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Staphylococcus aureus (S. aureus) can evade antibiotics and host immune defenses by persisting within infected cells. Here, we demonstrate that in infected host cells, S. aureus type VII secretion system (T7SS) extracellular protein B (EsxB) interacts with the stimulator of interferon genes (STING) protein and suppresses the inflammatory defense mechanism of macrophages during early infection. The binding of EsxB with STING disrupts the K48-linked ubiquitination of EsxB at lysine 33, thereby preventing EsxB degradation. Furthermore, EsxB-STING binding appears to interrupt the interaction of 2 vital regulatory proteins with STING: aspartate-histidine-histidine-cysteine domain-containing protein 3 (DHHC3) and TNF receptor-associated factor 6. This persistent dual suppression of STING interactions deregulates intracellular proinflammatory pathways in macrophages, inhibiting STING's palmitoylation at cysteine 91 and its K63-linked ubiquitination at lysine 83. These findings uncover an immune-evasion mechanism by S. aureus T7SS during intracellular macrophage infection, which has implications for developing effective immunomodulators to combat S. aureus infections.
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Proteínas de Bactérias , Macrófagos , Proteínas de Membrana , Infecções Estafilocócicas , Staphylococcus aureus , Sistemas de Secreção Tipo VII , Ubiquitinação , Staphylococcus aureus/imunologia , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Humanos , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Animais , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/metabolismo , Sistemas de Secreção Tipo VII/metabolismo , Sistemas de Secreção Tipo VII/imunologia , Sistemas de Secreção Tipo VII/genética , Camundongos , Evasão da Resposta Imune , Interações Hospedeiro-Patógeno/imunologiaRESUMO
Gymnosperms are mostly dioecious, and their staminate strobili undergo a longer developmental period than those of angiosperms. However, the underlying molecular mechanisms remain unclear. This study aimed to identify key genes and pathways involved in staminate strobilus development and dehiscence in Torreya grandis. Through weighted gene co-expression network analysis (WGCNA), we identified fast elongation-related genes enriched in carbon metabolism and auxin signal transduction, whereas dehiscence-related genes were abundant in alpha-linolenic acid metabolism and the phenylpropanoid pathway. Based on WGCNA, we also identified PHYTOCHROME-INTERACTING FACTOR4 (TgPIF4) as a potential regulator for fast elongation of staminate strobilus and 2 WRKY proteins (TgWRKY3 and TgWRKY31) as potential regulators for staminate strobilus dehiscence. Multiple protein-DNA interaction analyses showed that TgPIF4 directly activates the expression of TRANSPORT INHIBITOR RESPONSE2 (TgTIR2) and NADP-MALIC ENZYME (TgNADP-ME). Overexpression of TgPIF4 significantly promoted staminate strobilus elongation by elevating auxin signal transduction and pyruvate content. TgWRKY3 and TgWRKY31 bind to the promoters of the lignin biosynthesis gene PHENYLALANINE AMMONIA-LYASE (TgPAL) and jasmonic acid metabolism gene JASMONATE O-METHYLTRANSFERASE (TgJMT), respectively, and directly activate their transcription. Overexpression of TgWRKY3 and TgWRKY31 in the staminate strobilus led to early dehiscence, accompanied by increased lignin and methyl jasmonate levels, respectively. Collectively, our findings offer a perspective for understanding the growth of staminate strobili in gymnosperms.
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Regulação da Expressão Gênica de Plantas , Proteínas de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Flores/genética , Flores/crescimento & desenvolvimento , Cycadopsida/genética , Cycadopsida/metabolismo , Ciclopentanos/metabolismo , Oxilipinas/metabolismoRESUMO
Nucleation plays a critical role in many physical and biological phenomena that range from crystallization, melting and evaporation to the formation of clouds and the initiation of neurodegenerative diseases1-3. However, nucleation is a challenging process to study experimentally, especially in its early stages, when several atoms or molecules start to form a new phase from a parent phase. A number of experimental and computational methods have been used to investigate nucleation processes4-17, but experimental determination of the three-dimensional atomic structure and the dynamics of early-stage nuclei has been unachievable. Here we use atomic electron tomography to study early-stage nucleation in four dimensions (that is, including time) at atomic resolution. Using FePt nanoparticles as a model system, we find that early-stage nuclei are irregularly shaped, each has a core of one to a few atoms with the maximum order parameter, and the order parameter gradient points from the core to the boundary of the nucleus. We capture the structure and dynamics of the same nuclei undergoing growth, fluctuation, dissolution, merging and/or division, which are regulated by the order parameter distribution and its gradient. These experimental observations are corroborated by molecular dynamics simulations of heterogeneous and homogeneous nucleation in liquid-solid phase transitions of Pt. Our experimental and molecular dynamics results indicate that a theory beyond classical nucleation theory1,2,18 is needed to describe early-stage nucleation at the atomic scale. We anticipate that the reported approach will open the door to the study of many fundamental problems in materials science, nanoscience, condensed matter physics and chemistry, such as phase transition, atomic diffusion, grain boundary dynamics, interface motion, defect dynamics and surface reconstruction with four-dimensional atomic resolution.
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BACKGROUND: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare but highly heterogeneous renal cell carcinoma (RCC) entity, of which the clinical treatment landscape is largely undefined. This study aims to evaluate and compare the efficacy of different systemic treatments and further explore the molecular correlates. METHODS: Thirty-eight patients with metastatic TFE3-rRCC were enrolled. Main outcomes included progression-free survival (PFS), overall survival, objective response rate (ORR) and disease control rate. RNA sequencing was performed on 32 tumors. RESULTS: Patients receiving first-line immune checkpoint inhibitor (ICI) based combination therapy achieved longer PFS than those treated without ICI (median PFS: 11.5 vs. 5.1 months, P = 0.098). After stratification of fusion partners, the superior efficacy of first-line ICI based combination therapy was predominantly observed in ASPSCR1-TFE3 rRCC (median PFS: not reached vs. 6.5 months, P = 0.01; ORR: 67.5% vs. 10.0%, P = 0.019), but almost not in non-ASPSCR1-TFE3 rRCC. Transcriptomic data revealed enrichment of ECM and collagen-related signaling in ASPSCR1-TFE3 rRCC, which might interfere with the potential efficacy of anti-angiogenic monotherapy. Whereas angiogenesis and immune activities were exclusively enriched in ASPSCR1-TFE3 rRCC and promised the better clinical outcomes with ICI plus tyrosine kinase inhibitor combination therapy. CONCLUSIONS: The current study represents the largest cohort comparing treatment outcomes and investigating molecular correlates of metastatic TFE3-rRCC based on fusion partner stratification. ICI based combination therapy could serve as an effective first-line treatment option for metastatic ASPSCR1-TFE3 rRCC patients. Regarding with other fusion subtypes, further investigations should be performed to explore the molecular mechanisms to propose pointed therapeutic strategy accordingly.
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Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Proteínas de Fusão Oncogênica , Humanos , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/mortalidade , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Idoso , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Rearranjo Gênico , Biomarcadores Tumorais/genética , Resultado do Tratamento , Prognóstico , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
BACKGROUND: Data on the utilization and effects of prebiopsy prostate multiparametric magnetic resonance imaging (mpMRI) to support its routine use in real-world setting are still scarce. OBJECTIVE: To evaluate the change of clinical practice of prebiopsy mpMRI over time, and assess its diagnostic accuracy. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed data from 6168 patients who underwent primary prostate biopsy (PBx) between January 2011 and December 2021 and had prostate-specific antigen (PSA) values ranging from 3 to 100 ng/mL. INTERVENTION: Prebiopsy MRI at the time of PBx. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed general linear regression and to elucidate trends in the annual use of prebiopsy mpMRI and conducted multivariable logistic regression to evaluate the potential benefits of incorporating prebiopsy mpMRI for prostate cancer (PCa) detection. RESULTS AND LIMITATIONS: The utilization of prebiopsy mpMRI significantly increased from 9.2% in 2011 to 75.0% in 2021 (p < 0.001). In addition, prebiopsy mpMRI significantly reduced negative PBx by 8.6% while improving the detection of clinically significant PCa (csPCa) by 7.0%. Regression analysis showed that the utilization of prebiopsy mpMRI was significantly associated with a 48% (95% confidence interval [CI]: 1.19-1.84) and 36% (95% CI: 1.12-1.66) increased PCa detection rate in the PSA 3-10 ng/mL and 10-20 ng/mL groups, respectively; and a 34% increased csPCa detection rate in the PSA 10-20 ng/mL group (95% CI: 1.09-1.64). The retrospective design and the single center cohort constituted the limitations of this study. CONCLUSIONS: Our study demonstrated a notable rise in the utilization of prebiopsy mpMRI in the past decade. The adoption of this imaging technique was significantly associated with an increased probability of detecting prostate cancer. PATIENT SUMMARY: From 2011 to 2021, we demonstrated a steady increase in the utilization of prebiopsy mpMRI among biopsy-naïve men. We also confirmed the positive impact of prebiopsy mpMRI utilization on the detection of prostate cancer.
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Imageamento por Ressonância Magnética Multiparamétrica , Neoplasias da Próstata , Masculino , Humanos , Antígeno Prostático Específico , Próstata/diagnóstico por imagem , Próstata/patologia , Estudos Retrospectivos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Imageamento por Ressonância Magnética/métodos , Biópsia Guiada por Imagem/métodosRESUMO
BACKGROUND: KI67 is a well-known biomarker reflecting cell proliferation. We aim to elucidate the predictive role of KI67 in the efficacy of abiraterone for patients with advanced prostate cancer (PCa). METHODS: Clinicopathological data of 152 men with metastatic PCa, who received abiraterone therapy were retrospectively collected. The KI67 positivity was examined by immunohistochemistry using the prostate biopsy specimen. The predictive value of KI67 on the therapeutic efficacy of abiraterone was explored using Kaplan-Meier curve and Cox regression analysis. The endpoints included prostate-specific antigen (PSA) progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: In total, 85/152 (55.9%) and 67/152 (44.1%) cases, respectively, received abiraterone at metastatic hormone-sensitive (mHSPC) and castration-resistant PCa (mCRPC) stage. The median KI67 positivity was 20% (interquartile range: 10%-30%). Overall, KI67 rate was not correlated with PSA response. Notably, an elevated KI67-positive rate strongly correlated with unfavorable abiraterone efficacy, with KI67 ≥ 30% and KI67 ≥ 20% identified as the optimal cutoffs for prognosis differentiation in mHSPC (median PSA-PFS: 11.43 Mo vs. 26.43 Mo, p < 0.001; median rPFS: 16.63 Mo vs. 31.90 Mo, p = 0.003; median OS: 21.77 Mo vs. not reach, p = 0.005) and mCRPC (median PSA-PFS: 7.17 Mo vs. 12.20 Mo, p = 0.029; median rPFS: 11.67 Mo vs. 16.47 Mo, p = 0.012; median OS: 21.67 Mo vs. not reach, p = 0.073) patients, respectively. Multivariate analysis supported the independent predictive value of KI67 on abiraterone efficacy. In subgroup analysis, an elevated KI67 expression was consistently associated with unfavorable outcomes in the majority of subgroups. Furthermore, data from another cohort of 79 PCa patients with RNA information showed that those with KI67 RNA levels above the median had a significantly shorter OS than those below the median (17.71 vs. 30.72 Mo, p = 0.035). CONCLUSIONS: This study highlights KI67 positivity in prostate biopsy as a strong predictor of abiraterone efficacy in advanced PCa. These insights will assist clinicians in anticipating clinical outcomes and refining treatment decisions for PCa patients.
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Androstenos , Biomarcadores Tumorais , Antígeno Ki-67 , Neoplasias da Próstata , Humanos , Masculino , Antígeno Ki-67/análise , Antígeno Ki-67/metabolismo , Idoso , Androstenos/uso terapêutico , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Proliferação de Células/efeitos dos fármacos , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Resultado do Tratamento , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêuticoRESUMO
Fungal keratitis remains a major cause of severe visual loss in developing countries because of limited choices of therapy. The progression of fungal keratitis is a race between the innate immune system and the outgrowth of fungal conidia. Programmed necrosis (necroptosis), a type of proinflammatory cell death, has been recognized as a critical pathologic change in several diseases. However, the role and potential regulatory mechanisms of necroptosis have not been investigated in corneal diseases. The current study showed, for the first time, that fungal infection triggered significant corneal epithelial necroptosis in human/mouse/in vitro models. Moreover, a reduction in excessive reactive oxygen species release effectively prevented necroptosis. NLRP3 knockout did not affect necroptosis in vivo. In contrast, ablation of necroptosis via RIPK3 knockout significantly delayed migration and inhibited the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in macrophages, which enhanced the progression of fungal keratitis. Taking these findings together, the study indicated that overproduction of reactive oxygen species in fungal keratitis leads to significant necroptosis in the corneal epithelium. Furthermore, the necroptotic stimuli-mediated NLRP3 inflammasome serves as a driving force in host defense against fungal infection.
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Inflamassomos , Ceratite , Humanos , Animais , Camundongos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Necroptose , Apoptose/fisiologia , Proteínas Quinases/metabolismo , Estresse Oxidativo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismoRESUMO
Pneumocystis jirovecii is a prevalent opportunistic fungal pathogen that can lead to life-threatening Pneumocystis pneumonia in immunocompromised individuals. Given that timely and accurate diagnosis is essential for initiating prompt treatment and enhancing patient outcomes, it is vital to develop a rapid, simple, and sensitive method for P. jirovecii detection. Herein, we exploited a novel detection method for P. jirovecii by combining recombinase polymerase amplification (RPA) of nucleic acids isothermal amplification and the trans cleavage activity of Cas12a. The factors influencing the efficiency of RPA and Cas12a-mediated trans cleavage reaction, such as RPA primer, crRNA, the ratio of crRNA to Cas12a and ssDNA reporter concentration, were optimized. Our RPA-Cas12a-based fluorescent assay can be completed within 30-40 min, comprising a 25-30 min RPA reaction and a 5-10 min trans cleavage reaction. It can achieve a lower detection threshold of 0.5 copies/µL of target DNA with high specificity. Moreover, our RPA-Cas12a-based fluorescent method was examined using 30 artificial samples and demonstrated high accuracy with a diagnostic accuracy of 93.33%. In conclusion, a novel, rapid, sensitive, and cost-effective RPA-Cas12a-based detection method was developed and demonstrates significant potential for on-site detection of P. jirovecii in resource-limited settings.
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Técnicas de Amplificação de Ácido Nucleico , Pneumocystis carinii , Sensibilidade e Especificidade , Pneumocystis carinii/genética , Pneumocystis carinii/isolamento & purificação , Técnicas de Amplificação de Ácido Nucleico/métodos , Humanos , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Endodesoxirribonucleases/genética , Endodesoxirribonucleases/metabolismo , Proteínas Associadas a CRISPR/genética , DNA Fúngico/genética , Recombinases/metabolismo , Recombinases/genética , Proteínas de BactériasRESUMO
Manipulating radiation asymmetry of photonic structures is of particular interest in many photonic applications such as directional optical antenna, high efficiency on-chip lasers, and coherent light control. Here, we proposed a term of pseudopolarization to reveal the topological nature of radiation asymmetry in bilayer metagratings. Robust pseudopolarization vortex with an integer topological charge exists in P-symmetry metagrating, allowing for tunable directionality ranging from -1 to 1 in synthetic parameter space. When P-symmetry breaking, such vortex becomes pairs of C points due to the conservation law of charge, leading to the phase difference of radiation asymmetry from π/2 to 3π/2. Furthermore, topologically enabled coherent perfect absorption is robust with customized phase difference at will between two counterpropagating external light sources. This Letter can not only enrich the understanding of two particular topological photonic behaviors, i.e., bound state in the continuum and unidirectional guided resonance, but also provide a topological view on radiation asymmetry, opening an unexplored avenue for asymmetric light manipulation in on-chip laser, light-light switch, and quantum emitters.
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PURPOSE: Respiratory motion (RM) significantly impacts image quality in thoracoabdominal PET/CT imaging. This study introduces a unified data-driven respiratory motion correction (uRMC) method, utilizing deep learning neural networks, to solve all the major issues caused by RM, i.e., PET resolution loss, attenuation correction artifacts, and PET-CT misalignment. METHODS: In a retrospective study, 737 patients underwent [18F]FDG PET/CT scans using the uMI Panorama PET/CT scanner. Ninety-nine patients, who also had respiration monitoring device (VSM), formed the validation set. The remaining data of the 638 patients were used to train neural networks used in the uRMC. The uRMC primarily consists of three key components: (1) data-driven respiratory signal extraction, (2) attenuation map generation, and (3) PET-CT alignment. SUV metrics were calculated within 906 lesions for three approaches, i.e., data-driven uRMC (proposed), VSM-based uRMC, and OSEM without motion correction (NMC). RM magnitude of major organs were estimated. RESULTS: uRMC enhanced diagnostic capabilities by revealing previously undetected lesions, sharpening lesion contours, increasing SUV values, and improving PET-CT alignment. Compared to NMC, uRMC showed increases of 10% and 17% in SUVmax and SUVmean across 906 lesions. Sub-group analysis showed significant SUV increases in small and medium-sized lesions with uRMC. Minor differences were found between VSM-based and data-driven uRMC methods, with the SUVmax was found statistically marginal significant or insignificant between the two methods. The study observed varied motion amplitudes in major organs, typically ranging from 10 to 20 mm. CONCLUSION: A data-driven solution for respiratory motion in PET/CT has been developed, validated and evaluated. To the best of our knowledge, this is the first unified solution that compensates for the motion blur within PET, the attenuation mismatch artifacts caused by PET-CT misalignment, and the misalignment between PET and CT.
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BACKGROUND: Inflammation plays a pivotal role in the progression of prostate cancer (PCa). Several immune-inflammatory indices, including neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), lymphocyte to monocyte ratio (LMR) and platelet to lymphocyte ratio (PLR), lung immune prognostic index (LIPI), systemic inflammation response index (SIRI) and systemic immune inflammation index (SII), have demonstrated their prognostic values in several solid malignancies. However, Comparisons of superiority with these seven indices' predictive efficacy within metastatic hormone-sensitive PCa (mHSPC) and metastatic castration-resistant PCa (mCRPC) remain uncertain. METHODS: We retrospectively included 407 patients diagnosed with mHSPC and 158 patients with mCRPC at West China Hospital from 2005 to 2022. The seven immune-inflammatory indices were computed based on hematological data of mHSPC at initial diagnosis and mCRPC at progression to CRPC. Prognostic value for castration-resistant prostate cancer-free survival (CFS), overall survival (OS), prostate-specific antigen progression-free survival (PSA-PFS) and prostate-specific antigen (PSA) response was assessed using Kaplan-Meier curves, Cox regression models, and chi-square tests. The predictive performance of each immune-inflammatory index was assessed using the area under the curve (AUC) in time-dependent receiver operating characteristic curve (ROC) analysis and C-index calculation. RESULTS: All seven immune-inflammatory indices were significantly associated with CFS and OS in the mHSPC cohort, as well as with PSA response, PSA-PFS, and OS in the mCRPC cohort. In the mHSPC cohort, LIPI consistently exhibited higher AUC values compared to NLR, dNLR, LMR, PLR, SII, and SIRI for predicting CFS and OS. This indicates that LIPI had a superior discriminative ability compared to the other indices (C-index of LIPI: 0.643 and 0.686 for CFS and OS, respectively). Notably, the predictive advantage of LIPI over other indices in the mHSPC stage diminished in the mCRPC stage. CONCLUSIONS: This study firstly confirmed the prognostic value of SII, SIRI and LIPI in mHSPC and mCRPC, and revealed that LIPI had a higher predictive power than NLR, dNLR, LMR, PLR, SII and SIRI in mHSPC. These non-invasive indices can enable clinicians to quickly assess the prognosis of patients.
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Neutrófilos , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Idoso , Estudos Retrospectivos , Pessoa de Meia-Idade , Prognóstico , Neutrófilos/imunologia , Inflamação , Linfócitos/imunologia , Antígeno Prostático Específico/sangue , Curva ROC , Idoso de 80 Anos ou mais , Plaquetas/patologia , Plaquetas/imunologiaRESUMO
BACKGROUND: Poly (ADP- ribose) polymerase inhibitors (PARPi) has been increasingly adopted for metastatic castration-resistance prostate cancer (mCRPC) patients with homologous recombination repair deficiency (HRD). However, it is unclear which PARPi is optimal in mCRPC patients with HRD in 2nd -line setting. METHOD: We conducted a systematic review of trials regarding PARPi- based therapies on mCRPC in 2nd -line setting and performed a Bayesian network meta-analysis (NMA). Radiographic progression-free survival (rPFS) was assessed as primary outcome. PSA response and adverse events (AEs) were evaluated as secondary outcomes. Subgroup analyses were performed according to specific genetic mutation. RESULTS: Four RCTs comprised of 1024 patients (763 harbored homologous recombination repair (HRR) mutations) were identified for quantitative analysis. Regarding rPFS, olaparib monotherapy, rucaparib and cediranib plus olaparib showed significant improvement compared with ARAT. Olaparib plus cediranib had the highest surface under cumulative ranking curve (SUCRA) scores (87.5%) for rPFS, followed by rucaparib, olaparib and olaparib plus abiraterone acetate prednisone. For patients with BRCA 1/2 mutations, olaparib associated with the highest probability (98.1%) of improved rPFS. For patients with BRCA-2 mutations, olaparib and olaparib plus cediranib had similar efficacy. However, neither olaparib nor rucaparib showed significant superior effectiveness to androgen receptor-axis-targeted therapy (ARAT) in patients with ATM mutations. For safety, olaparib showed significantly lower ≥ 3 AE rate compared with cediranib plus olaparib (RR: 0.72, 95% CI: 0.51, 0.97), while olaparib plus cediranib was associated with the highest risk of all-grade AE. CONCLUSION: PARPi-based therapy showed considerable efficacy for mCRPC patients with HRD in 2nd -line setting. However, patients should be treated accordingly based on their genetic background as well as the efficacy and safety of the selected regimen. TRIAL REGISTRATION: CRD42023454079.
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Teorema de Bayes , Mutação , Ftalazinas , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Masculino , Ftalazinas/uso terapêutico , Ftalazinas/efeitos adversos , Ftalazinas/administração & dosagem , Metanálise em Rede , Piperazinas/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Proteína BRCA2/genética , Reparo de DNA por Recombinação/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Intervalo Livre de Progressão , Indóis/uso terapêutico , Indóis/efeitos adversos , Indóis/administração & dosagem , Proteína BRCA1/genética , Resultado do Tratamento , QuinazolinasRESUMO
BACKGROUND: Immune checkpoint inhibitors (ICI) combined with chemotherapy are efficacious for treating advanced non-small cell lung cancer (NSCLC); however, the effectiveness of this approach in the malignant pleural effusion (MPE) population is unclear. This study evaluated ICI plus chemotherapy in NSCLC patients with MPE. METHODS: Patients from 3 centers in China with NSCLC and MPE who received ICI plus chemotherapy (ICI Plus Chemo) or chemotherapy alone (Chemo) between December 2014 and June 2023 were enrolled. Clinical outcomes and adverse events (AEs) were compared. RESULTS: Of 155 eligible patients, the median age was 61.0 years old. Males and never-smokers accounted for 73.5% and 39.4%, respectively. Fifty-seven and 98 patients received ICI Plus Chemo or Chemo, respectively. With a median study follow-up of 10.8 months, progression-free survival (PFS) was significantly longer with ICI Plus Chemo than with Chemo (median PFS: 7.4 versus 5.7 months; HR = 0.594 [95% CI: 0.403-0.874], P = 0.008). Median overall survival (OS) did not differ between groups (ICI Plus Chemo: 34.2 versus Chemo: 28.3 months; HR = 0.746 [95% CI: 0.420-1.325], P = 0.317). The most common grade 3 or worse AEs included decreased neutrophil count (3 [5.3%] patients in the ICI Plus Chemo group vs. 5 [5.1%] patients in the Chemo group) and decreased hemoglobin (3 [5.3%] versus 10 [10.2%]). CONCLUSIONS: In patients with untreated NSCLC with MPE, ICI plus chemotherapy resulted in significantly longer PFS than chemotherapy and had a manageable tolerability profile, but the effect on OS may be limited.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Derrame Pleural Maligno , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Derrame Pleural Maligno/tratamento farmacológico , Derrame Pleural Maligno/patologia , Estudos Retrospectivos , FemininoRESUMO
This research focused on how upregulation of S100A9 contributed to the pathogenesis of the dry eye disease (DED) and whether S100A9 served as a promising therapeutic target in DED. Public single-cell RNA sequencing (scRNA-seq) data of a lacrimal gland excision (LGE) murine DED model was analyzed. LGE model was established and expression of protein was measured through immunofluorescence and Western blot. DED-related signs were evaluated through tear secretion and fluorescent staining. TUNEL was performed to detect the level of cell death. Briefly, S100A9 was recognized as a highly variable gene in the DED group. LGE model was successfully established, and S100A9 showed a time-dependent increase in the corneal epithelia. Autophagic blockage was predicted by the scRNA-seq data in DED, and further verified by decrease of LC3B-II/LC3B-I and increase of SQSTM1 and p-mTOR/mTOR, while S100A9 inhibitor paquinimod (PAQ) reversed the changes. PAQ also downregulated TLR4, and inhibition of TLR4 also alleviated autophagic blockage in DED. Finally, signs of DED, chronic corneal inflammation and cell death got a remission after either inhibition of S100A9 or TLR4. In general, we deduced a S100A9-TLR4-Autophagic blockage pathway in the pathogenesis of DED.
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In practical applications, analytical instruments are used for both qualitative and quantitative analysis. However, for high-field asymmetric-waveform ion mobility spectrometry (FAIMS), most studies to date have been focused on the qualitative analysis of substances, with limited research on quantitative analysis. Explored here is the feasibility of using deep learning in FAIMS for quantitative analysis, aided by redesigning the FAIMS upper computer. Integrating spectrum creation and deep learning analysis into the FAIMS upper computer boosts the processing and analysis of FAIMS data, laying a foundation for applying FAIMS practically. For analysis using image processing, multiple FAIMS spectral lines obtained under different conditions are converted into a three-dimensional thermodynamic map known as a FAIMS spectrum, and multiple FAIMS spectrum are preprocessed to obtain the data set of this experiment. The principles of partial-least-squares regression and the XGBoost and ResNeXt models are introduced in detail, and the data are analyzed using these models, while exploring the effects of different model parameters and determining their optimal values. The experimental results show that the pre-trained ResNeXt deep learning model performs the best on the test set, with a root mean square error of 0.86 mg/mL, indicating the potential of deep learning in realizing quantitative analysis of substances in FAIMS.
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Aprendizado Profundo , Espectrometria de Mobilidade Iônica , Espectrometria de Mobilidade Iônica/métodos , AcetonaRESUMO
BACKGROUND: WD repeat domain 12 (WDR12) plays a crucial role in the ribosome biogenesis pathway. However, its biological function in colorectal cancer (CRC) remains poorly understood. Therefore, this study aims to investigate the roles of WDR12 in the occurrence and progression of CRC, as well as its underlying mechanisms. METHODS: The expression of WDR12 was assessed through The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA) database. Functional experiments including Celigo assay, MTT assay, and Caspase-3/7 assay were conducted to validate the role of WDR12 in the malignant progression of CRC. Additionally, mRNA chip-sequencing and ingenuity pathway analysis (IPA) were performed to identify the molecular mechanism. RESULTS: WDR12 expression was significantly upregulated in CRC tissues compared to normal colorectal tissues. Knockdown of WDR12 reduced proliferation and promoted apoptosis of CRC cell lines in vitro and in vivo experiments. Furthermore, WDR12 expression had a significantly inverse association with diseases and functions, including cancer, cell cycle, DNA replication, recombination, cellular growth, proliferation and repair, as revealed by IPA analysis of mRNA chip-sequencing data. Moreover, the activation of cell cycle checkpoint kinases proteins in the cell cycle checkpoint control signaling pathway was enriched in the WDR12 knockdown CRC cell lines. Additionally, downregulation of rac family small GTPase 1 (RAC1) occurred upon WDR12 knockdown, thereby facilitating the proliferation and anti-apoptosis of CRC cells. CONCLUSION: Our study demonstrates that the WDR12/RAC1 axis promotes tumor progression in CRC. Therefore, WDR12 may serve as a novel oncogene and a potential target for individualized therapy in CRC. These findings provide an experimental foundation for the clinical development of drugs targeting the WDR12/RAC1 axis.
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OBJECTIVES: To develop and validate a prediction model for identifying non-prostate cancer (non-PCa) in biopsy-naive patients with PI-RADS category ≥ 4 lesions and PSA ≤ 20 ng/ml to avoid unnecessary biopsy. PATIENTS AND METHODS: Eligible patients who underwent transperineal biopsies at West China Hospital between 2018 and 2022 were included. The patients were randomly divided into training cohort (70%) and validation cohort (30%). Logistic regression was used to screen for independent predictors of non-PCa, and a nomogram was constructed based on the regression coefficients. The discrimination and calibration were assessed by the C-index and calibration plots, respectively. Decision curve analysis (DCA) and clinical impact curves (CIC) were applied to measure the clinical net benefit. RESULTS: A total of 1580 patients were included, with 634 non-PCa. Age, prostate volume, prostate-specific antigen density (PSAD), apparent diffusion coefficient (ADC) and lesion zone were independent predictors incorporated into the optimal prediction model, and a corresponding nomogram was constructed ( https://nomogramscu.shinyapps.io/PI-RADS-4-5/ ). The model achieved a C-index of 0.931 (95% CI, 0.910-0.953) in the validation cohort. The DCA and CIC demonstrated an increased net benefit over a wide range of threshold probabilities. At biopsy-free thresholds of 60%, 70%, and 80%, the nomogram was able to avoid 74.0%, 65.8%, and 55.6% of unnecessary biopsies against 9.0%, 5.0%, and 3.6% of missed PCa (or 35.9%, 30.2% and 25.1% of foregone biopsies, respectively). CONCLUSION: The developed nomogram has favorable predictive capability and clinical utility can help identify non-PCa to support clinical decision-making and reduce unnecessary prostate biopsies.
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Nomogramas , Antígeno Prostático Específico , Próstata , Procedimentos Desnecessários , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Idoso , Procedimentos Desnecessários/estatística & dados numéricos , Biópsia , Próstata/patologia , Próstata/diagnóstico por imagem , Estudos Retrospectivos , Neoplasias da Próstata/patologia , Neoplasias da Próstata/sangueRESUMO
PURPOSE: The aim of this study was to explore the benefit the metastasectomy for patients with metastatic non-clear cell carcinoma (non-ccRCC). METHODS: This study enrolled 120 patients with confirmed metastatic non-ccRCC from the RCC database of our center from 2008 to 2021. Patients without metastasectomy were grouped as radical nephrectomy without metastasectomy patients. The clinical outcomes included overall survival (OS) and progression-free survival (PFS). Cox regression and Kaplan-Meier analyses were used to assess potential factors that predict clinical benefits from metastasectomy. RESULTS: A total of 100 patients received radical nephrectomy alone, while the remaining 20 patients underwent both radical nephrectomy and metastasectomy. There was no significant difference in age between the two groups. Out of 100 patients who underwent radical nephrectomy, 60 were male, and out of 20 patients who had both radical nephrectomy and metastasectomy, 12 were male. Patients who underwent systemic therapy plus radical nephrectomy and metastasectomy had significantly better PFS (27.1 vs. 14.0, p = 0.032) and OS (67.3 vs. 24.0, p = 0.043) than those who underwent systemic therapy plus radical nephrectomy alone. Furthermore, for patients without liver metastasis (n = 54), systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.028) and OS (p = 0.043). Similarly, for patients with metachronous metastasis, systemic therapy plus radical nephrectomy and metastasectomy improved both PFS (p = 0.043) and OS (p = 0.032). None of the patients experienced serious perioperative complications (Clavien-Dindo Classification ≥ III grade). CONCLUSION: Metastasectomy in patients with metastatic non-ccRCC may provide clinical benefits in terms of improved PFS and OS, especially in patients without liver metastasis and those with metachronous metastasis.
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Carcinoma de Células Renais , Neoplasias Renais , Metastasectomia , Nefrectomia , Humanos , Masculino , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Neoplasias Renais/mortalidade , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Nefrectomia/métodos , Taxa de Sobrevida , Carcinoma de Células Renais/secundário , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/mortalidade , Idoso , Estudos de Coortes , AdultoRESUMO
With the increasingly serious problem of phosphorus deficiency in the subtropical zone, chemical fertilizers are widely used. But it pollutes the environment. Phosphorus-solubilizing microorganisms (PSMs) are referred to as a new solution to this problem. We explored the phosphorus-dissolving characteristics of PSB strains isolated from the rhizosphere soil of Torreya grandis to provide a theoretical basis for selecting the strain for managing phosphorus deficiency in subtropical soils and also provides a more sufficient theoretical basis for the utilization of PSMs. From 84 strains, three strains exhibiting high phosphorus solubility and strong IAA producing capacity were selected through a series of experiments. The phosphate-solubilizing capacity of the three selected strains W1, W74, and W83 were 339.78 mg/L, 332.57 mg/L, and 358.61 mg/L, respectively. Furthermore, W1 showed the strongest IAA secreting capacity of 8.62 mg/L, followed by W74 (7.58 mg/L), and W83 (7.59 mg/L). Determination by metabolites, it was observed that these three strains dissolved phosphorus by secreting a large amount of lactic acid, aromatic acid, and succinic acid. The genome of these PSBs were sequenced and annotated in this study. Our results revealed that PSB primarily promotes their metabolic pathway, especially carbon metabolism, to secrete plenty organic acids for dissolving insoluble phosphorus.
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Fósforo , Solo , Fosfatos/metabolismo , Bactérias/genética , Bactérias/metabolismo , Genômica , Microbiologia do SoloRESUMO
RATIONALE: During the detection of volatile organic compounds (VOC) using high-field asymmetric waveform ion mobility spectrometry (FAIMS), the ambient temperature significantly impacts the accuracy of planar FAIMS. To mitigate the influence of ambient temperature on detection accuracy and enhance resolution, a FAIMS system based on the inner impedance characteristics of a printed circuit board (PCB) was designed for temperature control. METHODS: This study, conducted under standard atmospheric pressure, aimed to assess the signal stability of a planar FAIMS instrument with and without temperature control, and the effect of temperature change on the detection ability of acetone, ethanol, and their mixture was studied using PCB self-heating. RESULTS: Experimental results demonstrated that the base noise in FAIMS with temperature control was 0.2 pA, whereas that in FAIMS without temperature control was 1.8 pA. Notably, with increasing temperature, the detection ability of FAIMS changes accordingly. The optimal relative detection ability of acetone was observed when the electrode plate was heated to 45°C under an electric field of 15 kV/cm. CONCLUSIONS: This study provides a novel approach to improve the resolving power of FAIMS systems and their signal-to-noise ratio. The utilization of a PCB-based temperature control proved effective in stabilizing FAIMS signal characteristics and optimizing detection capabilities, particularly for VOCs such as acetone. These findings have significant implications for improving the accuracy and resolving power of FAIMS systems in VOC detection applications.