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1.
PLoS One ; 19(4): e0302104, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38625864

RESUMEN

The explosive growth of dialogue data has aroused significant interest among scholars in abstractive dialogue summarization. In this paper, we propose a novel sequence-to-sequence framework called DS-SS (Dialogue Summarization with Factual-Statement Fusion and Dialogue Segmentation) for summarizing dialogues. The novelty of the DS-SS framework mainly lies in two aspects: 1) Factual statements are extracted from the source dialogue and combined with the source dialogue to perform the further dialogue encoding; and 2) A dialogue segmenter is trained and used to separate a dialogue to be encoded into several topic-coherent segments. Thanks to these two aspects, the proposed framework may better encode dialogues, thereby generating summaries exhibiting higher factual consistency and informativeness. Experimental results on two large-scale datasets SAMSum and DialogSum demonstrate the superiority of our framework over strong baselines, as evidenced by both automatic evaluation metrics and human evaluation.

2.
Ear Nose Throat J ; : 1455613241228079, 2024 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-38345004

RESUMEN

Objectives: Understanding the interaction between marital status and gender, race, and age is important for developing tailored interventions aimed at improving socio-emotional support for patients. Therefore, the objective of this study is to explore the correlation between marital status and hypopharynx squamous cell carcinoma (SCC) and whether the association varied by age, race, and gender. Methods: We examined the clinicopathological variables using chi-squared tests and we evaluated the association between survival and different variables using the methods of Kaplan-Meier. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. Results: A total of 1686 patients were analyzed. The rate of being married was lower among African American, and this rate decreased with higher tumor stage. While both married male and female survivors benefit from their marital status, subgroups analysis shows a differential in overall survival (OS) based on gender, with males benefiting more than females. Patients who were divorced/separated [male hazard ratio (HR) = 1.214, 95% confidence interval (CI): 0.985-1.495; female HR = 1. 159, 95% CI: 0.691-1.945], never married (male HR = 1.476, 95% CI: 1.234-1.765; female HR = 1.422, 95% CI: 0.901-2.245), and widowed (male HR = 1.795, 95% CI: 1.390-2.317; female HR = 1.663, 95% CI: 1.081-2.559) had increased hazard of OS compared with married/partnered patients. The effect of marital status was significantly associated with treatment outcome only in Caucasian patients who harbored well/moderately differentiated and nonmetastatic disease (P < .001). Conclusion: While there are survival benefits for married patients with hypopharynx SCC, married/partnered males may benefit more than females. Age, race, and gender could affect the correlation between marital status and survival.

3.
Cell Mol Life Sci ; 80(12): 349, 2023 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-37930405

RESUMEN

Atoh1 overexpression is essential for hair cell (HC) regeneration in the sensory epithelium of mammalian auditory and vestibular organs. However, Atoh1 overexpression alone cannot induce fully mature and functional HCs in the mammalian inner ear. In the current study, we investigated the effect of Atoh1 constitutive overexpression in native HCs by manipulating Atoh1 expression at different developmental stages. We demonstrated that constitutive overexpression of Atoh1 in native vestibular HCs did not affect cell survival but did impair vestibular function by interfering with the subtype differentiation of HCs and hair bundle development. In contrast, Atoh1 overexpression in cochlear HCs impeded their maturation, eventually leading to gradual HC loss in the cochlea and hearing dysfunction. Our study suggests that time-restricted Atoh1 expression is essential for the differentiation and survival of HCs in the inner ear, and this is pivotal for both hearing and vestibular function re-establishment through Atoh1 overexpression-induced HC regeneration strategies.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Oído Interno , Células Ciliadas Auditivas , Animales , Diferenciación Celular , Supervivencia Celular , Cóclea , Mamíferos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/fisiología
4.
World J Clin Cases ; 11(27): 6653-6663, 2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37900249

RESUMEN

BACKGROUND: Neurofibromas are benign tumors of a neurogenic origin. If these tumors occur without any other signs of neurofibromatosis, they are classified as isolated neurofibromas. Neurofibromas in the oral cavity mostly occur within soft tissues, indicating that solitary intraosseous neurofibromas in the mandible are rare. Due to the absence of specific clinical manifestations, early diagnosis and treatment of these tumors are difficult to achieve. CASE SUMMARY: A 37-year-old female patient visited our hospital due to numbness and swelling of the gums in the right lower molar area that had persisted for half a month. The patient's overall condition and intraoral examination revealed no significant abnormalities. She was initially diagnosed with a cystic lesion in the right mandible. However, after a more thorough examination, the final pathological diagnosis was confirmed to be neurofibroma. Complete tumor resection and partial removal of the right inferior alveolar nerve were performed. As of writing this report, there have been no signs of tumor recurrence for nine months following the surgery. CONCLUSION: This case report discusses the key features that are useful for differentiating solitary intraosseous neurofibromas from other cystic lesions.

5.
Dalton Trans ; 52(32): 11272-11284, 2023 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-37526923

RESUMEN

The activation capacity of molecular oxygen is an important indicator to evaluate the photocatalytic efficiency of photocatalysts. In this paper, WS2 nanosheet was deposited on hyper-crosslinked CTF-1-G (obtained by molecular expansion from covalent triazine framework CTF-1) to form a C-GW heterojunction, which promoted the photodegradation of pollutants and the activation of molecular oxygen. This novel C-GW heterojunction exhibited excellent degradation property for organic pollutants (tetracycline (TC), rhodamine B (RhB)) and activating molecular oxygen under visible light irradiation. Among them, C-GW15 could degrade 98% of 20 ppm TC in 60 min and 99% of 30 ppm RhB in 30 min, and it had the highest hydrogen generation rate and hydrogen production amount in 4 hours, which were 8.74 mmol h-1 g-1 and 34.94 mmol g-1, respectively. Meanwhile, C-GW15 had the strongest 3,3',5,5'-tetramethylbenzidine oxidation capacity and could generate 1.83 µmol of ˙O2- in 60 min and the production of H2O2 was 20.8 µmol L-1 in 40 min. The results of this study clearly indicated that the combination of WS2 and CTF-1-G can enhance the visible light absorption capacity and photogenerated carrier separation efficiency, thus promoting the photocatalytic performance. Finally, a Z-type photocatalytic mechanism was proposed based on radical capture, molecular oxygen activation experiments and electron spin resonance analysis. These findings will extend the fundamental understanding of the Z-type photocatalytic mechanism and provide new opportunities for the rational design of CTF heterojunctions for the treatment of environmental pollution and clean energy conversion.

6.
Ear Nose Throat J ; : 1455613231191010, 2023 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-37632345

RESUMEN

Background: The objective of this study is to assess whether the impact of marital status on oral tongue squamous cell carcinomas (OTSCC) prognosis varied by gender, age, and race. Methods: We examined the clinicopathological variables using chi-squared tests, and we evaluated the association between survival and different variables using the methods of Kaplan-Meier. Univariate and multivariate analyses were performed to determine the effects of each variable on survival. Results: A total of 5282 patients were analyzed. The rate of being married was higher among Asian or Caucasian, and this rate decreased with higher tumor stage. While both married male and female survivors benefit from their marital status, we found a differential in OS based on gender, with females benefiting more than males (male P = .038; female P = .009, respectively). Patients who were divorced/separated/widowed (male HR = 1.275, 95% CI: 1.085-1.499; female HR = 1.313, 95% CI: 1.083-1.593) and never married (male HR = 1.164, 95% CI: 0.983-1.378; female HR = 1.224, 95% CI: 0.958-1.565) had increased hazard of OS compared with married/partnered patients (male P = .038; female P = .009). Subgroups analysis shows that the effect of marital status was significantly associated with treatment outcome only in Caucasian patients aged 50 years or older who harbored non-metastatic disease and received surgery (P < .001). Conclusion: While there are survival benefits for married patients with OTSCC, married/partnered females may benefit more than males. Age, race, and gender could affect the correlation between marital status and survival.

7.
ACS Appl Mater Interfaces ; 14(49): 54885-54894, 2022 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-36459636

RESUMEN

Regulation of the exciton generation, diffusion, and carrier transport, as well as optimization of the non-radiative energy loss could further overcome the power conversion efficiency limitation of organic solar cells. However, the relationship between exciton properties and non-radiative energy loss has seldom been investigated. Herein, taking D18-series devices as the research model, the exciton diffusion length (LD) and hole transfer dynamics can be remarkably improved by the variation of electron-withdrawing halogen and the non-radiative energy loss simultaneously can be suppressed. By combining the analysis results of hole transfer, exciton diffusion, charge separation, and recombination, this work demonstrates that the photo-induced exciton in the chlorinated polymer donor can diffuse to a longer distance within the effective exciton lifetime, suppress the exciton recombination, and enhance device performance. The results define the relationship between the exciton behaviors and non-radiative energy loss and further reveal the significance of controlling the bulk heterojunction with superior photo-physical properties.

8.
Clin Transl Med ; 12(10): e1052, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36178017

RESUMEN

BACKGROUND: The inner ear organ is a delicate tissue consisting of hair cells (HCs) and supporting cells (SCs).The mammalian inner ear HCs are terminally differentiated cells that cannot spontaneously regenerate in adults. Epithelial non-hair cells (ENHCs) in the utricle include HC progenitors and SCs, and the progenitors share similar characteristics with SCs in the neonatal inner ear. METHODS: We applied single-cell sequencing to whole mouse utricles from the neonatal period to adulthood, including samples from postnatal day (P)2, P7 and P30 mice. Furthermore, using transgenic mice and immunostaining, we traced the source of new HC generation. RESULTS: We identified several sensory epithelial cell clusters and further found that new HCs arose mainly through differentiation from Sox9+ progenitor cells and that only a few cells were produced by mitotic proliferation in both neonatal and adult mouse utricles. In addition, we identified the proliferative cells using the marker UbcH10 and demonstrated that in adulthood the mitotically generated HCs were primarily found in the extrastriola. Moreover, we observed that not only Type II, but also Type I HCs could be regenerated by either mitotic cell proliferation or progenitor cell differentiation. CONCLUSIONS: Overall, our findings expand our understanding of ENHC cell fate and the characteristics of the vestibular organs in mammals over the course of development.


Asunto(s)
Células Ciliadas Auditivas , Células Ciliadas Vestibulares , Animales , Células Ciliadas Auditivas Internas , Mamíferos , Ratones , Ratones Transgénicos , Regeneración , Sáculo y Utrículo
9.
Front Microbiol ; 13: 898184, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35633695

RESUMEN

The fact that wild felines are carriers of pernicious infectious viruses should be a major concern due to the potential cross-species transmission between the felines and human or domestic animals. However, studies on the virus in the captive wild felines, especially in tigers, are thin on the ground. In this study, we screened four infectious viruses, namely, feline parvovirus (FPV), feline coronavirus (FCoV), canine distemper virus (CDV), and influenza A virus (IAV), in the blood samples of 285 captive Siberian tigers (Panthera tigris altaica) and in the spleen samples of two deceased lions (Panthera leo), which were collected from 2019 to 2021 in three Siberian Tiger Parks from the northeast of China. Nucleic acids isolated from the blood samples collected from tigers and the spleen samples collected from two deceased lions were positive for FPV by PCR, and the positive rate was 4.6% (13/285) in tigers. Furthermore, the VP2 gene of FPV was amplified by nested PCR, and the sequences of the VP2 gene from these six FPV positive strains shared 98.3-99.9% homology with the reference. The key amino acid sites of VP2 protein were consistent with that of FPV reference strains. Phylogenetic analysis based on the VP2 gene showed that in this study, FPV-positive strains were grouped within the FPV clade and closely related to the Asian strains clade. The results of this study showed that FPV circulated in the captive Siberian tigers and lions in northeastern China and provided valuable information for the study of FPV epidemiology in wild felines. Therefore, we suggest that regular antibody monitoring and booster immunization for tigers should be performed.

10.
Chemosphere ; 299: 134367, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35358559

RESUMEN

Per-and polyfluoroalkyl substances (PFASs) have been omnipresent in the environment and marine organisms. However, little is known about these compounds and their associations with hematological parameters in dogs. In this research, we investigated the concentrations and distributions of PFASs in the blood of dogs and explored the associations between PFASs concentrations in blood and hematological parameters. Perfluorooctanoate (PFOA) was found to be the dominant PFAS in the blood (54.23%), followed by perfluorobutyric acid (PFBA) (16.05%) and perfluorooctanesulfonate (PFOS) (12.05%). On average, PFASs concentration in dogs was 3.553 ng/mL (SD: 2.146). Moreover, age is a key factor influencing the levels of PFBA, PFOA, and PFBS in males, as well as seven PFASs (6:2 Cl-PFESA, PFBA, PFOA, PFOS, PFHxS, PFDA, and PFNA) in female dogs' blood. The results revealed that PFHxS in dietary food accounted for most of the total daily PFASs consumption. We also discovered that greater PFASs exposure (including PFOA and PFOS) could significantly increase amylase (AMY) and decrease cholesterol (CHOL) levels. Furthermore, there are linear relationships between PFDA, PFNA and many biochemical parameters (AMY, CHOL, albumin/globulin (A/G), blood urea nitrogen (BUN), alkaline phosphatase (ALP), creatinine (CREA)). Thus, PFAS accumulation has a certain influence on dogs' health, and we must pay attention to the potential threat posed by these elements to dogs.


Asunto(s)
Ácidos Alcanesulfónicos , Contaminantes Ambientales , Fluorocarburos , Animales , China , Dieta , Perros , Femenino , Fluorocarburos/análisis , Humanos , Masculino , Policia
11.
Transbound Emerg Dis ; 69(5): e1434-e1444, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35152562

RESUMEN

Our study investigated the prevalence of feline herpesvirus-1 (FHV-1), feline calicivirus (FCV), feline immunodeficiency virus (FIV), and feline leukemia virus (FeLV) in captive Siberian tigers in Northeastern China. A total of 324 blood samples and 33 nasopharyngeal swab samples of Siberian tigers collected from 2019 to 2021 in three cities were investigated by nested PCR. The results showed that 28.1% (91/324) tigers were infected with at least one virus; the positive rates of FHV-1, FCV, and FIV were 17.3%, 13.6%, and 0.9%, respectively; and the coinfection prevalence was 13.2%. No FeLV-positive sample was detected. And we found that the blood is the best for FCV, FIV, and FeLV detection, but nasopharyngeal swabs for FHV-1. By comparing the gD genes, TK gene, and gI gene of FHV-1, the homology of the three FHV-1 positive strains in this study was found to be 91.5%-99.9% shared with tigers and domestic cats. Based on a comparison of the nucleic acid sequences of 13 FCV strains, we found that the homology of strain HB-1926 with the other strains in this study was only about 77.7%, but shared 99.3% and 98.6% homology with Urnaba strain in American cat and TG1 strain in Chinese tiger, respectively. However, the other 12 FCV strains shared 87.1%-87.5% homology compared with the Chinese domestic cats. Phylogenetic tree analysis showed that the HB-1926 strain was not in the same clade as other strains. The fragments gag-p26, pol-RT, and pol-RNAse of Siberian tiger FIV shared more than 99% homology than domestic cats FIV subtype A. This study demonstrated that captive Siberian tigers in Northeastern China were exposed to FHV-1, FCV, and FIV, and it is necessary to develop more effective vaccines and improve daily management measures.


Asunto(s)
Calicivirus Felino , Enfermedades de los Gatos , Virus de la Inmunodeficiencia Felina , Ácidos Nucleicos , Tigres , Animales , Gatos , Virus de la Leucemia Felina , Filogenia , Prevalencia , Ribonucleasas/genética , Varicellovirus
12.
Bioconjug Chem ; 33(2): 321-332, 2022 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-35057618

RESUMEN

Preexisting serum albumin-polymer bioconjugates have been formed either through covalent conjugation or supramolecular interactions. However, the viability of producing a bioconjugate where both covalent conjugation and supramolecular interactions have been adopted is yet to be explored. In this work, the noncovalent interaction of two polymers bearing fatty acid-based end-functionalities were compared and the superior binder was carried forward for testing with serum albumin that possessed a polymer conjugated to its Cys34 residue. The studies demonstrated that an albumin-polymer bioconjugate equipped with polymers via both covalent and supramolecular interactions can be successfully achieved.


Asunto(s)
Polímeros , Albúmina Sérica , Estructura Molecular , Polímeros/química
13.
Arch Virol ; 167(2): 545-551, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35064833

RESUMEN

Feline immunodeficiency virus (FIV) naturally infects more than 20 kinds of felines and poses a serious threat to their health, but there has been little research on FIV in tigers. In this study, 320 captive Siberian tigers (225 from Harbin, 55 from Hailin, and 40 from Shenyang) were tested for FIV by nested PCR, and three Siberian tigers from Hailin were FIV positive (5.45%). From these three animals, FIV gene fragments, gag-p26 (444 nt) from samples HD094 and HD1786 and pol-RT (576 nt) and pol-RNase (730 nt) from sample HD631, were sequenced and found to share more than 99% sequence identity with FIV subtype A from domestic cats. This is the first time FIV has been detected in Siberian tigers in China.


Asunto(s)
Virus de la Inmunodeficiencia Felina , Tigres , Animales , Gatos , China/epidemiología , Virus de la Inmunodeficiencia Felina/genética
14.
Dig Dis Sci ; 67(7): 3166-3176, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-34342753

RESUMEN

BACKGROUND: Esophageal foreign body impaction is the most common cause of endoscopic emergency. However, there are limited available data on delayed endoscopic management of esophageal sharp-pointed food impaction. AIMS: To investigate cases of esophageal sharp-pointed food impaction with endoscopic removal findings. METHODS: This single-center retrospective study collected medical records to identify patients with esophageal sharp-pointed food impaction who underwent endoscopic removal between April 2018 and April 2020. The patients were divided into the early (endoscopic removal <12 h) and delayed intervention (>12 h) cohorts. RESULTS: Overall, 133 and 696 patients received early and delayed intervention, respectively. The success rate of endoscopic foreign body removal was 96.45%. The most common foreign body was fish bone (66.90%), and the most common shape was "I" (56.26%). Patients from the delayed intervention cohort received general anesthesia with a higher risk for perforation, and no foreign body was identified. The duration of endoscopy, distance between the foreign body/wound and the incisor, and longest diameter of the foreign body were not different between the groups. In multivariate analysis, male sex (odds ratio = 1.792 [1.159, 2.771]; P = 0.009), longer duration of impaction (odds ratio = 2.212 [1.121, 4.365]; P = 0.022) and endoscopy (odds ratio = 1.502 [1.253, 1.800]; P < 0.001), and longest diameter of the foreign body (odds ratio = 1.632 [1.329, 2.003]; P < 0.001) were associated with a higher incidence of perforation in patients with foreign body impaction. CONCLUSIONS: Endoscopic removal is a safe and effective treatment method for sharp-pointed food impaction. Delayed endoscopic removal can increase the risk of esophageal perforation.


Asunto(s)
Perforación del Esófago , Cuerpos Extraños , China , Endoscopía Gastrointestinal/métodos , Perforación del Esófago/epidemiología , Perforación del Esófago/etiología , Perforación del Esófago/cirugía , Femenino , Alimentos , Cuerpos Extraños/complicaciones , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/cirugía , Humanos , Masculino , Estudios Retrospectivos
15.
Small ; 17(50): e2103997, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34713581

RESUMEN

Wound care is still worthy of concern, and effective measures such as electrical stimulating therapy (EST) have sparked compellingly for wound repair. Especially, portable and point-of-care EST devices get extremely desired but these are often limited by inevitable external power sources, lack of biological functions, and mechanical properties conforming to skin tissue. Herein, a dress-on-person self-powered nanocomposite bioactive repairer of wound is designed. As such, the cooperation of the film prepared by layer-by-layer self-assembling 2-hydroxypropyltrimethyl ammonium chloride chitosan (HTCC), alginate (ALG), and poly-dopamine/Fe3+ nanoparticles (PFNs), with a self-powered nanogenerator (SN) driven by motion into a nanocomposite repairer (HAP/SN-NR) is conducted. The HAP/SN-NR not only guides cell behavior (proliferation and migration rate ≈61.7%, ≈52.3%), but also facilitates neovascularization (enhanced CD31 expression >4-fold) through its self-powered EST, and the endogenous wound closure with no inflammatory in rats owing to reactive oxygen species (ROS)-clearance of HAP/SN-NR in vitro/vivo through responsively releasing poly-dopamine nanoparticles at wound pH. Enormous efforts illustrate that the repairer is endowed with high self-adhesion to tissue, self-healing, and biodegradation, accelerating wound healing (50% closure ≈5 days). This strategy sheds light on novel multifunctional portable sensor-type dressings and propels the development of intelligent medical devices.


Asunto(s)
Nanocompuestos , Cicatrización de Heridas , Alginatos , Animales , Antiinflamatorios , Concentración de Iones de Hidrógeno , Ratas
16.
PeerJ ; 9: e12048, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34540367

RESUMEN

BACKGROUND: Germline mutations play an important role in the pathogenesis of lung cancer. Nonetheless, research on malignant ground glass opacity (GGO) nodules is limited. METHODS: A total of 13 participants with malignant GGO nodules were recruited in this study. Peripheral blood was used for exome sequencing, and germline mutations were analyzed using InterVar. The whole exome sequencing dataset was analyzed using a filtering strategy. KOBAS 3.0 was used to analyze KEGG pathway to further identify possible deleterious mutations. RESULTS: There were seven potentially deleterious germline mutations. NM_001184790:exon8: c.C1070T in PARD3, NM_001170721:exon4:c.C392T in BCAR1 and NM_001127221:exon46: c.G6587A in CACNA1A were present in three cases each; rs756875895 frameshift in MAX, NM_005732: exon13:c.2165_2166insT in RAD50 and NM_001142316:exon2:c.G203C in LMO2, were present in two cases each; one variant was present in NOTCH3. CONCLUSIONS: Our results expand the germline mutation spectrum in malignant GGO nodules. Importantly, these findings will potentially help screen the high-risk population, guide their health management, and contribute to their clinical treatment and determination of prognosis.

17.
Front Oncol ; 11: 694749, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34249751

RESUMEN

PURPOSE: To verify the practicality and safety of a treatment chair with six degrees of freedom (6DTC) through demonstrating the efficacy of the workflow in clinical settings and analyzing the obtained technical data, including intra-fraction patient movement during the use of the 6DTC. MATERIALS AND METHODS: A clinical study was designed and conducted to test the clinical treatment workflow and the safety of the 6DTC. Based on the demonstrated dosimetric advantages, fifteen patients with head and neck tumors were selected and treated with the 6DTC. The positional error at the first beam position (PE-B1) and the second beam position (PE-B2) were analyzed and compared with the results from daily quality assurance (QA) procedures of the 6DTC and imaging system performed each day before clinical treatment. The intra-fraction patient movement was derived from the total patient alignment positional error and the QA data based on a Gaussian distribution formulism. RESULTS: The QA results showed sub-millimeter mechanical accuracy of the 6DTC over the course of the clinical study. For 150 patient treatment fractions, the mean deviations between PE-B1 and PE-B2 were 0.13mm (SD 0.88mm), 0.25mm (SD 1.17mm), -0.57mm (SD 0.85mm), 0.02° (SD 0.35°), 0.00° (SD 0.37°), and -0.02° (SD 0.37°) in the x, y, z (translational), and u, v, w (rotational) directions, respectively. The calculated intra-fraction patient movement was -0.08mm (SD 0.56mm), 0.71mm (SD 1.12mm), -0.52mm (SD 0.84mm), 0.10° (SD 0.32°), 0.09° (SD 0.36°), and -0.04° (SD 0.36°) in the x, y, z, u, v, w directions, respectively. CONCLUSIONS: The performance stability of the 6DTC was satisfactory. The position accuracy and intra-fraction patient movement in an upright posture with the 6DTC were verified and found adequate for clinical implementation.

18.
ACS Med Chem Lett ; 12(3): 443-450, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33732413

RESUMEN

While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.

19.
J Immunother Cancer ; 9(1)2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33408094

RESUMEN

BACKGROUND: Hematopoietic progenitor kinase 1 (HPK1 or MAP4K1) has been demonstrated as a negative intracellular immune checkpoint in mediating antitumor immunity in studies with HPK1 knockout and kinase dead mice. Pharmacological inhibition of HPK1 is desirable to investigate the role of HPK1 in human immune cells with therapeutic implications. However, a significant challenge remains to identify a small molecule inhibitor of HPK1 with sufficient potency, selectivity, and other drug-like properties suitable for proof-of-concept studies. In this report, we identified a novel, potent, and selective HPK1 small molecule kinase inhibitor, compound K (CompK). A series of studies were conducted to investigate the mechanism of action of CompK, aiming to understand its potential application in cancer immunotherapy. METHODS: Human primary T cells and dendritic cells (DCs) were investigated with CompK treatment under conditions relevant to tumor microenvironment (TME). Syngeneic tumor models were used to assess the in vivo pharmacology of CompK followed by human tumor interrogation ex vivo. RESULTS: CompK treatment demonstrated markedly enhanced human T-cell immune responses under immunosuppressive conditions relevant to the TME and an increased avidity of the T-cell receptor (TCR) to recognize viral and tumor-associated antigens (TAAs) in significant synergy with anti-PD1. Animal model studies, including 1956 sarcoma and MC38 syngeneic models, revealed improved immune responses and superb antitumor efficacy in combination of CompK with anti-PD-1. An elevated immune response induced by CompK was observed with fresh tumor samples from multiple patients with colorectal carcinoma, suggesting a mechanistic translation from mouse model to human disease. CONCLUSION: CompK treatment significantly improved human T-cell functions, with enhanced TCR avidity to recognize TAAs and tumor cytolytic activity by CD8+ T cells. Additional benefits include DC maturation and priming facilitation in tumor draining lymph node. CompK represents a novel pharmacological agent to address cancer treatment resistance.


Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Ginsenósidos/administración & dosificación , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Sarcoma/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Neoplasias Óseas/inmunología , Neoplasias Óseas/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ginsenósidos/farmacología , Humanos , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Sarcoma/inmunología , Sarcoma/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
20.
Vet Med Sci ; 7(3): 1015-1022, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33314784

RESUMEN

Haematological and biochemical parameters play important roles in safeguarding animal health and preventing disease, but the blood reference values of many wild animals are still unknown. Recently, few descriptions of the blood parameters of Siberian tigers (Panthera tigris altaica) have been reported because these tigers comprise an endangered species; however, it is extremely difficult to obtain blood samples necessary for these analyses. This study presents 14 haematological and 16 biochemical parameters of 133 Siberian tigers, of which 112 and 21 were from Heilongjiang Siberian Tiger Park (HB) and Hailin Siberian Tiger Park (HD), China, respectively. Our study is the first to determine the following parameters in Siberian tigers: red blood cell volume distribution width, platelet count, mean platelet volume, amylase (AMY), sodium/potassium, globulin and albumin/globulin levels. As the data for total bilirubin and AMY were not statistically significant, no statistical analysis was conducted for these parameters. Few parameters were significantly different according to sex and region (p < 0.05). The concentration of alkaline phosphatase decreased with age, whereas the creatinine (CREA) increased with age. The CREA concentration of tigers raised in HB was much lower than that of tigers raised in HD. The data obtained in this study provide a reference for monitoring the health of wild and captive Siberian tigers and will add important information to the standards for haematological and biochemical parameters of wild felines.


Asunto(s)
Tigres/sangre , Animales , Animales de Zoológico/sangre , Análisis Químico de la Sangre/veterinaria , China , Especies en Peligro de Extinción , Femenino , Pruebas Hematológicas/veterinaria , Masculino
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