bluuebunny/crossref_metadata_2025 huggingface dataset:
An update on the use of cryoablation and immunotherapy for breast cancer
Authors: Olagunju Akindele , Forsman Tia , Ward Robert C.
Published: October 2022

The use of cryoablation, a minimally-invasive image-guided technique to target and kill cancer cells, continues to gain traction within the medical field and with patients. This includes the use of cryoablation for the treatment of small breast cancers and focal sites of metastatic disease. In comparison to open surgical approaches, length of hospital stay and recovery time are decreased with the use of cryoablation. Research studies have also found that cryoablation may actually enhance tumor susceptibility to immunotherapy agents. Immunotherapy enhances a person’s own immune system to identify and attack cancer cells. It is proposed that after cryoablation there is increased expression of tumor specific antigens which the body can recognize as foreign invaders and with the combination of immunotherapy, result in an even more robust and efficient attack on the cancer cells. In this review we aim to highlight some of the recent advances in cryoablation which support the potential for cryoablation to induce these tumor-specific immune responses and thus supporting the use of combining cryoablation and immunotherapy for the treatment of breast cancer.
Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes
Authors: Yang Mei-Ling , Kibbey Richard G. , Mamula Mark J.
Published: October 2022

Posttranslational protein modifications (PTMs) are an inherent response to physiological changes causing altered protein structure and potentially modulating important biological functions of the modified protein. Besides cellular metabolic pathways that may be dictated by PTMs, the subtle change of proteins also may provoke immune attack in numerous autoimmune diseases. Type 1 diabetes (T1D) is a chronic autoimmune disease destroying insulin-producing beta cells within the pancreatic islets, a result of tissue inflammation to specific autoantigens. This review summarizes how PTMs arise and the potential pathological consequence of PTMs, with particular focus on specific autoimmunity to pancreatic beta cells and cellular metabolic dysfunction in T1D. Moreover, we review PTM-associated biomarkers in the prediction, diagnosis and in monitoring disease activity in T1D. Finally, we will discuss potential preventive and therapeutic approaches of targeting PTMs in repairing or restoring normal metabolic pathways in pancreatic islets.
Improved intratumoral penetration of IL12 immunocytokine enhances the antitumor efficacy
Authors: Jung Keunok , Yoo Sojung , Kim Jung-Eun , Kim Wook , Kim Yong-Sung
Published: October 2022

Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (KD) mainly varying in their dissociation rates (koff) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (KD = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (KD = 0.54 or 46 nM) due to the slow koff from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (KD = 130 nM) and a faster koff. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.
Cytokine-primed umbilical cord mesenchymal stem cells enhanced therapeutic effects of extracellular vesicles on osteoarthritic chondrocytes
Authors: Nguyen Thu Huyen , Dao Huy Hoang , Duong Chau Minh , Nguyen Xuan-Hung , Hoang Diem Huong , Do Xuan-Hai , Truong Trung Quang , Nguyen Tu Dac , Nguyen Liem Thanh , Than Uyen Thi Trang
Published: October 2022

In recent years, extracellular vesicles (EVs) secreted by mesenchymal stem cells (MSCs) have emerged as a potential cell-free therapy against osteoarthritis (OA). Thus, we investigated the therapeutic effects of EVs released by cytokine-primed umbilical cord-derived MSCs (UCMSCs) on osteoarthritic chondrocyte physiology. Priming UCMSCs individually with transforming growth factor beta (TGFβ), interferon alpha (IFNα), or tumor necrosis factor alpha (TNFα) significantly reduced the sorting of miR-181b-3p but not miR-320a-3p; two negative regulators of chondrocyte regeneration, into EVs. However, the EV treatment did not show any significant effect on chondrocyte proliferation. Meanwhile, EVs from both non-priming and cytokine-primed UCMSCs induced migration at later time points of measurement. Moreover, TGFβ-primed UCMSCs secreted EVs that could upregulate the expression of chondrogenesis markers (COL2 and ACAN) and downregulate fibrotic markers (COL1 and RUNX2) in chondrocytes. Hence, priming UCMSCs with cytokines can deliver selective therapeutic effects of EV treatment in OA and chondrocyte-related disorders.
Early pathogenesis profiles across SARS-CoV-2 variants in K18-hACE2 mice revealed differential triggers of lung damages
Authors: Aw Zhen Qin , Mok Chee Keng , Wong Yi Hao , Chen Huixin , Mak Tze Minn , Lin Raymond T. P. , Lye David Chien , Tan Kai Sen , Chu Justin Jang Hann
Published: October 2022

The on-going COVID-19 pandemic has given rise to SARS-CoV-2 clades and variants with differing levels of symptoms and severity. To this end, we aim to systematically elucidate the changes in the pathogenesis as SARS-CoV-2 evolved from ancestral to the recent Omicron VOC, on their mechanisms (e.g. cytokine storm) resulting in tissue damage, using the established K18-hACE2 murine model. We reported that among the SARS-CoV-2 viruses tested, infection profiles were initially similar between viruses from early clades but started to differ greatly starting from VOC Delta, where the trend continues in Omicron. VOCs Delta and Omicron both accumulated a significant number of mutations, and when compared to VOCs Alpha, Beta, and earlier predecessors, showed reduced neurotropism and less apparent gene expression in cytokine storm associated pathways. They were shown to leverage on other pathways to cause tissue damage (or lack of in the case of Omicron). Our study highlighted the importance of elucidating the response profiles of individual SARS-CoV-2 iterations, as their propensity of severe infection via pathways like cytokine storm changes as more variant evolves. This will then affect the overall threat assessment of each variant as well as the use of immunomodulatory treatments as management of severe infections of each variant.
Anti-IL-6 therapies in central nervous system inflammatory demyelinating diseases
Authors: Jiao Li , Guo Shougang
Published: October 2022

Current treatments for central nervous system (CNS) inflammatory demyelinating diseases (IDDs) include corticosteroids, plasma exchange, intravenous immunoglobulin, and immunosuppressant drugs. However, some patients do not respond well to traditional therapies. In recent years, novel drugs, such as monoclonal antibodies, targeting the complement component C5, CD19 on B cells, and the interleukin-6 (IL-6) receptor, have been used for the treatment of patients with refractory CNS IDDs. Among these, tocilizumab and satralizumab, humanized monoclonal antibodies against the IL-6 receptor, have shown beneficial effects in the treatment of this group of diseases. In this review, we summarize current research progress and prospects relating to anti-IL-6 therapies in CNS IDDs.
The effects of rhein on D-GalN/LPS-induced acute liver injury in mice: Results from gut microbiome-metabolomics and host transcriptome analysis
Authors: Liu Shuhui , Yin Ruiying , Yang Ziwei , Wei Feili , Hu Jianhua
Published: October 2022

Background

Rhubarb is an important traditional Chinese medicine, and rhein is one of its most important active ingredients. Studies have found that rhein can improve ulcerative colitis by regulating gut microbes, but there are few reports on its effects on liver diseases. Therefore, this study aims to investigate these effects and underlying mechanisms.

Methods

Mice were given rhein (100 mg/kg), with both a normal control group and a model group receiving the same amount of normal saline for one week. Acute liver injury was induced in mice by intraperitoneal injection of D-GalN (800 mg/kg)/LPS (10 ug/kg). Samples (blood, liver, and stool) were then collected and assessed for histological lesions and used for 16S rRNA gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS) and RNA-seq analysis.

Results

The levels of ALT and AST in the Model group were abnormal higher compared to the normal control group, and the levels of ALT and AST were significantly relieved in the rhein group. Hepatic HE staining showed that the degree of liver injury in the rhein group was lighter than that in the model group, and microbiological results showed that norank_o:Clostridia_UCG-014, Lachnoclostridium, and Roseburia were more abundant in the model group compared to the normal control group. Notably, the rhein treatment group showed reshaped disturbance of intestinal microbial community by D-GalN/LPS and these mice also had higher levels of Verrucomicrobia, Akkermansiaceae and Bacteroidetes. Additionally, There were multiple metabolites that were significantly different between the normal control group and the model group, such as L-α-amino acid, ofloxacin-N-oxide, 1-hydroxy-1,3-diphenylpropan-2-one,and L-4-hydroxyglutamate semialdehyde, but that returned to normal levels after rhein treatment. The gene expression level in the model group also changed significantly, various genes such as Cxcl2, S100a9, Tnf, Ereg, and IL-10 were up-regulated, while Mfsd2a and Bhlhe41 were down-regulated, which were recovered after rhein treatment.

Conclusion

Overall, our results show that rhein alleviated D-GalN/LPS-induced acute liver injury in mice. It may help modulate gut microbiota in mice, thereby changing metabolism in the intestine. Meanwhile, rhein also may help regulate genes expression level to alleviate D-GalN/LPS-induced acute liver injury.
Clinical features and prognosis of MPO-ANCA and anti-GBM double-seropositive patients
Authors: Hu Xueling , Shen Chanjuan , Meng Ting , Ooi Joshua D. , Eggenhuizen Peter J. , Zhou Ya-ou , Luo Hui , Chen Jin-biao , Lin Wei , Gong Yizi , Xiong Qi , Xu Jia , Liu Ning , Xiao Xiangcheng , Tang Rong , Zhong Yong
Published: October 2022

Background

Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs.

Methods

109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs.

Results

In our study, we found that patients in the DPPs group were older than the other two groups (p = 0.007, MPO-AAV vs. DPPs; p < 0.001, DPPs vs. anti-GBM). The DPPs group had a higher value of serum creatinine (p = 0.041) and lower estimated glomerular filtration rate (eGFR) (p = 0.032) compared with MPO-AAV patients. On the contrary, the DPPs group had a lower serum creatinine (p = 0.003) compared with patients with anti-GBM group. The proportion of patients with cardiac system involvement in the DPPs group was higher than anti-GBM patients (p = 0.014). Cellular crescents could be generally observed in renal biopsy of DPPs and patients with anti-GBM glomerulonephritis. In addition, Bowman’s capsule rupture was more common in DPPs than MPO-AAV patients (p = 0.001). MPO-AAV had a better renal and overall survival outcome than DPPs (p < 0.001). There was no significant difference of renal and overall survival outcome between DPPs and patients with anti-GBM disease. The incidence of ESRD in DPPs was negatively associated with lymphocyte count (HR 0.153, 95% CI 0.027 to 0.872, p = 0.034) and eGFR (HR 0.847, 95% CI 0.726 to 0.989, p = 0.036). Elevated serum creatinine was confirmed as a risk factor of both renal (HR 1.003, 95% CI 1.000 to 1.005, p = 0.019) and patient survival in DPPs (HR1.461, 95% CI 1.050 to 2.033, p = 0.024).

Conclusion

In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.
Effect of surrounding landscape on Popillia japonica abundance and their spatial pattern within Wisconsin vineyards
Authors: Henden Jacob , Guédot Christelle
Published: October 2022

Landscapes surrounding agroecosystems can provide resources that may benefit insect pests. This project examined the influence of the surrounding landscape on the abundance and spatial pattern ofPopillia japonica(Coleoptera: Scarabaeidae) in vineyards. Twenty vineyards across Southern Wisconsin, spanning a gradient of 5-80% cropland in a 1.5km radius surrounding landscape, were sampled in 2017 and 2018 forP. japonicaadults and leaf injury. The distribution ofP. japonicaand leaf injury was assessed by sampling along a transect at the edge, halfway from the edge to the center, and at the center of each vineyard. The proportion of cropland and pasture in the surrounding landscape along with abiotic factors of temperature, precipitation, longitude, and pesticide use (determined using Environmental Impact Quotient) were included in models to explain the variation ofP. japonicaabundance and leaf injury. No significant relationship was observed between proportion cropland in the surrounding landscape andP. japonicaabundance or leaf injury. Combined effects of pasture, longitude, and temperature best explained variation in the abundance ofP. japonicaadults while longitude, temperature and EIQ best explained variability in leaf injury. Vineyards with more pastures in the surrounding landscape, located further east, and with higher temperatures, generally had moreP. japonicaadults and vineyards further east with higher temperature and lower EIQ pesticide use generally had higher levels of leaf injury. Additionally, variability in weekly temperature and precipitation influenced weekly abundance, with higher temperatures and less precipitation resulting in greater weekly abundance ofP. japonicaadults. Significantly more adultP. japonicaand greater leaf injury were found at the edges than in the center of vineyards. Our results suggest beetles from the surrounding landscape likely contribute to populations ofP. japonicaadults found feeding on vines on vineyard edges, andP. japonicaabundance and associated leaf injury are influenced by geographical location, local weather conditions, and pesticide use.
Comparative analysis of National Ocean Strategies of the Atlantic Basin countries
Authors: da Silva Marques Inês , Santos Conceição , Guerreiro José
Published: October 2022

In 2007 the European Union (EU) launched the Blue Book introducing the Integrated Maritime Policy (IMP) for the sustainable growth of the coastal regions of Member States. The IMP has several cross-cutting areas of intervention such as the Blue Growth Strategy, Maritime Spatial Planning, and Strategies for maritime basins. To ensure this policy’s implementation, the European Commission requested its coastal members to develop integrated maritime strategies. Furthermore, within the United Nations Decade of Ocean Science for Sustainable Development, it is also a priority of the EU to ensure compliance with the 2030 Agenda, in particular the SDG14. This study focuses on countries from the Atlantic Basin, namely France, Ireland, Portugal, Spain, and the UK (before Brexit) comparing key priorities and objectives of national ocean strategies of these countries and how they match IMP guidelines and the 2030 Agenda. The results show that one of the main focuses of these strategies is the mitigation and adaptation to climate change and nature conservation. On the other hand, desalination, exploration and prospection of oil and gas are the socioeconomic sectors of smaller significance. This study also demonstrated that Spain and UK’s ocean strategies cannot be considered as a national ocean strategy in the IMP concept. The national ocean strategy of Ireland was introduced almost 10 years ago, therefore can be considered outdated in several dimensions. France and Portugal are the only countries whose national ocean strategies are aligned with the objectives of the Atlantic Action Plan and the only ones that truly follow the guidelines of the EU Integrated Maritime Policy.
Reconstruction of long-term sea-level data gaps of tide gauge records using a neural network operator
Authors: Lee Eun-Joo , Kim Kiduk , Park Jae-Hun
Published: October 2022

The coastal sea level is an important factor in understanding and clarifying the physical processes in coastal seas. However, missing values and outliers of the sea level that occur for various reasons often disrupt the continuity of its time series. General-purpose time-series analysis and prediction methods are not tolerant of missing values, which is why researchers have attempted to fill these gaps. The disadvantage of conventional time-series reconstruction techniques is the low accuracy when missed sea-level records are longer than the timescales of coastal processes. To solve this problem, we used an artificial neural network, which is a novel tool for creating multivariate and nonlinear regression equations. The trained neural network weight set was designed to enable long-term reconstruction of sea level by acting as a one-step prediction operator. In addition, a data assimilation technique was developed and adapted to ensure seamless continuity between predicted and observed sea-level records. The application of our newly developed method to 3-day gaps of seal level records at 16 tide gauge stations around the Korean peninsula confirms that it can successfully reconstruct missing values with root-mean-squared errors of 0.5–1.1 cm on average.
Mixed layer eddies supply nutrients to enhance the spring phytoplankton bloom
Authors: Simoes-Sousa Iury T. , Tandon Amit , Pereira Filipe , Lazaneo Caue Z. , Mahadevan Amala
Published: October 2022

Mixed layer eddies resulting from baroclinic instability of fronts convert horizontal buoyancy gradients into vertical stratification, shoaling the mixed layer. In light-limited regimes – high-latitudes – this process can initiate phytoplankton blooms prior to the springtime warming. The question is whether mixed layer eddies can enhance the spring bloom by delivering nutrients from beneath the mixed layer. We couple a submesoscale-resolving model (SUB) with a simple ecosystem model and examine the role of mixed layer eddies on the development of the spring bloom. We compare the SUB simulation to two coarser resolution (10 km) simulations, one that includes a mixed layer eddy parameterization (MLE) and another that prescribes the restratification from SUB and advects the biogeochemical tracers using geostrophic velocities (NVF). The MLE simulates restratification of the mixed layer and bloom onset, but the spring bloom has a deficit of 10–13% in the new production compared to SUB. The NVF has the same restratification as SUB, and with no vertical flux of nutrients, leads to a spring bloom with a 32–40% new production deficit compared to SUB. Submesoscale processes lead to exchange across the mixed layer base, which is not represented in coarse resolution model simulations, even with mixed layer eddy parameterizations. Our results show that nutrients supplied by mixed layer eddies are important to enhance the spring bloom.
Potential common mechanism of four Chinese patent medicines recommended by diagnosis and treatment protocol for COVID-19 in medical observation period
Authors: Wang Lin , Wang Zheyi , Yang Zhihua , Wang Xingwang , Yan Liping , Wu Jianxiong , Liu Yue , Fu Baohui , Yang Hongtao
Published: October 2022

The global epidemic has been controlled to some extent, while sporadic outbreaks still occur in some places. It is essential to summarize the successful experience and promote the development of new drugs. This study aimed to explore the common mechanism of action of the four Chinese patent medicine (CPMs) recommended in the Medical Observation Period COVID-19 Diagnostic and Treatment Protocol and to accelerate the new drug development process. Firstly, the active ingredients and targets of the four CPMs were obtained by the Chinese medicine composition database (TCMSP, TCMID) and related literature, and the common action targets of the four TCMs were sorted out. Secondly, the targets of COVID-19 were obtained through the gene-disease database (GeneCards, NCBI). Then the Venn diagram was used to intersect the common drug targets with the disease targets. And GO and KEGG pathway functional enrichment analysis was performed on the intersected targets with the help of the R package. Finally, the results were further validated by molecular docking and molecular dynamics analysis. As a result, a total of 101 common active ingredients and 21 key active ingredients of four CPMs were obtained, including quercetin, luteolin, acacetin, kaempferol, baicalein, naringenin, artemisinin, aloe-emodin, which might be medicinal substances for the treatment of COVID-19. TNF, IL6, IL1B, CXCL8, CCL2, IL2, IL4, ICAM1, IFNG, and IL10 has been predicted as key targets. 397 GO biological functions and 166 KEGG signaling pathways were obtained. The former was mainly enriched in regulating apoptosis, inflammatory response, and T cell activation. The latter, with 92 entries related to COVID-19, was mainly enriched to signaling pathways such as Coronavirus disease—COVID-19, Cytokine-cytokine receptor interaction, IL-17 signaling pathway, and Toll-like receptor signaling pathway. Molecular docking results showed that 19/21 of key active ingredients exhibited strong binding activity to recognized COVID-19-related targets (3CL of SARS-CoV-2, ACE2, and S protein), even better than one of these four antiviral drugs. Among them, shinflavanone had better affinity to 3CL, ACE2, and S protein of SARS-CoV-2 than these four antiviral drugs. In summary, the four CPMs may play a role in the treatment of COVID-19 by binding flavonoids such as quercetin, luteolin, and acacetin to target proteins such as ACE2, 3CLpro, and S protein and acting on TNF, IL6, IL1B, CXCL8, and other targets to participate in broad-spectrum antiviral, immunomodulatory and inflammatory responses.
Identifying depression disorder using multi-view high-order brain function network derived from electroencephalography signal
Authors: Zhao Feng , Gao Tianyu , Cao Zhi , Chen Xiaobo , Mao Yanyan , Mao Ning , Ren Yande
Published: October 2022

Brain function networks (BFN) are widely used in the diagnosis of electroencephalography (EEG)-based major depressive disorder (MDD). Typically, a BFN is constructed by calculating the functional connectivity (FC) between each pair of channels. However, it ignores high-order relationships (e.g., relationships among multiple channels), making it a low-order network. To address this issue, a novel classification framework, based on matrix variate normal distribution (MVND), is proposed in this study. The framework can simultaneously generate high-and low-order BFN and has a distinct mathematical interpretation. Specifically, the entire time series is first divided into multiple epochs. For each epoch, a BFN is constructed by calculating the phase lag index (PLI) between different EEG channels. The BFNs are then used as samples, maximizing the likelihood of MVND to simultaneously estimate its low-order BFN (Lo-BFN) and high-order BFN (Ho-BFN). In addition, to solve the problem of the excessively high dimensionality of Ho-BFN, Kronecker product decomposition is used for dimensionality reduction while retaining the original high-order information. The experimental results verified the effectiveness of Ho-BFN for MDD diagnosis in 24 patients and 24 normal controls. We further investigated the selected discriminative Lo-BFN and Ho-BFN features and revealed that those extracted from different networks can provide complementary information, which is beneficial for MDD diagnosis.
Sexual dimorphism of early transcriptional reprogramming in degenerating peripheral nerves
Authors: Chernov Andrei V. , Shubayev Veronica I.
Published: October 2022

Sexual dimorphism is a powerful yet understudied factor that influences the timing and efficiency of gene regulation in axonal injury and repair processes in the peripheral nervous system. Here, we identified common and distinct biological processes in female and male degenerating (distal) nerve stumps based on a snapshot of transcriptional reprogramming 24 h after axotomy reflecting the onset of early phase Wallerian degeneration (WD). Females exhibited transcriptional downregulation of a larger number of genes than males. RhoGDI, ERBB, and ERK5 signaling pathways increased activity in both sexes. Males upregulated genes and canonical pathways that exhibited robust baseline expression in females in both axotomized and sham nerves, including signaling pathways controlled by neuregulin and nerve growth factors. Cholesterol biosynthesis, reelin signaling, and synaptogenesis signaling pathways were downregulated in females. Signaling by Rho Family GTPases, cAMP-mediated signaling, and sulfated glycosaminoglycan biosynthesis were downregulated in both sexes. Estrogens potentially influenced sex-dependent injury response due to distinct regulation of estrogen receptor expression. A crosstalk of cytokines and growth hormones could promote sexually dimorphic transcriptional responses. We highlighted prospective regulatory activities due to protein phosphorylation, extracellular proteolysis, sex chromosome-specific expression, major urinary proteins (MUPs), and genes involved in thyroid hormone metabolism. Combined with our earlier findings in the corresponding dorsal root ganglia (DRG) and regenerating (proximal) nerve stumps, sex-specific and universal early phase molecular triggers of WD enrich our knowledge of transcriptional regulation in peripheral nerve injury and repair.
Dramatic response to neoadjuvant savolitinib in marginally resectable lung adenocarcinoma with MET exon 14 skipping mutation: A case report and literature review
Authors: Tian Jiangfang , Lin Zhen , Chen Yueyun , Fu Yang , Ding Zhenyu
Published: October 2022

Mesenchymal–epithelial transition (MET) exon 14 skipping mutation (METex14) is a low-frequency driver mutation in metastatic non-small cell lung cancer (NSCLC) (3%–4%) and is associated with a poor prognosis. With the advent of selective MET inhibitors such as capmatinib, tepotinib, and savolitinib, the outcome for these patients was significantly improved. Here, we report a 76-year-old male patient with marginally resectable stage IIIB lung adenocarcinoma harboring METex14 who was successfully treated with savolitinib for neoadjuvant therapy. An 82% shrinkage of the primary tumor was observed, and only 5% of the tumor was viable by pathology in the following radical surgery. A dozen of studies tested the efficiency of neoadjuvant immunotherapy or immunochemotherapy, but for NSCLC with driver mutations, neoadjuvant targeted therapy might be more appropriate. We advocated the neoadjuvant MET TKI treatment for NSCLC.
Bioinformatics analysis and validation of the critical genes associated with adamantinomatous craniopharyngioma
Authors: Fang Chao , Zhou Lin , Huang Hui , Xu Hai Tong , Hong Tao , Zheng Su Yue
Published: October 2022

Adamantinomatous craniopharyngioma (ACP) is an epithelial tumor that arises when Rathke’s pouch remains during embryonic development. The pathogenesis of ACP remains unclear, and treatment options are limited. Here, we reveal the critical genes expressed in ACP and provide a basis for further research and treatment. The raw dataset GSE94349 was downloaded from the GEO database. We selected 24 ACP and 27 matched samples from individuals with no documented tumor complications (control group). Then, we screened for differentially expressed genes (DEGs) to identify key signaling pathways and associated DEGs. A total of 470 DEGs were identified (251 upregulated and 219 downregulated). Hierarchical clustering showed that the DEGs could precisely distinguish the ACP group from the control group (CG). Gene Ontology (GO) enrichment analysis indicated that the upregulated DEGs were mainly involved in cell adhesion, inflammatory responses, and extracellular matrix management. The downregulated DEGs were primarily involved in cell junction and nervous system development. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis indicated that the critical pathway was pathways in cancer. In the PPI network, CDH1, SHH, and WNT5A had the highest degrees of interaction and were associated with the formation of ACP. CDH1 was verified as a critical gene by quantitative reverse transcription–polymerase chain reaction (qRT-PCR) in ACP and CG samples. We found that CDH1 may play an important role in the pathways in cancer signaling pathway that regulates ACP development. The CDH1 gene may be a target for future research and treatment of ACP.
Significant response of pulmonary sarcomatoid carcinoma with obstructive atelectasis to treatment with the PD-1 inhibitor camrelizumab combined with transbronchial cryoablation: A case report and literature review
Authors: Nian Jiayun , Zhu Yong , Fu Qi , Yang Guowang , Wang Xiaomin
Published: October 2022

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer with high malignancy and poor prognosis. Chemotherapy or radiotherapy do not usually provide satisfactory results in patients with PSC, especially in those with advanced-stage cancer. Targeted therapy and immunotherapy are more precise therapies that may be effective in the treatment of PSC; however, further research is needed. Here, we present a case of stage III PSC with obstructive atelectasis, which is more challenging and hinders treatment. Treatment with the PD-1 inhibitor camrelizumab and transbronchial cryoablation showed significant clinical efficacy. This type of combined treatment has not been reported previously for PSC. Thus, this case may provide a valuable reference for future clinical practice and research.
Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure
Authors: Paolino Jonathan , Berliner Nancy , Degar Barbara
Published: October 2022

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of multiorgan system dysfunction that is caused by hypercytokinemia and persistent activation of cytotoxic T lymphocytes and macrophages. A nearly ubiquitous finding and a diagnostic criterion of HLH is the presence of cytopenias in ≥ 2 cell lines. The mechanism of cytopenias in HLH is multifactorial but appears to be predominantly driven by suppression of hematopoiesis by pro-inflammatory cytokines and, to some extent, by consumptive hemophagocytosis. Recognition of cytopenias as a manifestation of HLH is an important consideration for patients with bone marrow failure of unclear etiology.
Patterns and predictors of recurrence after laparoscopic resection of rectal cancer
Authors: Yang Hong , Chen Lei , Wu Xiuxiu , Zhang Chenghai , Yao Zhendan , Xing Jiadi , Cui Ming , Jiang Beihai , Su Xiangqian
Published: October 2022

Purpose

This study was designed to evaluate the patterns and predictors of recurrence in patients who underwent laparoscopic resection of rectal cancer.

Methods

Patients with rectal cancer receiving laparoscopic resection between April 2009 and March 2016 were retrospectively analyzed. The association of recurrence with clinicopathological characteristics was evaluated using multivariate analyses.

Results

A total of 405 consecutive patients were included in our study. Within a median follow-up time of 62 months, 77 patients (19.0%) experienced disease recurrence: 10 (2.5%) had locoregional recurrence (LR), 61 (15.1%) had distant metastasis (DM), and 6 (1.5%) developed LR and DM synchronously. The lung was the most common site of metastasis. Multivariate analyses indicated that involved circumferential resection margin (CRM) was the only independent predictor for LR (OR=13.708, 95% CI 3.478-54.026, P<0.001), whereas elevated baseline level of CA19-9 (OR=3.299, 95% CI 1.461-7.449, P=0.032), advanced pN stage (OR=2.292, 95% CI 1.177-4.462, P=0.015) and harvested lymph nodes less than 12 (OR=2.418, 95% CI 1.245-4.695, P=0.009) were independently associated with DM. Patients receiving salvage surgery showed superior 3-year survival compared with palliative treatment after relapse (90.9% vs. 20.5%; P=0.017). The estimated 5-year DFS and CSS for the entire cohort was 80.2% and 83.1%, respectively.

Conclusions

DM was more common than LR after laparoscopic resection of rectal cancer, and there were several clinicopathological factors related to LR and DM. Involved CRM and suboptimal lymph node yield were adverse surgery-related factors of tumor recurrence, which should be paid more attention to during the operation.
Extended adjuvant endocrine therapy for women with hormone receptor-positive early breast cancer: A meta-analysis with trial sequential analysis of randomized controlled trials
Authors: Xie Ming , Zhong Yan , Yang Yide , Shen Fang , Nie Yue
Published: October 2022

Objectives

The aim of the current study is to explore the association between extended adjuvant endocrine treatment and prognosis of women with hormone receptor-positive (HR+) early breast cancer.

Methods

Databases including PubMed, Web of Science, Embase and the Cochrane Library databases were electronically searched to identify randomized controlled trials (RCTs) that reported extended endocrine therapy for women with HR+ early breast cancer. The retrieval time was limited from inception to September 2022. Two reviewers independently screened literature, extracted data, and assessed risk bias of included studies. Meta-analysis was performed by using R software Version 4.1.2 and STATA Version 12.0.

Results

A total of 15 RCTs involving 29497 cases were included. The overall analysis showed that compared with the control, extended adjuvant endocrine therapy increased disease-free survival (DFS) (HR=0.814, 95% CI: 0.720-0.922, 95% PI: 0.556-1.194), overall survival (OS) (HR=0.885, 95% CI: 0.822-0.953, 95% PI: 0.771-1.035), relapse-free survival (RFS) (HR=0.833, 95% CI: 0.747-0.927, 95% PI: 0.575-1.159), distant metastatic-free survival (DMFS) (HR=0.824, 95% CI: 0.694-0.979, 95% PI: 0.300-2.089) and reduced new breast cancer cumulative incidence (NBCCI) (HR=0.484, 95% CI: 0.403-0.583, 95% PI: 0.359-0.654). For adverse events, extended adjuvant endocrine treatment was associated with a significantly higher risk of bone fracture (RR=1.446, 95% CI: 1.208-1.730, 95% PI: 1.154-1.854) and osteoporosis (RR=1.377, 95% CI: 1.018-1.862, 95% PI: 0.347-5.456).

Conclusion

Our study showed that extended adjuvant endocrine therapy increased DFS, OS, RFS, DMFS, the incidence of bone fracture and osteoporosis, and reduced NBCCI.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero, identifier (CRD42022351295)
Evaluation of systemic inflammatory and nutritional indexes in locally advanced gastric cancer treated with adjuvant chemoradiotherapy after D2 dissection
Authors: Wang Shu-Bei , Chen Jia-Yi , Xu Cheng , Cao Wei-Guo , Cai Rong , Cao Lu , Cai Gang
Published: October 2022

Background

Many studies have shown that the peripheral blood inflammatory index and nutritional index, such as the platelet lymphocyte ratio (PLR), neutrophil lymphocyte ratio (NLR), lymphocyte monocyte ratio (LMR), systemic inflammation response index (SIRI), pan-immune-inflammation value (PIV), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI), are independent prognostic factors for tumors. The present study aimed to investigate the prognostic role of these peripheral blood indexes before treatment in locally advanced gastric cancer (LAGC) treated with adjuvant chemoradiotherapy after D2 dissection.

Methods

A total of 89 patients with LAGC who underwent D2 gastrectomy and adjuvant chemoradiotherapy at our hospital from 2010–2018 were eligible. Systemic inflammatory indicators before treatment were evaluated. Receiver operating characteristic curve (ROC), Kaplan–Meier analysis, and Cox regression were utilized for prognosis evaluation.

Results

The median follow-up time was 29.1 (4.1–115.8) months. The overall survival at 3 years (OS) and the disease-free survival (DFS) were 78.9% and 59.1%, respectively. According to the ROC curve for 3-year DFS, the best cut-off values of pre-treatment NLR, PLR, LMR, SII, SIRI, PIV and PNI were 1.7, 109.3, 2.9, 369.2, 0.58, 218.7, and 48, respectively. Multivariate Cox regression analysis showed that NLR was an independent prognostic factor for DFS (HR 2.991, 95%CI 1.085–8.248, P = 0.034). Kaplan-Meier analysis showed that a higher NLR (>1.70) was significantly associated with a poorer OS (3-year OS: 68.8% vs 92.9%, P = 0.045) and DFS (3-year DFS: 47.5% vs 80.9%, P = 0.005). In terms of the free locoregional recurrence rate (LRR), the prognosis of patients with high NLR was also significantly worse than those with low NLR (70.2% vs 96.0%, P = 0.017). Paraaortic lymph nodes were the most common site of LRR (7/14 patients). The seven cases of paraaortic lymph node metastasis occurred in patients with high NLR.

Conclusions

In our retrospective analysis, we found that pretreatment NLR could serve as a prognostic factor for survival in LAGC treated with adjuvant chemoradiotherapy after D2 dissection, especially for the prediction of LRR and paraaortic lymph node metastasis. Prospective studies are needed to confirm our findings.
Platycodin D sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway
Authors: Liu Yanfei , Tian Shifeng , Yi Ben , Feng Zhiqiang , Chu Tianhao , Liu Jun , Zhang Chunze , Zhang Shiwu , Wang Yijia
Published: October 2022

Cetuximab is a monoclonal antibody against epidermal growth factor receptor that blocks downstream signaling pathways of receptor tyrosine kinases, including Ras/Raf/MAPK and PI3K/Akt, thereby inhibiting tumor cell proliferation and inducing cancer cell apoptosis. Owing to KRAS mutations, the effectiveness of cetuximab is usually limited by intrinsic drug resistance. Continuous activation of the PI3K/Akt signaling pathway is another reason for cetuximab resistance. Platycodin-D, a bioactive compound isolated from the Chinese herb Platycodon grandiflorum, regulates Akt in different trends based on tissue types. To investigate whether platycodin-D can sensitize KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the PI3K/Akt signaling pathway, HCT116 and LoVo cells were treated with cetuximab and platycodin-D. LY294002 and SC79 were used to regulate Akt to further evaluate whether platycodin-D sensitizes cells to cetuximab by inhibiting Akt. Our results confirmed that platycodin-D increased the cytotoxic effects of cetuximab, including inhibition of growth, migration, and invasion, via downregulation of PI3K and Akt phosphorylation in HCT116 and LoVo cells both in vitro and in vivo. Given these data, platycodin-D may sensitize KRAS-mutant colorectal cancer cells to cetuximab via inhibition of the PI3K/Akt signaling pathway.
Peripheral tuberculin purified protein derivative specific T cell immunoreactivity dynamics in non-muscle invasive bladder cancer patients receiving bacillus Calmette-Guerin instillation treatment
Authors: Duan Huangqi , Xia Weimin , Xu Ding , Chen Yingying , Ding Yu , Wang Chen , Sun Ruiming , Yao Chengcheng , Zhang Shun , Wu Yu , Ji Ping , Wang Shujun , Qian Subo , Wang Ying , Shen Haibo
Published: October 2022

Intravesical bacillus Calmette-Guerin (BCG) instillation is recommended as an adjuvant therapy for intermediate-risk and high-risk non-muscle invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBt) with nearly 70% reoccurrence. In the present study, we investigated the dynamics of peripheral purified protein derivative (PPD)-specific immune responses along the treatment. Intravesical BCG instillation caused a significant increase in peripheral PPD-specific IFN-γ release of NMIBC patients, when compared to those receiving chemo-drug instillation. Through a follow-up study, we detected rapid increase in PPD-specific IFN-γ, IL-2, and IL-17A producing CD4+and CD8+T cells in the induction phase. Interestingly, the frequencies of PPD-specific IFN-γ and IL-2 producing CD4+and CD8+T cells decreased dramatically after induction treatment and were restored after BCG re-instillation, whereas IL-17A-producing T cells remained at the maintenance phase. However, we only observed that the percentages of peripheral CD8+T cells were significantly higher in BCG responder patients than those in BCG refractory patients at the baseline with the potential of predicting the recurrence. A more dramatic increase in PPD-specific IFN-γ and IL-2 producing CD4+and CD8+T cells after one and two dose BCG instillations was observed in refractory NMIBC patients. Therefore, regional BCG instillation induced transient peripheral PPD-specific T cell responses, which could be restored through repetitive BCG instillation. Higher proportions of peripheral CD8+T cells at baseline were associated with better responses to BCG instillation for the prevention of recurrence of bladder cancer.
Ultrastructural analysis of zinc oxide nanospheres enhances anti-tumor efficacy against Hepatoma
Authors: Hassan Amr , Al-Salmi Fawziah A. , Abuamara Tamer M. M. , Matar Emadeldin R. , Amer Mohamed E. , Fayed Ebrahim M. M. , Hablas Mohamed G. A. , Mohammed Tahseen S. , Ali Haytham E. , Abd EL-fattah Fayez M. , Abd Elhay Wagih M. , Zoair Mohammad A. , Mohamed Aly F. , Sharaf Eman M. , Dessoky Eldessoky S. , Alharthi Fahad , Althagafi Hussam Awwadh E. , Abd El Maksoud Ahmed I.
Published: October 2022

Zinc oxide nanomaterial is a potential material in the field of cancer therapy. In this study, zinc oxide nanospheres (ZnO-NS) were synthesized by Sol-gel method using yeast extract as a non-toxic bio-template and investigated their physicochemical properties through various techniques such as FTIR, XR, DLS, and TEM. Furthermore, free zinc ions released from the zinc oxide nanosphere suspended medium were evaluated by using the ICP-AS technique. Therefore, the cytotoxicity of ZnO nanospheres and released Zn ions on both HuH7 and Vero cells was studied using the MTT assay. The data demonstrated that the effectiveness of ZnO nanospheres on HuH7 was better than free Zn ions. Similarly, ZnO-Ns were significantly more toxic to HuH7 cell lines than Vero cells in a concentration-dependent manner. The cell cycle of ZnO-Ns against Huh7 and Vero cell lines was arrested at G2/M. Also, the apoptosis assay using Annexin-V/PI showed that apoptosis of HuH7 and Vero cell lines by ZnO nanospheres was concentration and time-dependent. Caspase 3 assay results showed that the apoptosis mechanism may be intrinsic and extrinsic pathways. The mechanism of apoptosis was determined by applying the RT-PCR technique. The results revealed significantly up-regulated Bax, P53, and Cytochrome C, while the Bcl2 results displayed significant down-regulation and the western blot data confirmed the RT-PCR data. There is oxidative stress of the ZnO nanospheres and free Zn+2 ions. Results indicated that the ZnO nanospheres and free Zn+2 ions induced oxidative stress through increasing reactive oxygen species (ROS) and lipid peroxidation. The morphology of the HuH7 cell line after exposure to ZnO nanospheres at different time intervals revealed the presence of the chromatin condensation of the nuclear periphery fragmentation. Interestingly, the appearance of canonical ultrastructure features of apoptotic morphology of Huh7, Furthermore, many vacuoles existed in the cytoplasm, the majority of which were lipid droplets, which were like foamy cells. Also, there are vesicles intact with membranes that are recognized as swollen mitochondria.