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1.
Medicine (Baltimore) ; 103(38): e39638, 2024 Sep 20.
Article in English | MEDLINE | ID: mdl-39312323

ABSTRACT

RATIONALE: Multiple primary malignant neoplasms with tuberculosis are rare. The interaction between tuberculosis and tumor remains unclear. Moreover, the treatment of multiple primary tumors combined with tuberculosis is relatively complicated. Herein, we report a case of metachronous triple primary carcinoma complicated with pulmonary tuberculosis. OBJECTIVE: This report aims to analyze the clinical characteristics of 3 primary tumors combined with tuberculosis. We report the long-term survival of this patient after personalized treatment and this patient have a good quality of life. DIAGNOSES AND INTERVENTIONS: A 55-year-old male patient was diagnosed with squamous cell carcinoma of the lower thoracic esophagus (cT4bN1M0 IVA) and received concurrent chemoradiotherapy, followed by 2 cycles consolidate chemotherapy. During the follow-up, he was diagnosed with secondary tuberculosis (TB) and accepted anti-TB treatment. During anti-TB treatment, he was diagnosed with squamous cell carcinoma of the oropharynx (cT1N0M0 I P16(-)), then he received radical radiation therapy. However, within a year, the patient was diagnosed with oral squamous cell carcinoma (cT3N0M0 IIIA). He accepted an individualized chemotherapy with paclitaxel combined with capecitabine. Moreover, immunohistochemistry of the patient's 3 biopsies indicated positive P53 expression. OUTCOMES: Since the patient suffered from esophageal cancer, oropharyngeal cancer, and oral floor cancer, no tumor recurrence or metastasis was observed. And he has a good quality of life. Tuberculosis, TP53 mutation, radiotherapy, smoking, and drinking history may be risk factors for multiple primary tumors. LESSONS: The treatment of multiple primary tumors combined with pulmonary tuberculosis is complicated. Individualized treatment allows patients to achieve long-term survival while also having a good quality of life. Limitations in this case: surgery may be an alternative strategy for the patient, but the patient refused surgery.


Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Tuberculosis, Pulmonary , Humans , Male , Middle Aged , Tuberculosis, Pulmonary/complications , Esophageal Neoplasms/complications , Esophageal Neoplasms/therapy , Esophageal Neoplasms/pathology , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/therapy , Neoplasms, Second Primary , Neoplasms, Multiple Primary/complications , Neoplasms, Multiple Primary/therapy , Neoplasms, Multiple Primary/pathology
2.
J Intensive Med ; 4(4): 480-481, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39310062

ABSTRACT

Ultra-low tidal volume (ULT) is an appealing alternative for severe acute respiratory distress syndrome (ARDS) patients with the aim to alleviate excess lung stress and strain. A recent article showed that ULT without extracorporeal carbon dioxide removal did not improve prognosis in moderate-to-severe coronavirus disease 2019-related ARDS patients. However, several reasons should be considered before drawing the definite conclusion about the ULT strategy in severe ARDS.

3.
PLoS One ; 19(9): e0310214, 2024.
Article in English | MEDLINE | ID: mdl-39292665

ABSTRACT

Image stitching is a traditional but challenging computer vision task. The goal is to stitch together multiple images with overlapping areas into a single, natural-looking, high-resolution image without ghosts or seams. This article aims to increase the field of view of gastroenteroscopy and reduce the missed detection rate. To this end, an improved depth framework based on unsupervised panoramic image stitching of the gastrointestinal tract is proposed. In addition, preprocessing for aberration correction of monocular endoscope images is introduced, and a C2f module is added to the image reconstruction network to improve the network's ability to extract features. A comprehensive real image data set, GASE-Dataset, is proposed to establish an evaluation benchmark and training learning framework for unsupervised deep gastrointestinal image splicing. Experimental results show that the MSE, RMSE, PSNR, SSIM and RMSE_SW indicators are improved, while the splicing time remains within an acceptable range. Compared with traditional image stitching methods, the performance of this method is enhanced. In addition, improvements are proposed to address the problems of lack of annotated data, insufficient generalization ability and insufficient comprehensive performance in image stitching schemes based on supervised learning. These improvements provide valuable aids in gastrointestinal examination.


Subject(s)
Algorithms , Image Processing, Computer-Assisted , Humans , Image Processing, Computer-Assisted/methods , Gastrointestinal Tract/diagnostic imaging , Deep Learning , Unsupervised Machine Learning , Endoscopy, Gastrointestinal/methods
4.
Transl Psychiatry ; 14(1): 381, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39294121

ABSTRACT

Alcohol use disorder (AUD) is a profound psychiatric condition marked by disrupted connectivity among distributed brain regions, indicating impaired functional integration. Previous connectome studies utilizing functional magnetic resonance imaging (fMRI) have predominantly focused on undirected functional connectivity, while the specific alterations in directed effective connectivity (EC) associated with AUD remain unclear. To address this issue, this study utilized multivariate pattern analysis (MVPA) and spectral dynamic causal modeling (DCM). We recruited 32 abstinent men with AUD and 30 healthy controls (HCs) men, and collected their resting-state fMRI data. A regional homogeneity (ReHo)-based MVPA method was employed to classify AUD and HC groups, as well as predict the severity of addiction in AUD individuals. The most informative brain regions identified by the MVPA were further investigated using spectral DCM. Our results indicated that the ReHo-based support vector classification (SVC) exhibits the highest accuracy in distinguishing individuals with AUD from HCs (classification accuracy: 98.57%). Additionally, our results demonstrated that ReHo-based support vector regression (SVR) could be utilized to predict the addiction severity (alcohol use disorders identification test, AUDIT, R2 = 0.38; Michigan alcoholism screening test, MAST, R2 = 0.29) of patients with AUD. The most informative brain regions for the prediction include left pre-SMA, right dACC, right LOFC, right putamen, and right NACC. These findings were validated in an independent data set (35 patients with AUD and 36 HCs, Classification accuracy: 91.67%; AUDIT, R2 = 0.17; MAST, R2 = 0.20). The results of spectral DCM analysis indicated that individuals with AUD exhibited decreased EC from the left pre-SMA to the right putamen, from the right dACC to the right putamen, and from the right LOFC to the right NACC compared to HCs. Moreover, the EC strength from the right NACC to left pre-SMA and from the right dACC to right putamen mediated the relationship between addiction severity (MAST scores) and behavioral measures (impulsive and compulsive scores). These findings provide crucial evidence for the underlying mechanism of impaired self-control, risk assessment, and impulsive and compulsive alcohol consumption in individuals with AUD, providing novel causal insights into both diagnosis and treatment.


Subject(s)
Alcoholism , Frontal Lobe , Magnetic Resonance Imaging , Humans , Male , Alcoholism/physiopathology , Alcoholism/diagnostic imaging , Adult , Frontal Lobe/physiopathology , Frontal Lobe/diagnostic imaging , Connectome , Corpus Striatum/diagnostic imaging , Corpus Striatum/physiopathology , Case-Control Studies , Middle Aged , Neural Pathways/physiopathology , Neural Pathways/diagnostic imaging , Young Adult
6.
Anal Methods ; 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39253940

ABSTRACT

Determination of mercury species over solid waste from natural gas processing plants is a prerequisite for solid waste decontamination and mercury recycling. The temperature-programmed decomposition and desorption method (TPDD) is a promising technique to determine the mercury species over solid waste. Mercury species over solid wastes with complex components and similar desorption temperature, however, cannot always be determined using only the TPDD method. In the present study, the EPA 3200 method was applied to optimize the TPDD process for speciation of the mercury compound over solid wastes collected from a natural gas processing plant, including four spent adsorbents and three sludges. The mercury species with similar desorption temperatures over solid wastes were completely separated by the EPA 3200 method optimized TPDD process. The mercury species over spent adsorbents and sludges could be determined based on the fingerprints of the mercury compounds. The mercury compounds over spent adsorbents were specified to be Hg0 and/or M-Hg amalgam, HgS(black) and HgO(red), of which HgS(black) was the primary mercury compound. However, the mercury species over sludge were analyzed to be Hg0 and/or M-Hg amalgam, HgCl2(minor), HgS(black), HgO(yellow) and HgS(red). The mercury recovery rates of solid wastes ranged from 73% to 120%. With the above results, it was considered that the EPA 3200 method optimized TPDD process was a promising method to specify and semi-quantify the mercury compounds in solid waste.

7.
Sci Rep ; 14(1): 20791, 2024 Sep 06.
Article in English | MEDLINE | ID: mdl-39251697

ABSTRACT

Insole blanking production technology plays a vital role in contemporary machining and manufacturing industries. Existing insole blanking production models have limitations because most robots are required to accurately position the workpiece to a predetermined location, and special auxiliary equipment is usually required to ensure the precise positioning of the robot. In this paper, we present an adaptive blanking robotic system for different lighting environments, which consists of an industrial robot arm, an RGB-D camera configuration, and a customized insole blanking table and mold. We introduce an innovative edge detection framework that utilizes color features and morphological parameters optimized through particle swarm optimization (PSO) techniques to Adaptive recognition of insole edge contours. A path planning framework based on FSPS-BIT* is also introduced, which integrates the BIT* algorithm with the FSPS algorithm for efficient path planning of the robotic arm.

8.
Sensors (Basel) ; 24(17)2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39275688

ABSTRACT

In this paper, a three-layer structure of silver particle (AgNP)-dielectric-metal is proposed and constructed based on the characteristics of AgNPs that can excite LSPR (Localized Surface Plasmon Resonance) in free space. In order to overcome the problem of AgNPs easily oxidizing in the air, this paper synthesizes AgNPs using the improved Tollens method and effectively suppresses the coffee-ring effect by changing the solution evaporation conditions, so that the distribution of AgNPs in the deposition area is relatively uniform. The structure proposed in this paper takes advantage of the flexibility of nanoparticle application. The AgNPs deposited on the dielectric layer can effectively localize energy and regulate the LSPR of the device well. The structure can not only achieve precise regulation of the LSPR resonance peak of AgNPs but also can be used as a SERS substrate.

9.
Phytopathology ; 2024 Sep 08.
Article in English | MEDLINE | ID: mdl-39244657

ABSTRACT

The commercialized genetically modified (GM) papaya cultivars have protected papaya from the devastating disease caused by papaya ringspot virus (PRSV). However, papaya leaf distortion mosaic virus (PLDMV), which causes similar infection symptoms but is serologically distinct from PRSV, was found as a competitive threat to the papaya industry. Our study surveyed the occurrence of PRSV and PLDMV as well as the transgenic markers of the 35S promoter from cauliflower mosaic virus (CaMV 35S) and the neomycin phosphotransferase II (NPT II) gene in feral papaya plants, which were found frequently growing outside of cultivated papaya fields on Hainan Island. In total, 123 feral papayas, comprising 62 (50.4%) GM plants and 61 (49.6%) non-GM ones, were sampled. Among them, 23 (18.7%) were positive for PRSV, 49 (39.8%) were positive for PLDMV, including 5 plants co-infected by PRSV and PLDMV, and 56 (45.5%) plants were free of either virus. In traditional papaya growing regions, we detected fewer PRSV-infected plants (2 in 33, 6%) than in other regions (21 in 90, 23%). But overall, whether transgenic or not made no significance in PRSV incidence (P=0.230), with 9 PRSV-infected plants among 62 GM papayas and 14 among 61 non-GM papayas. Phylogenetic and genetic differentiation analysis showed a clear correlation between PRSV and PLDMV populations and their geographical origins. Negative selection was estimated for the selected gene regions of both viruses. Notably, PLDMV has deviated from neutral evolution and experienced population expansion, exhibiting increased genetic diversity and is becoming the predominant threat to papaya in Hainan.

10.
Adv Sci (Weinh) ; : e2403067, 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39234800

ABSTRACT

To investigate how cell elongation impacts extracellular electron transfer (EET) of electroactive microorganisms (EAMs), the division of model EAM Shewanella oneidensis (S. oneidensis) MR-1 is engineered by reducing the formation of cell divisome. Specially, by blocking the translation of division proteins via anti-sense RNAs or expressing division inhibitors, the cellular length and output power density are all increased. Electrophysiological and transcriptomic results synergistically reveal that the programmed cell elongation reinforces EET by enhancing NADH oxidation, inner-membrane quinone pool, and abundance of c-type cytochromes. Moreover, cell elongation enhances hydrophobicity due to decreased cell-surface polysaccharide, thus facilitates the initial surface adhesion stage during biofilm formation. The output current and power density all increase in positive correction with cellular length. However, inhibition of cell division reduces cell growth, which is then restored by quorum sensing-based dynamic regulation of cell growth and elongation phases. The QS-regulated elongated strain thus enables a cell length of 143.6 ± 40.3 µm (72.6-fold of that of S. oneidensis MR-1), which results in an output power density of 248.0 ± 10.6 mW m-2 (3.41-fold of that of S. oneidensis MR-1) and exhibits superior potential for pollutant treatment. Engineering cellular length paves an innovate avenue for enhancing the EET of EAMs.

11.
Ann Hematol ; 2024 Sep 05.
Article in English | MEDLINE | ID: mdl-39235490

ABSTRACT

This study aimed to investigate the effect of hetrombopag combined with conventional treatment on immune function in patients with severe aplastic anemia (SAA). Patients were categorized into the control group (n = 50, receiving conventional treatment only) and experimental group (n = 50, receiving hetrombopag combined with conventional treatment). Before treatment and at weeks 18, 24, and 52 after treatment, the two groups were compared in routine blood test indicators, natural killer (NK) cell activity, and peripheral blood inflammatory factor levels. The overall remission rate and incidence of adverse events were also compared between the two groups. Outpatient or telephone follow-up was performed before treatment and at weeks 18, 24, and 52 after treatment to observe patients' immune function, treatment outcome, quality of life, and adverse events. Hemoglobin (Hb), and platelet count (PLT) (P < 0.05), and a rise in NK cell activity (P < 0.05). Interleukin (IL-10) levels were significantly higher, while IL-6 levels were significantly lower in the experimental group compared to the control group (P < 0.05). After receiving the treatment, all scores of SF-36 domains in both groups were higher than before treatment, particularly with higher scores in the experimental group (P < 0.05). Hetrombopag combined with conventional treatment improved the immune function and hematopoiesis of patients with SAA.

12.
Article in English | MEDLINE | ID: mdl-39288190

ABSTRACT

In this investigation, transparent photothermal coatings utilizing plasmonic copper chalcogenide (Cu2-xS) nanoparticles were designed and fabricated for the deicing of glass surfaces. Cu2-xS nanoparticles, chosen for their high near-infrared (NIR) absorption and efficient photothermal conversion, were analyzed via finite difference time domain (FDTD) simulations to optimize nanoparticle morphology, thus avoiding costly trial-and-error synthesis. FDTD simulations determined that Cu2-xS nanorods (Cu-NRs) with an optimal aspect ratio of 2.2 had superior NIR absorption. Guided by FDTD simulations, the composite coating composed of Cu-NRs in clear acrylic resin paint was brush-coated to glass, achieving 62.4% visual transmittance and over 95% NIR absorbance. Photothermal conversion tests exhibited a significant temperature increase, with the coating reaching 65 °C under NIR irradiation within 6 min. The dynamic deicing process of ice beads on the coating at -20 °C completed within 220s, in contrast to the frozen state on glass coated with clear acrylic resin paint. Furthermore, heat transfer simulations in COMSOL illustrated melting initiation at the ice-coating interface and subsequent progression through the ice layer. This simulation-driven synthesis method and photothermal testing offer a design framework for the fabrication of photothermal deicing coatings with applications for automobiles, buildings, and aircraft in cold environments.

13.
J Agric Food Chem ; 72(37): 20483-20495, 2024 Sep 18.
Article in English | MEDLINE | ID: mdl-39248366

ABSTRACT

Mechanical stimuli can affect plant growth, development, and defenses. The role of water spray stimulation, as a prevalent mechanical stimulus in the environment, in crop growth and defense cannot be overlooked. In this study, the effects of water spray on tomato plant growth and defense against the chewing herbivore Helicoverpa armigera and necrotrophic fungus Botrytis cinerea were investigated. Suprathreshold water spray stimulus (LS) was found to enhance tomato plant defenses against pests and pathogens while concurrently modifying plant architecture. The results of the phytohormone and chemical metabolite analysis revealed that LS improved the plant defense response via jasmonic acid (JA) signaling. LS significantly elevated the level of a pivotal defensive metabolite, chlorogenic acid, and reduced the emissions of volatile organic compounds (VOCs) from tomato plants, thereby defending against pest and pathogen attacks. The most obvious finding to emerge from this study is that LS enhances tomato plant defenses against biotic stresses, which will pave the way for further work on the application of mechanical stimuli for pest management.


Subject(s)
Botrytis , Cyclopentanes , Oxylipins , Plant Diseases , Solanum lycopersicum , Volatile Organic Compounds , Water , Solanum lycopersicum/microbiology , Solanum lycopersicum/parasitology , Solanum lycopersicum/immunology , Solanum lycopersicum/chemistry , Solanum lycopersicum/metabolism , Water/metabolism , Animals , Botrytis/physiology , Plant Diseases/microbiology , Plant Diseases/parasitology , Cyclopentanes/metabolism , Oxylipins/metabolism , Volatile Organic Compounds/chemistry , Volatile Organic Compounds/metabolism , Moths/physiology , Plant Growth Regulators/metabolism , Plant Growth Regulators/pharmacology , Stress, Physiological , Herbivory , Plant Defense Against Herbivory
14.
Pestic Biochem Physiol ; 204: 106073, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39277386

ABSTRACT

Riptortus pedestris (Hemiptera: Alydidae) is a notable soybean pest, with diapause and non-diapause individuals showing different sensitivities to aggregation pheromones. This study aimed to investigate how R. pedestris detects aggregation pheromones through electroantennogram (EAG) and behavioral experiments, transcriptome sequencing and qRT-PCR, as well as competitive fluorescence-binding assay. Results indicated that diapausing females and males of R. pedestris exhibited a heightened EAG response and were more attracted to the aggregation pheromone components compared to their non-diapause counterparts. Transcriptome sequencing and qRT-PCR analyses revealed significantly higher expression of RpedOBP1 in the antennae of diapause females and males compared to non-diapausing R. pedestris. The competitive fluorescence-binding assay demonstrated that RpedOBP1 displayed the strongest binding affinity to E2HE2H, suggesting its crucial role in recognizing the aggregation pheromone. These findings have the potential to inform the development of integrated pest management strategies utilizing behavioral approaches for bean bug control.


Subject(s)
Insect Proteins , Pheromones , Animals , Insect Proteins/metabolism , Insect Proteins/genetics , Female , Male , Pheromones/metabolism , Hemiptera/physiology , Hemiptera/genetics , Hemiptera/metabolism , Arthropod Antennae/metabolism , Receptors, Odorant/metabolism , Receptors, Odorant/genetics
15.
Biometrics ; 80(3)2024 Jul 01.
Article in English | MEDLINE | ID: mdl-39253988

ABSTRACT

The US Food and Drug Administration launched Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development, calling for the paradigm shift from finding the maximum tolerated dose to the identification of optimal biological dose (OBD). Motivated by a real-world drug development program, we propose a master-protocol-based platform trial design to simultaneously identify OBDs of a new drug, combined with standards of care or other novel agents, in multiple indications. We propose a Bayesian latent subgroup model to accommodate the treatment heterogeneity across indications, and employ Bayesian hierarchical models to borrow information within subgroups. At each interim analysis, we update the subgroup membership and dose-toxicity and -efficacy estimates, as well as the estimate of the utility for risk-benefit tradeoff, based on the observed data across treatment arms to inform the arm-specific decision of dose escalation and de-escalation and identify the OBD for each arm of a combination partner and an indication. The simulation study shows that the proposed design has desirable operating characteristics, providing a highly flexible and efficient way for dose optimization. The design has great potential to shorten the drug development timeline, save costs by reducing overlapping infrastructure, and speed up regulatory approval.


Subject(s)
Antineoplastic Agents , Bayes Theorem , Computer Simulation , Dose-Response Relationship, Drug , Maximum Tolerated Dose , Humans , Antineoplastic Agents/administration & dosage , Drug Development/methods , Drug Development/statistics & numerical data , Models, Statistical , United States , United States Food and Drug Administration , Neoplasms/drug therapy , Research Design , Biometry/methods
16.
J Mol Med (Berl) ; 102(10): 1199-1215, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39138828

ABSTRACT

Fibrosis is an important pathological change in inflammatory bowel disease (IBD), but the mechanism has yet to be elucidated. WNT2B high­expressed fibroblasts are enriched in IBD intestinal tissues, although the precise function of this group of fibroblasts remains unclear. This study investigated whether WNT2B high­expressed fibroblasts aggravated intestinal tissue damage and fibrosis. Our study provides evidence that WNT2B high­expressed fibroblasts and NK cells were enriched in colitis tissue of patients with IBD. WNT2B high­expressed fibroblasts secreted wnt2b, which bound to FZD4 on NK cells and activated the NF-κB and STAT3 pathways to enhance IL-33 expression. TCF4, a downstream component of the WNT/ß-catenin pathway, bound to p65 and promoted binding to IL-33 promoter. Furthermore, Salinomycin, an inhibitor of the WNT/ß-catenin pathway, inhibited IL-33 secretion in colitis, thereby reducing intestinal inflammation.Knocking down WNT2B reduces NK cell infiltration and IL-33 secretion in colitis, and reduce intestinal inflammation and fibrosis. In conclusion, WNT2B high­expressed fibroblasts activate NK cells by secreting wnt2b, which activates the WNT/ß-catenin and NF-κB pathways to promote IL-33 expression and secretion, potentially culminating in the induction of colonic fibrosis in IBD. KEY MESSAGES: WNT2B high-expressed fibroblasts and NK cells are enriched in colitis tissue, promoting NK cells secreting IL-33. Wnt2b activates NF-κB and STAT3 pathways promotes IL-33 expression by activating p65 and not STAT3. syndrome TCF4 binds to p65 and upregulates the NF- κB pathway. Salinomycin reduces NK cell infiltration and IL-33 secretion in colitis. Knocking down WNT2B mitigates inflammation and fibrosis in chronic colitis.


Subject(s)
Fibroblasts , Fibrosis , Inflammatory Bowel Diseases , Interleukin-33 , Killer Cells, Natural , Wnt Proteins , Humans , Fibroblasts/metabolism , Animals , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Interleukin-33/metabolism , Interleukin-33/genetics , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Wnt Proteins/metabolism , Wnt Proteins/genetics , Mice , Wnt Signaling Pathway , Male , NF-kappa B/metabolism , Mice, Inbred C57BL , Female , Colitis/metabolism , Colitis/immunology , Glycoproteins
18.
J Laparoendosc Adv Surg Tech A ; 34(9): 845-850, 2024 Sep.
Article in English | MEDLINE | ID: mdl-39150373

ABSTRACT

Background: Lumbar hernia is a rare disease with low incidence, and no golden standard surgical procedure has been established for lumbar hernias. The single-incision laparoscopic totally extraperitoneal sublay (SIL-TES) technique became a novel surgical technique for lumbar hernias. Methods: This retrospective study included 20 patients who underwent SIL-TES repair for lumbar hernia between April 2020 and March 2024. The baseline patient characteristics, intraoperative data, postoperative data, satisfaction score, and Carolina Comfort Scale scores were collected. Results: The results revealed that the SIL-TES technique for lumbar hernia repair is associated with a low complication rate, nonrecurrence, high satisfaction score, and high quality of life after surgery. Conclusions: The SIL-TES technique could be a feasible and effective surgical technique for lumbar hernias. A controlled study is needed for further confirmation.


Subject(s)
Herniorrhaphy , Laparoscopy , Humans , Laparoscopy/methods , Female , Retrospective Studies , Male , Middle Aged , Herniorrhaphy/methods , Aged , Adult , Lumbosacral Region/surgery , Quality of Life , Treatment Outcome
19.
J Med Chem ; 67(17): 15328-15352, 2024 Sep 12.
Article in English | MEDLINE | ID: mdl-39172943

ABSTRACT

Based on the founding member of imipridones, ONC201, a class of dehydrogenated imipridone derivatives was designed, synthesized, and evaluated in a series of biochemical and biological assays as human caseinolytic protease P (hClpP) activators. Mechanism studies for one of the most potent compounds, XT6, indicated that it can potently bind to both recombinant and cellular hClpP, effectively promote the formation of hClpP tetradecamer, efficiently induce the degradation of hClpP substrates, robustly upregulate the expression of ATF4, and strongly inhibit the phosphorylations of AKT and ERK. More importantly, XT6 exhibited a promising pharmacokinetic profile in rats and could penetrate the blood brain barrier. It showed highly potent in vivo antitumor activity in a MIAPACA2 cell line derived pancreatic cancer model in BALB/c nude mice.


Subject(s)
Antineoplastic Agents , Mice, Inbred BALB C , Mice, Nude , Animals , Humans , Male , Mice , Rats , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Discovery , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Rats, Sprague-Dawley , Structure-Activity Relationship , Xenograft Model Antitumor Assays
20.
Diabetes Obes Metab ; 2024 Aug 20.
Article in English | MEDLINE | ID: mdl-39164879

ABSTRACT

AIM: To investigate the extent to which joint risk factor control might attenuate the excess risk of chronic kidney disease (CKD) in participants with obesity. PATIENTS AND METHODS: We included a total of 97 538 participants who were obese at baseline and matched 97 538 normal weight control participants from the UK Biobank in the analysis. The degree of joint risk factor control was assessed based on six major CKD risk factors, including blood pressure, glycated haemoglobin, low-density lipoprotein cholesterol, albuminuria, smoking and physical activity. The Cox proportional hazards models were used to estimate associations between the degree of risk factor control and risk of CKD, following participants from their baseline assessment until the occurrence of CKD, death, or the end of the follow-up period. RESULTS: Among participants with obesity, joint risk factor control showed an association with a stepwise reduction of incident CKD risk. Each additional risk factor control corresponded to an 11% (hazard ratio: 0.89; 95% confidence interval: 0.86-0.91) reduced risk of CKD among participants with obesity, with the optimal controlling of all six risk factors associated with a 49% (hazard ratio: 0.51; 95% confidence interval: 0.43-0.61) decrease in risk of CKD. Furthermore, in individuals with obesity who jointly controlled all six risk factors, the excess risk of CKD associated with obesity was effectively neutralized compared with normal weight control subjects. Notably, the protective correlations between the degree of joint risk factor control and the incidence of CKD were more pronounced in men compared with women, in individuals with a lower healthy food score versus a higher score, and among diabetes medication users as opposed to non-users (pinteraction = 0.017, 0.033 and 0.014, respectively). CONCLUSION: The joint risk factor control is associated with an inverse association of CKD risk in an accumulative manner among individuals with obesity. Achieving ideal control over risk factors may effectively counterbalance the excessive risk of CKD typically associated with obesity.

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