bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer
Authors: Chang Yuanyuan , Wang Yin , Li Boyi , Lu Xingzhong , Wang Ruiru , Li Hui , Yan Bo , Gu Aiqin , Wang Weimin , Huang Aimi , Wu Shuangxiu , Li Rong
Published: September 2021

Circulating tumor cells (CTCs) have important applications in clinical practice on early tumor diagnosis, prognostic prediction, and treatment evaluation. Platinum-based chemotherapy is a fundamental treatment for non-small cell lung cancer (NSCLC) patients who are not suitable for targeted drug therapies. However, most patients progressed after a period of treatment. Therefore, revealing the genetic information contributing to drug resistance and tumor metastasis in CTCs is valuable for treatment adjustment. In this study, we enrolled nine NSCLC patients with platinum-based chemotherapy resistance. For each patient, 10 CTCs were isolated when progression occurred to perform single cell–level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed formalin-fixed and paraffin-embedded samples and progressive biopsy specimens were also selected to perform WES. Comparisons of distinct mutation profiles between primary and progressive specimens as well as CTCs reflected different evolutionary mechanisms between CTC and lymph node metastasis, embodied in a higher proportion of mutations in CTCs shared with paired progressive lung tumor and hydrothorax specimens (4.4–33.3%) than with progressive lymphatic node samples (0.6–11.8%). Functional annotation showed that CTCs not only harbored cancer-driver gene mutations, including frequent mutations of EGFR and TP53 shared with primary and/or progressive tumors, but also particularly harbored cell cycle–regulated or stem cell–related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc., most of which derived from primary tumor samples and played crucial roles in chemo-drug resistance and metastasis for NSCLCs. Thus, detection of genetic information in CTCs is a feasible strategy for studying drug resistance and discovering new drug targets when progressive tumor specimens were unavailable.
Gene Targets Network Analysis for the Revealing and Guidance of Molecular Driving Mechanism of Lung Cancer
Authors: Huang Risheng , Xiang Xiao , Zhang Kangliang , Zheng Yuanliang , Wang Chichao , Hu Guanqiong
Published: September 2021

The objective was to explore the function of gene differential expressions between lung cancer tissues and the interaction between the relevant encoded proteins, thereby analyzing the important genes closely related to lung cancer. A total of 120 samples from the GEO database (including two groups, i.e., 60 lung cancer in situ specimens and 60 normal specimens) were taken as the research objects, which were submitted to the analysis of signaling pathway, biological function enrichment, and protein interactions to reveal the molecular driving mechanism of lung cancer. Results: A total of 875 differentially expressed genes were obtained, including 291 up-regulated genes and 584 down-regulated genes. The up-regulated genes were mainly involved in biological processes such as protein metabolism, protein hydrolysis, mitosis, and cell division. Down-regulated genes were mainly involved in neutrophil chemotaxis, inflammatory response, immune response, and angiogenesis. The protein expression of high expression genes and low expression genes in patients were higher than those in the control group. The protein corresponding to the high expression gene was highly expressed in the patient group. Meanwhile, the proteins corresponding to the low expression genes were also expressed in the patient group, which showed that although the proteins corresponding to the low expression genes were low in the patients, they were still the target genes related to lung cancer. In conclusion, the molecular driving mechanism in lung cancer was mainly related to protein metabolism, proteolysis, mitosis, and cell division. It was found that TOP2A, CCNB1, CCNA2, CDK1, and TTK might be the critical target genes of lung cancer.
Landscape of T Cells Transcriptional and Metabolic Modules During HIV Infection Based on Weighted Gene Co-expression Network Analysis
Authors: Xu Jianting , Pan Jiahui , Liu Xin , Zhang Nan , Zhang Xinyue , Wang Guoqing , Zhang Wenyan
Published: September 2021

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS). HIV infection affects the functions and metabolism of T cells, which may determine the fate of patients; however, the specific pathways activated in different T-cell subtypes (CD4+ and CD8+ T cells) at different stages of infection remain unclear. We obtained transcriptome data of five individuals each with early HIV infection, chronic progressive HIV infection, and no HIV infection. Weighted gene co-expression network analysis was used to evaluate changes in gene expression to determine the antiviral response. An advanced metabolic algorithm was then applied to compare the alterations in metabolic pathways in the two T-cell subtypes at different infection stages. We identified 23 and 20 co-expressed gene modules in CD4+ T and CD8+ T cells, respectively. CD4+ T cells from individuals in the early HIV infection stage were enriched in genes involved in metabolic and infection-related pathways, whereas CD8+ T cells were enriched in genes involved in cell cycle and DNA replication. Three key modules were identified in the network common to the two cell types: NLRP1 modules, RIPK1 modules, and RIPK2 modules. The specific role of NLRP1 in the regulation of HIV infection in the human body remains to be determined. Metabolic functional analysis of the two cells showed that the significantly altered metabolic pathways after HIV infection were valine, leucine, and isoleucine degradation; beta-alanine metabolism; and PPAR signaling pathways. In summary, we found the core gene expression modules and different pathways activated in CD4+ and CD8+ T cells, along with changes in their metabolic pathways during HIV infection progression. These findings can provide an overall resource for establishing biomarkers to facilitate early diagnosis and potential guidance for new targeted therapeutic strategies.
TNF-Alpha Pathway Alternation Predicts Survival of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer
Authors: Lin Anqi , Zhang Hongman , Meng Hui , Deng Ze , Gu Tianqi , Luo Peng , Zhang Jian
Published: September 2021

Translational research on immune checkpoint inhibitors (ICIs) has been underway. However, in the unselected population, only a few patients benefit from ICIs. Therefore, screening predictive markers of ICI efficacy has become the current focus of attention. We collected mutation and clinical data from an ICI-treated non-small cell lung cancer (NSCLC) cohort. Then, a univariate Cox regression model was used to analyze the relationship between tumor necrosis factor α signaling mutated (TNFα-MT) and the prognosis of immunotherapy for NSCLC. We retrospectively collected 36 NSCLC patients (local-cohort) from the Zhujiang Hospital of Southern Medical University and performed whole-exome sequencing (WES). The expression and mutation data of The Cancer Genome Atlas (TCGA)-NSCLC cohort were used to explore the association between TNFα-MT and the immune microenvironment. A local cohort was used to validate the association between TNFα-MT and immunogenicity. TNFα-MT was associated with significantly prolonged overall survival (OS) in NSCLC patients after receiving immunotherapy. Additionally, TNFα-MT is related to high immunogenicity (tumor mutational burden, neoantigen load, and DNA damage response signaling mutations) and enrichment of infiltrating immune cells. These results suggest that TNFα-MT may serve as a potential clinical biomarker for NSCLC patients receiving ICIs.
Immunomodulatory Effect of MSCs and MSCs-Derived Extracellular Vesicles in Systemic Lupus Erythematosus
Authors: Yang Chunjuan , Sun Jianmei , Tian Yipeng , Li Haibo , Zhang Lili , Yang Jinghan , Wang Jinghua , Zhang Jiaojiao , Yan Shushan , Xu Donghua
Published: September 2021

Systemic lupus erythematosus (SLE) is a common autoimmune connective tissue disease with unclear etiology and pathogenesis. Mesenchymal stem cell (MSC) and MSC derived extracellular vesicles (EVs) play important roles in regulating innate and adaptive immunity, which are involved in many physiological and pathological processes and contribute to the immune homeostasis in SLE. The effects of MSCs and EVs on SLE have been drawing more and more attention during the past few years. This article reviews the immunomodulatory effects and underlying mechanisms of MSC/MSC-EVs in SLE, which provides novel insight into understanding SLE pathogenesis and guiding the biological therapy.
NEK7-Mediated Activation of NLRP3 Inflammasome Is Coordinated by Potassium Efflux/Syk/JNK Signaling During Staphylococcus aureus Infection
Authors: Liu Ruiqing , Liu Yashan , Liu Chang , Gao Aijiao , Wang Lin , Tang Huixin , Wu Qiang , Wang Xia , Tian Derun , Qi Zhi , Shen Yanna
Published: September 2021

Staphylococcus aureus (S. aureus) is a foodborne pathogen that causes severe diseases, such as endocarditis, sepsis, and bacteremia. As an important component of innate immune system, the NLR family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in defense against pathogen infection. However, the cellular mechanism of NLRP3 inflammasome activation during S. aureus infection remains unknown. In the present study, we found that spleen tyrosine kinase (Syk) and c-Jun N-terminal kinase (JNK) were rapidly phosphorylated during S. aureus infection. Moreover, a Syk/JNK inhibitor and Syk/JNK siRNA not only reduced NLRP3 inflammasome-associated molecule expression at the protein and mRNA levels, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation, and interleukin-1β (IL-1β), and IL-18 release but also rescued the decreased NIMA-related kinase 7 (NEK7) expression level following suppression of the NEK7-NLRP3 interaction in macrophages. Interestingly, Syk/JNK phosphorylation levels and NLRP3 inflammasome-associated molecule expression were decreased by blockade of K+ efflux. Furthermore, activation of the NLRP3 inflammasome and a lower NEK7 protein level were found in vivo upon S. aureus infection. Taken together, our data indicated that S. aureus infection induces a K+ efflux/Syk/JNK/NEK7-NLRP3 signaling pathway and the subsequent activation of the NLRP3 inflammasome for the release of proinflammatory cytokines. This study expands our understanding of the basic molecular mechanism regulating inflammation and provides potential value for anti-infective drug development against S. aureus infection.
Elevated Temperatures Shorten the Spawning Period of Silver Carp (Hypophthalmichthys molitrix) in a Large Subtropical River in China
Authors: Xia Yuguo , Li Xinhui , Yang Jiping , Zhu Shuli , Wu Zhi , Li Jie , Li Yuefei
Published: September 2021

Global warming is influencing the life history traits of fishes globally. However, the impacts of elevated temperature on fish reproduction are diverse in different regions. Previous studies have revealed that the spawning timing of silver carp (Hypophthalmichthys molitrix) in the Pearl River, in China, has changed over the past decade. However, few studies have explored the potential reasons, which are critical for determining fishing-moratorium periods and developing sustainable fisheries. The current study used discharge suitability index (DSI), temperature suitability index (TSI), correlation and time-series analyses to determine (i) the optimal discharge and temperature for silver carp spawning; (ii) relationships among the thermal regime, hydrological parameters, and spawning timing based on an 11-year time-series dataset. Our results indicated that the most suitable discharge and temperature for silver carp spawning were 13,000–15,000 m3/s and 25–26°C, respectively. The start date of spawning fluctuated with a slight tendency to delay, while the spawning peak and end date obviously occurred earlier during the study period. Correlation analyses suggested that the increasing average temperature between January and March likely caused the initial spawning delay. Moreover, elevated temperatures in August and September probably promoted the anticipated end of silver carp spawning. However, increases in discharge did not significantly correlate with the start of spawning but were significantly and positively correlated with the spawning peak. These results indicated that elevated temperatures shorten the spawning period of silver carp in the Pearl River. Moreover, the initial spawning of silver carp seems to be triggered by temperature rather than changes in discharge; flow pulses can probably create more suitable spawning niches forH.molitrix. This study enhances our understanding of the effect of warming on fish reproduction in subtropical regions.
Decreasing Biological Production and Carbon Export Due to the Barrier Layer: A Case Study in the Bay of Bengal
Authors: Zhang Huangchen , Zhou Linbin , Li Kaizhi , Ke Zhixin , Tan Yehui
Published: September 2021

A freshwater-induced barrier layer (BL) is a common physical phenomenon both in coastal waters and the open ocean. To examine the effects of BL on the biological production and the associated carbon export, a physical-biogeochemical survey was conducted in the Bay of Bengal. Severe depletions of surface phosphorus and the deepening of the nutricline were observed at the BL-affected stations due to the vertical mixing prohibition. The lowered surface chlorophyll a (Chl a) and squeezed deep Chl a maximum (DCM) layer also resulted in the ~18% lowered vertically integrated Chl a at the said stations. The composition of the net-sampled zooplankton was altered, and the abundance decreased by half at the BL-affected station (29.68 ind. m−3) compared with the unaffected station (55.52 ind. m−3). Such reductions in major zooplankton groups were confirmed by a video plankton recorder (VPR). The VPR observation indicated that there was a lower (by one-half) abundance of detritus at the BL-affected station, while the much lower carbon export flux rates were estimated to be at the BL-affected station (0.31 mg C m−2 d−1) rather than the unaffected station (0.77 mg C m−2 d−1). An idealized one-dimensional nutrient-phytoplankton-detritus model identified that the existence of BL can lead to decreased surface nutrients and phytoplankton concentrations, squeezed DCM layers, and lower detritus abundances. Finally, this study indicated that BL layers inhibit biological production and reduce carbon export, thus playing an important role in the ocean biogeochemical cycles.
Nutrient Pollution and Its Dynamic Source-Sink Pattern in the Pearl River Estuary (South China)
Authors: Tao Wei , Niu Lixia , Dong Yanhong , Fu Tao , Lou Quansheng
Published: September 2021

Nutrient enrichment and its quantitative cause-effect chains of the biogeochemical processes have scarcely been documented in the Pearl River Estuary (South China). Field investigations of nutrient samples taken between 1996 and 2018 showed significant differences in nitrogen and phosphorus with times and sites. The concentrations of DIN and DIP gradually increased over the past two decades, with good fitted linear curves (R2 = 0.31 for DIN, R2 = 0.92 for DIP); while the temporal variation in DSi was non-significant. Higher levels of nitrogen and silicate mainly appeared in the upper estuary because of the riverine influence. The phosphorus pollution was accumulated in the northeast (e.g., Shenzhen bay). The aquatic environment was highly sensitive to nutrient pollution and eutrophication risk, which accordingly corresponded to high phytoplankton production and biodiversity. Phosphorus was the limiting factor of phytoplankton growth in this estuary, and more frequently caused the eutrophication risks and blooms. The nutrient pollution was largely influenced by riverine inputs, quantified by PCA-generation, and the contributions of coastal emission and atmospheric deposition were followed. The two-end member mixing model differentiated the physical alterations from the biological activity and identified the dynamic source-sink patterns of nutrient species. Nitrogen and silicate had relatively conservative behaviors in the estuary and phosphate showed an active pattern.
Case Report: Detection of Double ROS1 Translocations, SDC4-ROS1 and ROS1-GK, in a Lung Adenocarcinoma Patient and Response to Crizotinib
Authors: Xu Long , Chen Xiaoxia , Huo Hong , Liu Yongye , Yang Xiaodan , Gu Dejian , Yuan Mingming , Zhang Min , Chen Rongrong , Wang Jiayin , Zheng Zhendong
Published: September 2021

ROS1 rearrangement, identified in ~2% of non-small cell lung cancer (NSCLC), has defined a distinctive molecular subtype. Patients with ROS1 fusion have been shown to be highly sensitive to treatment with crizotinib. However, the efficacy of crizotinib in NSCLC patients with double ROS1 fusions remains to be elucidated. Here, we report a 40-year-old male diagnosed with stage IIIA lung adenocarcinoma. Two ROS1 fusions [SDC4-ROS1 (EX2:EX32) and ROS1-GK (EX31:EX13)] were detected simultaneously in tumor tissue of this patient by next-generation sequencing. Crizotinib was administered, and the patient showed a partial response in lung lesions. Nevertheless, a brain lesion was found at 8 months after treatment. The slightly short duration of response may be related to the presence of ROS1-GK rearrangement. This case proved that patients with SDC4-ROS1 and ROS1-GK fusions may be sensitive to crizotinib, but short progression-free survival of this case showed that the presence of ROS1-GK rearrangement may affect the efficacy of crizotinib. A large-scale investigation on the efficacy of ROS1 inhibitors in patients with complex ROS1 fusions should be conducted in the future.
Delayed Initiation of ECMO Is Associated With Poor Outcomes in Patients With Severe COVID-19: A Multicenter Retrospective Cohort Study
Authors: Li Xuyan , Hu Ming , Zheng Ruiqiang , Wang Yishan , Kang Hanyujie , Jiang Li , Zhong Ming , Sang Ling , Zheng Xia , Pan Chun , Zhang Wei , Qiu Haibo , Du Bin , Tong Zhaohui
Published: September 2021

Background: Extracorporeal membrane oxygenation (ECMO) is a rapidly evolving therapy for acute lung and/or heart failure. However, the information on the application of ECMO in severe coronavirus disease 2019 (COVID-19) is limited, such as the initiation time. Especially in the period and regions of ECMO instrument shortage, not all the listed patients could be treated with ECMO in time. This study aimed to investigate and clarify the timing of ECMO initiation related to the outcomes of severe patients with COVID-19. The results show that ECMO should be initiated within 24 h after the criteria are met.

Methods: In this retrospective, multicenter cohort study, we enrolled all ECMO patients with confirmed COVID-19 at the three hospitals between December 29, 2019 and April 5, 2020. Data on the demographics, clinical presentation, laboratory profile, clinical course, treatments, complications, and outcomes were collected. The primary outcomes were successful ECMO weaning rate and 60-day mortality after ECMO. Successful weaning from ECMO means that the condition of patients improved with adequate oxygenation and gas exchange, as shown by the vital signs, blood gases, and chest X-ray, and the patient was weaned from ECMO for at least 48 h.

Results: A total of 31 patients were included in the analysis. The 60-day mortality rate after ECMO was 71%, and the ECMO weaning rate was 26%. Patients were divided into a delayed ECMO group [3 (interquartile range (IQR), 2–5) days] and an early ECMO group [0.5 (IQR, 0–1) days] based on the time between meeting the ECMO criteria and ECMO initiation. In this study, 14 and 17 patients were included in the early and delayed treatment groups, respectively. Early initiation of ECMO was associated with decreased 60-day mortality after ECMO (50 vs. 88%, P = 0.044) and an increased ECMO weaning rate (50 vs. 6%, P = 0.011).

Conclusions: In ECMO-supported patients with COVID-19, delayed initiation of ECMO is a risk factor associated with a poorer outcome.

Trial Registration: Clinical trial submission: March 19, 2020. Registry name: A medical records-based study for the clinical application of extracorporeal membrane oxygenation in the treatment of severe respiratory failure patients with novel coronavirus pneumonia (COVID-19). Chinese Clinical Trial Registry: https://www.chictr.org.cn/showproj.aspx?proj=51267,identifier:~ChiCTR2000030947.
Qing-Re-Xiao-Zheng Formula Modulates Gut Microbiota and Inhibits Inflammation in Mice With Diabetic Kidney Disease
Authors: Gao Yabin , Yang Ruibing , Guo Lan , Wang Yaoxian , Liu Wei Jing , Ai Sinan , Woon Ting Hui , Wang Zheng , Zhai Yuanyuan , Wang Zhen , Peng Liang
Published: September 2021

Evidence indicates that the metabolic inflammation induced by gut microbiota dysbiosis contributes to diabetic kidney disease. Prebiotic supplementations to prevent gut microbiota dysbiosis, inhibit inflammatory responses, and protect the renal function in DKD. Qing-Re-Xiao-Zheng formula (QRXZF) is a Traditional Chinese Medicine (TCM) formula that has been used for DKD treatment in China. Recently, there are growing studies show that regulation of gut microbiota is a potential therapeutic strategy for DKD as it is able to reduce metabolic inflammation associated with DKD. However, it is unknown whether QRXZF is effective for DKD by regulating of gut microbiota. In this study, we investigated the reno-protective effect of QRXZF by exploring its potential mechanism between gut microbiota and downstream inflammatory pathways mediated by gut-derived lipopolysaccharide (LPS) in the kidney. High-fat diet (HFD) and streptozotocin injection-induced DKD mice model was established to assess the QRXZF effect in vivo. Mice treated with QRXZF for 8 weeks had significantly lower levels of urinary albumin, serum cholesterol and triglycerides. The renal injuries observed through histological analysis were attenuated as well. Also, mice in the QRXZF group had higher levels of Zonula occludens protein-1 (ZO-1) expression, lower levels of serum fluorescein-isothiocyanate (FITC)-dextran and less-damaged colonic mucosa as compared to the DKD group, implying the benefit role for the gut barrier integrity. QRXZF treatment also reversed gut dysbiosis and reduced levels of gut-derived LPS. Notably, the expression of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB), which are important inflammation pathways in DKD, were suppressed in the QRXZF groups. In conclusion, our results indicated that the reno-protective effects of QRXZF was probably associated with modulating gut microbiota and inhibiting inflammatory responses in the kidney.
SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer
Authors: Sobah Mohamed Luban , Liongue Clifford , Ward Alister C.
Published: September 2021

Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
Genotypic and Phenotypic Characterization of Antimicrobial Resistance Profiles in Non-typhoidal Salmonella enterica Strains Isolated From Cambodian Informal Markets
Authors: Schwan Carla L. , Lomonaco Sara , Bastos Leonardo M. , Cook Peter W. , Maher Joshua , Trinetta Valentina , Bhullar Manreet , Phebus Randall K. , Gragg Sara , Kastner Justin , Vipham Jessie L.
Published: September 2021

Non-typhoidalSalmonella entericais a pathogen of global importance, particularly in low and middle-income countries (LMICs). The presence of antimicrobial resistant (AMR) strains in market environments poses a serious health threat to consumers. In this study we identified and characterized the genotypic and phenotypic AMR profiles of 81 environmentalS. entericastrains isolated from samples from informal markets in Cambodia in 2018–2019. AMR genotypes were retrieved from the NCBI Pathogen Detection website (https://www.ncbi.nlm.nih.gov/pathogens/) and using ResFinder (https://cge.cbs.dtu.dk/services/)Salmonellapathogenicity islands (SPIs) were identified with SPIFinder (https://cge.cbs.dtu.dk/services/). Susceptibility testing was performed by broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI) standard guidelines M100-S22 using the National Antimicrobial Resistance Monitoring System (NARMS) Sensititre Gram Negative plate. A total of 17 unique AMR genes were detected in 53% (43/81) of the isolates, including those encoding tetracycline, beta-lactam, sulfonamide, quinolone, aminoglycoside, phenicol, and trimethoprim resistance. A total of 10 SPIs (SPI-1, 3–5, 8, 9, 12–14, and centisome 63 [C63PI]) were detected in 59 isolates. C63PI, an iron transport system in SPI-1, was observed in 56% of the isolates (n= 46). SPI-1, SPI-4, and SPI-9 were present in 13, 2, and 5% of the isolates, respectively. The most common phenotypic resistances were observed to tetracycline (47%;n= 38), ampicillin (37%;n= 30), streptomycin (20%;n= 16), chloramphenicol (17%;n= 14), and trimethoprim-sulfamethoxazole (16%;n= 13). This study contributes to understanding the AMR genes present inS. entericaisolates from informal markets in Cambodia, as well as support domestic epidemiological investigations of multidrug resistance (MDR) profiles.
Zika Virus Requires the Expression of Claudin-7 for Optimal Replication in Human Endothelial Cells
Authors: Zoladek Jim , Legros Vincent , Jeannin Patricia , Chazal Maxime , Pardigon Nathalie , Ceccaldi Pierre-Emmanuel , Gessain Antoine , Jouvenet Nolwenn , Afonso Philippe V.
Published: September 2021

Zika virus (ZIKV) infection has been associated with a series of neurological pathologies. In patients with ZIKV-induced neurological disorders, the virus is detectable in the central nervous system. Thus, ZIKV is capable of neuroinvasion, presumably through infection of the endothelial cells that constitute the blood-brain barrier (BBB). We demonstrate that susceptibility of BBB endothelial cells to ZIKV infection is modulated by the expression of tight-junction protein claudin-7 (CLDN7). Downregulation of CLDN7 reduced viral RNA yield, viral protein production, and release of infectious viral particles in several endothelial cell types, but not in epithelial cells, indicating that CLDN7 implication in viral infection is cell-type specific. The proviral activity of CLDN7 in endothelial cells is ZIKV-specific since related flaviviruses were not affected by CLDN7 downregulation. Together, our data suggest that CLDN7 facilitates ZIKV infection in endothelial cells at a post-internalization stage and prior to RNA production. Our work contributes to a better understanding of the mechanisms exploited by ZIKV to efficiently infect and replicate in endothelial cells and thus of its ability to cross the BBB.
Angiogenesis Inhibitors in Personalized Combination Regimens for the Treatment of Advanced Refractory Cancers
Authors: Crook Timothy , Patil Darshana , Nagarkar Rajnish , Gaya Andrew , Plowman Nicholas , Limaye Sewanti , Srivastava Navin , Akolkar Dadasaheb , Ranade Anantbhushan , Bhatt Amit , Datta Vineet , Bose Chirantan , Apurwa Sachin , Patil Sanket , Kumar Prashant , Srinivasan Ajay , Datar Rajan
Published: September 2021

Background: Angiogenic factors are commonly activated in solid tumors and present a viable therapeutic target. However, anticancer treatment with angiogenesis inhibitors (AGI) is limited to a few cancers, mostly as monotherapy and not selected based on molecular indications. We aimed to determine whether patient-specific combination regimens with AGI and other anticancer agents when selected based on multi-analyte tumor interrogation (ETA: Encyclopedic Tumor Analysis) can expand the scope of AGIs in advanced refractory solid organ cancers with improved treatment responses.

Methods: We evaluated treatment outcomes in 60 patients with advanced, refractory solid organ cancers who received ETA-guided combination regimens of AGI with other targeted, endocrine or cytotoxic agents. Radiological evaluation of treatment response was followed by determination of Objective Response Rate (ORR), Disease Control Rate (DCR), Progression Free Survival (PFS) and Overall Survival (OS).

Results: Among the 60 patients, Partial Response (PR) was observed in 28 cases (46.7%), Stable Disease (SD) was observed in 29 cases (48.3%) and Disease Progression (PD, within 60 days) was observed in 3 cases (5.0%). The ORR was 46.7% and DCR was 95.0%. At the most recent follow-up the median PFS (mPFS) was 5.0 months and median OS (mOS) was 8.9 months. There were no Grade 4 therapy related adverse events or treatment related deaths.

Conclusion: ETA-guided patient-specific combination regimens with AGI and other anti-neoplastic agents, can yield improved outcomes over AGI monotherapy. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011,808. LIQUID IMPACT ID CTRI/2019/02/017,548.
Abnormalities of Localized Connectivity in Obsessive-Compulsive Disorder: A Voxel-Wise Meta-Analysis
Authors: Qing Xiuli , Gu Li , Li Dehua
Published: September 2021

Background: A large amount of resting-state functional magnetic resonance imaging (rs-fMRI) studies have revealed abnormalities of regional homogeneity (ReHo, an index of localized intraregional connectivity) in the obsessive-compulsive disorder (OCD) in the past few decades, However, the findings of these ReHo studies have remained inconsistent. Hence, we performed a meta-analysis to investigate the concurrence across ReHo studies for clarifying the most consistent localized connectivity underpinning this disorder.

Methods: A systematic review of online databases was conducted for whole-brain rs-fMRI studies comparing ReHo between OCD patients and healthy control subjects (HCS). Anisotropic effect size version of the seed-based d mapping, a voxel-wise meta-analytic approach, was adopted to explore regions of abnormal ReHo alterations in OCD patients relative to HCS. Additionally, meta-regression analyses were conducted to explore the potential effects of clinical features on the reported ReHo abnormalities.

Results: Ten datasets comprising 359 OCD patients and 361 HCS were included. Compared with HCS, patients with OCD showed higher ReHo in the bilateral inferior frontal gyri and orbitofrontal cortex (OFC). Meanwhile, lower ReHo was identified in the supplementary motor area (SMA) and bilateral cerebellum in OCD patients. Meta-regression analysis demonstrated that the ReHo in the OFC was negatively correlated with illness duration in OCD patients.

Conclusions: Our meta-analysis gave a quantitative overview of ReHo findings in OCD and demonstrated that the most consistent localized connectivity abnormalities in individuals with OCD are in the prefrontal cortex. Meanwhile, our findings provided evidence that the hypo-activation of SMA and cerebellum might be associated with the pathophysiology of OCD.
A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows
Authors: Cerritelli Francesco , Frasch Martin G. , Antonelli Marta C. , Viglione Chiara , Vecchi Stefano , Chiera Marco , Manzotti Andrea
Published: September 2021

The autonomic nervous system (ANS) is one of the main biological systems that regulates the body's physiology. Autonomic nervous system regulatory capacity begins before birth as the sympathetic and parasympathetic activity contributes significantly to the fetus' development. In particular, several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal, and postnatal life: from the regulation of inflammation through the anti-inflammatory cholinergic pathway, which may affect the functioning of each organ, to the production of hormones involved in bioenergetic metabolism. In addition, the vagus nerve has been recognized as the primary afferent pathway capable of transmitting information to the brain from every organ of the body. Therefore, this hypothesis paper aims to review the development of ANS during fetal and perinatal life, focusing particularly on the vagus nerve, to identify possible “critical windows” that could impact its maturation. These “critical windows” could help clinicians know when to monitor fetuses to effectively assess the developmental status of both ANS and specifically the vagus nerve. In addition, this paper will focus on which factors—i.e., fetal characteristics and behaviors, maternal lifestyle and pathologies, placental health and dysfunction, labor, incubator conditions, and drug exposure—may have an impact on the development of the vagus during the above-mentioned “critical window” and how. This analysis could help clinicians and stakeholders define precise guidelines for improving the management of fetuses and newborns, particularly to reduce the potential adverse environmental impacts on ANS development that may lead to persistent long-term consequences. Since the development of ANS and the vagus influence have been shown to be reflected in cardiac variability, this paper will rely in particular on studies using fetal heart rate variability (fHRV) to monitor the continued growth and health of both animal and human fetuses. In fact, fHRV is a non-invasive marker whose changes have been associated with ANS development, vagal modulation, systemic and neurological inflammatory reactions, and even fetal distress during labor.
Adaptive Parameter Modulation of Deep Brain Stimulation Based on Improved Supervisory Algorithm
Authors: Zhu Yulin , Wang Jiang , Li Huiyan , Liu Chen , Grill Warren M.
Published: September 2021

Clinically deployed deep brain stimulation (DBS) for the treatment of Parkinson’s disease operates in an open loop with fixed stimulation parameters, and this may result in high energy consumption and suboptimal therapy. The objective of this manuscript is to establish, through simulation in a computational model, a closed-loop control system that can automatically adjust the stimulation parameters to recover normal activity in model neurons. Exaggerated beta band activity is recognized as a hallmark of Parkinson’s disease and beta band activity in model neurons of the globus pallidus internus (GPi) was used as the feedback signal to control DBS of the GPi. Traditional proportional controller and proportional-integral controller were not effective in eliminating the error between the target level of beta power and the beta power under Parkinsonian conditions. To overcome the difficulties in tuning the controller parameters and improve tracking performance in the case of changes in the plant, a supervisory control algorithm was implemented by introducing a Radial Basis Function (RBF) network to build the inverse model of the plant. Simulation results show the successful tracking of target beta power in the presence of changes in Parkinsonian state as well as during dynamic changes in the target level of beta power. Our computational study suggests the feasibility of the RBF network-driven supervisory control algorithm for real-time modulation of DBS parameters for the treatment of Parkinson’s disease.
MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons
Authors: Mou Yongchao , Dein Joshua , Chen Zhenyu , Jagdale Mrunali , Li Xue-Jun
Published: September 2021

Charcot-Marie-Tooth (CMT) disease is one of the most common genetically inherited neurological disorders and CMT type 2A (CMT 2A) is caused by dominant mutations in the mitofusin-2 (MFN2) gene. MFN2 is located in the outer mitochondrial membrane and is a mediator of mitochondrial fusion, with an essential role in maintaining normal neuronal functions. Although loss of MFN2 induces axonal neuropathy, the detailed mechanism by which MFN2 deficiency results in axonal degeneration of human spinal motor neurons remains largely unknown. In this study, we generated MFN2-knockdown human embryonic stem cell (hESC) lines using lentivirus expressing MFN2 short hairpin RNA (shRNA). Using these hESC lines, we found that MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging. Notably, MFN2-knockodwn spinal motor neurons exhibited CMT2A disease-related phenotypes, including extensive perikaryal inclusions of phosphorylated neurofilament heavy chain (pNfH), frequent axonal swellings, and increased pNfH levels in long-term cultures. Importantly, MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency. Our results reveal that MFN2 knockdown induced axonal degeneration of spinal motor neurons and defects in mitochondrial morphology and function. The impaired mitochondrial transport in MFN2-knockdown spinal motor neurons is mediated, at least partially, by the altered motor proteins, providing potential therapeutic targets for rescuing axonal degeneration of spinal motor neurons in CMT2A disease.
Long Noncoding RNA NTT Context-Dependently Regulates MYB by Interacting With Activated Complex in Hepatocellular Carcinoma Cells
Authors: Chang Ya-Sian , Lee Ya-Ting , Yen Ju-Chen , Chang Yuli C. , Lin Li-Li , Chan Wen-Ling , Chang Wei-Chiao , Lin Shyr-Yi , Chang Jan-Gowth
Published: September 2021

Background

Long noncoding RNA (lncRNA) mediates the pathogenesis of various diseases, including cancer and cardiovascular, infectious, and metabolic diseases. This study examined the role of lncRNA NTT in the development and progression of cancer.

Methods

The expression of NTT was determined using tissues containing complementary DNA (cDNA) from patients with liver, lung, kidney, oral, and colon cancers. The expression of cis-acting genes adjacent to the NTT locus (CTGF, STX7, MYB, BCLAF1, IFNGR1, TNFAIP3, and HIVEP2) was also assessed. We used knockdown and chromatin immunoprecipitation (ChIP) assays to identify the cis-acting genes that interact with NTT.

Results

NTT was most significantly downregulated in hepatocellular carcinoma (HCC), while a higher NTT level correlated with a shorter survival time of patients with HCC. Multivariate analysis indicated NTT was not an independent predictor for overall survival. MYB was significantly upregulated, and its increased expression was associated with dismal survival in HCC patients, similar to the results for NTT. NTT knockdown significantly decreased cellular migration. ChIP of HCC cell lines revealed that NTT is regulated by the transcription factor ATF3 and binds to the MYB promoter via the activated complex. Additionally, when NTT was knocked down, the expression of MYB target genes such as Bcl-xL, cyclinD1, and VEGF was also downregulated. NTT could play a positive or negative regulator for MYB with a context-dependent manner in both HCC tissues and animal model.

Conclusion

Our study suggests that NTT plays a key role in HCC progression via MYB-regulated target genes and may serve as a novel therapeutic target.
Combination of Total Psoas Index and Albumin–Globulin Score for the Prognosis Prediction of Bladder Cancer Patients After Radical Cystectomy: A Population-Based Study
Authors: Wang Keyi , Gu Yongzhe , Ni Jinliang , Zhang Houliang , Xie Jinbo , Xu Tianyuan , Geng Jiang , Mao Weipu , Peng Bo
Published: September 2021

Background

Sarcopenia as the loss of skeletal muscle mass is related with poor postoperative survival. This work purposed to evaluate the prognostic prediction of the total psoas index (TPI), albumin–globulin score (AGS), and the combination of TPI and AGS (CTA) in bladder cancer (BCa) patients after radical cystectomy.

Methods

BCa patients that received radical cystectomy between 2012 and 2020 were retrieved from our medical center. The calculation of TPI was based on the plain computed tomography images. The predictive effects of TPI, AGS, and CTA grade on survival of BCa patients were analyzed and compared with the albumin–globulin ratio (AGR) through the receiver operating characteristic (ROC) curves. A nomogram was further established based on the Cox regression results from CTA grade and clinicopathological characteristics, which are verified by the decision curve analysis (DCA).

Results

A total of 112 eligible patients diagnosed as BCa were included in this study for retrospective analysis. The patients with lower TPI or higher AGS grade (1/2) contained poorer overall survival (OS) and disease-free survival (DFS). Divided by CTA grade, there were 35 (31.25%) patients in grade 1 associated with the best postoperative prognosis, which was accompanied with increased TPI and decreased AGS. The CTA grade could better predict postoperative outcomes compared with TPI, AGR, and AGS for the highest area under the curve (AUC; 0.674 of OS and 0.681 of DFS). The 3- and 5-year OS and DFS nomograms were conducted based on CTA grade and clinical variables, with a higher predictive performance than the TNM stage.

Conclusion

This study revealed that the novel index CTA functioned as an effective prognostic predictor for postoperative OS and DFS of BCa patients after radical cystectomy. Preoperative assessment of CTA would contribute to optimizing clinical therapies.
Different Primary Sites of Hypopharyngeal Cancer Have Different Lymph Node Metastasis Patterns: A Retrospective Analysis From Multi-Center Data
Authors: Zhang Xiwei , Zhang Ye , Yu Xiaoduo , Sun Ying , Miao Susheng , Liu Shaoyan , Li Zhengjiang , Yi Junlin , An Changming
Published: September 2021

Background

Most hypopharyngeal cancers (HPCs) develop lymph node metastasis (LNM) at initial diagnosis. Understanding the pattern of LNM in HPC could help both surgeons and radiologists make decisions in the management of cervical lymph nodes.

Methods

A total of 244 newly diagnosed HPC patients between January 2010 and December 2018 were recruited from three specialized cancer hospitals in mainland China. All patients received pre-treatment magnetic resonance imaging (MRI), and definitive radiotherapy with or without concurrent chemotherapy. We reassessed the features of the primary tumor (tumor size, primary location, and extent of invasion) and the involvement of lymph nodes at each level. According to the incidence of LNM, these levels were sequenced and sorted into drainage stations. Univariate and multivariate analyses were used to determine the risk factors for bilateral and regional lymph node metastasis.

Results

The cohort consisted of 195 piriform sinus cancers (PSC), 47 posterior wall cancers (PWC), and 2 post-cricoid cancers (PCC). A total of 176 patients (72.1%) presented with MRI-detectable LNMs. The overall LNM rates for level II-VI and retropharyngeal lymph nodes (RPLNs) were 59.0%, 52.9%, 14.3%, 1.6%, 2.9%, and 16.4%, respectively. Based on the prevalence of LNM at each level, we hypothesize that the lymphatic drainage of PSC was carried out in sequence along three stations: Level II and III (61.0% and 55.4%), Level IV and RPLN (15.9% and 11.3%), and Level V and VI (1.5% and 3.1%). For PWCs, lymphatic drainage is carried out at two stations: Level II, III, and RPLN (48.9%, 40.4%, and 34.0%) and Level IV-VI (6.4%, 0%, and 2.1%). According to univariate and multivariate analyses, posterior wall invasion was significantly correlated with bilateral LNM (P = 0.030, HR = 2.853 95%CI, 1.110-7.338) and RPLN metastasis (P = 0.017, HR = 2.880 95%CI, 1.209-6.862). However, pyriform sinus invasion was less likely to present with bilateral LNM (P = 0.027, HR = 0.311, 95%CI, 0.111-0.875) and RPLN metastasis (P = 0.028, HR = 0.346, 95%CI, 0.134-0.891).

Conclusions and Relevance

The primary tumor site and extent of invasion are related to the pattern of lymph node metastasis. That is, the metastasis would drainage station by station along different directions.
Salvage Therapy With Polatuzumab Vedotin, Bendamustine, and Rituximab Prior to Allogeneic Hematopoietic Transplantation in Patients With Aggressive Lymphomas Relapsing After Therapy With Chimeric Antigen Receptor T-Cells—Report on Two Cases
Authors: Gerhardt Kristin , Jentzsch Madlen , Georgi Thomas , Sretenović Aleksandra , Cross Michael , Bach Enrica , Monecke Astrid , Leiblein Sabine , Hoffmann Sandra , Todorović Milena , Bila Jelena , Sabri Osama , Schwind Sebastian , Franke Georg-Nikolaus , Platzbecker Uwe , Vučinić Vladan
Published: September 2021

Up to 60% of patients with aggressive B-cell lymphoma who receive chimeric antigen receptor (CAR) T-cell therapy experience treatment failure and subsequently have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a potentially curative approach for patients in this situation. Induction of a deep response prior to alloHSCT is crucial for long-term outcomes, but the optimal bridging strategy following relapse after CAR T-cell therapy has not yet been established. Polatuzumab vedotin, an antibody drug conjugate targeting CD79b, is a novel treatment option for use in combination with rituximab and bendamustine (Pola-BR) in relapsed or refractory disease. Patients: We report two heavily pretreated patients with primary refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBCL) respectively who relapsed after therapy with CAR T-cells with both nodal and extranodal manifestations of the disease. After application of three courses of Pola-BR both patients achieved a complete metabolic remission. Both patients underwent alloHSCT from a human leukocyte antigen (HLA)-mismatched donor following conditioning with busulfan and fludarabine and are disease free 362 days and 195 days after alloHSCT respectively. We conclude that Pola-BR can be an effective bridging therapy before alloHSCT of patients relapsing after CAR T-cell therapy. Further studies will be necessary to define the depth and durability of remission of this salvage regimen before alloHSCT.
Melanoma Plasticity: Promoter of Metastasis and Resistance to Therapy
Authors: Huang Fan , Santinon François , Flores González Raúl Ernesto , del Rincón Sonia V.
Published: September 2021

Melanoma is the deadliest form of skin cancer. Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, most patients are not cured. Therapy resistance remains a significant clinical challenge. Melanoma comprises phenotypically distinct subpopulations of cells, exhibiting distinct gene signatures leading to tumor heterogeneity and favoring therapeutic resistance. Cellular plasticity in melanoma is referred to as phenotype switching. Regardless of their genomic classification, melanomas switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and often therapy-resistant state. In this review we discuss potential mechanisms underpinning melanoma phenotype switching, how this cellular plasticity contributes to resistance to both targeted therapies and immunotherapies. Finally, we highlight novel strategies to target plasticity and their potential clinical impact in melanoma.