Publications by authors named "Zhihui Liu"

274 Publications

Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab.

J Immunother Cancer 2022 Jun;10(6)

Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Background: Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.

Methods: Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNA (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor.

Results: A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (Δcholine) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNA and Δcholine was prognostic for both OS and PFS. Multivariable analyses show Δcholine was a prognostic factor for PFS independent of ΔctDNA, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.

Conclusions: This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and Δcholine suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.

Trial Registration Number: NCT03702309.
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http://dx.doi.org/10.1136/jitc-2021-004378DOI Listing
June 2022

Effective Treatment of Low-Grade Myofibroblastic Sarcoma with Apatinib: A Case Report and Literature Review.

Pharmgenomics Pers Med 2022 7;15:573-582. Epub 2022 Jun 7.

Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People's Republic of China.

Low-grade myofibroblastic sarcoma (LGMS) is a rare, poorly differentiated, malignant tumor. The disease mainly occurs in the head and neck and rarely metastasizes at any age. Currently, there is no consensus regarding the treatment of metastatic LGMS. Here, we report the case of a 45-year-old man who was admitted to our hospital with cough for two weeks and abdominal pain for one week. Preoperative computed tomography revealed a large mass (116×35 mm) in both the lungs and jejunal mass (maximum diameter, 32 mm). The tumor was excised, and immunohistochemical staining was positive for SMA and CD117 and negative for desmin and CD34, indicating a case of LGMS. The patient was effectively treated with apatinib (250 mg/day) after failure of imatinib, liposomal doxorubicin, and ifosfamide. The progression-free survival time was 8.5 months, and the overall survival time was 17 months after treatment with apatinib. No grade 3 or 4 side effects were observed, except hand-foot syndrome. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) were performed on the patient's jejunal tumor and para-cancerous tissue samples, and bioinformatics analysis was performed on the results. WES identified five mutations in MKI67, OR2J2, EPPK1, FCGBP, and OR10G4. RNA-seq revealed that 1422 genes were upregulated and 1890 genes were downregulated. The differentially expressed genes were mainly enriched in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, neuroactive ligand-receptor interaction signaling pathway, and cAMP signaling pathway. Our study indicated that apatinib may be a potential novel and effective treatment for LGMS.
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http://dx.doi.org/10.2147/PGPM.S359492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9188403PMC
June 2022

Vocal Attractiveness Matters: Social Preferences in Cooperative Behavior.

Front Psychol 2022 26;13:877530. Epub 2022 May 26.

School of Psychology, Liaoning Normal University, Dalian, China.

Research has shown the phenomenon that "what sounds beautiful is good" is a stereotype. It is not clear whether vocal attractiveness affects social decision-making in economic games. Using a modified trust game task, we investigated the neural mechanism of the influence of vocal attractiveness on cooperative decision-making. Participants first heard the voice (attractive or unattractive) of the partner. They had enough time to decide whether to cooperate with the partner for a chance to earn monetary rewards. The behavioral results showed that participants made more invest choices in the attractive partner condition, and they were more likely to cooperate with the female partners in the unattractive voice condition. The event-related potential (ERP) analysis for voice stimuli showed that attractive voices induced larger N1 amplitude than unattractive voices only in the male voice condition. And female voices elicited smaller N1 and larger P2 amplitudes than male voices in both the attractive and unattractive voices condition. A larger P3 amplitude was evoked by female voices and attractive voices. In addition, a more positive late positive complex (LPC) was induced by male voices and attractive voices. This study suggested that attractive voices facilitated cooperative behavior, providing evidence for the "beauty premium" effect of the attractive voices. Moreover, participants were more likely to cooperate with female partners. In the early stage, gender information and male vocal attractiveness were processed automatically, suggesting that male vocal attractiveness was processed preferentially than the female voice. In the late stage, participants allocated attention to both male and female vocal attractiveness.
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http://dx.doi.org/10.3389/fpsyg.2022.877530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9177437PMC
May 2022

Ginsenoside Rc Promotes Bone Formation in Ovariectomy-Induced Osteoporosis In Vivo and Osteogenic Differentiation In Vitro.

Int J Mol Sci 2022 May 31;23(11). Epub 2022 May 31.

Department of Stomatology, Jilin University, Changchun 130000, China.

Ginsenoside Rc is one of the active components used in traditional Chinese medicine. We aim to explore how ginsenoside Rc can be used in the treatment of osteoporosis. Micro-CT demonstrated that the treatment of ovariectomized (OVX) mice with ginsenoside Rc significantly inhibited the decrease in bone mineral density, bone volumetric fraction, and trabecular number, and the increase in trabecular separation. Histological staining, qRT-PCR, and Western blot demonstrated that ginsenoside Rc enhances the microstructure of trabecular bone, and promotes the expression of bone formation-related genes. Alkaline phosphatase (ALP) staining, Alizarin Red staining, qRT-PCR, and Western blotting demonstrated that ginsenoside Rc dose-dependently promoted the osteogenic differentiation of MC3T3-E1 cells. A ginsenoside Rc-induced increase in the expression of β-catenin, p-GSK-3β, collagen-1, ALP, and RUNX-2 family transcription factor-2 was significantly attenuated upon 10 μM XAV-939 treatment, while the decrease in the expression of GSK-3β and p-β-catenin was significantly enhanced. Ginsenoside Rc promotes bone formation in ovariectomy-induced osteoporosis in vivo and promotes osteogenic differentiation in vitro via the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.3390/ijms23116187DOI Listing
May 2022

Visualizing the Knowledge Domain in Health Education: A Scientometric Analysis Based on CiteSpace.

Int J Environ Res Public Health 2022 May 25;19(11). Epub 2022 May 25.

School of Physical Education (Main Campus), Zhengzhou University, Zhengzhou 450001, China.

Objectives: This study aimed to visualize the evidence in the global research on health education to better improve the nation's health literacy and to guide future research.

Method: We searched the Web of Science (Core Collection) electronic databases. The search strategies: topic: ("Health Education" OR "Education, Health" OR "Community Health Education" OR "Education, Community Health" OR "Health Education, Community") AND document: (Article) AND language:(English). Articles of evidence from January 2011 to December 2021 with those words in the title or abstract or keywords will be included in this review. We used the Citespace 5.6.R5 (64-bit) to investigate and determine the thematic patterns, and emerging trends of the knowledge domain, and presented a narrative account of the findings.

Result: We analyzed 10,273 eligible articles. It showed that BMC Public Health displays the most prolific journals. Author MARCO PAHOR is highlighted in health education. The University of Sydney has published the most studies about health education. The USA plays an important role in these studies. Specifically, the visualization shows several hotspots: disease prevalence surveys and a specific population of knowledge, attitude and practice surveys, health intervention, chronic and non-communicable management, youth-health action, sexual and reproductive health, and physical activity promotion. Furthermore, document co-citation analysis indicated that there are 10 main clusters, which means the research front in health education. Meanwhile, by the citation detected, COVID-19, has achieved universal health coverage in related studies, however, public health education and the health workforce might be more popular in the coming years.

Conclusion: Health education is an effective measure to shift the concept of public health and improve healthy living standards. The present study facilitates an extensive understanding of the basic knowledge and research frontiers that are pivotal for the developmental process of health education and allows scholars to visualize the identification modes and tendencies.
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http://dx.doi.org/10.3390/ijerph19116440DOI Listing
May 2022

Health related quality of life outcomes following stereotactic body radiotherapy in patients with oligo-metastatic disease: A systematic review and individual patient data meta-analysis.

Radiother Oncol 2022 Jun 6;173:163-169. Epub 2022 Jun 6.

Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada; Interdepartmental Division of Critical Care Medicine, University of Toronto, Canada.

Introduction: Published health-related quality of life (HRQOL) outcomes are lacking in patients treated for oligo-metastatic disease (OMD). The aim of this systematic review and individual patient data meta-analysis is to determine the effect of stereotactic body radiotherapy (SBRT) on HRQOL outcomes of patients with OMD.

Methods: Studies screened included adults with extra-cranial OMD, defined as ≤ 5 metastases, SBRT intended as definitive treatment, and HRQOL as primary or secondary outcome. Primary outcome was change in HRQOL at 12-months from baseline in patients with OMD who received SBRT (versus not), reported as standardized mean difference (SMD).

Results: A total of 7556 publications were identified, four studies met inclusion criteria (2 single arm interventional studies and 2 randomised controlled trials [RCTs]), and individual patient data was available from 3 studies (175 patients). In the two RCTs, there was no SS difference in the SMD between patients who received SBRT and those that did not (0.09 [95 % CI -0.32, 0.5], P = 0.66). On meta-analysis of patients (N = 107) who received SBRT the SMDwas -0.23 (95 % CI [-0.42, -0.04], versus -0.25 (95 % CI [-0.57, 0.07]) in those who did not (N = 37) receive SBRT, demonstrating a small deterioration from baseline.

Conclusion: In patients with OMD, there is no difference in HRQOL at 12-months from baseline between patients who received SBRT and those that did not. However, a small HRQOL deterioration was found in both groups of patients. More in-depth analysis of relevant HRQOL domains, in the setting of OMD, is required to better understand the potential impact of SBRT.
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http://dx.doi.org/10.1016/j.radonc.2022.05.033DOI Listing
June 2022

Identification of EMT-Related Genes and Prognostic Signature With Significant Implications on Biological Properties and Oncology Treatment of Lower Grade Gliomas.

Front Cell Dev Biol 2022 17;10:887693. Epub 2022 May 17.

Department of Neurosurgery, Emergency Medicine Center, Zhejiang Provincial People's Hospital, Affiliated to Hangzhou Medical College, Hangzhou, China.

The epithelial-mesenchymal transition (EMT) is an important process that drives progression, metastasis, and oncology treatment resistance in cancers. Also, the adjacent non-tumor tissue may affect the biological properties of cancers and have potential prognostic implications. Our study aimed to identify EMT-related genes in LGG samples, explore their impact on the biological properties of lower grade gliomas (LGG) through the multi-omics analysis, and reveal the potential mechanism by which adjacent non-tumor tissue participated in the malignant progression of LGG. Based on the 121 differentially expressed EMT-related genes between normal samples from the GTEx database and LGG samples in the TCGA cohort, we identified two subtypes and constructed EMTsig. Because of the genetic, epigenetic, and transcriptomic heterogeneity, malignant features including clinical traits, molecular traits, metabolism, anti-tumor immunity, and stemness features were different between samples with C1 and C2. In addition, EMTsig could also quantify the EMT levels, variation in prognosis, and oncology treatment sensitivity of LGG patients. Therefore, EMTsig could assist us in developing objective diagnostic tools and in optimizing therapeutic strategies for LGG patients. Notably, with the GSVA, we found that adjacent non-tumor tissue might participate in the progression, metastasis, and formation of the tumor microenvironment in LGG. Therefore, the potential prognostic implications of adjacent non-tumor tissue should be considered when performing clinical interventions for LGG patients. Overall, our study investigated and validated the effects of EMT-related genes on the biological properties from multiple perspectives, and provided new insights into the function of adjacent non-tumor tissue in the malignant progression of LGG.
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http://dx.doi.org/10.3389/fcell.2022.887693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152435PMC
May 2022

Characterization of the Ferroptosis-Related Genes for Prognosis and Immune Infiltration in Low-Grade Glioma.

Front Genet 2022 26;13:880864. Epub 2022 Apr 26.

Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Although ferroptosis has been validated to play a crucial role in some types of tumors, the influence of ferroptosis-related genes (FRGs) on the immune microenvironment in low-grade glioma (LGG) remains unclear. In this research, we screen the FRGs to assess the prognosis value and immune microenvironment in LGG, to provide reliable diagnosis and treatment evidence for the clinic. A total of 1,239 patients of LGG samples were selected for subsequent analyses from The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and the Repository of Molecular Brain Neoplasia Data datasets. Univariate Cox regression analysis was used to screen for prognostic FRGs. Consensus clustering was utilized to determine ferroptosis subtypes of LGG patients. Next, the prognostic model was constructed based on differentially expressed FRGs and validation in the validating datasets. The immune microenvironment, biological pathway, and hypoxia score were explored by single-sample gene set enrichment analysis. The potential response of chemotherapy and immune checkpoint blockade therapy was also estimated. In addition, the correlation between the risk score and autophagy-related genes was examined by the Pearson correlation coefficient. A total of three ferroptosis subtypes were identified by consensus clustering for prognostic FRGs which exhibited different outcomes, clinicopathological characteristics, and immune microenvironment. Afterward, a prognostic model that performed great predictive ability based on nine prognostic FRGs has been constructed and validated. Moreover, the prognostic model had the potential to screen the sensitivity to chemotherapy and immunotherapy in LGG patients. Finally, we also found that the prognostic model has a great connection to autophagy and hypoxia. We developed a ferroptosis-related prognostic model which strongly linked to diagnosis, treatment, prognosis, and recurrence of LGG. This study also reveals the connection between ferroptosis and tumor immune microenvironment.
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http://dx.doi.org/10.3389/fgene.2022.880864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9086515PMC
April 2022

Combined 18F-FDG PET/CT Radiomics and Sarcopenia Score in Predicting Relapse-Free Survival and Overall Survival in Patients With Esophagogastric Cancer.

Clin Nucl Med 2022 May 11. Epub 2022 May 11.

Joint Department of Medical Imaging, Toronto General Hospital, University Health Network.

Purpose: The aim of this study was to determine if radiomic features combined with sarcopenia measurements on pretreatment 18F-FDG PET/CT can improve outcome prediction in surgically treated adenocarcinoma esophagogastric cancer patients.

Patients And Methods: One hundred forty-five esophageal adenocarcinoma patients with curative therapeutic intent and available pretreatment 18F-FDG PET/CT were included. Textural features from PET and CT images were evaluated using LIFEx software (lifexsoft.org). Sarcopenia measurements were done by measuring the Skeletal Muscle Index at L3 level on the CT component. Univariable and multivariable analyses were conducted to create a model including the radiomic parameters, clinical features, and Skeletal Muscle Index score to predict patients' outcome.

Results: In multivariable analysis, we combined clinicopathological parameters including ECOG, surgical T, and N staging along with imaging derived sarcopenia measurements and radiomic features to build a predictor model for relapse-free survival and overall survival. Overall, adding sarcopenic status to the model with clinical features only (likelihood ratio test P = 0.03) and CT feature (P = 0.0037) improved the model fit for overall survival. Similarly, adding sarcopenic status (P = 0.051), CT feature (P = 0.042), and PET feature (P = 0.011) improved the model fit for relapse-free survival.

Conclusions: PET and CT radiomics derived from combined PET/CT integrated with clinicopathological parameters and sarcopenia measurement might improve outcome prediction in patients with nonmetastatic esophagogastric adenocarcinoma.
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http://dx.doi.org/10.1097/RLU.0000000000004253DOI Listing
May 2022

Skin γδ T Cells and Their Function in Wound Healing.

Front Immunol 2022 11;13:875076. Epub 2022 Apr 11.

State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

For the skin immune system, γδ T cells are important components, which help in defensing against damage and infection of skin. Compared to the conventional αβ T cells, γδ T cells have their own differentiation, development and activation characteristics. In adult mice, dendritic epidermal T cells (DETCs), Vγ4 and Vγ6 γδ T cells are the main subsets of skin, the coordination and interaction among them play a crucial role in wound repair. To get a clear overview of γδ T cells, this review synopsizes their derivation, development, colonization and activation, and focuses their function in acute and chronic wound healing, as well as the underlining mechanism. The aim of this paper is to provide cues for the study of human epidermal γδ T cells and the potential treatment for skin rehabilitation.
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http://dx.doi.org/10.3389/fimmu.2022.875076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035842PMC
April 2022

A Multi-Parameter Integrated Sensor Based on Selectively Filled D-Shaped Photonic Crystal Fiber.

Materials (Basel) 2022 Apr 12;15(8). Epub 2022 Apr 12.

Guangxi Key Laboratory of Wireless Broadband Communication and Signal Processing, School of Information and Communication, Guilin University of Electronic Technology, Guilin 541004, China.

We propose and numerically investigate a multi-parameter integrated sensor based on a selectively filled D-shaped photonic crystal fiber (PCF). The simple structure can be used to comprehensively detect refractive index, magnetic field, temperature, and voltage. According to the surface plasmon resonance and directional coupling effect, the PCF is coated with a gold nano-film to detect the refractive index of the external environment. In addition, magnetic fluid (water-based FeO), toluene, and nematic liquid crystal (NLC E7) are selectively filled into different cladding air holes of the D-shaped PCF to realize the different sensing of the magnetic field, temperature, and voltage. The measurement of refractive index, magnetic field, temperature, and voltage are independent of each other, so these four parameters can be measured simultaneously. The sensing characteristics of the proposed structure are investigated systematically by the finite element method. The results show that the sensitivities of refractive index, magnetic field, temperature, and voltage are 4600 nm/RIU, 1.375 nm/Oe, 15.143 nm/°C, and 0.971 nm/V, respectively. The presented design based on materials selectively filled with D-shaped PCF might enable promising application in multi-parameter optical sensing.
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http://dx.doi.org/10.3390/ma15082811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9026482PMC
April 2022

Deletion of Calsyntenin-3, an atypical cadherin, suppresses inhibitory synapses but increases excitatory parallel-fiber synapses in cerebellum.

Elife 2022 04 14;11. Epub 2022 Apr 14.

Department of Molecular and Cellular Physiology, Stanford University, Stanford, United States.

Cadherins contribute to the organization of nearly all tissues, but the functions of several evolutionarily conserved cadherins, including those of calsyntenins, remain enigmatic. Puzzlingly, two distinct, non-overlapping functions for calsyntenins were proposed: As postsynaptic neurexin ligands in synapse formation, or as presynaptic kinesin adaptors in vesicular transport. Here, we show that, surprisingly, acute CRISPR-mediated deletion of calsyntenin-3 in mouse cerebellum in vivo causes a large decrease in inhibitory synapse, but a robust increase in excitatory parallel-fiber synapses in Purkinje cells. As a result, inhibitory synaptic transmission was suppressed, whereas parallel-fiber synaptic transmission was enhanced in Purkinje cells by the calsyntenin-3 deletion. No changes in the dendritic architecture of Purkinje cells or in climbing-fiber synapses were detected. Sparse selective deletion of calsyntenin-3 only in Purkinje cells recapitulated the synaptic phenotype, indicating that calsyntenin-3 acts by a cell-autonomous postsynaptic mechanism in cerebellum. Thus, by inhibiting formation of excitatory parallel-fiber synapses and promoting formation of inhibitory synapses in the same neuron, calsyntenin-3 functions as a postsynaptic adhesion molecule that regulates the excitatory/inhibitory balance in Purkinje cells.
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http://dx.doi.org/10.7554/eLife.70664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9064300PMC
April 2022

Developmental toxicity of glyphosate on embryo-larval zebrafish (Danio rerio).

Ecotoxicol Environ Saf 2022 May 7;236:113493. Epub 2022 Apr 7.

Henan International Joint Laboratory of Aquatic Toxicology and Health Protection, College of Life Science, Henan Normal University, Xinxiang, Henan 453007, China. Electronic address:

Glyphosate (GLY) induces developmental toxicity in fish, but research on the toxicity mechanism is limited. In this study, zebrafish embryos were exposed for 120 hpf to 0.7, 7, and 35 mg L GLY. The results show that GLY treatment induced developmental toxicity in the fish, including premature hatching, reduced heartbeats, pericardial and yolk sac oedema, swim bladder deficiency, and shortened body length, which was possibly due to a significantly decreased triiodothyronine (T3)/thyroxine (T4) ratio and the abnormal expression patterns of hypothalamic-pituitary-thyroid (HPT) (crh, tshβ, tr α, tr β, and t tr ) and growth hormone/insulin-like growth factor (GH/IGF) axis-related genes (gh, ghrα, ghrβ, igf1, igf1rα, and igf1rβ) in larvae exposed to GLY. In addition, GLY exposure altered the levels of SOD and CAT, increased ROS, promoted malondialdehyde (MDA) content, and significantly altered the levels of endoplasmic reticulum (ER) stress signalling pathway factors (perk, eif2α, gadd34, atf4, ire1α, xbp1, atf6, hspa5, and chop), suggesting that GLY treatment induced oxidative injury and ER stress in the larvae. Further research showed that treatment with a higher concentration of GLY upregulated the levels of iNOS, IL-1β, and TNF-α while inhibiting the expression of IL-10 and TGF-β, suggesting that GLY causes an inflammatory reaction in the larvae. In addition, we also found that apoptosis was induced in the larvae, which was determined by acridine orange staining and abnormal expression of p53, caspase-3, -8, and -9. Taken together, our results demonstrate that GLY exposure altered the T3/T4 ratio, disturbed the expression patterns of HPT and GH/IGF axis-related genes, and induced oxidative and ER stress, inflammatory reactions, and apoptosis in the zebrafish larvae. This investigation contributes to improved understanding of the developmental toxicity mechanism of GLY in fish.
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http://dx.doi.org/10.1016/j.ecoenv.2022.113493DOI Listing
May 2022

Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2022 Apr 4:e29697. Epub 2022 Apr 4.

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

Purpose: To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT).

Methods And Materials: Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40).

Results: Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs.

Conclusions: Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.
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http://dx.doi.org/10.1002/pbc.29697DOI Listing
April 2022

Association between ambient air pollution and daily hospital visits for cardiovascular diseases in Wuhan, China: a time-series analysis based on medical insurance data.

Int J Environ Health Res 2022 Mar 25:1-12. Epub 2022 Mar 25.

School of Health Sciences, Wuhan University, Wuhan, China.

Although evidence showed the adverse effects of air pollution on cardiovascular disease (CVDs), few studies were based on medically insured populations. We applied a generalized additive Poisson model (GAM) to estimate the short-term effects of ambient air pollution on a group of medically insured population in Wuhan, China. We extracted daily air pollution data, meteorological data, and daily hospital visits for CVDs. We found that the ambient air pollutants sulfur dioxide (SO), nitrogen dioxide (NO), ground-level ozone (O) particulate matter (PM) with an aerodynamic diameter ≤10 μm (PM), and those ≤2.5 μm (PM) all increased the risk of daily hospital visits for CVDs. We also found that the effect of air pollution on daily hospital visits for CVDs is greater in the cold season than in the warm season. Our findings can be used as evidence that supports the formulation of policies for air pollution and CVDs.
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http://dx.doi.org/10.1080/09603123.2022.2035323DOI Listing
March 2022

Dendritic epidermal T cells secreting exosomes promote the proliferation of epidermal stem cells to enhance wound re-epithelialization.

Stem Cell Res Ther 2022 03 21;13(1):121. Epub 2022 Mar 21.

State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

Background: Efficient re-epithelialization is important for successful skin wound healing. The proportion of epidermal stem cells (EpSCs) and dendritic epidermal T cells (DETCs) determines the extent of wound re-epithelialization, especially in large areas of skin tissue loss. However, it remains unknown whether and how DETCs regulate the status of EpSCs to impact wound re-epithelialization.

Methods: To investigate how DETCs regulate EpSCs in skin re-epithelialization, we utilized normal or full-thickness skin deficient wide type (WT) mice and Tcrσ knockout (Tcrσ) mice with DETCs or DETCs-derived exosomes (Exos) treatment. Flow cytometry analysis (FCAS), BrdU labelled experiments, immunofluorescence and immunohistochemical assays were performed to detect the proportion of EpSCs in the epidermis. Wound closure rate and re-epithelialization were assayed by a macroscopical view and hematoxylin-eosin (H&E) staining. EpSCs in vitro were co-cultured with DETCs in a transwell-dependent or -independent manner, or supplement with GW4869 or Exos (5 µg/mL, 15 µg/mL and 45 µg/mL), and the proliferation of EpSCs was detected by means of FCAS and CFSE.

Results: Our data showed that the proportion of CD49fCD71 cells, K15 cells and BrdU cells in the normal epidermis of Tcrδ mice had no significant difference compared to WT mice. For wounded Tcrδ mice, DETCs treatment increase the proportion of CD49fCD71 cells, K15 cells and BrdU cells in the epidermis around the wound in comparison to PBS treatment. DETCs significantly increased the number of CD49fCD7 cells and K15 cells through transwell-dependent or -independent manners relative to control group. Furthermore, Exos stimuli remarkedly promote the proliferation of EpSCs compared to control group, while the increasement was suppressed when DETCs were interfered with GW4869. Gross observation and H&E staining showed that Exos significantly accelerated wound closure and increased re-epithelialization length in Tcrδ mice when compared to control mice. Additionally, we found in vivo that Exos observably facilitated the proliferation of CD49fCD7 cells and K15 cells.

Conclusions: We revealed that DETCs enhanced the proliferation of EpSCs in the epidermis around the wounds to accelerate re-epithelialization in which Exos played important roles in the remote regulation of EpSCs proliferation. Together, these findings suggest a mechanistic link among DETC-derived exosomes, the proliferation of EpSCs, and wound re-epithelialization in the skin.
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http://dx.doi.org/10.1186/s13287-022-02783-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935714PMC
March 2022

5-Methylcytosine Related LncRNAs Reveal Immune Characteristics, Predict Prognosis and Oncology Treatment Outcome in Lower-Grade Gliomas.

Front Immunol 2022 3;13:844778. Epub 2022 Mar 3.

Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

5-Methylcytosine (m5C) methylation is an important RNA modification pattern that can participate in oncogenesis and progression of cancers by affecting RNA stability, expression of oncogenes, and the activity of cancer signaling pathways. Alterations in the expression pattern of long non-coding RNAs (lncRNAs) are potentially correlated with abnormalities in the m5C regulation features of cancers. Our aim was to reveal the mechanisms by which lncRNAs regulated the m5C process, to explore the impact of aberrant regulation of m5C on the biological properties of lower-grade gliomas (LGG), and to optimize current therapeutic. By searching 1017 LGG samples from the Cancer Genome Atlas and Chinese Glioma Genome Atlas, we first clarified the potential impact of m5C regulators on LGG prognosis in this study and used univariate Cox analysis and least absolute shrinkage and selection operator regression to explore clinically meaningful lncRNAs. Consequently, we identified four lncRNAs, including LINC00265, CIRBP-AS1, GDNF-AS1, and ZBTB20-AS4, and established a novel m5C-related lncRNAs signature (m5CrLS) that was effective in predicting prognosis. Notably, mutation rate, WHO class II, IDH mutation, 1p/19q co-deletion and MGMT promoter methylation were increased in the low m5CrLS score group. Patients with increased m5CrLS scores mostly showed activation of tumor malignancy-related pathways, increased immune infiltrating cells, and decreased anti-tumor immune function. Besides, the relatively high expression of immune checkpoints also revealed the immunosuppressed state of patients with high m5CrLS scores. In particular, m5CrLS stratification was sensitive to assess the efficacy of LGG to temozolomide and the responsiveness of immune checkpoint blockade. In conclusion, our results revealed the molecular basis of LGG, provided valuable clues for our understanding of m5C-related lncRNAs, and filled a gap between epigenetics and tumor microenvironment.
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http://dx.doi.org/10.3389/fimmu.2022.844778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8927645PMC
May 2022

Construction of a unique fluorescent probe for rapid and highly sensitive detection of glutathione in living cells and zebrafish.

Talanta 2022 Jun 3;243:123364. Epub 2022 Mar 3.

Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, China. Electronic address:

A rhodamine-based fluorescent probe (Rho-GSH) was rationally designed and synthesized, using nitrobenzene as recognition group for monitoring and imaging GSH in vitro and in vivo. In the presence of GSH, Rho-GSH undergoes sequential nucleophilic substitution and spiro-ring-opening reaction, resulting the fluorescence increase of probe, which enables quantitative detection of GSH with "off-on" fluorescence. The cascade reaction also enables Rho-GSH to rapidly detect GSH (3 s). In addition, Rho-GSH exhibited outstanding selectivity in detecting GSH vs cysteine (Cys) and homocysteine (Hcy). Based on the outstanding detection performance and superior biocompatibility of Rho-GSH, it was used to visualize GSH in vitro and in vivo, demonstrating its highly selectivity for GSH detection (with respect to Cys and Hcy). Rho-GSH can help visually distinguishing cancer cells from normal cells by fluorescence imaging, demonstrating the overexpression of GSH in cancer cells. Because of the outstanding analytical capabilities of Rho-GSH for GSH detection, Rho-GSH may be useful for cancer diagnosis and clinical evaluation.
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http://dx.doi.org/10.1016/j.talanta.2022.123364DOI Listing
June 2022

Effects of statin therapy and treatment duration on cardiovascular disease risk in patients with nephrotic syndrome: A nested case-control study.

Pharmacotherapy 2022 04 3;42(4):311-319. Epub 2022 Mar 3.

Department of Cardiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

Background: Although statins are the cornerstone of lipid management, hardly any of the existing studies on statin treatment of dyslipidemia in nephrotic syndrome (NS) addressed patient-centered outcomes of cardiovascular events.

Objective: To evaluate whether statin treatment impacts the outcomes of cardiovascular events in patients with NS.

Design: A single-center, retrospective, nested case-control study analyzed data from the First Affiliated Hospital of Army Medical University.

Patients: Patients diagnosed with NS from January 1, 1999, to November 30, 2014, were selected and followed up for 5 years.

Measurements And Main Results: A total of 2706 patients with NS were enrolled in this study cohort. Among these, 115 patients diagnosed with cardiovascular disease (CVD) at the end of the observational period and 235 CVD-free controls enrolled by 1:2 matching with gender, age, and index time were included in the study. Propensity score matching was used to match (1:1) the baseline characteristics of the cases and controls. The chi-square test was performed based on whether the patient used a statin as an exposure factor, and binary logistic regression analysis of the association between cardiovascular events and statin therapy duration was conducted. Subgroup analyses for relevant variables were also performed. The chi-square test showed that statin therapy was significantly associated with a reduction in CVD risk in patients with NS (p = 0.002). Furthermore, the risk of cardiovascular events in patients with NS decreased as the length of statin treatment increased (OR = 0.82 [95% CI 0.73-0.89], p < 0.001).

Conclusions: For NS patients with dyslipidemia, statin therapy may be used to decrease CVD risk, and extended treatment was associated with more significant risk reduction.
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http://dx.doi.org/10.1002/phar.2675DOI Listing
April 2022

P311 Facilitates the Angiogenesis and Wound Healing Function of MSCs by Increasing VEGF Production.

Front Immunol 2022 28;13:821932. Epub 2022 Jan 28.

State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.

As a potential clinical therapeutic cell for injured tissue repair, mesenchymal stem cells (MSCs) have attracted increasing attention. Enhancing the pro-healing function of MSCs has gradually become an essential topic in improving the clinical efficacy of MSCs. Recently, studies have shown that neuronal protein 3.1 (P311) plays a crucial role in promoting skin wound healing, suggesting P311 gene modification may improve the pro-healing function of MSCs. In this study, we demonstrated that increasing the expression of P311 could significantly enhance the ability of MSCs to lessen the number of inflammatory cells, increase the expression of IL10, reduce the levels of TNF-α and IFN-γ, increase collagen deposition, promote angiogenesis, and ultimately accelerate skin wound closure and improve the quality of wound healing. Importantly, we uncovered that P311 enhanced the pro-angiogenesis function of MSCs by increasing the production of vascular endothelial growth factor (VEGF) and . Mechanistically, we revealed that the mTOR signalling pathway was closely related to the regulation of P311 on VEGF production in MSCs. Together, our data displayed that P311 gene modification in MSCs augments their capabilities to promote skin wound closure, which might bring the dawn for its clinical application in the future.
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http://dx.doi.org/10.3389/fimmu.2022.821932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8831272PMC
March 2022

Recommended first-line management of brain metastases from melanoma: A multicenter survey of clinical practice.

Radiother Oncol 2022 03 2;168:89-94. Epub 2022 Feb 2.

Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, Canada. Electronic address:

Background: Radiotherapy (RT) and surgery (Sx) are effective in treating brain metastases. However, immune checkpoint inhibitors (ICI) have shown activity against asymptomatic melanoma brain metastases (MBM). BRAF/MEK inhibitors can be used to treat BRAF V600 mutation positive (BRAF+) MBM.

Method: We conducted an international survey among experts from medical oncology (MO), clinical oncology (CO), radiation oncology (RO), and neurosurgery (NS) about treatment recommendations for patients with asymptomatic BRAF+ or BRAF mutation negative (BRAF-) MBM. Eighteen specific clinical scenarios were presented and a total of 267 responses were collected. Answers were grouped and compared using Fisher's exact test.

Results: In most MBM scenarios, survey respondents, regardless of specialty, favored RT in addition to systemic therapy. However, for patients with BRAF+ MBM, MO and CO were significantly more likely than RO and NS to recommend BRAF/MEK inhibitors alone, without the addition of RT, including the majority of MO (51%) for patients with 1-3 MBM, all <2 cm. Likewise, for BRAF- MBM, MO and CO more commonly recommended single or dual agent ICI only and dual agent ICI therapy alone was the most common recommendation from MO or CO for MBM <2 cm. When at least 1 of 3 MBM (BRAF+ or BRAF-) was >2 cm, upfront Sx was recommended by all groups with the exception that MO and RO recommended RT for BRAF- MBM.

Conclusions: In most clinical settings involving asymptomatic MBM, experts recommended RT in addition to systemic therapy. However, recommendations varied significantly according to specialty, with MO and CO more commonly recommending dual systemic therapy alone for up to 9 BRAF- MBM <2 cm.
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http://dx.doi.org/10.1016/j.radonc.2022.01.037DOI Listing
March 2022

Novel Immune-Related Gene-Based Signature Characterizing an Inflamed Microenvironment Predicts Prognosis and Radiotherapy Efficacy in Glioblastoma.

Front Genet 2021 17;12:736187. Epub 2022 Jan 17.

Department of Neurosurgery, Zhejiang Provincial People's Hospital, Hangzhou, China.

Effective treatment of glioblastoma (GBM) remains an open challenge. Given the critical role of the immune microenvironment in the progression of cancers, we aimed to develop an immune-related gene (IRG) signature for predicting prognosis and improving the current treatment paradigm of GBM. Multi-omics data were collected, and various bioinformatics methods, as well as machine learning algorithms, were employed to construct and validate the IRG-based signature and to explore the characteristics of the immune microenvironment of GBM. A five-gene signature (ARPC1B, FCGR2B, NCF2, PLAUR, and S100A11) was identified based on the expression of IRGs, and an effective prognostic risk model was developed. The IRG-based risk model had superior time-dependent prognostic performance compared to well-studied molecular pathology markers. Besides, we found prominent inflamed features in the microenvironment of the high-risk group, including neutrophil infiltration, immune checkpoint expression, and activation of the adaptive immune response, which may be associated with increased hypoxia, epidermal growth factor receptor (EGFR) wild type, and necrosis. Notably, the IRG-based risk model had the potential to predict the effectiveness of radiotherapy. Together, our study offers insights into the immune microenvironment of GBM and provides useful information for clinical management of this desperate disease.
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http://dx.doi.org/10.3389/fgene.2021.736187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8801921PMC
January 2022

Impact of Definitive Chemoradiation on Quality-of-Life Changes for Patients With Anal Cancer: Long-term Results of a Prospective Study.

Dis Colon Rectum 2022 05;65(5):642-653

Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: Maintaining and improving quality of life (QOL) are important goals of anal cancer management. This disease is generally curable, with many long-term survivors.

Objective: Long-term QOL after chemoradiation for patients with anal cancer was evaluated.

Design: This was a prospective cohort study.

Settings: This study used data from a prospective study of patients with anal cancer who were treated with chemoradiation between 2008 and 2013.

Patients: Patients with anal cancer who were treated with image-guided intensity-modulated radiation therapy were included.

Interventions: English-speaking patients completed European Organization for Research and Treatment of Cancer cancer-specific (C30) and site-specific (CR29) QOL questionnaires at baseline, at end of radiation, at 3 and 6 months, and then annually.

Main Outcomes Measures: Long-term QOL was evaluated clinically (a change in score of ≥10 points was considered clinically significant) and statistically (using repeated-measurement analysis) by comparing the subscale scores at 1, 2, and 3 years with baseline scores. Subanalysis compared patients who received a radiation dose of 45 to 54 Gy versus 63 Gy.

Results: Ninety-six patients were included (median follow-up of 56.5 months). The symptom and functional scales showed a clinically significant decline at the end of treatment with improvement by 3 months after treatment. There was a long-term statistically significant decline in dyspnea, body image, bowel embarrassment, fecal incontinence, and hair loss, and there was long-term statistically and clinically significant worsening of impotence. Higher radiation dose (63 Gy) was not associated with significantly worse QOL.

Limitations: Limitations included single-institution, single-arm study design, and lack of dose reconstruction (ie, analyses were based on prescribed, rather than delivered, dose).

Conclusions: Patients with anal cancer treated with chemoradiation reported recovery of overall QOL to baseline levels. Specific symptoms remained bothersome, emphasizing the need to address and manage the chemoradiation-induced symptoms, during treatment and in the long term. See Video Abstract at http://links.lww.com/DCR/B905.

Impacto De La Quimiorradiacin Definitiva En Cambios En La Calidad De Vida De Los Pacientes Con Cncer Anal Resultados A Largo Plazo De Un Estudio Prospective: ANTECEDENTES:Mantener y mejorar la calidad de vida son objetivos importantes del tratamiento del cáncer anal, ya que esta enfermedad generalmente es curable, con muchos sobrevivientes a largo plazo.OBJETIVO:Se evaluó la calidad de vida a largo plazo después de la quimiorradiación en pacientes con cáncer anal.DISEÑO:Este fue un estudio de cohorte prospectivo.ENTORNO CLINICO:Utilizamos datos de un estudio prospectivo en pacientes con cáncer anal tratados con quimiorradiación entre 2008-2013.PACIENTES:Los pacientes con cáncer anal fueron tratados con radioterapia de intensidad modulada guiada por imágenes.INTERVENCIONES:Los pacientes de habla inglesa completaron los cuestionarios de calidad de vida específicos de cáncer (C30) y específicos del sitio (CR29) de la Organización Europea para la Investigación y el Tratamiento del Cáncer al inicio, al final de la radiación, 3 y 6 meses, y luego anualmente.PRINCIPALES MEDIDAS DE RESULTADOS:Se evaluó a largo plazo la calidad de vida clínicamente (un cambio en la puntuación de ≥10 puntos se consideraron clínicamente significativo) y estadísticamente (usando análisis de medición repetida) comparando las subescalas de puntuación al 1, 2, y 3 años. Con puntuaciones de referencia. El subanálisis comparó pacientes que recibieron 45-54 Gy versus 63 Gy.RESULTADOS:Se incluyeron un total de 96 pacientes (mediana de seguimiento: 56,5 meses). La mayoría de las escalas funcionales y de síntomas mostraron una disminución clínicamente significativa al final del tratamiento con una mejoría a los 3 meses posteriores al tratamiento. Hubo una disminución estadísticamente significativa a largo plazo en disnea, imagen corporal, vergüenza intestinal, incontinencia fecal y pérdida de cabello; y hubo un empeoramiento a largo plazo estadística y clínicamente significativo en impotencia. La dosis de radiación más alta (63 Gy) no se asoció con una calidad de vida significativamente peor.LIMITACIONES:Institución única, diseño de estudio de un solo brazo y falta de recomposición de la dosis (es decir, los análisis se basan en la dosis prescrita, en lugar de la administrada).CONCLUSIÓNES:Los pacientes con cáncer anal tratados con quimiorradiación reportaron una recuperación de la QOL en general a los niveles de base. Síntomas específicos siguieron siendo molestos, lo que enfatiza la necesidad de resolver y tartar los síntomas inducidos por la quimiorradiación no solo durante el tratamiento, sino a largo plazo. Consulte Video Resumen en http://links.lww.com/DCR/B905. (Traducción- Dr. Francisco M. Abarca-Rendon).
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May 2022

Mining the Biomarkers and Associated-Drugs for Esophageal Squamous Cell Carcinoma by Bioinformatic Methods.

Tohoku J Exp Med 2022 01;256(1):27-36

The First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine.

Esophageal squamous cell carcinoma (ESCC) showed limited treatment outcome and poor prognosis. This study aimed to screen potential biomarkers and drugs in ESCC. Firstly, GSE26886, GSE111044 and GSE77861 were downloaded from the Gene Expression Omnibus (GEO) database. Next, the differentially expressed genes (DEGs) between cancer and noncancerous tissues were analyzed by the GEO2R. The Gene Ontology (GO) annotation, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, the protein-protein interaction (PPI) analysis and hub genes screened were conducted by some bioinformatic methods, respectively. Lastly, the hub genes and potential drugs were verified by the GEPIA2 and the QuartataWeb database. The results showed that 13 up-regulated genes and 81 down-regulated genes were identified. In GO terms, DEGs were mainly associated with cell proliferation, cell migration and cell differentiation. DEGs did not cluster into the KEGG pathway. After hub genes validated, nine genes (FLG, COL1A1, COL1A2, PSCA, SCEL, PPL, ACPP, CNFN, and A2ML1) expression trends showed no change. Moreover, higher COL1A1 or COL1A2 expression for ESCC patients showed poor prognosis. Finally, five drugs used for promoting blood coagulation were identified. Probably, these drugs could show anticancer effects by promoting blood coagulation or inhibiting vascular formation in cancers, which offers a novel idea for the treatment of ESCC.
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http://dx.doi.org/10.1620/tjem.256.27DOI Listing
January 2022

Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency.

Nat Med 2022 01 6;28(1):125-135. Epub 2022 Jan 6.

Neuro-Oncology, Department of Neurosurgery, and Department of Medicine, Division of Hematology/Medical Oncology, Medical University of South Carolina, Charleston, SC, USA.

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.
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http://dx.doi.org/10.1038/s41591-021-01581-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8799468PMC
January 2022

Anal Adenocarcinoma: A Rare Entity in Need of Multidisciplinary Management.

Dis Colon Rectum 2022 02;65(2):189-197

Department of Radiation Oncology, University of Toronto, Toronto, ON, Canada.

Background: Anal adenocarcinoma is a rare clinical entity for which the optimal management is not defined.

Objective: This study aimed to describe the multidisciplinary management and outcomes of patients with anal adenocarcinoma.

Design: This is a retrospective cohort study.

Setting: This study was conducted at a quaternary cancer center.

Patients: Men and women with anal adenocarcinoma treated between 1995 and 2016 were selected.

Interventions: Fifty-two patients were treated with either chemoradiotherapy or trimodality therapy including radiation therapy, chemotherapy, and surgical resection.

Main Outcome Measures: Local failure, regional failure, and distant metastasis rates were estimated using the cumulative incidence method. The Kaplan-Meier method was used to estimate progression-free survival and overall survival. The multivariable Cox proportional hazards model was used to evaluate the clinical predictors of outcome.

Results: There was a higher 5-year rate of local failure in patients treated with chemoradiotherapy compared with trimodality therapy (53% vs 10%; p < 0.01). The 5-year incidence of distant metastases was 29% (trimodality therapy) versus 30% (chemoradiotherapy; p = 0.9); adjuvant chemotherapy did not reduce the incidence of distant metastases (p = 0.8). Five-year overall survival was 73% (trimodality therapy) versus 49.4% (chemoradiotherapy; p = 0.1). On multivariable analysis, factors associated with worse overall survival were treatment with chemoradiotherapy, cT3-4 category disease, and node-positive disease.

Limitations: This study is limited by its small sample size and retrospective nature.

Conclusions: Although treatment may continue to be tailored to individual patients, better outcomes with a trimodality therapy approach were observed. See Video Abstract at http://links.lww.com/DCR/B708.ADENOCARCINOMA ANAL: UNA ENTIDAD POCO FRECUENTE EN NECESIDAD DE UN MANEJO MULTIDISCIPLINARIO.

Antecedentes: El adenocarcinoma anal es una entidad clínica poco frecuente por lo que aún no se define el manejo óptimo.

Objetivo: Describir el manejo multidisciplinario y los resultados de los pacientes con adenocarcinoma anal.

Diseo: Estudio de cohorte retrospectivo.

Entorno Clinico: Centro de cáncer cuaternario.

Pacientes: Hombres y mujeres con adenocarcinoma anal tratados entre 1995 y 2016.

Intervenciones: Cincuenta y dos pacientes fueron tratados con quimiorradioterapia o terapia trimodal que incluyó: radioterapia, quimioterapia y resección quirúrgica.

Principales Medidas De Valoracion: Se estimaron las tasas de falla local, falla regional y metástasis a distancia mediante el método de incidencia acumulada. Se utilizó el método de Kaplan-Meier para estimar la supervivencia libre de progresión y la supervivencia global. Los riesgos proporcionales de multivariable Cox se utilizaron para evaluar los predictores clínicos de los resultados.

Resultados: Hubo una mayor tasa de falla local a cinco años en pacientes tratados con quimiorradioterapia en comparación con terapia trimodal (53% vs 10%; p < 0,01). La incidencia a cinco años de metástasis a distancia fue del 29% (terapia trimodal) versus 30% (quimiorradioterapia) (p = 0,9); la quimioterapia adyuvante no redujo la incidencia de metástasis a distancia (p = 0,8). La supervivencia global a cinco años fue del 73% (terapia trimodal) versus 49,4% (quimiorradioterapia); p = 0,1. En el análisis multivariable, los factores asociados con una peor supervivencia general fueron el tratamiento con quimiorradioterapia, enfermedad de categoría cT3-4 y enfermedad con ganglios positivos.

Limitaciones: Este estudio está limitado por su pequeño tamaño de muestra y su naturaleza retrospectiva.

Conclusiones: Aunque el tratamiento puede seguir adaptándose a pacientes individuales, se observaron mejores resultados con un enfoque TTM. Conslute Video Resumen en http://links.lww.com/DCR/B708. (Traducción- Dr. Francisco M. Abarca-Rendon).
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http://dx.doi.org/10.1097/DCR.0000000000002281DOI Listing
February 2022

Improvement of PD-1 Blockade Efficacy and Elimination of Immune-Related Gastrointestinal Adverse Effect by mTOR Inhibitor.

Front Immunol 2021 20;12:793831. Epub 2021 Dec 20.

Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China.

During the past decades, immunotherapy, especially the antibody-mediated immune checkpoint blockade (ICB) has shown durable tumor inhibition and changed the paradigm of cancer treatment. However, a growing body of evidence suggests that ICB treatment induces severe immune-related adverse events (irAEs), and the side effect even leads to the discontinuation of lifesaving treatment. Here, we found that ICB treatment induces colitis in melanoma patients and promotes the infiltration of CD8 effector T cells into colitic lesions. Further transcriptomic dissection indicated the PI3K-AKT-mTOR pathway was highly activated in CD8 effector T cells of colitic lesions. Moreover, we developed a mouse melanoma model to recapitulate the gastrointestinal toxicity of anti-PD-1 treatment in clinical settings. Anti-PD-1 treatment significantly contributed to the infiltration of CD8 T cells, and correspondingly induced severe enteritis. Immunohistochemistry experiments showed that the PI3K-AKT-mTOR pathway of T cells was activated by anti-PD-1 treatment. Blockade of the pathway with mTOR inhibitor sirolimus not only inhibits tumor growth but also suppresses the T cell infiltration in colitic lesions. More importantly, combination with sirolimus and anti-PD-1 synergistically inhibits tumor growth inducing the immunogenic cell death of tumor cells . In summary, our research demonstrated the principle of mTOR inhibitor and anti-PD-1 combinatorial therapeutic regimen, which provided a novel therapeutic strategy for irAEs in clinics.
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http://dx.doi.org/10.3389/fimmu.2021.793831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721049PMC
February 2022

lncRNA Expression-Based Risk Scoring System Can Predict Survival of Tumor-Positive Patients with Hepatocellular Carcinoma.

Asian Pac J Cancer Prev 2021 Dec 1;22(12):3741-3753. Epub 2021 Dec 1.

Department of Medical Oncology, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Nanning 530021, People's Republic of China.

Background: Long non-coding RNAs (lncRNAs) play critical roles in the progression of hepatocellular carcinoma (HCC). The aim of this study was to explore whether lncRNA expression profiles can predict prognosis of HCC patients with tumors.

Methods: Expression of lncRNAs in HCC patients based on data in The Cancer Genome Atlas (TCGA) was examined by uni- and multivariate cox analysis to identify associations between clinical features and overall survival (OS) or recurrence-free survival (RFS). Based on our finding that both were independently associated with tumor status, we examined lncRNAs differentially expressed between patients with or without tumors. An lncRNA-based risk scoring system was developed to predict OS and RFS in tumor-positive patients, and it was assessed using uni- and multivariate cox analyses. Potential functions of the prognostic lncRNAs were explored.

Results: A risk scoring system to predict OS for HCC patients with tumors was developed based on the expression of six lncRNAs (AC090921.1, AC012640.1, AL158839.1, AL356056.1, AL359853.1 and C10orf91), and a corresponding scoring system to predict RFS was developed from nine lncRNAs (AL356056.1, AL158839.1, MIR7-3HG, AL445493.2, AP000808.1, AP003354.2, PLCE1-AS1, TH2LCRR and LINC01447). Both risk scoring systems gave areas under receiver operating characteristic curves >0.7. Uni- and multivariate cox analyses showed that both risk scoring systems independently predicted survival even after adjusting for clinical factors. The lncRNAs related to OS may be involved in complement and coagulation cascades, while those related to RFS may be involved in the cell cycle.

Conclusion: Risk scoring system based on these lncRNAs may be useful for predicting prognosis of tumor-positive HCC patients.
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http://dx.doi.org/10.31557/APJCP.2021.22.12.3741DOI Listing
December 2021

Three new compounds from the dried root bark of and their cytotoxicity against HeLa cells.

Nat Prod Res 2021 Dec 29:1-8. Epub 2021 Dec 29.

Development and Utilization Key Laboratory of Northeast Plant Materials, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, China.

Three new compounds () and twelve known compounds () were isolated from the -butanol extraction of the 70% ethanol extract of the dried root barks of . The structures of new compounds were identified by chemical evidence and extensive analysis of spectroscopic data (HR-ESI-MS, 1 D and 2 D NMR) and ECD calculations. All isolated compounds were evaluated for their cytotoxicity against HeLa cells using MTT assay and the results showed that daphnoretin (compound ) owned the highest cytotoxicity against HeLa cells (IC=28.89 μmol/L).
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http://dx.doi.org/10.1080/14786419.2021.2016749DOI Listing
December 2021

Antitumor effects of the small molecule DMAMCL in neuroblastoma via suppressing aerobic glycolysis and targeting PFKL.

Cancer Cell Int 2021 Nov 24;21(1):619. Epub 2021 Nov 24.

Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.

Background: Neuroblastoma (NB) is a common solid malignancy in children that is associated with a poor prognosis. Although the novel small molecular compound Dimethylaminomicheliolide (DMAMCL) has been shown to induce cell death in some tumors, little is known about its role in NB.

Methods: We examined the effect of DMAMCL on four NB cell lines (NPG, AS, KCNR, BE2). Cellular confluence, survival, apoptosis, and glycolysis were detected using Incucyte ZOOM, CCK-8 assays, Annexin V-PE/7-AAD flow cytometry, and Seahorse XFe96, respectively. Synergistic effects between agents were evaluated using CompuSyn and the effect of DMAMCL in vivo was evaluated using a xenograft mouse model. Phosphofructokinase-1, liver type (PFKL) expression was up- and down-regulated using overexpression plasmids or siRNA.

Results: When administered as a single agent, DMAMCL decreased cell proliferation in a time- and dose-dependent manner, increased the percentage of cells in SubG1 phase, and induced apoptosis in vitro, as well as inhibiting tumor growth and prolonging survival in tumor-bearing mice (NGP, BE2) in vivo. In addition, DMAMCL exerted synergistic effects when combined with etoposide or cisplatin in vitro and displayed increased antitumor effects when combined with etoposide in vivo compared to either agent alone. Mechanistically, DMAMCL suppressed aerobic glycolysis by decreasing glucose consumption, lactate excretion, and ATP production, as well as reducing the expression of PFKL, a key glycolysis enzyme, in vitro and in vivo. Furthermore, PFKL overexpression attenuated DMAMCL-induced cell death, whereas PFKL silencing promoted NB cell death.

Conclusions: The results of this study suggest that DMAMCL exerts antitumor effects on NB both in vitro and in vivo by suppressing aerobic glycolysis and that PFKL could be a potential target of DMAMCL in NB.
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http://dx.doi.org/10.1186/s12935-021-02330-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8613996PMC
November 2021
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