: Chan Suk Tak , Mercaldo Nathaniel D. , Kwong Kenneth K. , Hersch Steven M. , Rosas Herminia D.
Published: July 2021

There is increasing evidence that impairments of cerebrovascular function and/or abnormalities of the cerebral vasculature might contribute to early neuronal cell loss in Huntington’s disease (HD). Studies in both healthy individuals as well as in patients with other neurodegenerative disorders have used an exogenous carbon dioxide (CO2) challenge in conjunction with functional magnetic resonance imaging (fMRI) to assess regional cerebrovascular reactivity (CVR). In this study, we explored potential impairments of CVR in HD. Twelve gene expanded HD individuals, including both pre-symptomatic and early symptomatic HD and eleven healthy controls were administered a gas mixture targeting a 4–8 mmHg increase in CO2 relative to the end-tidal partial pressure of CO2 (PETCO2) at rest. A Hilbert Transform analysis was used to compute the cross-correlation between the time series of regional BOLD signal changes (ΔBOLD) and increased PETCO2, and to estimate the response delay of ΔBOLD relative to PETCO2. After correcting for age, we found that the cross-correlation between the time series for regional ΔBOLD and for PETCO2 was weaker in HD subjects than in controls in several subcortical white matter regions, including the corpus callosum, subcortical white matter adjacent to rostral and caudal anterior cingulate, rostral and caudal middle frontal, insular, middle temporal, and posterior cingulate areas. In addition, greater volume of dilated perivascular space (PVS) was observed to overlap, primarily along the periphery, with the areas that showed greater ΔBOLD response delay. Our preliminary findings support that alterations in cerebrovascular function occur in HD and may be an important, not as yet considered, contributor to early neuropathology in HD.
Dynamic Aging: Channeled Through Microenvironment
Authors: Tan Qing , Liang Na , Zhang Xiaoqian , Li Jun
Published: July 2021

Aging process is a complicated process that involves deteriorated performance at multiple levels from cellular dysfunction to organ degeneration. For many years research has been focused on how aging changes things within cell. However, new findings suggest that microenvironments, circulating factors or inter-tissue communications could also play important roles in the dynamic progression of aging. These out-of-cell mechanisms pass on the signals from the damaged aging cells to other healthy cells or tissues to promote systematic aging phenotypes. This review discusses the mechanisms of how senescence and their secretome, NAD+ metabolism or circulating factors change microenvironments to regulate systematic aging, as well as the potential therapeutic strategies based on these findings for anti-aging interventions.