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1.
J Formos Med Assoc ; 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38653676

ABSTRACT

BACKGROUND: /Purpose: The Pediatric Eating Assessment Tool-10 (Pedi-EAT-10) is a caregiver-administrated subjective questionnaire for evaluating swallowing and feeding disorders among children. This study translated the Pedi-EAT-10 into Traditional Chinese and tested the translated version's reliability and validity. METHODS: Pedi-EAT-10 was translated into Traditional Chinese by experts and finalized after discussion and testing. A total of 168 participants, consisting of 32 children with dysphagia from a tertiary medical center and 136 healthy controls from its Children Care Center for Employees, were recruited. All participants were assessed by an otolaryngologist and speech-language pathologist. The reliability, validity, and efficacy of the translated Pedi-EAT-10 were analyzed to ensure it could be used to identify pediatric dysphagia and feeding problems. RESULTS: The Traditional Chinese version of the Pedi-EAT-10 had significant clinical discriminative validity between the dysphagia group and the control group (total score = 9.6 vs. 2.6, P < 0.001), acceptable test-retest reliability (intraclass correlation = 0.63), and excellent internal consistency (Cronbach's α = 0.91 for the entire cohort). The overall performance of the test for distinguishing children with dysphagia from normal controls was acceptable, and the area under the curve was 74.8% (sensitivity = 71.9%; specificity = 69.9%). The optimal cutoff score was ≥3 on the Youdex index. CONCLUSIONS: The Traditional Chinese version of the Pedi-EAT-10 has fair reliability and validity and can be quickly and easily completed by caregivers. The translated Ped-EAT-10 can be used as a first-line tool for assessing the need for further referral and instrumental examination.

2.
Int Wound J ; 21(4): e14758, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38629618

ABSTRACT

A meta-analysis was conducted to comprehensively explore the effects of platelet-rich plasma (PRP) combined with negative pressure wound therapy (NPWT) in treating patients with chronic wounds. Computer searches were conducted, from database infection to November 2023, in EMBASE, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure databases for randomized controlled trials (RCTs) on the use of PRP combined with NPWT technology for treating chronic wounds. Two researchers independently screened the literature, extracted data and conducted quality assessments according to the inclusion and exclusion criteria. Stata 17.0 software was employed for data analysis. Overall, 18 RCTs involving 1294 patients with chronic wounds were included. The analysis revealed that, compared with NPWT alone, the use of PRP combined with NPWT technology significantly improved the healing rate (odds ratios [OR] = 1.92, 95% confidence intervals [CIs]: 1.43-2.58, p < 0.001) and total effective rate (OR = 1.31, 95% CI: 1.23-1.39, p < 0.001), and also significantly shortened the healing time of the wound (standardized mean difference = -2.01, 95% CI: -2.58 to -1.45, p < 0.001). This study indicates that the treatment of chronic wounds with PRP combined with NPWT technology can significantly enhance clinical repair effectiveness and accelerate wound healing, with a high healing rate, and is worth further promotion and practice.


Subject(s)
Negative-Pressure Wound Therapy , Platelet-Rich Plasma , Humans , Bandages , Wound Healing
3.
Macromol Rapid Commun ; 44(1): e2200273, 2023 Jan.
Article in English | MEDLINE | ID: mdl-35583906

ABSTRACT

Herein, the direct morphological evidence of the extension-induced phase-separated structures in the electrospinning jet observed by high-speed video imaging and by light scattering technique is reported. Model solutions of poly(vinyl alcohol) (PVA)/water are electrospun. Two types of internal structures, that is, long strings and short ellipsoids, are found. A light scattering model is derived for the Vv scattering configuration to account for the scattered intensities contributed from the liquid jet itself and those from the internal structures. For the severely stretching jet of PVA/water, the Vv intensity profile is dominant by the internal structures to mask the scattering contribution from the jet itself. Moreover, the Hv intensity profile reflects the anisotropy of the oriented chains parallel to the jet axis. For the 7 wt% solution, the derived extension rate in the vicinity of the Taylor cone apex is about 3420 s-1 , which is higher than the Rouse relaxation rate measured by rheometer. It is concluded that extension-induced phase separation of the single-phase PVA solution is likely to occur in Taylor-cone apex to trigger the self-assembly process for producing strings (and/or bulges) in the flowing jet, which eventually transform to become the nanofibers, after solvent removal, to be collected on the grounded collector.


Subject(s)
Nanofibers , Polyvinyl Alcohol , Polyvinyl Alcohol/chemistry , Nanofibers/chemistry , Water/chemistry , Anisotropy
4.
Hum Mol Genet ; 29(9): 1454-1464, 2020 06 03.
Article in English | MEDLINE | ID: mdl-32277753

ABSTRACT

The mutations in the genes encoding the subunits of complex I of the mitochondrial electron transport chain are the most common cause of Leber's hereditary optic neuropathy (LHON), a maternal hereditary disease characterized by retinal ganglion cell (RGC) degeneration. The characteristics of incomplete penetrance indicate that nuclear genetic and environmental factors also determine phenotypic expression of LHON. Therefore, further understanding of the role of mutant mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit proteins and nuclear genetic factors/environmental effects in the etiology of LHON is needed. In this study, we generated human-induced pluripotent stem cells (hiPSCs) from healthy control, unaffected LHON mutation carrier, and affected LHON patient. hiPSC-derived RGCs were used to study the differences between affected and unaffected carriers of mitochondrial DNA point mutation m.11778G > A in the MT-ND4 gene. We found that both mutated cell lines were characterized by increase in reactive oxygen species production, however, only affected cell line had increased levels of apoptotic cells. We found a significant increase in retrograde mitochondria and a decrease in stationary mitochondria in the affected RGC axons. In addition, the messenger RNA and protein levels of KIF5A in the LHON-affected RGCs were significantly reduced. Antioxidant N-acetyl-L-cysteine could restore the expression of KIF5A and the normal pattern of mitochondrial movement in the affected RGCs. To conclude, we found essential differences in the mutually dependent processes of oxidative stress, mitochondrial transport and apoptosis between two LHON-specific mutation carrier RGC cell lines, asymptomatic carrier and disease-affected, and identified KIF5A as a central modulator of these differences.


Subject(s)
Kinesins/genetics , Mitochondria/genetics , NADH Dehydrogenase/genetics , Optic Atrophy, Hereditary, Leber/genetics , Oxidative Stress/genetics , Acetylcysteine/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cell Line/drug effects , DNA, Mitochondrial/genetics , Electron Transport Complex I/genetics , Electron Transport Complex I/metabolism , Gene Expression Regulation/genetics , Humans , Induced Pluripotent Stem Cells/metabolism , Mitochondria/metabolism , Mitochondria/pathology , Optic Atrophy, Hereditary, Leber/metabolism , Optic Atrophy, Hereditary, Leber/pathology , Point Mutation/genetics , Reactive Oxygen Species/metabolism , Retinal Degeneration/genetics , Retinal Degeneration/pathology , Retinal Ganglion Cells/metabolism , Retinal Ganglion Cells/pathology
5.
Biochem Biophys Res Commun ; 516(3): 983-990, 2019 08 27.
Article in English | MEDLINE | ID: mdl-31272718

ABSTRACT

Gallbladder carcinoma (GBC) is always diagnosed at an advanced stage, and patients often miss the opportunity for surgery. Gemcitabine (GEM) and platinum-based drugs, including oxaliplatin (OXA), are mainstays of chemotherapy. However, drug resistance causes treatment failure. Hence, salvage mechanisms are critical to improve outcomes. This study revealed the positive correlation between placenta-specific protein 8 (PLAC8) overexpression and PD-L1 overexpression in GBC. Given the roles of PLAC8 and PD-L1 in chemotherapy resistance, GEM-resistant and OXA-resistant cell lines (SGC966GR and SGC966OR, respectively) were established to test whether and how PLAC8 and PD-L1 function in chemotherapy resistance. Drug-insensitive SGC966GR and SGC966OR cells upregulated MRP and MDR1 and had high expression of PLAC8. PLAC8 blockade using siRNA reversed chemotherapy resistance and downregulated MRP and MDR1 in SGC966GR and SGC966OR cells, suggesting that PLAC8 mediates chemotherapy resistance in GBC. Consistent with the increased mRNA levels of PD-L1 after the acquisition of resistance, PLAC8 knockdown reduced PD-L1 mRNA expression in SGC966GR and SGC966OR cells. In conclusion, PLAC8 overexpression in GBC patients positively correlated with PD-L1 expression. PLAC8 conferred resistance to GEM and OXA by upregulating PD-L1 expression, and PLAC8 or PD-L1 blockade may have potential for overcoming chemotherapy resistance, providing therapeutic options for chemotherapy-refractory GBC patients.


Subject(s)
Antineoplastic Agents/pharmacology , B7-H1 Antigen/genetics , Drug Resistance, Neoplasm/genetics , Epithelial Cells/drug effects , Gene Expression Regulation, Neoplastic , Proteins/genetics , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , B7-H1 Antigen/metabolism , Cell Line, Tumor , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Gallbladder/metabolism , Gallbladder/pathology , Humans , Multidrug Resistance-Associated Proteins/genetics , Multidrug Resistance-Associated Proteins/metabolism , Oxaliplatin/pharmacology , Proteins/antagonists & inhibitors , Proteins/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Signal Transduction , Gemcitabine
6.
Nanotechnology ; 31(8): 085704, 2019 Nov 05.
Article in English | MEDLINE | ID: mdl-31689690

ABSTRACT

Atomistic molecular dynamics simulations are performed to study the thermal stability of bulk superlattices consisting of alkylthiol-coated gold nanocrystals. Using nanocrystals passivated by dodecanethiol chains, we show that the gold superlattice possesses a remarkable high-temperature stability, in agreement with experiment. When heated from room temperature, the superlattice expands slightly at lower temperature (<500 K) and then exhibits a considerable lattice contraction above 500 K, while maintaining the intact crystal structure up to 710 K. Once the temperature increases above 720 K, the gold superlattice becomes structurally unstable due to the local sintering of adjacent nanocrystals. Continuous heating to 750 K drives a large number of gold nanocrystals to coalesce and finally results in a tremendous destruction of the superstructure. The structural change and instability of superlattice are mainly attributed to the ligand desorption from nanocrystal surface induced by the variation in temperature. Furthermore, longer ligand length can effectively improve the thermal stability of gold superlattices. These findings are expected to provide a deep microscopic understanding of the thermal stability of superlattice materials.

7.
J Chem Phys ; 150(3): 034702, 2019 Jan 21.
Article in English | MEDLINE | ID: mdl-30660164

ABSTRACT

Atomistic molecular dynamics simulations are performed to study the potential of mean force (PMF) between two asymmetric gold nanocrystals (NCs) capped by alkylthiols in a vacuum. We systematically investigate the dependence of the PMF on the sizes and capping ligand lengths of two NCs. The results show that the potential well depth scales linearly with increasing total length of two capping ligands on asymmetric dimers, but it hardly depends on the NC size. The predicted equilibrium distance between two asymmetric NCs grows significantly and linearly with the total size of two NCs and exhibits only a slight increase with increasing total ligand length. These findings are explained in terms of the amount of ligand interdigitation between NC surfaces as well as its alterations caused by the change in ligand length and NC size. Furthermore, we introduce a simple formula to estimate the equilibrium distance of two asymmetric NCs. On the basis of the computed PMFs, we propose an empirical two-body potential between asymmetric capped gold NCs.

8.
Blood ; 122(16): 2837-47, 2013 Oct 17.
Article in English | MEDLINE | ID: mdl-23943653

ABSTRACT

PU-H71 is a purine-scaffold Hsp90 inhibitor that, in contrast to other Hsp90 inhibitors, displays unique selectivity for binding the fraction of Hsp90 that is preferentially associated with oncogenic client proteins and enriched in tumor cells (teHsp90). This property allows PU-H71 to potently suppress teHsp90 without inducing toxicity in normal cells. We found that lymphoma cells infected by Epstein-Barr virus or Kaposi sarcoma-associated herpes virus (KSHV) are exquisitely sensitive to this compound. Using PU-H71 affinity capture and proteomics, an unbiased approach to reveal oncogenic networks, we identified the teHsp90 interactome in KSHV(+) primary effusion lymphoma cells. Viral and cellular proteins were identified, including many involved in nuclear factor (NF)-κB signaling, apoptosis, and autophagy. KSHV vFLIP is a viral oncoprotein homologous to cFLIPs, with NF-κB-activating and antiapoptotic activities. We show that teHsp90 binds vFLIP but not cFLIPs. Treatment with PU-H71 induced degradation of vFLIP and IKKγ, NF-κB downregulation, apoptosis and autophagy in vitro, and more importantly, tumor responses in mice. Analysis of the interactome revealed apoptosis as a central pathway; therefore, we tested a BCL2 family inhibitor in primary effusion lymphoma cells. We found strong activity and synergy with PU-H71. Our findings demonstrate PU-H71 affinity capture identifies actionable networks that may help design rational combinations of effective therapies.


Subject(s)
Benzodioxoles/chemistry , HSP90 Heat-Shock Proteins/metabolism , Herpesviridae Infections/metabolism , Neoplasms/metabolism , Neoplasms/virology , Purines/chemistry , Viral Proteins/metabolism , Animals , Apoptosis , Autophagy , Cell Line, Tumor , Cell Proliferation , Gammaherpesvirinae , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Humans , Mice , NF-kappa B/metabolism , Neoplasm Transplantation , Proteome , Proteomics/methods , Signal Transduction
9.
Br J Haematol ; 166(6): 849-61, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24957109

ABSTRACT

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one-third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib-sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti-tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.


Subject(s)
Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Lymphoma, Mantle-Cell/drug therapy , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase , Cell Cycle/drug effects , Cell Death/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Knockdown Techniques , Humans , Lymphoma, Mantle-Cell/metabolism , MAP Kinase Signaling System/drug effects , Phosphorylation/drug effects , Piperidines , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Tumor Cells, Cultured
10.
Cytotherapy ; 16(10): 1371-83, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24996595

ABSTRACT

BACKGROUND AIMS: The purpose of this study was to examine neurotrophic and neuroprotective effects of limbus stroma-derived mesenchymal stromal cells (L-MSCs) on cortical neurons in vitro and in vivo. METHODS: Cultured L-MSCs were characterized by flow cytometry and immunofluorescence through the use of specific MSC marker antibodies. Conditioned media were collected from normoxia- and hypoxia-treated L-MSCs to assess neurotrophic effects. Neuroprotective potentials were evaluated through the use of in vitro hypoxic cortical neuron culture and in vivo rat focal cerebral ischemia models. Neuronal morphology was confirmed by immunofluorescence with the use of anti-MAP2 antibody. Post-ischemic infarct volume and motor behavior were assayed by means of triphenyltetrazolium chloride staining and open-field testing, respectively. Human growth antibody arrays and enzyme-linked immunoassays were used to analyze trophic/growth factors contained in conditioned media. RESULTS: Isolated human L-MSCs highly expressed CD29, CD90 and CD105 but not CD34 and CD45. Mesenchymal lineage cell surface expression pattern and differentiation capacity were identical to MSCs derived form human bone marrow and adipose tissue. The L-MSC normoxic and hypoxic conditioned media both promoted neurite outgrowth in cultured cortical neurons. Hypoxic conditioned medium showed superior neurotrophic function and neuroprotective potential with reduced ischemic brain injury and improved functional recovery in rat focal cerebral ischemia models. Human growth factor arrays and enzyme-linked immunoassays measurements showed neuroprotective and growth-associated cytokines (vascular endothelial growth factor [VEGF], VEGFR3, brain-derived neurotrophic factor, insulin-like growth factor -2 and hepatocyte growth factor) contained in conditioned media. Hypoxic exposure caused VEGF and brain-derived neurotrophic factor upregulation, possibly contributing to neurotrophic and neuroprotective effects. CONCLUSIONS: L-MSCs can secrete various neurotrophic factors stimulating neurite outgrowth and protecting neurons against brain ischemic injury through paracrine mechanism.


Subject(s)
Brain Ischemia/therapy , Limbus Corneae/cytology , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Neurogenesis , Animals , Cell Differentiation/drug effects , Cells, Cultured , Culture Media, Conditioned/pharmacology , Humans , Male , Nerve Growth Factors/metabolism , Nerve Growth Factors/pharmacology , Neurons/cytology , Neurons/drug effects , Neurons/physiology , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacology , Rats , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor A/metabolism
11.
Biosens Bioelectron ; 267: 116739, 2024 Sep 07.
Article in English | MEDLINE | ID: mdl-39270359

ABSTRACT

In response to the pervasive issue of herbicide pollution in environmental water bodies, particularly from herbicides used extensively in agriculture, traditional chemical-based water quality analysis methods have proven costly and time-consuming, often failing to meet regulatory standards. To overcome these limitations, global environmental agencies have turned to rapidly-growing species like duckweed as bioindicators for herbicide and pesticide contamination. However, conventional biological assessment methods, such as the 168-h duckweed growth inhibition test, are slow and lack real-time monitoring capabilities. To address this challenge, we developed an innovative approach by integrating opto-mechanical technology with duckweed to create a cost-effective biosensor for herbicide detection, priced under $10 USD per system. This advancement allows for the rapid detection of herbicide impacts on duckweed growth within just 48 h, significantly improving upon traditional methods. Our biosensor achieves detection limits of 10 ppm (p < 0.05) for glyphosate and 1 ppm (p < 0.05) for glufosinate, both prominent herbicides globally. This mini-biosensing platform offers a practical alternative to the official method, which requires 168 h and higher thresholds (36.4 ppm for glyphosate and 34.0 ppm for glufosinate) for routine environmental analysis. Thus, these duckweed-based optical biosensors represent a promising advancement in environmental monitoring, enhancing accessibility and efficacy for widespread adoption globally.

12.
Biomed Pharmacother ; 170: 116006, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38091640

ABSTRACT

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.


Subject(s)
Arthritis, Rheumatoid , Heme Oxygenase-1 , Rats , Humans , Animals , Heme Oxygenase-1/metabolism , Chondrocytes/metabolism , NF-E2-Related Factor 2/metabolism , Rats, Sprague-Dawley , Oxidative Stress , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Cytokines/metabolism , Apoptosis
13.
Blood ; 118(24): 6342-52, 2011 Dec 08.
Article in English | MEDLINE | ID: mdl-22025527

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the role of SYK in its pathogenesis is not completely understood. Using tissue microarray, we demonstrated for the first time that SYK protein is activated in 27 of 61 (44%) primary human DLBCL tissues. Among DLBCL cell lines, 7 were sensitive and 3 were resistant to a highly specific SYK inhibitor, PRT060318. In sensitive DLBCL cells, SYK inhibition blocked the G(1)-S transition and caused cell-cycle arrest. This effect was reproduced by genetic reduction of SYK using siRNA. A detailed analysis of the BCR signaling pathways revealed that the consequence of SYK inhibition on PLCγ2 and AKT, as opposed to ERK1/2, was responsible for cell-cycle arrest. Genetic knock-down of these key molecules decelerated the proliferation of lymphoma cells. In addition, BCR signaling can be blocked by PRT060318 in primary lymphoma cells. Together, these findings provide insights into cellular pathways required for lymphoma cell growth and support the rationale for considering SYK inhibition as a potentially useful therapy for DLBCL. The results further suggest the possibility of using PLCγ2 and AKT as biomarkers to predict therapeutic response in prospective clinical trials of specific SYK inhibitors.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Resistance, Neoplasm , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Lymphoma, Large B-Cell, Diffuse/drug therapy , Neoplasm Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Biomarkers/metabolism , Cell Line, Tumor , G1 Phase/drug effects , Gene Expression Regulation, Neoplastic , Humans , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Lymph Nodes/drug effects , Lymph Nodes/metabolism , Lymph Nodes/pathology , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Molecular Targeted Therapy , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Phospholipase C gamma/antagonists & inhibitors , Phospholipase C gamma/genetics , Phospholipase C gamma/metabolism , Phosphorylation/drug effects , Protein Processing, Post-Translational/drug effects , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , RNA, Messenger/metabolism , RNA, Small Interfering , Signal Transduction/drug effects , Syk Kinase , Tumor Cells, Cultured
14.
Oncogene ; 42(6): 409-420, 2023 02.
Article in English | MEDLINE | ID: mdl-36482202

ABSTRACT

SHP1, a tyrosine phosphatase, negatively regulates B-cell receptor (BCR) signaling. Ibrutinib selectively inhibits BTK and has been approved for the treatment of several types of B-cell lymphomas, but not yet in diffuse large B-cell lymphoma (DLBCL). A phase 3 clinical trial of ibrutinib-containing regimen has been completed to evaluate its activity in subtypes or subsets of DLBCL patients. Although the subtype of activated B-cell like (ABC) DLBCL is characterized by chronic active BCR signaling, only a fraction of ABC-DLBCL patients seem to benefit from ibrutinib-containing regimen. New alternative predictive biomarkers are needed to identify patients who better respond. We investigated if SHP1 plays a role in defining the level of the BCR activity and impacts the response to ibrutinib. A meta-analysis revealed that lack of SHP1 protein expression as well as SHP1 promoter hypermethylation is strongly associated with NHL including DLBCL. On a tissue microarray of 95 DLBCL samples, no substantial difference in SHP1 expression was found between the GCB and non-GCB subtypes of DLBCL. However, we identified a strong reverse correlation between SHP1 expression and promoter methylation suggesting that promoter hypermethylation is responsible for SHP1 loss. SHP1 knockout in BCR-dependent GCB and ABC cell lines increased BCR signaling activities and sensitize lymphoma cells to the action of ibrutinib. Rescue of SHP1 in the knockout clones, on the other hand, restored BCR signaling and ibrutinib resistance. Further, pharmacological inhibition of SHP1 in both cell lines and patient-derived primary cells demonstrate that SHP1 inhibition synergized with ibrutinib in suppressing tumor cell growth. Thus, SHP1 loss may serve as an alternative biomarker to cell-of-origin to identify patients who potentially benefit from ibrutinib treatment. Our results further suggest that reducing SHP1 pharmacologically may represent a new strategy to augment tumor response to BCR-directed therapies. Schematic diagram summarizing the major findings. Left panel. When SHP1 is present and functional, it negatively regulates the activity of the BCR pathway. Right pane. When SHP1 is diminished or lost, cells depend more on the increased BCR signaling and making them vulnerable to BTK inhibitor, ibrutinib. Diagram was generated using BioRender.


Subject(s)
Lymphoma, Large B-Cell, Diffuse , Signal Transduction , Humans , Protein Tyrosine Phosphatase, Non-Receptor Type 6/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 6/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Cell Line, Tumor , Biomarkers
15.
Article in English | MEDLINE | ID: mdl-37730436

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is a heterogenous group of lymphoid malignancies. Based on gene expression profiling, it has been subdivided into germinal center (GC)-derived and activated B-cell (ABC) types. Advances in molecular methodologies have further refined the subclassification of DLBCL, based on recurrent genetic abnormalities. Here, we describe a distinct case of DLBCL that presented in leukemic form. DNA sequencing targeting 275 genes revealed pathogenically relevant mutations of CD79B, MyD88, TP53, TBL1XR1, and PIM1 genes, indicating that this lymphoma would be best classified as MCD/C5 DLBCL, an ABC subtype. Despite an initial good clinical response to BTK inhibitor ibrutinib, anti-CD20 antibody rituxan, alkylating agent bendamustine, and hematopoietic stem-cell transplant, the lymphoma relapsed, accompanied by morphologic and molecular evidence of disease progression. Specifically, the recurrent tumor developed loss of TP53 heterozygosity (LOH) and additional chromosomal changes central to ABC DLBCL pathogenesis, such as PRDM1 loss. Acquired resistance to ibrutinib and rituxan was indicated by the emergence of BTK and FOXO1 mutations, respectively, as well as apparent activation of alternative cell-activation pathways, through copy-number alterations (CNAs), detected by high-resolution chromosomal microarrays. In vitro, studies of relapsed lymphoma cells confirmed resistance to standard BTK inhibitors but sensitivity to vecabrutinib, a noncovalent inhibitor active against both wild-type as well as mutated BTK. In summary, we provide in-depth molecular characterization of a de novo leukemic DLBCL and discuss mechanisms that may have contributed to the lymphoma establishment, progression, and development of drug resistance.


Subject(s)
Aniline Compounds , Lymphoma, Large B-Cell, Diffuse , Neoplasm Recurrence, Local , Piperidines , Humans , Rituximab , Genomics , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology
18.
J Phys Condens Matter ; 34(38)2022 Jul 22.
Article in English | MEDLINE | ID: mdl-35839749

ABSTRACT

Molecular dynamics simulations are performed to study the mechanical properties and deformation mechanisms of a heterogeneous face-centered cubic/ body-centered cubic Cu/Ta nanolayered composite under uniaxial tension and compression. The results show that the stress-strain curves exhibit two main yield points in tension while only one yield point during compression, and the deformation primarily experiences three stages. The first stage is linearly elastic at small strains, followed by the nucleation and propagation of dislocations and stacking faults in the Cu layers, and eventually the Ta layers yield to plastic deformation. The yield of the specimen is mainly determined by the dislocation evolution in the hard phase (i.e. Ta layers), which leads to a sharp drop in the stress-strain curve. We show that the heterogeneous nanolayered composite exhibits a good deformation compatibility during compression but an obvious deformation incompatibility between Cu and Ta layers in tension. The temperature effect is also systematically investigated. It is revealed that the yield of the specimen at higher temperature depends only on the dislocation evolution in the thick Ta layers, and the yield strengths in tension and compression both decrease with the increasing temperature. In particular, our computations show that high temperature can significantly suppress the dislocation activities in the Cu layers during deformation, which results in a lower dislocation density of the Cu layers compared with that of the Ta layers and thus causing an incompatible fashion among the constituent layers.

19.
Biomedicines ; 10(3)2022 Mar 19.
Article in English | MEDLINE | ID: mdl-35327514

ABSTRACT

Cancer-associated fibroblasts (CAFs) are critical for cancer occurrence and progression in the tumor microenvironment (TME), due to their versatile roles in extracellular matrix remodeling, tumor-stroma crosstalk, immunomodulation, and angiogenesis. CAFs are the most abundant stromal component in the TME and undergo epigenetic modification and abnormal signaling cascade activation, such as transforming growth factor-ß (TGF-ß) and Wnt pathways that maintain the distinct phenotype of CAFs, which differs from normal fibroblasts. CAFs have been considered therapeutic targets due to their putative oncogenic functions. Current digestive system cancer treatment strategies often result in lower survival outcomes and fail to prevent cancer progression; therefore, comprehensive characterization of the tumor-promoting and -restraining CAF activities might facilitate the design of new therapeutic approaches. In this review, we summarize the enormous literature on natural compounds that mediate the crosstalk of CAFs with digestive system cancer cells, discuss how the biology and the multifaceted functions of CAFs contribute to cancer progression, and finally, pave the way for CAF-related antitumor therapies.

20.
Front Oncol ; 12: 1008537, 2022.
Article in English | MEDLINE | ID: mdl-36313701

ABSTRACT

Background: Endoscopic biopsy is the pivotal procedure for the diagnosis of gastric cancer. In this study, we applied whole-slide images (WSIs) of endoscopic gastric biopsy specimens to develop an endoscopic gastric biopsy assistant system (EGBAS). Methods: The EGBAS was trained using 2373 WSIs expertly annotated and internally validated on 245 WSIs. A large-scale, multicenter test dataset of 2003 WSIs was used to externally evaluate EGBAS. Eight pathologists were compared with the EGBAS using a man-machine comparison test dataset. The fully manual performance of the pathologists was also compared with semi-manual performance using EGBAS assistance. Results: The average area under the curve of the EGBAS was 0·979 (0·958-0·990). For the diagnosis of all four categories, the overall accuracy of EGBAS was 86·95%, which was significantly higher than pathologists (P< 0·05). The EGBAS achieved a higher κ score (0·880, very good κ) than junior and senior pathologists (0·641 ± 0·088 and 0·729 ± 0·056). With EGBAS assistance, the overall accuracy (four-tier classification) of the pathologists increased from 66·49 ± 7·73% to 73·83 ± 5·73% (P< 0·05). The length of time for pathologists to manually complete the dataset was 461·44 ± 117·96 minutes; this time was reduced to 305·71 ± 82·43 minutes with EGBAS assistance (P = 0·00). Conclusions: The EGBAS is a promising system for improving the diagnosis ability and reducing the workload of pathologists.

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