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JOURNAL/nrgr/04.03/01300535-202505000-00025/figure1/v/2024-07-28T173839Z/r/image-tiff Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair. We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling, influencing their activation such that they can promote neurological recovery. However, the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear. In this study, we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-α expression but suppressed insulin-like growth factor-1 expression. However, recombinant complement receptor 2-conjugated Crry (CR2-Crry) reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia, CXCL12, and tumor necrosis factor-α. Additionally, we observed that, in response to stimulation (including stimulation by CXCL12 secreted by activated microglia), CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4, Crry, and Akt signaling to modulate microglial activation. In agreement with these in vitro experimental results, we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation, leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice. Notably, these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury, cerebral edema, and neurological disorders post-closed head injury. In conclusion, our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry, thereby promoting induced neural stem cell-mediated improvement of neuronal injury, cerebral edema, and neurological disorders following closed head injury.
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Polydopamine has gained considerable attention in the biomaterial domain owing to its excellent biocompatibility, antioxidant activity, photothermal effect and adhesion property. Herein, copper sulfide (Cu2-xS) wrapped in mesoporous polydopamine (MPDA) was synthesized through in-situ polymerization, followed by the surface modification with cationic polyethyleneimine (PEI). The mussel-inspired MPDA matrix successfully prevented the oxidation and agglomeration of Cu2-xS nanoparticles, and regulated the release of copper ions and reactive oxygen species (ROS) levels. Surface-modified PEI endow MPDA@Cu2-xS with positive charges, facilitating their rapid contact with negatively charged bacteria through electrostatic interactions. The pH-dependent Cu+/Cu2+ release and NIR-responsive ROS generation were confirmed using molecular probes and electron spin resonance (ESR). The MPDA@Cu2-xS/PEI showed significantly enhanced antibacterial activity and reduced cytotoxicity for NIH3T3 cells. Under NIR irradiation (1.0 W/cm2, 10 min), germicidal efficiency against Escherichia coli (E. coli) and Staphyloccocus aureus (S. aureus) could reach 100 % and 99.94 %, respectively. The exceptional antibacterial activities of MPDA@Cu2-xS/PEI was mainly attributed to the synergistic photothermal effect, controlled release of copper ions and ROS generation, as well as electrostatic interaction. More importantly, the MPDA@Cu2-xS/PEI composite exhibited excellent biocompatibility and biosafety. Overall, this organic/inorganic hybrid holds great potential as a promising candidate for wound treatment.
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Persistence of human immunodeficiency virus (HIV) reservoirs prevents viral eradication, and consequently HIV-infected patients require lifetime treatment with antiretroviral therapy (ART) [1-5]. Currently, there are no effective therapeutics to prevent HIV rebound upon ART cessation. Here we describe an HIV/SIV Rev-dependent lentiviral particle that can be administered to inhibit viral rebound [6-9]. Using simian immunodeficiency virus (SIV)-infected rhesus macaques as a model, we demonstrate that the administration of pre-assembled SIV Rev-dependent lentiviral particles into SIVmac239-infected Indian rhesus macaques can lead to reduction of viral rebound upon ART termination. One of the injected animals, KC50, controlled plasma and CNS viremia to an undetectable level most of the time for over two years after ART termination. Surprisingly, detailed molecular and immunological characterization revealed that viremia control was concomitant with the induction of neutralizing antibodies (nAbs) following the administration of the Rev-dependent vectors. This study emphasizes the importance of neutralizing antibodies (nAbs) for viremia control [10-15], and also provides proof of concept that the Rev-dependent vector can be used to target viral reservoirs, including the CNS reservoirs, in vivo. However, future large-scale in vivo studies are needed to understand the potential mechanisms of viremia control induced by the Rev-dependent vector.
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Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated death. Emerging evidence suggests that autophagy plays a critical role in HCC tumorigenesis, metastasis, and prognosis. Choline is an essential nutrient related to prolonged survival and reduced risk of HCC. However, it remains unclear whether this phenomenon is mediated by autophagy. Methods: Two HCC cell lines (HUH-7 and Hep3B) were used in the present study. Cell growth was evaluated by cell counting kit 8 (CCK-8), colony formation, and in vivo mouse xenografts assays. Cell motility was calculated by wound healing and transwell assays. Autophagosomes were measured by transmission electron microscope (TEM), and autophagy flux was detected by mRFP-GFP-labeled LC3 protein. The mRNA level of genes was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels were detected by Western blotting (WB). Results: We found that choline inhibited the proliferation, migration, and invasion of HCC cells by downregulating autophagy in vitro and in vivo. Upregulated expression of the solute carrier family 5 member 7 (SLC5A7), a specific choline transporter, correlated with better HCC prognosis. We further discovered that choline could promote SLC5A7 expression, upregulate cytoplasm p53 expression to impair the AMPK/mTOR pathway, and attenuate autophagy. Finally, we found that choline acted synergistically with sorafenib to attenuate HCC development in vitro and in vivo. Conclusions: Our findings provide novel insights into choline-mediated autophagy in HCC, providing the foothold for its future application in HCC treatment.
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The objective of this study is to evaluate the in vitro and in vivo degradation profile and biocompatibility of poly-L-lactic acid (PLLA) porous microspheres (PMs) for their potential application as injectable microcarrier or micro-scaffolds materials in the research and clinical use of craniofacial cartilage repair. In this study, PLLA PMs prepared exhibited spherical shape and uniform surface pores followed by 24-week evaluations for degradation behavior and biocompatibility. In vitro degradation analysis encompassed morphological examination, pH monitoring, molecular weight analysis, thermodynamic assessment, and chemical structure analysis. After 12 weeks of in vitro degradation, PMs maintained a regular porous spherical structure. Molecular weight and glass transition temperature of PLLA PMs decreased over time, accompanying with an initial increase and subsequent decrease in crystallinity. Enzymatic degradation caused morphological changes and accelerated degradation in the in vitro studies. Finally, in vivo evaluations involved subcutaneous implantation of PLLA PMs in rats, demonstrating biocompatibility by enhancing type I and type III collagen regeneration as observed in histological analysis. The results demonstrated that PLLA PMs were able to maintain their spherical structure for 12 weeks, promoting the generation of collagen at the implantation site, meeting the time requirements for craniofacial cartilage repair.
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Materiales Biocompatibles , Ensayo de Materiales , Microesferas , Poliésteres , Poliésteres/química , Animales , Porosidad , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ratas , Peso Molecular , Andamios del Tejido/química , Masculino , Concentración de Iones de Hidrógeno , Ratas Sprague-DawleyRESUMEN
Inspired by adaptive natural organisms and living matter, soft actuators appeal to a variety of innovative applications such as soft grippers, artificial muscles, wearable electronics, and biomedical devices. However, their fabrication is typically limited in laboratories or a few enterprises since specific instruments, strong stimuli, or specialized operation skills are inevitably involved. Here a straightforward "cloth-to-clothes-like" method to prepare soft actuators with a low threshold by combining the hysteretic behavior of liquid crystal elastomers (LCEs) with the exchange reaction of dynamic covalent bonds, is proposed. Due to the hysteretic behavior, the LCEs (resemble "cloth") effectively retain predefined shapes after stretching and releasing for extended periods. Subsequently, the samples naturally become soft actuators (resemble "clothes") via the exchange reaction at ambient temperatures. As a post-synthesis method, this strategy effectively separates the production of LCEs and soft actuators. LCEs can be mass-produced in bulk by factories or producers and stored as prepared, much like rolls of cloth. When required, these LCEs can be customized into soft actuators as needed. This strategy provides a robust, flexible, and scalable solution to engineer soft actuators, holding great promise for mass production and universal applications.
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Purpose: Evidence has indicated that PDZD11 is involved in regulating adherens junction. However, the distinct effect of its aberrant expression on epithelial ovarian cancer (EOC) awaits clarification. Methods: In this study, public databases (Gene Expression Omnibus, The Cancer Genome Atlas, and The Genotype-Tissue Expression), online analysis tools (Kaplan-Meier plotter and TIMER), and data analysis methods (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and the CIBERSORT algorithm) were fully utilized to analyze the differential expression, diagnostic efficiency, prognostic significance, potential function, and correlation with immune infiltration of PDZD11. The differential expression of PDZD11 was tested by immunohistochemistry in EOC tissues (78 cases) and control tissues (37 cases). Results: Our results indicate that PDZD11 was remarkably overexpressed in EOC, which was associated with advanced cancer stages, no lymphatic metastasis status, and poor prognosis. Moreover, PDZD11 played a role in cell adhesion, cell proliferation, and immune responses. Also, PDZD11 was significantly related to the abundances of infiltrating immune cells in EOC, including neutrophils, macrophages, dendritic cells, CD8+ T cells, and CD4+ T cells, and its expression was positively co-expressed with well-known immune checkpoints, including TIGIT, TIM3, LAG3, CTLA4, and PD-1. Conclusion: These results suggest that PDZD11 could be a potential diagnostic and prognostic biomarker associated with immune infiltration in EOC, and our findings might help elucidate the function of PDZD11 in carcinogenesis.
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While the forests on Mount Taishan are predominantly man-made, there is a notable vertical variation in vegetation. This study employs the method of cloud model, quantifying uncertainty (fuzziness and randomness) of things. Utilizing digital elevation model (DEM) and vegetation distribution data, we constructed elevation cloud models for Mount Taishan's deciduous broad-leaved, temperate coniferous, and mixed coniferous-broadleaved forests. Using three numerical features of the cloud model-Expectation (EX), Entropy (EN), and Hyper-entropy (HE)-we quantitatively analyzed the macro regularity and local heterogeneity of Mount Taishan's forests vertical distribution from the perspective of uncertainty theory. The results indicate: (1) The EX of the core zone elevation of deciduous broad-leaved forest is 716.65 m, temperate coniferous forest is 1053.51 m, and mixed coniferous-broadleaved forest is 1384.09 m. The variation range of the core zone distribution height is smaller in the mixed coniferous-broadleaved forest (EN: 53.74 m) compared to deciduous broad-leaved forest (EN: 99.63 m) and temperate coniferous forest (EN: 121.70 m). (2) The fuzziness and randomness of the distribution height of the lower extension zones of deciduous broad-leaved forest and temperate coniferous forest (EN: 75.15 m, 184.56 m; HE: 24.09 m, 63.54 m) are greater than those of the upper extension zones (EN: 44.75 m, 42.49 m; HE: 14.48 m, 13.23 m). (3) The distribution fuzziness and randomness within temperate coniferous forests exceed those of deciduous broad-leaved forests. Within the core zones, the uncertainty regarding the vertical distribution of vegetation across different aspects remains consistent, which retains the characteristic of man-made forests. However, in transition areas, there is significant disparity, reflecting the adaptive relationship between vegetation and its environment to some extent. In the upper and lower extension zones of deciduous broad-leaved forests, the EX values for the vertical distribution height of mixed coniferous and broad-leaved forests differ significantly from those of deciduous broad-leaved forests (the difference is 22.82-39.15 m), yet closely resemble those of temperate coniferous forests (the difference is 4.79-7.94 m). This suggests a trend wherein deciduous broad-leaved tree species exhibit a proclivity to encroach upon coniferous forest habitats. The elevation cloud model of vertical vegetation zones provides a novel perspective and method for the detailed analysis of Mount Taishan's vegetation vertical differentiation.
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Bosques , China , Modelos Teóricos , Árboles/crecimiento & desarrollo , Tracheophyta/crecimiento & desarrollo , EcosistemaRESUMEN
PURPOSE: PIWI-interacting RNAs (piRNAs) are a type of noncoding small RNA that can interact with PIWI-like RNA-mediated gene silencing (PIWIL) proteins to affect biological processes such as transposon silencing through epigenetic effects. Recent studies have found that piRNAs are widely dysregulated in tumors and associated with tumor progression and a poor prognosis. Therefore, this study aimed to investigate the effect of piR-1919609 on the proliferation, apoptosis, and drug resistance of ovarian cancer cells. METHODS: In this study, we used small RNA sequencing to screen and identify differentially expressed piRNAs in primary ovarian cancer, recurrent ovarian cancer, and normal ovaries. A large-scale verification study was performed to verify the expression of piR-1919609 in different types of ovarian tissue, including ovarian cancer tissue and normal ovaries, by RT-PCR and to analyze its association with the clinical prognosis of ovarian cancer. The expression of PIWILs in ovarian cancer was verified by RT-PCR, Western blotting and immunofluorescence. The effects of piR-1919609 on ovarian cancer cell proliferation, apoptosis and drug resistance were studied through in vitro and in vivo models. RESULTS: (1) piR-1919609 was highly expressed in platinum-resistant ovarian cancer tissues (p < 0.05), and this upregulation was significantly associated with a poor prognosis and a shorter recurrence time in ovarian cancer patients (p < 0.05). (2) PIWIL2 was strongly expressed in ovarian cancer tissues (p < 0.05). It was expressed both in the cytoplasm and nucleus of ovarian cancer cells. (3) Overexpression of piR-1919609 promoted ovarian cancer cell proliferation, inhibited apoptosis, and promoted tumor growth in nude mice. (4) Inhibition of piR-1919609 effectively reversed ovarian cancer drug resistance. CONCLUSION: In summary, we showed that piR-1919609 is involved in the regulation of drug resistance in ovarian cancer cells and might be an ideal potential target for reversing platinum resistance in ovarian cancer.
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Apoptosis , Proliferación Celular , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neoplasias Ováricas , ARN Interferente Pequeño , Ensayos Antitumor por Modelo de Xenoinjerto , Femenino , Humanos , Resistencia a Antineoplásicos/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Animales , Ratones , Línea Celular Tumoral , ARN Interferente Pequeño/genética , Pronóstico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Modelos Animales de Enfermedad , Platino (Metal)/uso terapéutico , Platino (Metal)/farmacologíaRESUMEN
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .
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Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Anciano , Adulto , Quimioterapia de Mantención , Método Doble Ciego , Ftalazinas/uso terapéutico , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Supervivencia sin Progresión , Proteína BRCA2/genética , Anciano de 80 o más Años , Proteína BRCA1/genética , Piperazinas , QuinazolinasRESUMEN
OBJECTIVE: To investigate the visual outcomes and optimal timing for repeat surgery in cases of postoperative hematoma following transsphenoidal surgery for pituitary neuroendocrine tumors (PitNETs). METHODS: A retrospective study was conducted on 28 patients who developed evident postoperative hematoma out of a total of 9,010 patients. The hematomas were classified into three types based on their CT appearance. Type 1a - mild high density with no tension, Type 1b - thin-layer high density; Type 2a - solid high density with large empty cavities, Type 2b - solid high density with small empty cavities; Type 3 -solid high density with no cavity showing high tension. Patient data were collected for analysis. RESULTS: The study cohort comprised 10 female and 18 male patients, with a mean age of 51.5±11.9 years. Most patients presented with large adenomas (median diameter 36mm). Postoperative visual sight improved in 12 patients, remained stable in 11 patients, and worsened in 5 patients. Notably, no patients experienced worsened visual sight beyond twenty-four hours after the operation. Among the five patients with visual deterioration, four had CT type 3 hematoma (4/6, 66.7%), and one had CT type 2b hematoma (1/9, 11.1%). Patients in the type 3 CT group were significantly more prone to experience visual deterioration compared to those in the type 2 group (odds ratio [OR] 2.154 [95% CI 1.858-611.014], P=.027). Four patients underwent repeat surgery after visual deterioration, resulting in visual improvement following a prolonged recovery period. Postoperative hematoma had limited impact on pituitary dysfunction and hyponatremia. CONCLUSION: Our study reveals a significant association between postoperative hematoma CT types and visual deterioration. For patients with stable visual sight and type 1 or 2a hematoma, conservative strategies may be considered. Conversely, type 2b and 3 patients are at higher risk of visual deterioration, especially within the first 24 hours after the operation. Consequently, early reoperation before vision worsens may be a prudent approach to reduce risks and improve visual outcomes, particularly in type 3 patients.
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Adenoma , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Reoperación , Estudios Retrospectivos , Tumores Neuroendocrinos/cirugía , Neoplasias Hipofisarias/cirugía , Neoplasias Hipofisarias/patología , Adenoma/cirugía , Adenoma/patología , Hematoma/diagnóstico por imagen , Hematoma/etiología , Hematoma/cirugía , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: NF2-schwannomatosis (NF2) is an autosomal dominant disorder prone to hearing loss. Auditory brainstem implants (ABIs) offer a promising solution for hearing rehabilitation in NF2. OBJECTIVE: To synthesize existing literature on ABI implantation in NF2, focusing on audiological outcomes and ABI-related complications. METHODS: The systematic review followed PRISMA guidelines and was registered in the PROSPERO database (CRD42022362155). Relevant studies were identified by searching PubMed, EMBASE, CENTRAL, CMB, and CNKI from inception to August 2023. Data on environmental sound discrimination, open-set discrimination, closed-set discrimination, and ABI-related complications were extracted and subjected to meta-analysis. Publication bias was evaluated using funnel plots and Egger's test. RESULTS: Thirty-three studies were included. The pooled estimate was 58% (95% CI 49-66%) for environmental sound discrimination and 55% (95% CI 40-69%) for closed-set discrimination. Regarding open-set discrimination, the pooled estimates were 30% (95% CI 19-42%) for sound only, 46% (95% CI 37-54%) for lip-reading only, and 63% (95% CI 55-70%) for sound plus lip-reading. The pooled occurrence of ABI-related complications was 33% (95% CI 15-52%). CONCLUSION: This meta-analysis underscores the effectiveness and safety of ABIs in NF2, providing valuable insights for evidence-based decision-making and hearing rehabilitation strategies.
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Implantación Auditiva en el Tronco Encefálico , Implantes Auditivos de Tronco Encefálico , Neurilemoma , Neurofibromatosis , Neurofibromatosis 2 , Neoplasias Cutáneas , Humanos , Neurofibromatosis 2/complicaciones , Neurofibromatosis 2/cirugía , Resultado del Tratamiento , Audición , Estudios RetrospectivosRESUMEN
Carbon monoxide (CO) as an endogenous gas signaling molecule possesses important physiological functions and is of great significance in the treatment of various diseases. Real-time tracking of CO in living organisms has become a research hotspot in recent years. This article presents a lysosomal targeted near-infrared ratio fluorescence probe (TBM-CO) for selective detection of CO based on the dicyanoisophorone skeleton and morpholine fragment. The probe TBM-CO with weak ICT effect can be transformed to precursor TBM-NH2 with strong ICT effect by the traditional Tsuji-Trost reaction procession in the presence of Pd2+ ions. The mechanism was proved by DFT calculation or the MS and HPLC results respectively. In the near-infrared region an obvious ratio fluorescence intensity change (F686 / F616) is observed in vitro spectral experiments. The concentration titration experiments indicate that there is a good liner relationship between the ratio fluorescence intensity and the concentration in the range of 0 to 50 µM (R2 = 0.996) and the detection limit is calculated as 0.38 µM. The cell fluorescence imaging and co-localization experiments further demonstrate that TBM-CO is able to detect the exogenous and endogenous CO in lysosomal subcellular organelle. Finally, it was used to detect the changes of CO concentration in living mice successfully. In short, a probe with three advantages of near-infrared emission, ratiometric fluorescence and organelle targeting was reported and used to detect CO successfully in cells and in living mice.
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Monóxido de Carbono , Colorantes Fluorescentes , Ratones , Animales , Microscopía Fluorescente/métodos , Transducción de Señal , LisosomasRESUMEN
Carbon monoxide (CO) gas therapy has shown great potential as a very promising approach in the ongoing fight against tumors. However, delivering unstable CO to the tumor site and safely releasing it for maximum efficacy still have unsatisfactory outcomes. In this study, we've developed nanotheranostics (IN-DPPCO NPs) based on conjugated polymer IN-DPP and carbon monoxide (CO) carrier polymer mPEG(CO) for photothermal augmented gas therapy. The IN-DPPCO NPs can release CO with the hydrogen peroxide (H2O2) overexpressed in the tumor microenvironment. Meanwhile, IN-DPPCO NPs exhibit strong absorption in the near-infrared window, showing a high photothermal conversion efficiency of up to 41.5% under 808 nm laser irradiation. In vitro and in vivo experiments demonstrate that these nanotheranostics exhibit good biocompatibility. Furthermore, the synergistic CO/photothermal therapy shows enhanced therapeutic efficacy compared to gas therapy alone. This work highlights the great promise of conjugated polymer nanoparticles as versatile nanocarriers for spatiotemporally controlled and on-demand delivery of gaseous messengers to achieve precision cancer theranostics.
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Peróxido de Hidrógeno , Neoplasias , Humanos , Monóxido de Carbono , Fototerapia , Neoplasias/terapia , Polímeros , Microambiente TumoralRESUMEN
OBJECTIVE: Despite pituitary neuroendocrine tumor (PitNET) being extra-axial tumors without direct damage to brain tissue, patients with PitNET exhibit neuropsychological impairments. However, it remains unclear whether there are neuropsychological differences between PitNET and intra-axial tumors that directly destroy the brain parenchyma. This prospective study aims to clarify this distinction to inform decision-making for intracranial tumors of diverse origins. METHODS: A total of 146 patients with PitNET, 74 patients with glioma representing intra-axial tumors, and 52 age-, sex-, and education-matched healthy controls were recruited. All patients received standard treatment and postoperative rehabilitation. Clinical data were meticulously collected, and neuropsychological tests were administered to all participants both before and 3 months after surgery. RESULTS: Both PitNET and glioma patients experience the dual burden of cognitive and affective deficits. However, the feature of these deficits differs substantially. In PitNET patients, the deficits are relatively mild and focal, whereas in glioma patients, they are severe and extensive. Specifically, PitNET patients exhibit deficits in memory, anxiety, and negative affect. In contrast, glioma patients display deficits in executive function, attention, anxiety, positive/negative affect, and empathy. Notably, except for persistent memory deficits, the majority of neuropsychological scores declines in PitNET patients are restorable and can reach improvement within a short period after standard surgical therapy and perioperative management. Conversely, glioma patients not only fail to show improvements but also demonstrate worsening in terms of general cognition and memory postoperatively. INTERPRETATION: As an extra-axial tumor, PitNET may exhibit distinctive cognitive and affective functioning compared to intra-axial tumors, highlighting the need for specific treatment approaches for PitNET patients.
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Trastornos del Conocimiento , Glioma , Tumores Neuroendocrinos , Humanos , Estudios Prospectivos , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/cirugía , Trastornos del Conocimiento/psicología , Función EjecutivaRESUMEN
PURPOSE: Bone metastasis is a significant contributor to morbidity and mortality in advanced prostate cancer, and early diagnosis is challenging due to its insidious onset. The use of machine learning to obtain prognostic information from pathological images has been highlighted. However, there is a limited understanding of the potential of early prediction of bone metastasis through the feature combination method from various sources. This study presents a method of integrating multimodal data to enhance the feasibility of early diagnosis of bone metastasis in prostate cancer. METHODS AND MATERIALS: Overall, 211 patients diagnosed with prostate cancer (PCa) at Gansu Provincial Hospital between January 2017 and February 2023 were included in this study. The patients were randomized (8:2) into a training group (n = 169) and a validation group (n = 42). The region of interest (ROI) were segmented from the three magnetic resonance imaging (MRI) sequences (T2WI, DWI, and ADC), and pathological features were extracted from tissue sections (hematoxylin and eosin [H&E] staining, 10 × 20). A deep learning (DL) model using ResNet 50 was employed to extract deep transfer learning (DTL) features. The least absolute shrinkage and selection operator (LASSO) regression method was utilized for feature selection, feature construction, and reducing feature dimensions. Different machine learning classifiers were used to build predictive models. The performance of the models was evaluated using receiver operating characteristic curves. The net clinical benefit was assessed using decision curve analysis (DCA). The goodness of fit was evaluated using calibration curves. A joint model nomogram was eventually developed by combining clinically independent risk factors. RESULTS: The best prediction models based on DTL and pathomics features showed area under the curve (AUC) values of 0.89 (95% confidence interval [CI], 0.799-0.989) and 0.85 (95% CI, 0.714-0.989), respectively. The AUC for the best prediction model based on radiomics features and combining radiomics features, DTL features, and pathomics features were 0.86 (95% CI, 0.735-0.979) and 0.93 (95% CI, 0.854-1.000), respectively. Based on DCA and calibration curves, the model demonstrated good net clinical benefit and fit. CONCLUSION: Multimodal radiomics and pathomics serve as valuable predictors of the risk of bone metastases in patients with primary PCa.
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Neoplasias Óseas , Aprendizaje Profundo , Neoplasias de la Próstata , Masculino , Humanos , Radiómica , Imagen por Resonancia Magnética , Neoplasias Óseas/diagnóstico por imagen , Algoritmos , Neoplasias de la Próstata/diagnóstico por imagen , Estudios RetrospectivosRESUMEN
Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 µg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1ß, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1ß. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N6-methyladenosine (m6A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m6A-YTHDF2-dependent manner.
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Betaína , Disfunción Cognitiva , Animales , Ratas , Ratas Sprague-Dawley , Betaína/farmacología , Piroptosis , Interleucina-18 , Microglía , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Caspasa 1 , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Homocisteína , Interleucina-1beta , InflamasomasRESUMEN
BACKGROUND: The crucial role of mitophagy in tumor progression has been recognized. Therefore, our study aimed to investigate the potential correlation between pituitary adenoma invasiveness and the mitophagy processes. METHODS: In this study, we used transcriptomics of postoperative tissue from 32 patients and quantitative proteomics of 19 patients to screen for mitophagy-related invasion genes in pituitary adenomas. The invasive predictive value of target genes was analyzed by Lasso regression model, CytoHubba plugin and expression validation. Co-expression correlation analysis was used to identify paired proteins for target genes, and a predictive model for pituitary adenoma invasiveness was constructed by target genes and paired proteins and assessed using ROC analysis, calibration curves and DCA. GO function, pathway (GSEA or GSVA) and immune cell analysis (ssGSEA or CIBERSORT) were further utilized to explore the action mechanism of target gene. Finally, immunohistochemistry and cell function experiments were used to detect the differential expression and key roles of the target genes in pituitary adenomas. RESULTS: Finally, Heat shock protein family D member 1 (HSPD1) was identified as a target gene. The quality of a predictive model for pituitary adenoma invasiveness consisting of HSPD1 and its paired protein expression profiles was satisfactory. Moreover, the expression of HSPD1 was significantly lower in invasive pituitary adenomas than in non-invasive pituitary adenomas. Downregulation of HSPD1 may be significantly related to invasion process, mitochondria-related pathway and immune cell regulation in pituitary adenomas. CONCLUSION: The downregulation of HSPD1 may serve as a predictive indicator for identifying invasive pituitary adenomas.
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BACKGROUND AND OBJECTIVES: Lineage-based classification has critical clinical implications in pituitary neuroendocrine tumor (PitNET). As the most prevalent subtype of multilineage PitNET, PitNET originating from both pituitary-specific positive transcription factor 1 (Pit1) and steroidogenic factor-1 (SF1) lineages (Pit1/SF1-adenoma) is expected to exhibit rich and varied clinical behaviors. A comprehensive understanding of the clinical and pathological characteristics of Pit1/SF1-adenoma will provide mechanistic insight and influence the prognosis and treatment of PitNET. METHODS: A retrospective study was conducted by reviewing 57 cases of Pit1/SF1-adenoma between 2018 and 2022. We also included 88 cases of PitNET arising from Pit1 cell lineage (Pit1-adenoma) and 70 cases of PitNET arising from SF1 cell lineage (SF1-adenoma) as controls. Comprehensive data, including demographic, symptom, endocrinal, radiological, surgical, pathological, and prognostic information, were systematically collected. All specimens were immunostained for pituitary transcription factors (PTFs) and pituitary hormones. RESULTS: The detection rate was 8.0% for Pit1/SF1-adenoma within PitNET surgical specimens. Pit1/SF1-adenoma displayed a male predominance, with the mean diagnosis age falling between Pit1-adenoma and SF1-adenoma. The endocrine activity of Pit1/SF1-adenoma was lower than Pit1-adenoma but higher than SF1-adenoma. Pit1/SF1-adenoma had a higher incidence of cavernous sinus invasion (56.1%) than both Pit1-adenoma (38.6%, P = .039) and SF1-adenoma (27.1%, P = .001). Furthermore, Pit1/SF1-adenoma showed more postoperative complications than Pit1-adenoma (29.8% vs 8.0%, P = .001). Nonfunctional Pit1/SF1-adenoma had a higher radiological tumor recurrence rate than nonfunctional SF1-adenoma (34.8% vs 10.9%, P = .021). Notably, the immunostaining pattern was diverse in Pit1/SF1-adenoma, with various combinations of staining intensity for PTFs and 15 combinations for 6 pituitary hormones. Intriguingly, various PTFs combinations had no different impact on the outcome of Pit1/SF1-adenoma. CONCLUSION: Pit1/SF1-adenoma represents a unique pathological subtype of PitNET, characterized by distinctive clinical behaviors. Identifying Pit1/SF1-adenoma can facilitate more precise management of PitNET by the practical use of Pit1/SF1 immunostaining.
RESUMEN
Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the data panel for the "Huh7+BSA" experiment shown in Fig. 1D on p. 2852, showing the relative size of lipid droplets as determined in morphological studies using oil red O staining, had also appeared previously in the following article published by the same research group [Li D, Cheng M, Niu Y, Chi X, Liu X, Fan J, Fan H, Chang Y and Yang W: Identification of a novel human long non-coding RNA that regulates hepatic lipid metabolism by inhibiting SREBP-1c. Int J Biol Sci 13: 349-357, 2017]. Upon examining their original data, the authors have realized that this data panel was inadvertently selected incorrectly in Fig. 1, and the revised version of Fig. 1, containing the correct data panel for Fig. 1D, is shown on the next page. Note that this error did not significantly affect the results or the conclusions reported in this paper. All the authors agree to the publication of this Corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to correct this error. Moreover, the authors apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 18: 2850-2856, 2018; DOI: 10.3892/mmr.2018.9278].