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1.
Obes Med ; : 100312, 2021 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-33426364

RESUMO

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a pandemic since WHO made the statement on March 11, 2020. The infection is causing a high mortality in old people, especially those with obesity, type 2 diabetes (T2D) or cardiovascular diseases (CVD). Extra cautions are needed in the treatment of those patients. The CVD drugs ACEIs and ARBs, as well as the T2D drugs GLP-1R agonists, were shown to activate angiotensin-converting enzyme 2 (ACE2) expression in experimental animals. Elevated ACE2 expression may accelerate virus entrance into the host cells during the infection for its replication. However, expression of the soluble ACE2, may neutralize the virus to limit the infection and replication. Given that obese, diabetes and CVD patients often take those medicines in the treatment and prevention of blood pressure and glucose elevation, it remains to be determined whether those medicines represent friend or foe in the treatment of COVID-19. We suggest that retrospective studies should be conducted to determine the exact impact of those medicines in obese, diabetic, or CVD patients who had COVID-19. Results obtained will provide guidance whether those drugs can be utilized in COVID-19 patients with obesity, diabetic, or CVD.

2.
J Clin Invest ; 131(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393503

RESUMO

The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non-small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.

3.
Nat Cell Biol ; 23(1): 87-98, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33420488

RESUMO

Prostate cancer shows remarkable clinical heterogeneity, which manifests in spatial and clonal genomic diversity. By contrast, the transcriptomic heterogeneity of prostate tumours is poorly understood. Here we have profiled the transcriptomes of 36,424 single cells from 13 prostate tumours and identified the epithelial cells underlying disease aggressiveness. The tumour microenvironment (TME) showed activation of multiple progression-associated transcriptomic programs. Notably, we observed promiscuous KLK3 expression and validated the ability of cancer cells in altering T-cell transcriptomes. Profiling of a primary tumour and two matched lymph nodes provided evidence that KLK3 ectopic expression is associated with micrometastases. Close cell-cell communication exists among cells. We identified an endothelial subset harbouring active communication (activated endothelial cells, aECs) with tumour cells. Together with sequencing of an additional 11 samples, we showed that aECs are enriched in castration-resistant prostate cancer and promote cancer cell invasion. Finally, we created a user-friendly web interface for users to explore the sequenced data.

4.
Oncogene ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33420372

RESUMO

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.

5.
Crit Care Med ; 49(2): 311-323, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33332817

RESUMO

OBJECTIVES: In many jurisdictions, ethical concerns require surrogate humane endpoints to replace death in small animal models of acute lung injury. Heterogenous selection and reporting of surrogate endpoints render interpretation and generalizability of findings between studies difficult. We aimed to establish expert-guided consensus among preclinical scientists and laboratory animal veterinarians on selection and reporting of surrogate endpoints, monitoring of these models, and the use of analgesia. DESIGN: A three-round consensus process, using modified Delphi methodology, with researchers who use small animal models of acute lung injury and laboratory animal veterinarians who provide care for these animals. Statements on the selection and reporting of surrogate endpoints, monitoring, and analgesia were generated through a systematic search of MEDLINE and Embase. Participants were asked to suggest any additional potential statements for evaluation. SETTING: A web-based survey of participants representing the two stakeholder groups (researchers, laboratory animal veterinarians). Statements were rated on level of evidence and strength of support by participants. A final face-to-face meeting was then held to discuss results. SUBJECTS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Forty-two statements were evaluated, and 29 were rated as important, with varying strength of evidence. The majority of evidence was based on rodent models of acute lung injury. Endpoints with strong support and evidence included temperature changes and body weight loss. Behavioral signs and respiratory distress also received support but were associated with lower levels of evidence. Participants strongly agreed that analgesia affects outcomes in these models and that none may be necessary following nonsurgical induction of acute lung injury. Finally, participants strongly supported transparent reporting of surrogate endpoints. A prototype composite score was also developed based on participant feedback. CONCLUSIONS: We provide a preliminary framework that researchers and animal welfare committees may adapt for their needs. We have identified knowledge gaps that future research should address.

6.
J Med Chem ; 64(1): 385-403, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33382613

RESUMO

Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1H-pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure-activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.

8.
Proc Natl Acad Sci U S A ; 117(52): 33426-33435, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318209

RESUMO

Precise genetic engineering in specific cell types within an intact organism is intriguing yet challenging, especially in a spatiotemporal manner without the interference caused by chemical inducers. Here we engineered a photoactivatable Dre recombinase based on the identification of an optimal split site and demonstrated that it efficiently regulated transgene expression in mouse tissues spatiotemporally upon blue light illumination. Moreover, through a double-floxed inverted open reading frame strategy, we developed a Cre-activated light-inducible Dre (CALID) system. Taking advantage of well-defined cell-type-specific promoters or a well-established Cre transgenic mouse strain, we demonstrated that the CALID system was able to activate endogenous reporter expression for either bulk or sparse labeling of CaMKIIα-positive excitatory neurons and parvalbumin interneurons in the brain. This flexible and tunable system could be a powerful tool for the dissection and modulation of developmental and genetic complexity in a wide range of biological systems.

9.
EMBO Mol Med ; : e12798, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33283987

RESUMO

Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co-targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE2 ) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE2 -bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid-derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP-16. TP-16 effectively blocked the function of IMCs and enhanced cytotoxic T-cell-mediated tumor elimination in vivo. Cell co-culture experiments revealed that TP-16 promoted T-cell proliferation, which was impaired by tumor-derived CD11b+ myeloid cells. Notably, TP-16 and anti-PD-1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP-16 increased responsiveness to anti-PD-1 therapy in an IMC-related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4-expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer.

10.
Discov Med ; 30(159): 39-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33357361

RESUMO

Newcastle disease virus (NDV) replicates in the cytoplasm and disintegrates the host genome or participates in recombination, and has a strong affinity for tumor cells. These characteristics make it safer and more attractive than retroviruses or certain other DNA viruses, and one of the most potential oncolytic viruses used in oncolytic therapy. The construction of recombinant NDV (rNDV) using reverse genetics technology with NDV as a gene delivery vector has also enabled NDV in gene therapy approaches for treating cancer and other diseases. rNDV can not only stably express exogenous therapeutic genes, but also enhance the ability of the virus to kill tumor cells and induce host anti-tumor immune response. This article reviews the molecular characteristics, anti-tumor mechanisms, and the applications of NDV in cancer therapy.

11.
Aging (Albany NY) ; 122020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33260149

RESUMO

Current evidence is inconsistent regarding the impact of metabolic syndrome (MetS) on sex hormones and reproductive function, and this meta-analysis aimed to illuminate the association. A literature search was conducted in public databases to identify all relevant studies, and study-specific standardized mean differences (SMD) and 95% confidence intervals (CI) were pooled using a random-effects model. Finally, 21 studies were identified with a total of 2923 MetS cases and 14062 controls. In males, MetS cases had a lower level of testosterone, inhibin B, total sperm count, sperm concentration, sperm normal morphology, sperm total motility, sperm progressive motility and sperm vitality, and a higher level of DNA fragmentation and mitochondrial membrane potential. In females, MetS cases had a higher level of testosterone. No significant difference was detected for follicle-stimulating hormone, luteinizing hormone, oestradiol, prolactin, anti-Müllerian hormone and semen volume in males, and for oestradiol, follicle-stimulating hormone, luteinizing hormone and progesterone in females. In conclusion, this meta-analysis indicated the impact of MetS on sex hormones and reproductive function, and MetS cases had a potential risk of infertility.

12.
Sensors (Basel) ; 20(23)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266203

RESUMO

For engineering structures, strain flexibility-based approaches have been widely used for structural health monitoring purposes with prominent advantages. However, the applicability and robustness of the method need to be further improved. In this paper, a novel damage index based on differences in uniform load strain field (ULSF) is developed for plate-like structures. When estimating ULSF, the strain flexibility matrix (SFM) based on mass-normalized strain mode shapes (SMSs) is needed. However, the mass-normalized strain mode shapes (SMSs) are complicated and difficult to obtain when the input, i.e., the excitation, is unknown. To address this issue, the proportional strain flexibility matrix (PSFM) and its simplified construction procedure are proposed and integrated into the frames of ULSF, which can be easily obtained when the input is unknown. The identification accuracy of the method under the damage with different locations and degrees is validated by the numerical examples and experimental examples. Both the numerical and experimental results demonstrate that the proposed method provides a reliable tool for output-only damage detection of plate-like structures without estimating the mass-normalized strain mode shapes (SMSs).

14.
Intensive Care Med Exp ; 8(1): 63, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33108583

RESUMO

BACKGROUND: There are limited therapeutic options directed at the underlying pathological processes in acute respiratory distress syndrome (ARDS). Experimental therapeutic strategies have targeted the protective systems that become deranged in ARDS such as surfactant. Although results of surfactant replacement therapy (SRT) in ARDS have been mixed, questions remain incompletely answered regarding timing and dosing strategies of surfactant. Furthermore, there are only few truly clinically relevant ARDS models in the literature. The primary aim of our study was to create a clinically relevant, reproducible model of severe ARDS requiring extracorporeal membrane oxygenation (ECMO). Secondly, we sought to use this model as a platform to evaluate a bronchoscopic intervention that involved saline lavage and SRT. METHODS: Yorkshire pigs were tracheostomized and cannulated for veno-venous ECMO support, then subsequently given lung injury using gastric juice via bronchoscopy. Animals were randomized post-injury to either receive bronchoscopic saline lavage combined with SRT and recruitment maneuvers (treatment, n = 5) or recruitment maneuvers alone (control, n = 5) during ECMO. RESULTS: PaO2/FiO2 after aspiration injury was 62.6 ± 8 mmHg and 60.9 ± 9.6 mmHg in the control and treatment group, respectively (p = 0.95) satisfying criteria for severe ARDS. ECMO reversed the severe hypoxemia. After treatment with saline lavage and SRT during ECMO, lung physiologic and hemodynamic parameters were not significantly different between treatment and controls. CONCLUSIONS: A clinically relevant severe ARDS pig model requiring ECMO was established. Bronchoscopic saline lavage and SRT during ECMO did not provide a significant physiologic benefit compared to controls.

15.
Eur Respir J ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122335

RESUMO

RATIONALE: Transplantation of lungs from donation after circulatory death (DCD) in addition to donation after brain death (DBD) became routine worldwide to address the global organ shortage. The development of ex vivo lung perfusion (EVLP) for donor lung assessment and repair contributed to the increased use of DCD lungs. We hypothesise that better understanding of the differences between lungs from DBD and DCD donors, and between EVLP and directly transplanted (non-EVLP) lungs, will lead to discovery of the injury specific targets for donor lung repair and reconditioning. METHODS: Tissue biopsies from human DBD (n=177) and DCD (n=65) donor lungs assessed with or without EVLP, were collected at the end of cold ischemic time. All samples were processed with microarray assay. Gene expression, network and pathway analyses were performed using R, Ingenuity Pathway Analysis and STRING. Results were validated with protein assay, multiple logistic regression and 10-fold cross validation. RESULTS: Our analyses showed that lungs from DBD donors have up-regulation of inflammatory cytokines and pathways. In contrast, DCD lungs display a transcriptome signature of pathways associated with cell death, apoptosis and necrosis. Network centrality revealed specific drug targets to rehabilitate the DBD lungs. Moreover, in DBD lungs, TNFR1/2 signalling pathways and macrophage migration inhibitory factor associated pathways were activated in the EVLP group. A panel of genes that differentiate the EVLP from non-EVLP group in DBD lungs was identified. CONCLUSION: The examination of gene expression profiling indicates that DBD and DCD lungs have distinguishable biological transcriptome signatures.

16.
Cancers (Basel) ; 12(9)2020 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-32933182

RESUMO

B cell aplasia caused by "on-target off-tumor" toxicity is one of the clinical side effects during CD19-targeted chimeric antigen receptor (CAR) T (CD19-CAR-T) cells treatment for B cell malignancies. Persistent B cell aplasia was observed in all patients with sustained remission, which increased the patients' risk of infection. Some patients even died due to infection. To overcome this challenge, the concept of incorporating an inhibitory CAR (iCAR) into CAR-T cells was introduced to constrain the T cells response once an "on-target off-tumor" event occurred. In this study, we engineered a novel KIR/PD-1-based inhibitory CAR (iKP CAR) by fusing the extracellular domain of killer cell immunoglobulin-like receptors (KIR) 2DL2 (KIR2DL2) and the intracellular domain of PD-1. We also confirmed that iKP CAR could inhibit the CD19 CAR activation signal via the PD-1 domain and CD19-CAR-T cells bearing an iKP CAR (iKP-19-CAR-T) exerted robust cytotoxicity in vitro and antitumor activity in the xenograft model of CD19+HLA-C1- Burkitt's lymphoma parallel to CD19-CAR-T cells, whilst sparing CD19+HLA-C1+ healthy human B cells both in vitro and in the xenograft model. Meanwhile, iKP-19-CAR-T cells exhibited more naïve, less exhausted phenotypes and preserved a higher proportion of central memory T cells (TCM). Our data demonstrates that the KIR/PD-1-based inhibitory CAR can be a promising strategy for preventing B cell aplasia induced by CD19-CAR-T cell therapy.

17.
Am J Physiol Lung Cell Mol Physiol ; 319(6): L932-L940, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32996780

RESUMO

For patients with end-stage lung disease, lung transplantation is a lifesaving therapy. Currently however, the number of patients who require a transplant exceeds the number of donor lungs available. One of the contributing factors to this is the conservative mindset of physicians who are concerned about transplanting marginal lungs due to the potential risk of primary graft dysfunction. Ex vivo lung perfusion (EVLP) technology has allowed for the expansion of donor pool of organs by enabling assessment and reconditioning of these marginal grafts before transplant. Ongoing efforts to optimize the therapeutic potential of EVLP are underway. Researchers have adopted the use of different large and small animal models to generate translational preclinical data. This includes the use of rejected human lungs, pig lungs, and rat lungs. In this review, we summarize some of the key current literature studies relevant to each of the major EVLP model platforms and identify the advantages and disadvantages of each platform. The review aims to guide investigators in choosing an appropriate species model to suit their specific goals of study, and ultimately aid in translation of therapy to meet the growing needs of the patient population.


Assuntos
Lesão Pulmonar/terapia , Transplante de Pulmão , Perfusão , Disfunção Primária do Enxerto , Animais , Humanos , Pulmão/cirurgia , Transplante de Pulmão/métodos , Perfusão/métodos , Disfunção Primária do Enxerto/prevenção & controle , Disfunção Primária do Enxerto/terapia , Respiração Artificial/métodos
18.
Drug Metab Dispos ; 48(11): 1129-1136, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32878767

RESUMO

Cytochrome P450 2J2 (CYP2J2) enzyme attracts more attention because it not only metabolizes clinical drugs but also mediates the biotransformation of important endogenous substances and the regulation of physiologic function. Although CYP2J2 is very important, few animal models are available to study its function in vivo In particular, a CYP2J gene knockout (KO) rat model for drug metabolism and pharmacokinetics is not available. In this report, the CRISPR/Cas9 technology was used to delete rat CYP2J3/10, the orthologous genes of CYP2J2 in humans. The CYP2J3/10 KO rats were viable and fertile and showed no off-target effect. Compared with wild-type (WT) rats, the mRNA and protein expression of CYP2J3/10 in liver, small intestine, and heart of KO rats were completely absent. At the same time, CYP2J4 mRNA expression and protein expression were significantly decreased in these tissues. Further in vitro and in vivo metabolic studies of astemizole, a typical substrate of CYP2J, indicated that CYP2J was functionally inactive in KO rats. The heart function indexes of WT and KO rats were also measured and compared. The myocardial enzymes, including creatine kinase-muscle brain type (CK-MB), creatine kinase (CK), and CK-MB/CK ratio, of KO rats increased by nearly 140%, 80%, and 60%, respectively. In conclusion, this study successfully developed a new CYP2J3/10 KO rat model, which is a useful tool to study the function of CYP2J in drug metabolism and cardiovascular disease. SIGNIFICANCE STATEMENT: Human CYP2J2 is involved not only in clinical drug metabolism but also in the biotransformation of important endogenous substances. Therefore, it is very important to construct new animal models to study its function in vivo. This study successfully developed a new CYP2J knockout rat model by using CRISPR/Cas9 technology. This rat model provides a useful tool to study the role of CYP2J in drug metabolism and diseases.

19.
Cancer Immunol Res ; 8(11): 1426-1439, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32933967

RESUMO

P2X7, a crucial sensor of extracellular ATP, is widely distributed in different immune cells as a potent stimulant of inflammation and immunity. P2X7 is also highly expressed in immunosuppressive cells such as tumor-associated macrophages (TAM) and even tumor cells. However, the function and potential applications of P2X7-mediated immunosuppressive responses in the tumor microenvironment remain unclear. Here, we demonstrated that P2X7 was highly expressed in TAMs and that P2X7 deficiency impaired the "M2-like" polarization of TAMs via downregulation of STAT6 and IRF4 phosphorylation both in vivo and in vitro P2X7 deficiency restricted the progression of urethane-induced lung carcinogenesis and Lewis lung cancer by decreasing tumor cell proliferation and angiogenesis, promoting T-cell mobilization, and reversing M2-like TAM polarization. Thus, deletion or blockade of P2X7 was therapeutic for lung cancer. Furthermore, resistance to both immunotherapy (anti-PD-1 antibody) and chemotherapy (cisplatin) was overcome by coadministration of the P2X7 inhibitors O-ATP, A-438079 hydrochloride, and A-740003. Therefore, our data revealed a vital role of P2X7 in tumor formation through regulating TAM polarization, suggesting the therapeutic potential of P2X7 blockade in patients with lung cancer.

20.
Artigo em Inglês | MEDLINE | ID: mdl-32958268

RESUMO

OBJECTIVES: Ex vivo lung perfusion provides an innovative method to assess and repair donor lungs. The current Toronto ex vivo lung perfusion protocol can reliably and reproducibly preserve lungs for 12 hours. A longer ex vivo lung perfusion preservation time could enable the application of more advanced repair therapies and the rescue of more donor lungs for lung transplant. Our objective was to achieve stable 24-hour normothermic ex vivo lung perfusion. METHODS: We systematically examined 3 modifications of ex vivo lung perfusion perfusate administration in a large animal 24-hour ex vivo lung perfusion model. Pig lungs were assigned to 4 groups (n = 5 per group): (1) control; (2) continuous replacement of ex vivo lung perfusion perfusate; (3) modified feed, which used a modified solution to maintain perfusate osmolality by adjusting glucose and sodium levels; and (4) total parenteral nutrition, in which we added parenteral nutrition to the perfusate. RESULTS: Only 1 lung in the control group completed 24-hour ex vivo lung perfusion. However, 24-hour perfusion was achieved in 4 lungs in the continuous replacement group, 3 lungs in the modified feed group, and 4 lungs in the total parenteral nutrition group. The total parenteral nutrition group achieved significantly longer stable perfusion time compared with control (P = .03). Lung function was significantly improved and inflammatory cytokine production was reduced in the continuous replacement and total parenteral nutrition groups compared with control. CONCLUSIONS: Modifications of ex vivo lung perfusion perfusate toward achieving a stable homeostatic state can extend perfusion time for up to 24 hours. Although these modifications allow for prolonged ex vivo lung perfusion, further research will be required to develop stable lung support beyond 24 hours.

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