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The current standard of care for anal squamous cell carcinoma (ASCC) is definitive concurrent chemoradiotherapy (CRT). However, about a third of patients may experience treatment failure. Recently, immunotherapy has emerged as a novel strategy for metastatic ASCC patients. We evaluated the efficacy and safety of surgery, CRT alone, and CRT with immunotherapy (CRT-I) in 100 nonmetastatic ASCC patients, treated from April 2012 through May 2023, by determining survival outcomes and acute adverse events. The median (range) follow-up was 30.7 (7.6 to 134.9) months. The study cohort 3-year overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were 80.7 %, 62.2 %, 71.1 %, and 67.6 %, respectively. The Surgery group had significantly lower rates than the CRT and CRT-I groups for 3-year PFS (33.1% vs. 65.2% vs. 92.9 %, P < 0.001), DMFS (46.7% vs. 74.6% vs. 92.9 %, P = 0.002) and LRFS (37.0% vs. 73.3% vs. 92.9 %, P < 0.001), respectively. All patients receiving CRT-I were alive at last follow-up. Of 100 patients, 26 (26.0 %) experienced severe (≥ grade 3) acute toxicity. Of 24 patients receiving CRT-I, 8 (33.3 %) had severe acute toxicity. Using immunohistochemistry, peritumoural stromal infiltration by CD8+ T cells was significantly higher after CRT-I compared to before CRT-I and to after CRT alone. The addition of immunotherapy to CRT may be an effective first-line treatment option with favourable survival outcomes and acceptable toxicity for patients with ASCC. A prospective, randomized trial assessing the efficacy of CRT combined with a PD-1 inhibitor in patients with locally advanced ASCC is in progress.
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Inherently chiral calixarenes have garnered significant attention due to their distinctive properties, yet the development of efficient catalytic asymmetric synthesis methods remains a critical challenge. Herein, we report the asymmetric synthesis of calix[4]arenes featuring inherent or both inherent and axial chirality via a cobalt-catalyzed C-H activation/annulation strategy in high yield with excellent enantio- and diastereoselectivity (up to > 99% ee and > 20:1 dr). Electrooxidation was also suitable for this transformation to obviate the sacrificial metal oxidants, underscoring the environmentally friendly potential of this approach. A key octahedral cobaltacycle intermediate was synthesized and characterized, providing valuable insights into the mode of enantio- and diastereocontrol of this protocol. Noteworthy photoluminescence quantum yields of up to 0.94 were measured, underscoring the potential of these compounds in the domain of organic fluorescent materials.
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BACKGROUND: There is currently a lack of comprehensive evidence regarding the correlation between Alternate Mediterranean Diet (AMED) and the survival of patients with ovarian cancer (OC). This prospective cohort study first assessed the association of AMED, not only pre-diagnosis and post-diagnosis but also the change from pre-diagnosis to post-diagnosis with OC survival. METHODS: A total of 560 OC patients were included in the study, and their dietary intake was assessed using a reliable 111-item food frequency questionnaire. The overall survival (OS) of the patients was monitored through active follow-up and review of medical records until February 16th, 2023. Cox proportional hazard regression models were utilized to compute the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). RESULTS: Out of the total 560 patients with OC, 211 (37.68%) succumbed during a median follow-up period of 44.40 months (interquartile range: 26.97-61.37). Comparative analysis indicated a significant association between the highest tertiles of pre-diagnosis (HR = 0.59; 95% CI 0.38-0.90; Ptrend < 0.05) and post-diagnosis (HR = 0.61; 95% CI 0.41-0.91; Ptrend < 0.05) AMED intake and improved OS as opposed to the lowest tertile. Additionally, a significant linear trend was observed for AMED and OC survival. Notably, decreased intake (more than 5% change) and significantly increased intake (more than 15% change) of AMED from pre-diagnosis to post-diagnosis were linked to worse and better OS, respectively, when compared to the stable intake group (change within 5%). Furthermore, patients displaying consistently higher AMED intake both before and after diagnosis experienced enhanced OS in comparison to those with consistently low AMED intake (HRHigh-High vs. Low-Low = 0.47; 95% CI 0.31-0.70). CONCLUSION: High pre-diagnosis and post-diagnosis AMED was associated with an improved OS in patients with OC, suggesting that maintaining a consistently high intake of AMED could potentially benefit the prognosis of OC.
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Dieta Mediterrânea , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/dietoterapia , Estudos Prospectivos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Adulto , Estimativa de Kaplan-Meier , IdosoRESUMO
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.
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Chemically induced proximity modalities such as targeted protein degradation (TPD) hold promise for expanding the number of proteins that can be manipulated pharmacologically. However, current TPD strategies are often limited to proteins with preexisting ligands. Molecular glues (e.g. glutarimide ligands for CUL4CRBN), offer the potential to target undruggable proteins. Yet, their rational design is largely unattainable due to the unpredictability of the 'gain-of-function' nature of the glue interaction upon chemical modification of ligands. We recently reported a covalent trans-labelling glue mechanism which we named 'Template-assisted covalent modification', where an electrophile decorated BRD4 inhibitor was effectively delivered to a cysteine residue on DCAF16 due to an electrophile-induced BRD4-DCAF16 interaction. Herein, we report our efforts to evaluate how various electrophilic modifications to the BRD4 binder, JQ1, affect DCAF16 recruitment and subsequent BRD4 degradation efficiency. We discovered a moderate correlation between the electrophile-induced BRD4-DCAF16 ternary complex formation and BRD4 degradation. Moreover, we show that a more solvent-exposed warhead presentation optimally recruits DCAF16 and promotes BRD4 degradation. The diversity of covalent attachments in this class of BRD4 degraders suggests a high tolerance and tunability for the BRD4-DCAF16 interaction. This offers a new avenue for rational glue design by introducing covalent warheads to known binders.
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Predicting material properties has always been a challenging task in materials science. With the emergence of machine learning methodologies, new avenues have opened up. In this study, we build upon our recently developed graph neural network (GNN) approach to construct models that predict four distinct material properties. Our graph model represents materials as element graphs, with chemical formulas serving as the only input. This approach ensures permutation invariance, offering a robust solution to prior limitations. By employing bootstrap methods to train this individual GNN, we further enhance the reliability and accuracy of our predictions. With multi-task learning, we harness the power of extensive datasets to boost the performance of smaller ones. We introduce the inaugural version of the Materials Properties Prediction (MAPP) framework, empowering the prediction of material properties solely based on chemical formulas.
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OBJECTIVE: Knowledge of longitudinal changes in posttraumatic stress disorder (PTSD) and posttraumatic growth (PTG) may help survivors recover better. Yet, researchers dispute the population-based typologies of PTSD and PTG as well as the temporal transition between these subpopulations across time, especially among adolescents. Thus, the transition pattern still needs further research. Besides, parent-child factors (parenting styles, parent-child cohesion, and parental attachment styles) may influence the transition, but it keeps unclear. In the study, we aimed to solve these questions. METHOD: A three-wave investigation was conducted among 620 adolescents, 12 months, 21 months, and 27 months, after the Jiuzhaigou earthquake by using self-report measures on PTSD, PTG, and parent-child factors at the three time points. Finally, 339 of them finished the three-wave investigation. RESULTS: Latent profile analysis models showed that three heterogeneous classes of PTSD and PTG existed across time: low-affected (low-level PTSD and PTG), thriving (low-level PTSD but high-level PTG), and struggling (high-level PTSD and PTG) groups. Random intercept latent transition analysis model suggested that samples mainly stayed in the original classes across time, with three main transitional paths: from struggling group to thriving group, from thriving group to low-affected group, and from low-affected group to struggling group. Besides, the study also found that parental rejection, overprotection, and anxious attachment were the possible factors that kept the stability of the struggling group. Parent-child cohesion increased the stability of the thriving group across time. Anxious attachment may worsen PTSD among adolescents and lower the stability of low-affected groups across time. CONCLUSIONS: Coexisting and transitional patterns exist in PTSD and PTG across time. Wrong parenting styles and insecure attachments can exacerbate PTSD symptoms and diminish adolescents' resilience, but parent-child cohesion can facilitate their growth after trauma. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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BACKGROUND: Ogden type V tibial tubercle avulsion fracture is an unusual type of physial injury. Thus, little is known about its mechanism of injury and treatment. The type of osteosynthesis is variable and depends on the experience of the surgeon. We commonly used cancellous screws fixation combined with tension band wiring for displaced fracture of the anterior tibial tuberosity. CASE PRESENTATION: The present manuscript describes a case of a Han nationality 13-year-old boy who presented with severe pain of the left knee, which began after landing following a high jump. He had no significant past medical history apart from a high body mass index of 30.3. Radiographs revealed that he had an unusual Ogden type V tibial tubercle avulsion fracture. He was treated by open reduction and combined fixation with cannulated screws and tension-band wiring. After 3 months, the fracture healed without any complications or knee symptoms with full range of motion. He underwent reoperation for symptomatic hardware, which was removed at 5 months after initial surgery, and returned to his prior level of sporting activity at 1 year follow-up. CONCLUSION: Our case suggests that excellent functional outcome could be achievable by open reduction with the combination of internal fixation and tension-band wiring for Ogden type V tibial tubercle avulsion fracture. This type of osteosynthesis could not only achieve anatomical reduction and stable fixation for such fractures, but also avoid further damage to the proximal tibial epiphysis, which prevents serious complications, such difference in leg length.
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Parafusos Ósseos , Fixação Interna de Fraturas , Fratura Avulsão , Fraturas da Tíbia , Humanos , Masculino , Adolescente , Fixação Interna de Fraturas/métodos , Fraturas da Tíbia/cirurgia , Fraturas da Tíbia/diagnóstico por imagem , Fratura Avulsão/cirurgia , Fratura Avulsão/diagnóstico por imagem , Resultado do Tratamento , Radiografia , Fios Ortopédicos , Amplitude de Movimento Articular , Reoperação , Redução Aberta/métodosRESUMO
Background: Disulfidptosis regulate various biological processes in cancer. However, there is limited research on the genes related to disulfidptosis in predicting the prognosis of hepatocellular carcinoma (HCC). We aimed to develop a reliable disulfidptosis-related gene signature, which will characterize different HCC subtypes and predict their prognosis. Methods: The Cancer Genome Atlas (TCGA)-HCC dataset, comprising RNA sequencing data and clinical information, was obtained from the TCGA database. The crucial disulfidptosis-related genes were selected for bioinformatic analysis in HCC. HCC tumor classification was established through a consistent cluster analysis. The prognosis and immune-cell infiltration were investigated in association with a disulfidptosis-related HCC model. Results: In TCGA-HCC patients, a total of 3,621 prognostic genes and 30 key prognostic disulfidptosis-related genes were identified. Using key prognostic disulfidptosis-related genes, TCGA-HCC patients were categorized into low- and high-risk clusters. The upregulated differentially expressed genes (DEGs) in high-risk cluster 1 (C1) could significantly impact cell cycle, DNA replication, and the p53 signaling pathway, whereas the pathways associated with the downregulated DEGs in high-risk C1 could significantly impact metabolism of xenobiotics by cytochrome P450, the PPAR signaling pathway, and tyrosine metabolism. Furthermore, the immune activity of the high-risk C1 group was different to that of the low-risk cluster 2 (C2) group. The 13 disulfidptosis-related genes were finally screened using least absolute shrinkage and selection operator (LASSO) regression analysis, including ANP32E, BOP1, RPN1, SLC7A11, PPIH, PCBP2, ME1, PRDX1, FLNC, INF2, MYH11, LRPPRC, and HNRNPM. Conclusions: The genes related to disulfidptosis are closely associated with tumor classification and immunity in patients with HCC. This is the first gene signature related to disulfidptosis demonstrated a strong predictive performance for the prognosis of HCC, which provide new perspectives for the diagnosis and treatment of HCC.
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Bone metastasis remains a clinical challenge and is still considered incurable. While nanoparticles-based drug delivery and photothermal therapy (PTT) show promise in treating subcutaneous solid tumor, their therapeutic outcome in treating bone metastasis is limited, due to the inaccessibility of bone metastatic site and the complexity of bone metastasis. Herein, we reported a simple nanoplatform composed of thermo-sensitive liposomes (TSL) and gold nanorods (GNR) to treat bone metastasis through improved chemotherapy combined with GNR-assisted PTT. Lipid combination of TSL was firstly tailored to regulate its stability under physiological condition as well as its sensitivity in responding to PTT-caused mild hyperthermia. The obtained TSL with loaded drug was then combined with GNR to form the nanoplatform through unsophisticated incubation. Cell experiments revealed that upon near-infrared (NIR) irradiation, the nanoplatform effectively inhibited the viability and migration ability of tumor cells through PTT, PTT-triggered thermo-sensitive drug release, and PTT-augmented sensitivity of tumor cells to drug. In a murine model of bone metastasis, the nanoplatform enabled effective delivery of loaded drug and GNR to bone metastatic site for rapid drug release upon local NIR irradiation. Through killing tumor cells and rebalancing the turnover of osteoclasts and osteoblasts, the nanoplatform largely preserved bone structure for pain relief and survival extension. Inspired by the simplicity of nanoplatform acquirement and treatment operation, the strategy of liposomes-based thermo-sensitive drug delivery in combination with GNR-assisted PTT is considered greatly promising in treating bone metastasis.
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CONTEXT AND RESULTS: The structure, mechanical, electronic, vibration, and hydrogen bonding properties of a novel high-energy and low-sensitivity 5, 5'-dinitroamino-3, 3'-azo-oxadiazole 4, 7-diaminopyridazino [4, 5-c] furoxan salt have been studied by density functional theory. The calculated vibrational properties show that the low-frequency mode is mainly contributed by the vibration of the -NO2 group, and the high-frequency mode is mainly contributed by the vibration of the -NH2 group and the N7-H3 bond which protonates the cation. In addition, it is analyzed that the first bond to break may be the N-NO2 bond. The calculated hydrogen bond properties indicate that the hydrogen bond between water molecules and cations is N7-H3 O5 (1.563 Å), which is the shortest hydrogen bond among all hydrogen bonds. The presence of this exceptionally short hydrogen bond renders the N7-H3 and H6-O5 bonds resistant to disruption at high frequencies, underscoring the pivotal role of hydrogen bonding in stabilizing the structure of energetic materials. Given the absence of experimental and theoretical data on the electronic, mechanical, and vibrational properties of the material thus far, our calculations offer valuable theoretical insights into the ionic salts of high energy and low sensitivity. COMPUTATIONAL METHODS: All calculations have been carried out based on density functional theory (DFT) and implemented in the CASTEP code. The mode-conserving pseudopotential is utilized to describe the plane wave expansion function, while the PBE functional within the generalized gradient approximation (GGA) is employed to characterize the exchange-correlation interaction. Additionally, dispersion correction is applied using Grimme's DFT-D method.
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BACKGROUND: Ambient air pollution might serve as a prognostic factor for ovarian cancer (OC) survival, yet the relationships between plant-based diet indices (PDIs) and OC survival remain unclear. We aimed to investigate the associations of comprehensive air pollution and PDIs with OC survival and explored the effects of air pollution-diet interactions. METHODS: The present study encompassed 658 patients diagnosed with OC. The overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) were evaluated by a self-reported validated food frequency questionnaire. In addition, an air pollution score (APS) was formulated by summing the concentrations of particulate matter with a diameter of 2.5 microns or less, ozone, and nitrogen dioxide. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95â¯% confidence intervals (CIs). The potential interactions of APS with PDIs in relation to overall survival (OS) were assessed on both multiplicative and additive scales. RESULTS: Throughout a median follow-up of 37.60 (interquartile: 24.77-50.70) months, 123 deaths were confirmed. Comparing to the lowest tertiles, highest uPDI was associated with lower OS of OC (HR = 2.06, 95â¯% CI = 1.30, 3.28; P-trend < 0.01), whereas no significant associations were found between either overall PDI or hPDI and OC survival. Higher APS (HR for per interquartile range = 1.27, 95â¯% CI = 1.01, 1.60) was significantly associated with worse OC survival, and the association was exacerbated by adherence to uPDI. Notably, an additive interaction was identified between combined air pollution and uPDI (P < 0.005 for high APS and high uPDI). We also found that adherence to overall PDI aggravated associations of air pollution with OC survival (P-interaction = 0.006). CONCLUSIONS: Joint exposure to various ambient air pollutants was significantly associated with lower survival among patients with OC, particularly for those who predominantly consumed unhealthy plant-based foods.
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Poluentes Atmosféricos , Poluição do Ar , Neoplasias Ovarianas , Material Particulado , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Ovarianas/mortalidade , Poluição do Ar/efeitos adversos , Poluição do Ar/estatística & dados numéricos , Material Particulado/análise , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/efeitos adversos , Adulto , Dieta Vegetariana , Modelos de Riscos Proporcionais , Ozônio/análise , Idoso , Dióxido de Nitrogênio/análise , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/efeitos adversos , Estudos de Coortes , Dieta Baseada em PlantasRESUMO
Metal-organic frameworks (MOFs) have attained broad research attention in the areas of sensors, resistive memories, and optoelectronic synapses on the merits of their intriguing physical and chemical properties. In this review, recent progress on the synthesis of MOFs and their electronic applications is introduced and discussed. Initially, the crystal structures and properties of MOFs encompassing optical, electrical, and chemical properties are discussed in brief. Subsequently, advanced synthesis methods for MOFs are introduced, categorized into hydrothermal approach, microwave synthesis, mechanochemical synthesis, and electrochemical deposition. After that, the various roles of MOFs in widespread applications, including sensing, information storage, optoelectronic synapses, machine learning, and artificial intelligence, are discussed, highlighting their versatility and the innovative solutions they provide to long-standing challenges. Finally, an outlook on remaining challenges and a future perspective for MOFs are proposed.
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Spin-crossover (SCO) ferroelectrics with dual-function switches have attracted great attention for significant magnetoelectric application prospects. However, the multiferroic crystals with SCO features have rarely been reported. Herein, a molecular multiferroic Fe(II) crystalline complex [FeII(C8-F-pbh)2] (1-F, C8-F-pbh = (1Z,N'E)-3-F-4-(octyloxy)-N'-(pyridin-2-ylmethylene)-benzo-hydrazonate) showing the coexistence of ferroelectricity, ferroelasticity, and SCO behavior is presented for the first time. By H/F substitution, the low phase transition temperature (270 K) of the non-fluorinated parent compound is significantly increased to 318 K in 1-F, which exhibits a spatial symmetry breaking 222F2 type ferroelectric phase transition with clear room-temperature ferroelectricity. Besides, 1-F also displays a spin transition between high- and low-spin states, accompanied by the d-orbital breaking within the t2g 4eg 2 and t2g 6eg° configuration change of octahedrally coordinated FeII center. Moreover, the 222F2 type ferroelectric phase transition is also a ferroelastic one, verified by the ferroelectric domains reversal and the evolution of ferroelastic domains. To the knowledge, 1-F is the first multiferroic SCO molecular crystal. This unprecedented finding sheds light on the exploration of molecular multistability materials for future smart devices.
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CONTEXT: Energy-containing materials such as explosives have attracted considerable interest recently. In the field of high-energy materials, tetrazine and its derivatives can largely meet the requirements of high nitrogen content and oxygen balance. Nitrogen-rich energetic salts are important research subjects. Nitrogen-rich salt of 3,6-dinitramino-1,2,4,5-tetrazine is a high-energy nitrogen-rich material, but there are few related studies. This paper systematically studies the crystal structure and electronic, vibrational, and thermodynamic properties of (NH4)2(DNAT). The lattice parameters of (NH4)2(DNAT) are observed to align well with the experimental values. The properties of electrons are analyzed by band structure and density of states (DOS). The phonon dispersion curves indicate that the compound is dynamically stable. The vibrational modes of bonds and chemical groups are described in detail, and the peaks in the Raman and infrared spectra are assigned to different vibration modes. Based on the vibration characteristics, thermodynamic properties such as enthalpy (H), Helmholtz free energy (F), entropy (S), Gibbs free energy (G), constant volume heat capacity (CV), and Debye temperature (Θ) are analyzed. This article can pave the way for subsequent work or provide data support to other researchers, promoting further research. METHODS: In this study, we utilized the density functional theory (DFT) for our calculations. The exchange-correlation potential and van der Waals interactions were characterized based on the GGA-PBE + G function calculation. We obtained Brillouin zone integrals using Monkhorst-Pack k-point grids, with the k-point of the Brillouin zone set to a 2 × 2 × 2 grid. During the self-consistent field operation, we set the total energy convergence tolerance to 5 × 10-6 eV per atom. The cut-off energy for the calculation was established at 830 eV. Additionally, the states of H (1s1), C (2s2 2p2), N (2s2 2p3), and O (2s2 2p4) were treated as valence electrons in our study.
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CONTEXT AND RESULTS: The structure, electronic and optical properties of single-layer transition metallic chalcogenides ZrX3 (X = S, Se, Te) have been studied by density functional theory. The electron energy dispersion curve shows that ZrX3 has semiconductor properties, in which the conduction band is mainly contributed by the correlated states of the Zr-d orbital, and the valence band is mainly contributed by the correlated states of the X-p orbital. It is found that b-axis and biaxial strain have great influence on the bandgap and the shift of density of states is also large. At the same time, the peak value of density of states increases greatly when biaxial strain is applied. It is of guiding significance for selecting suitable substrates to prepare two-dimensional ZrX3 materials to study their electronic properties. The calculation of optical constants confirms that ZrX3 has strong optical anisotropy. In the visible range, the light absorption efficiency of ZrX3 in the direction of electric field polarization [100] is higher than that in the direction of [010]. The reflectance spectral results show that ZrS3 and ZrSe3 in the [100] directions have the highest reflectance, and ZrTe3 in the [010] direction has the highest reflectance, even in the long electromagnetic radiation range (up to 10 eV), which is of great significance for the construction of visible optical devices. COMPUTATIONAL METHOD: All computations have been carried out based on density functional theory (DFT) as implemented in the CASTEP code. The pseudo-potential is adopted by the norm conserving, and the exchange correlation functional is adopted by the Perdew-Burke-Ernzerhof in local generalized gradient approximation (GGA).
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[This corrects the article DOI: 10.3389/fphar.2020.586725.].