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1.
Theriogenology ; 198: 344-355, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36640739

RESUMO

Spermatogenesis is an intricate developmental process occurring in testes by which spermatogonial stem cells (SSCs) self-renew and differentiate into mature sperm. The molecular mechanisms for SSC self-renewal and differentiation, while have been well studied in mice, may differ between mice and domestic animals including pigs. To gain knowledge about the molecular mechanisms for porcine SSC self-renewal and differentiation that have so far been poorly understood, here we isolated and enriched prospermatogonia from neonatal porcine testes, and exposed the cells to retinoic acid, a direct inducer for spermatogonial differentiation. We then identified that retinoic acid could induce porcine prospermatogonial differentiation, which was accompanied by a clear transcriptomic alteration, as revealed by the RNA-sequencing analysis. We also compared retinoic acid-induced in vitro porcine spermatogonial differentiation with the in vivo process, and compared retinoic acid-induced in vitro spermatogonial differentiation between pigs and mice. Furthermore, we analyzed retinoic acid-induced differentially expressed long non-coding RNAs (lncRNAs), and demonstrated that a pig-specific lncRNA, lncRNA-106504875, positively regulated porcine spermatogonial proliferation by targeting the core transcription factor ZBTB16. Taken together, these results would help to elucidate the roles of retinoic acid in porcine spermatogonial differentiation, thereby contributing to further knowledge about the molecular mechanisms underlying porcine SSC development and, in the long run, to optimization of both long-term culture and induced differentiation systems for porcine SSCs.


Assuntos
RNA Longo não Codificante , Tretinoína , Masculino , Animais , Camundongos , Suínos , Tretinoína/farmacologia , Sêmen , Espermatogônias , Testículo , Espermatogênese , Diferenciação Celular
2.
J Environ Manage ; 331: 117300, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36657207

RESUMO

Waste activated sludge has been frequently used as mixed substrate to produce polyhydroxyalkanoate (PHA). However, insufficient research on microbial metabolism has led to difficulties in regulating PHA accumulation in mixed microbial cultures (MMCs). To explore the variation of functional genes during domestication and the effect of different pH conditions on metabolic pathways during PHA accumulation, MMCs were domesticated by adding acetate and propionate with aerobic dynamic feeding strategy for 60 days. As the domestication progressed, the microbial community diversity declined and PHA-producing bacteria, Brevundimonas, Dechloromonas and Hyphomonas, were enriched. Through bacterial function prediction by PICRUSt the gene rpoE involved in starvation resistance of bacteria was enriched after the domestication. The pH value of 8.5 was the best condition for PHA accumulation in MMCs, under which a maximum PHA content reached 23.50% and hydroxybutyric (HB)/hydroxyvaleric (HV) reached 2.22. Untargeted metabolomics analysis exhibited that pH conditions of 7 and 8.5 could promote the up-regulation of significant differential metabolites, while higher alkaline conditions caused the inhibition of metabolic activity. Functional annotation showed that pH condition of 8.5 significantly affected Pyrimidine metabolism, resulting in an increase in PHA production. Regarding the pathways of PHA biosynthesis, acetoacetate was found to be significant in the metabolism of hydroxybutyric, and the alkaline condition could restrain the conversion from hydroxybutyric (HB) to the acetoacetate to protect PHB accumulation in MMCs compared with neutral condition. Taken together, the present results can advance the fundamental understanding of metabolic function in PHA accumulation under different pH conditions.

3.
J Environ Manage ; 331: 117245, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36681034

RESUMO

Models and information and communication technology (ICT) can assist in the effective supervision of urban receiving water bodies and drainage systems. Single model-based decision tools, e.g., water quality models and the pollution source identification (PSI) method, have been widely reported in this field. However, a systematic pathway for environmental decision support system (EDSS) construction by integrating advanced single techniques has rarely been reported, impeding engineering applications. This paper presents an integrated supervision framework (UrbanWQEWIS) involving monitoring-early warning-source identification-emergency disposal to safeguard the urban water quality, where the data, model, equipment and knowledge are smoothly and logically linked. The generic architecture, all-in-one equipment and three key model components are introduced. A pilot EDSS is developed and deployed in the Maozhou River, China, with the assistance of environmental Internet of Things (IoT) technology. These key model components are successfully validated via in situ monitoring data and dye tracing experiments. In particular, fluorescence fingerprint-based qualitative PSI and Bayesian-based quantitative PSI methods are effectively coupled, which can largely reduce system costs and enhance flexibility. The presented supervision framework delivers a state-of-the-art management tool in the digital water era. The proposed technical pathway of EDSS development provides a valuable reference for other regions.

4.
Dalton Trans ; 2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36688608

RESUMO

A rare cadmium-containing windmill-like heteropolyoxoniobate macrocycle has been successfully synthesized with stable 1-D cyclic cluster aggregates. The compound exhibited promising basic catalytic ability for Knoevenagel condensation with a high yield under mild reaction conditions and high cycling stability. The theoretical calculation showed that the promising basic catalytic ability is due to the dense and stronger basic sites of the surface terminal O atoms.

5.
J Med Virol ; 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36597904

RESUMO

Traditional observational studies have suggested a potential association between trans fatty acids (TFAs), which are considered to be health-damaging fatty acids, and COVID-19. However, whether there is a causal relationship between them is currently unclear. We aimed to investigate the causal link between genetically determined TFAs and COVID-19. We performed univariate and multivariate Mendelian randomization (MR) studies using summary statistics from the European Pedigree TFAs (n= 8013), COVID-19 susceptibility (n= 159840), COVID-19 hospitalization (n= 44986), and COVID-19 severity (n= 18152) genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was used as the primary MR analysis, and several other methods were used as supplements. In univariate MR analysis, higher levels of circulating trans, cis-18:2 TFAs were positively associated with a higher COVID-19 hospitalization rate (P<0.0033; OR=1.637; 95% CI: 1.116-2.401) and COVID-19 severity (P<0.0033; OR=2.575; 95% CI: 1.412-4.698). Furthermore, in multivariate MR analysis, trans, cis-18:2 had an independent and significant causal association with a higher COVID-19 hospitalization rate (P=0.00044; OR=1.862; 95% CI= 1.316-2.636) and COVID-19 severity (P=0.0016; OR=2.268; 95% CI=1.361-3.779) after the five TFAs were adjusted for each other. Together, our findings provide evidence that trans, cis-18:2 TFAs have an independent and robust causal effect on COVID-19 hospitalization and severity. This article is protected by copyright. All rights reserved.

6.
Signal Transduct Target Ther ; 8(1): 8, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36596785

RESUMO

Brain tumors, although rare, contribute to distinct mortality and morbidity at all ages. Although there are few therapeutic options for brain tumors, enhanced biological understanding and unexampled innovations in targeted therapies and immunotherapies have considerably improved patients' prognoses. Nonetheless, the reduced response rates and unavoidable drug resistance of currently available treatment approaches have become a barrier to further improvement in brain tumor (glioma, meningioma, CNS germ cell tumors, and CNS lymphoma) treatment. Previous literature data revealed that several different signaling pathways are dysregulated in brain tumor. Importantly, a better understanding of targeting signaling pathways that influences malignant behavior of brain tumor cells might open the way for the development of novel targeted therapies. Thus, there is an urgent need for a more comprehensive understanding of the pathogenesis of these brain tumors, which might result in greater progress in therapeutic approaches. This paper began with a brief description of the epidemiology, incidence, risk factors, as well as survival of brain tumors. Next, the major signaling pathways underlying these brain tumors' pathogenesis and current progress in therapies, including clinical trials, targeted therapies, immunotherapies, and system therapies, have been systemically reviewed and discussed. Finally, future perspective and challenges of development of novel therapeutic strategies in brain tumor were emphasized.


Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/tratamento farmacológico , Encéfalo/patologia , Transdução de Sinais , Imunoterapia
7.
Analyst ; 2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36594781

RESUMO

Here, hydrophilic carbon dots (H-CDs) are prepared by a facile room temperature method. The strength of hydrogen bonds can be controlled by introducing proton and aprotic solvents, respectively, so as to realize the tunable aggregation state of H-CDs. Because of the ultrasensitive response to dimethyl sulfoxide (DMSO), H-CDs can serve as optical probes for detecting DMSO in a linear range of 0.005% to 0.75% and with a detection limit of 0.001%.

8.
BMC Oral Health ; 23(1): 14, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627695

RESUMO

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ) is a serious debilitating disease caused by anti-resorption and anti-angiogenesis drugs, significantly affecting patients' quality of life. Recent studies suggested that primary gingival wound healing may effectively prevent the development of MRONJ. This study aimed to evaluate the effects of low-level light therapy (LLLT) on promoting gingival wound healing in extraction sockets of MRONJ-like mice and preventing the occurrence of MRONJ. Furthermore, we explored underlying mechanisms. METHODS: Mice were randomly divided into the Ctrl, Zol, and Zol + LLLT groups. Administration of zoledronate and tooth extraction of bilateral maxillary second molars were used to build the MRONJ model, and LLLT was locally administered into the tooth sockets to examine the effect of LLLT. Next, to explore the function of IL-1RA, we performed LLLT with interleukin-1 receptor antagonist (IL-1RA) neutralizing antibody (named Zol + LLLT + IL-1RA NAb group) or negative control antibodies for tooth extraction in subsequent rescue animal experiments. Stereoscope observations, micro-computed tomography, and histological examination were conducted to evaluate gingival wound healing and bone regeneration in tooth sockets. The effects of LLLT on the migration capacities of zoledronate-treated epithelial cells were assessed in vitro. RESULTS: LLLT promoted primary gingival wound healing without exposed necrotic bone. Micro-computed tomography results showed higher bone volume and mineral density of the tooth sockets after LLLT. Histology analysis showed complete gingival coverage, obvious bone regeneration, and reduced soft tissue inflammation, with down-regulated pro-inflammation cytokines, like interleukin-1 beta (IL-1ß) and tumor necrosis factor-α (TNF-α), and up-regulated IL-1RA expression in the gingival tissue in the LLLT group. The rescue assay further showed that the effects of LLLT promoting gingival wound healing and preventing MRONJ might be partially abolished by IL-1RA neutralizing antibodies. In vitro studies demonstrated that LLLT accelerated zoledronate-treated epithelial cell migration. CONCLUSIONS: LLLT might promote primary gingival wound healing and contribute to subsequent bone regeneration of the tooth extractions in MRONJ-like lesions via IL-1RA-mediated pro-inflammation signaling suppression.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos , Conservadores da Densidade Óssea , Doenças da Gengiva , Terapia com Luz de Baixa Intensidade , Animais , Camundongos , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças da Gengiva/radioterapia , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Qualidade de Vida , Extração Dentária , Cicatrização , Microtomografia por Raio-X , Ácido Zoledrônico/efeitos adversos
9.
Int J Biol Macromol ; : 123219, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36642357

RESUMO

Histone deacetylase 6 (HDAC6) is the only member of the HDAC family that resides primarily in the cytoplasm with two catalytic domains and a ubiquitin-binding domain. HDAC6 is highly expressed in various solid tumors and participates in a wide range of biological activities, including hormone receptors, the p53 signaling pathway, and the kinase cascade signaling pathway due to its unique structural foundation and abundant substrate types. Additionally, HDAC6 can function as an oncogenic factor in solid tumors, boosting tumor cell proliferation, invasion and metastasis, drug resistance, stemness, and lowering tumor cell immunogenicity, so assisting in carcinogenesis. Pan-HDAC inhibitors for cancer prevention are associated with potential cardiotoxicity in clinical investigations. It's interesting that HDAC6 silencing didn't cause any significant harm to normal cells. Currently, the use of HDAC6 specific inhibitors, individually or in combination, is among the most promising therapies in solid tumors. This review's objective is to give a general overview of the structure, biological functions, and mechanism of HDAC6 in solid tumor cells and in the immunological milieu and discuss the preclinical and clinical trials of selective HDAC6 inhibitors. These endeavors highlight that targeting HDAC6 could effectively kill tumor cells and enhance patients' immunity during solid tumor therapy.

10.
mBio ; : e0317622, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625591

RESUMO

The rapid spread and strong immune evasion of the SARS-CoV-2 Omicron subvariants has raised serious concerns for the global COVID-19 pandemic. These new variants exhibit generally reduced fusogenicity and increased endosomal entry pathway utilization compared to the ancestral D614G variant, the underlying mechanisms of which remain elusive. Here, we show that the C-terminal S1 mutations of the BA.1.1 subvariant, H655Y and T547K, critically govern the low fusogenicity of Omicron. Notably, H655Y also dictates the enhanced endosome entry pathway utilization. Mechanistically, T547K and H655Y likely stabilize the spike trimer conformation as suggested by increased molecular interactions in structural modeling and enhanced S1 shedding of their reversion mutants K547T and Y655H in viral producer cells. Importantly, the H655Y mutation also determines the low fusogenicity and enhanced dependence on the endosomal entry pathway of other Omicron subvariants, including BA.2, BA.2.12.1, BA.4/5, and BA.2.75. Together, these results uncover mechanisms governing Omicron subvariant entry and provide insights into altered Omicron tissue tropism and pathogenesis. IMPORTANCE Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and reduced disease severity; however, the underlying mechanism is not fully understood. In addition, whether the most recent Omicron subvariants, including BA.5 and BA.2.75, use the same pathway as their ancestor for entry is currently not known. In this study, we show that T547K and H655Y mutations in the C terminus of the S1 subunit critically determine the enhanced dependence on the endosomal entry pathway as well as the reduced cell-cell fusion activity of Omicron BA.1, BA.1.1, and other subvariants. Further experiments and molecular modeling suggest that H655Y and K547T stabilize the spike trimer conformation, likely contributing to the decreased fusogenicity and endosomal entry. Our work uncovers novel mechanisms underlying the distinct entry pathway of Omicron subvariants and advances our understanding of their biological characteristics.

11.
Artigo em Inglês | MEDLINE | ID: mdl-36690855

RESUMO

The intensive and long-term use of atrazine (ATZ) has led to the contamination of agricultural soils and non-target organisms, posing a series of threats to human health through the transmission of the food chain. In this study, a 60-day greenhouse pot experiment was carried out to explore the phytoremediation by Chrysopogon zizanioides L. (vetiver). The uptake, accumulation, distribution, and removal of ATZ were investigated, and the degradation mechanisms were elucidated. The results showed that the growth of vetiver was inhibited in the first 10 days of the incubation; subsequently, the plant recovered rapidly with time going. Vetiver grass was capable of taking up ATZ from the soil, with root concentration factor ranging from 2.36 to 15.55, and translocating to the shoots, with shoot concentration factor ranging from 7.51 to 17.52. The dissipation of ATZ in the rhizosphere soil (97.51%) was significantly higher than that in the vetiver-unplanted soil (85.14%) at day 60. Metabolites were identified as hydroxyatrazine (HA), deethylatrazine (DEA), deisopropylatrazine (DIA), and didealkylatrazine (DDA) in the samples of the shoots and roots of vetiver as well as the soils treated with ATZ. HA, DEA, DIA, and DDA were reported first time as metabolites of ATZ in shoots and roots of vetiver grown in soil. The presence of vetiver changed the formation and distribution of the dealkylated products in the rhizosphere soil, which remarkably enhanced the occurrence of DEA, DIA, and DDA. Arthrobacter, Bradyrhizobium, Nocardioides, and Rhodococcus were the major atrazine-degrading bacterial genera, which might be responsible for ATZ degradation in the rhizosphere soil. Our findings suggested that vetiver grass can significantly promote ATZ degradation in the soil, and it could be a strategy for remediation of the atrazine-contaminated agricultural soil.

12.
Arthritis Res Ther ; 25(1): 9, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36639641

RESUMO

OBJECTIVE: To investigate the clinical characteristics and the site of pulmonary involvement in Takayasu arteritis (TAK) patients with pulmonary artery involvement (PAI). METHODS: We retrospectively investigated data of 141 TAK patients. The clinical and image data of the patients with and without PAI were analyzed and compared. The patients were followed up. The major outcome was all-cause mortality. The minor outcome was exacerbation or new occurrence of PAI, which leads to disease progression events. RESULTS: For the 141 TAK patients considered, PAI was detected in 65 (46.1%) patients. TAK patients with PAI had a significantly higher cumulative incidence of events than those without PAI (P < 0.001). The frequencies of the following were significantly higher in TAK with PAI than those in TAK without PAI: disease duration [median 96 months (IQR: 24-174) vs. median 42 months (IQR: 6-120); P = 0.012], hemoptysis (10.8% vs. 1.32%; P = 0.040), oppression in the chest (40.0% vs. 21.1%; P = 0.014), fever (23.1% vs. 9.21%; P = 0.024), Mycobacterium tuberculosis infection (21.5% vs. 6.57%; P = 0.010), pulmonary hypertension (PAH) (21.5% vs. 2.6%; P < 0.001), pulmonary infarction (41.5% vs. 0%; P < 0.001), and hypoxemia (18.5% vs. 1.3%; P < 0.001). Multivariate logistic regression analysis of data of TAK patients with symptom presentation showed that oppression in the chest (OR: 2.304; 95% CI: 1.024-5.183; P = 0.044) and thoracic aorta involvement (OR: 2.819; 95% CI: 1.165-6.833; P = 0.022) were associated with PAI. The cluster analysis performed for data of TAK patients with PAI revealed that the cluster characterized as the upper lobe of the right lung (Cluster1) had the worst prognosis. CONCLUSION: In TAK, PAI is associated with thoracic aorta involvement. In TAK patients with PAI, the involvement of the upper lobe of the right lung is characterized with the worst prognosis.


Assuntos
Hipertensão Pulmonar , Arterite de Takayasu , Humanos , Arterite de Takayasu/epidemiologia , Artéria Pulmonar , Estudos Retrospectivos , Análise por Conglomerados
13.
Pharmaceuticals (Basel) ; 16(1)2023 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-36678594

RESUMO

BACKGROUND: Although ibrutinib has been widely used to treat haematological malignancies, many studies have reported associated cardiovascular events. These studies were primarily animal experiments and clinical trials. For more rational clinical drug use, a study based on post-marketing data is necessary. AIM: Based on post-marketing data, we investigated the clinical features, time to onset, and outcomes of potential cardiovascular toxicities of ibrutinib. METHODS: This disproportionality study utilised data from the 2014-2021 United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. We used two disproportionality methods information component (IC) and reporting odds ratio (ROR)) to detect the potential cardiovascular toxicities of ibrutinib. Positive signals were defined as IC025 > 0 and ROR025 > 1. RESULTS: A total of 10 cardiovascular events showed positive signals: supraventricular tachyarrhythmias, haemorrhagic central nervous system vascular conditions, ventricular tachyarrhythmias, cardiac failure, ischaemic central nervous system vascular conditions, cardiomyopathy, conduction defects, myocardial infarction, myocardial infarction disorders of sinus node function, and torsade de pointes/QT prolongation. Cardiomyopathy and supraventricular tachyarrhythmias were the two most common signals. Disorders of sinus node function were observed for the first time, which may be a new adverse effect of ibrutinib. CONCLUSIONS: This pharmacovigilance study systematically explored the adverse cardiovascular events of ibrutinib and provided new safety signals based on past safety information. Attention should be paid to some high-risk signals.

14.
Cell Death Differ ; 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681781

RESUMO

cGAS/DncV-like nucleotidyltransferase (CD-NTase) family members are immune sensors that synthesize diverse nucleotide signals to initiate antiviral response in bacteria and animals. As a founding member of CD-NTase enzyme, cGAS has been identified as a key sensor for cytoplasmic DNA and type I interferons (IFNs) signaling in metazoan. However, the functions of other metazoan CD-NTases remain enigmatic. Here, we showed that Mab-21 domain-containing protein 2 (MB21D2), another member of the CD-NTase family, plays a positive role in modulating the cGAS-STING signaling in myeloid cells. Deficiency of MB21D2 in THP-1 cells or mice macrophages led to impaired production of type I interferon upon DNA stimulation. Consistently, Mb21d2-/- mice showed more susceptible to infection with DNA virus and faster growth of melanoma, compared to its counterparts. Mechanistically, MB21D2 specially bound with the N-terminal of cGAS, facilitated its liquid phase condensation and DNA-binding activity, leading to the enhanced production of cGAMP and subsequent IFN-ß production. Thus, our findings unveiled that the CD-NTase family member MB21D2 contributes to host antiviral and antitumor responses by enhancing cGAS activation.

15.
Heliyon ; 9(1): e12461, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36685424

RESUMO

Valproic acid (VPA) is a commonly used antiepileptic drug (AED). Aplastic crisis is defined as acute arrest of hematopoiesis. Stevens-Johnson syndrome (SJS) is a fatal cutaneous adverse drug reaction. We herein report a rare case of aplastic crisis and SJS in a single pediatric patient that were probably caused by VPA. A 2-year-old girl was involved in a car accident. She was diagnosed with skull fractures, cerebral contusions, pulmonary contusions, and fractures of the left iliac bone by computed tomography. VPA was administered as prophylaxis for post-traumatic epilepsy. From day 13, she developed repeated high fevers, and multiple antibiotics were ineffective; she was then transferred to our pediatric intensive care unit. After transfer, she developed liver function impairment, decreased peripheral blood cell counts, and skin damage. After withdrawal of the VPA and administration of prednisone, intravenous immunoglobulin, local skin care, and nutritional support, her body temperature normalized and her hematopoietic function and skin lesions successively resolved. She was transferred out of the pediatric intensive care unit on day 56 and discharged on day 70. At the 6-month follow-up, a blood examination was normal, and repeat computed tomography revealed multiple softening foci of the bilateral brain and less subdural effusion than before. To our knowledge, no report to date has described aplastic crisis and SJS in a single patient. The purpose of this paper is to increase clinicians' knowledge in the treatment of adverse drug reactions (ADRs) and emphasize the importance of standardized application and strict monitoring of VPA in patients with post-traumatic brain trauma.

16.
Adv Ther ; 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36648737

RESUMO

INTRODUCTION: The randomized phase III KEYNOTE-522 trial demonstrated that addition of pembrolizumab to neoadjuvant chemotherapy provided a significant improvement in event-free survival and a favorable trend in overall survival for high-risk early-stage triple-negative breast cancer (eTNBC). This analysis evaluated the cost-effectiveness of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single-agent adjuvant treatment after surgery vs. neoadjuvant chemotherapy for patients with high-risk eTNBC in the USA. METHODS: The analysis was conducted from a US third-party public healthcare payer perspective. A multistate transition model was developed using efficacy and safety data from the KEYNOTE-522 trial. The model included four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death to simulate patients' lifetime disease course. Quality-adjusted life years (QALYs) were calculated on the basis of EuroQoL-5 Dimensions utility data collected in KEYNOTE-522. Costs for drug acquisition/administration, adverse events, disease management, and subsequent therapies were reported (2021 US dollars). Costs and outcomes were discounted at 3% annually. A series of sensitivity analyses were performed to test the robustness of the main results. RESULTS: In the base case scenario, pembrolizumab plus chemotherapy followed by pembrolizumab resulted in expected gains of 3.37 life years (LYs) and 2.90 QALYs, and an incremental cost of $79,046 versus chemotherapy. The incremental cost per QALY gained was $27,285, which is lower than all commonly cited US willingness-to-pay thresholds. Sensitivity analyses showed the results were robust over plausible values of key model inputs and assumptions. CONCLUSIONS: Compared with neoadjuvant chemotherapy, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single-agent adjuvant treatment after surgery is considered a cost-effective option for high-risk eTNBC in the USA.

17.
PeerJ ; 11: e14614, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36650838

RESUMO

Background: Hypertrophic cardiomyopathy (HCM) and hypertension coexist fairly frequently in clinical practice. However, the evidence about the impact of hypertension on the prognosis of HCM is limited. The present study aims to investigate the impact of hypertension on the prognosis of HCM patients. Methods: A total of 468 HCM patients were enrolled, and patients were divided into hypertension group (31.8%) and non-hypertension group (68.2%). The primary study endpoint was HCM-related death, consisting of heart failure (HF)-related death, stroke-related death and sudden cardiac death (SCD). Associations between hypertension and HCM-related death were analyzed by Cox regression models with the use of propensity score matching (PSM) as primary analysis. Results: There were 55 HCM-related death during a median follow-up time of 4.6 years, and the mortality rate was 2.53 per 100 person years. Kaplan-Meier analysis based on the crude cohort or PSM cohort revealed no significant difference regarding the HCM-related death between the two groups. In the crude cohort, both univariable and multivariable Cox regression analysis indicated that hypertension was not significantly associated with HCM-related death with hazard ratios (HR) at 0.74 (95% CI [0.40-1.36], p value: 0.329) and 0.77 (95% CI [0.35-1.71], p value: 0.521), respectively. Similarly, no strong evidence for an association was observed between hypertension and HCM-related death in the PSM cohort with unadjusted HR at 0.90 (95% CI [0.34-2.41]; p value: 0.838) and adjusted HR at 0.77 (95% CI [0.35-1.71]; p value: 0.521), respectively. Other propensity score methods, including overlap weighting and inverse probability treatment weighting demonstrated similar results. Sensitivity analysis also indicated that the concomitant hypertension did not significantly increase the risk of HF-related death, stroke-related death or SCD in HCM patients. Conclusion: HCM-related death did not significantly differ between hypertension and non-hypertension groups, suggesting a negative impact of hypertension on the clinical prognosis of HCM patients.


Assuntos
Cardiomiopatia Hipertrófica , Insuficiência Cardíaca , Hipertensão , Acidente Vascular Cerebral , Humanos , Estudos Retrospectivos , Fatores de Risco , Cardiomiopatia Hipertrófica/complicações , Morte Súbita Cardíaca , Insuficiência Cardíaca/complicações , Hipertensão/epidemiologia , Prognóstico , Acidente Vascular Cerebral/complicações
18.
Mater Today Bio ; 18: 100535, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36654965

RESUMO

The repair of annulus fibrosus (AF) defect after discectomy in the intervertebral disc (IVD) has presented a challenge over the past decade. Hostile microenvironments in the IVD, including, compression and hypoxia, are critical issues that require special attention. Till date, little information is available on potential strategies to cope with the hypoxia dilemma in AF defect sites. In this study, perfluorotributylamine (PFTBA) core-shell fibers were fabricated by coaxial electrospinning to construct oxygen-releasing scaffold for promoting endogenous repair in the AF after discectomy. We demonstrated that PFTBA fibers (10% chitosan, chitosan: PCL, 1:6) could release oxygen for up to 144 â€‹h. The oxygen released from PFTBA fibers was found to protect annulus fibrosus stem cells (AFSCs) from hypoxia-induced apoptosis. In addition, the PFTBA fibers were able to promote proliferation, migration and extracellular matrix (ECM) production in AFSCs under hypoxia, highlighting their therapeutic potential in AF defect repair. Subsequent in vivo studies demonstrated that oxygen-supplying fibers were capable of ameliorating disc degeneration after discectomy, which was evidenced by improved disc height and morphological integrity in rats with the oxygen-releasing scaffolds. Further transcriptome analysis indicated that differential expression genes (DEGs) were enriched in "oxygen transport" and "angiogenesis", which likely contributed to their beneficial effect on endogenous AF regeneration. In summary, the oxygen-releasing scaffold provides novel insights into the oxygen regulation by bioactive materials and raises the therapeutic possibility of oxygen supply strategies for defect repair in AF, as well as other aerobic tissues.

19.
Artigo em Inglês | MEDLINE | ID: mdl-36658098

RESUMO

Solid-state lithium batteries are promising and safe energy storage devices for mobile electronics and electric vehicles. In this work, we report a facile in situ polymerization of 1,3-dioxolane electrolytes to fabricate integrated solid-state lithium batteries. The in situ polymerization and formation of solid-state dioxolane electrolytes on interconnected carbon nanotubes (CNTs) and active materials is the key to realizing a high-performance battery with excellent interfacial contact among CNTs, active materials and electrolytes. Therefore, the electrodes could be tightly integrated into batteries through the CNTs and electrolyte. Electrons/ions enable full access to active materials in the whole electrode. Electrodes with a low resistance of 4.5 Ω â–¡-1 and high lithium-ion diffusion efficiency of 2.5×10-11 cm2 s-1 can significantly improve the electrochemical kinetics. Subsequently, the batteries demonstrated high energy density, amazing charge/discharge rate and long cycle life.

20.
Blood Adv ; 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36661340

RESUMO

As a member of the RUNT domain family core-binding transcription factors, RUNX1 is crucial for multiple stages of hematopoiesis and its mutation can cause familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML). Previous work has established that RUNX1 is involved in the maturation of megakaryocytes and the production of platelets. Recently studies have shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of vWF and CD41 at the apex of the HSC hierarchy, termed MK-HSCs, which can give rise to megakaryocytes without going through the traditional differentiation trajectory from HSC via MPP and MEP. Here, by using Runx1F/FMx1-Cre mouse model we discovered that the MK-HSC to megakaryocyte direct differentiation can happen within one cell division and RUNX1 is an important regulator in the process. Runx1 knockout results in a drastic decrease in platelet counts and a severe defect in the differentiation from MK-HSCs to megakaryocytes. Single cell RNA sequencing (RNAseq) analysis shows that MK-HSCs have a distinct gene expression signature compared with non-MK-HSCs, and Runx1 deletion alters the platelet and megakaryocyte related gene expression in MK-HSCs. Further bulk RNAseq and Cut & Run analyses show that RUNX1 binds to multiple essential megakaryocyte/platelet developmental genes such as Spi1, Selp and Itga2b and regulates their expressions in MK-HSCs. Thus, by modulating the expression of megakaryocyte-related genes, RUNX1 governs the direct differentiation of MK-HSCs to megakaryocytes and platelets.

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