Synthesis and Properties of A Strained Triple Nanohoop.

A strained triple nanohoop with a shared central benzene unit is synthesized using a threefold intramolecular ring-closing approach. Among the five possible constitutional isomers, the isomer with the highest D3h symmetry is isolated, the structure of which contains three nanohoop blades and a central hexaphenylbenzene unit. The structure is elucidated using NMR spectroscopy and mass spectrometry. The optical and electrochemical properties are investigated, revealing a moderate fluorescence quantum yield of 40%. A water-soluble nanomaterial is prepared using a nanoparticle encapsulation method, and a fluorescence quantum yield of 10% is retained, which demonstrates the potential of the nanomaterial in biological systems.

Characteristics and prognostic value of gut microbiota in follicular lymphoma.

The pathogenesis and progression of follicular lymphoma (FL) depends on immune evasion mechanisms. The gut microbiota has been reported to be associated with the development and outcome of several human diseases by modulating host immunity. Thus, the present study investigated the characteristics and prognostic value of the gut microbiota in FL. Fecal samples from treatment-naïve patients with FL (n=28) and healthy controls (n=18) were prospectively collected. The gut microbiota diversity and composition were examined by 16S ribosomal RNA sequencing. The results demonstrated that patients with FL had distinct microbiota compositions. The relative abundance of the Ruminococcaceae family was significantly increased in patients with FL (P=0.01). Furthermore, a high level of Ruminococcus was identified as a strong indicator of tumor burden (P=0.001), and was related to the FL International Prognostic Index score and serum lactate dehydrogenase levels. The present results indicated an association between the gut microbiota and FL prognosis. Findings from the present study may provide a rational foundation for further investigation of the role of gut microbiota in lymphoma management.

Clinical characteristics and prognoses in pediatric neuroblastoma with bone or liver metastasis: data from the SEER 2010-2019.

BACKGROUND: To investigate clinical characteristics, prognoses, and impacts of treatments on prognoses of neuroblastoma patients with bone or liver metastasis. METHODS: This retrospective cohort study extracted data from the Surveillance, Epidemiology, and End Results (SEER) database 2010-2019. The outcomes were 3-year cancer-specific survival (CSS) and 5-year CSS. Multivariable COX risk proportional models were established to assess the association between metastasis types and CSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Totally 425 patients with metastatic neuroblastoma were eligible for 3-year CSS analysis and 320 for 5-year CSS analysis. For 3-year follow-up, 62 (14.59%) patients had liver metastasis alone, 289 (0.68%) had bone metastasis alone, and 74 (17.41%) had both liver and bone metastasis. For 5-year follow-up, 44 (13.75%) patients had liver metastasis alone, 223 (69.69%) had bone metastasis alone, and 53 (16.56%) had both liver and bone metastasis. Significant differences were observed in age, tumor size, surgery for the primary site, chemotherapy, radiation, brain metastasis, lung metastasis, and vital status between patients with liver metastasis alone, bone metastasis alone, and both liver and bone metastasis (all P < 0.05). Compared with patients with liver metastasis alone, patients with bone metastasis alone (HR = 2.30, 95%CI: 1.10-4.82, P = 0.028) or both (HR = 2.35, 95%CI: 1.06-5.20, P = 0.035) had significantly poorer 3-year CSS; patients with bone metastasis alone (HR = 2.32, 95%CI: 1.14-4.70, P = 0.020) or both liver and bone metastasis (HR = 2.33, 95%CI: 1.07-5.07, P = 0.032) exhibited significantly worse 5-year CSS than those with liver metastasis alone. In patients with bone metastasis, those with chemotherapy had significantly better 3-year CSS than those without (HR = 0.24, 95%CI: 0.07-0.75, P = 0.014). Among patients with liver metastasis, receiving radiation was associated with significantly worse 3-year CSS (HR = 2.00, 95%CI: 1.05-3.81, P = 0.035). CONCLUSION: Compared with patients with liver metastasis alone, those with bone metastasis alone or both had poorer 3- and 5-year CSS. For patients with bone metastasis, undergoing chemotherapy was associated with better 3-year CSS. For patients with liver metastasis, receiving radiation was associated with worse 3-year CSS.

The Gut Microbiome Correlated to Chemotherapy Efficacy in Diffuse Large B-Cell Lymphoma Patients.

The gut microbiome (GMB) has been extensively reported to be associated with the development and prognosis of human diseases. This study aims to investigate the relationship between GMB composition and chemotherapy efficacy in diffuse large B-cell lymphoma (DLBCL). We demonstrated that DLBCL patients at diagnosis have altered GMB compositions. Significant enrichment of the Proteobacteria phylum in DLBCL patients was observed. Gene analysis showed a high abundance of virulence factors genes. We found baseline GMB to be associated with clinical outcomes. The emergence of Lactobacillus fermentum was correlated with better treatment outcome. Our pilot results suggested a correlation between GMB composition and DLBCL development and prognosis. Clues from our study, together with previous research, provided a rational foundation for further investigation on the pathogenesis, prognosis value, and targeted therapy of GMB in DLBCL.

Spin-Distribution-Directed Regioselective Substitution Strategy for Highly Stable Olympicenyl Radicals.

The synthesis of bench-stable conjugated π-radicals is challenging owing to the lack of modular approaches, which greatly hampers their practical material screens and applications. Here, we demonstrate a spin-distribution-directed regioselective substitution strategy to introduce substituents into the specific positions of an olympicenyl radical in a stepwise manner, resulting in a series of highly stable radical species. The substituents can also adjust the crystal packing by means of steric and electronic factors, enabling the changing from a π-dimer to a pseudo-one-dimensional chain. The first single crystal organic field-effect transistor device based on a graphenic radical is fabricated in air, showing a hole mobility of up to 0.021 cm2 V-1 s-1 and excellent device stability. This approach may be generalized to diverse spin-delocalized open-shell organic radicals.

IU1 and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer.

BACKGROUND: Androgen deprivation therapy (ADT) is one of the main treatment modalities for prostate cancer (PCa); however, almost all patients treated with ADT eventually progress into castration-resistant PCa (CRPC). Although second-generation androgen receptor (AR) antagonists, such as enzalutamide, have been approved for CRPC treatment, AR signaling in CRPC cells is reactivated through multiple mechanisms, resulting in resistance to treatment and tumor progression with a very poor prognosis. The present study aimed to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with AR degrader IU1 on PCa cells. METHODS: The joint effects of enzalutamide and IU1 on PCa cell proliferation and apoptosis and associated cell signaling were evaluated in vitro. Mechanistically, the ubiquitination level and half-life of AR were examined under the combination treatment. The binding of IU1 and enzalutamide to AR was further verified using cellular thermal shift analysis and isothermal dose-response curve fingerprinting. RESULTS: The combination of IU1 and three AR antagonists showed synergistic effects in different prostate cell lines. IU1 and enzalutamide synergistically promoted the degradation of AR and AR-V7 proteins, as well as suppressed the expression levels of AR and AR-V7 downstream target genes at the transcriptional and protein levels. The combination also synergistically blocked the PCa cell cycle and promoted apoptosis in PCa cell lines. Mechanistically, the combination promoted increased levels of AR ubiquitination. In CRPC cell lines and in the presence of increased androgen concentrations, enzalutamide was still able to bind AR competitively with androgens, reducing the stability of AR and thus promoting the degradation effect of IU1 on AR, synergistically producing an inhibitory effect on PCa cells. CONCLUSION: Taken together, our findings suggest that the combination of AR degrader and enzalutamide potentially represents a new therapeutic strategy for CRPC.

Clinical application of novel integrated suctioning semi-rigid ureteroscopic lithotripsy.

INTRODUCTION: Urinary calculi are frequently encountered in urology. Traditionally, the lack of a perfect water injection and drainage system means the observation field is affected during ureteroscopy. Here, we explored the effect and clinical value of a new integrated suctioning semi-rigid ureteroscopic lithotripsy (URSL) for treating ureteral calculi. MATERIAL AND METHODS: A total of 180 patients were successfully enrolled in this study (60 in each group). Group A included patients who underwent a traditional semi-rigid URSL, group B included patients who underwent a suctioning semi-rigid URSL with a sheath being connected to a vacuum device, and group C included patients who underwent a new type of suctioning integrated rigid URSL with a novel designed ureteroscope. RESULTS: In total, 164 cases of URSL were completed in one stage. Compared with group A, group C had a higher stone-clearance rate at 30 days postoperatively, shorter operation time, and fewer hospitalization days (p < .05); compared with group B, group C had a higher one-stage operation success rate, shorter operation time, and fewer hospitalization days (p < .05). CONCLUSIONS: Comparatively, the new suctioning integrated semi-rigid URSL is advantageous for treating upper urinary calculi, considering the reduced operation time, length of hospital stay, and low invasiveness.

Subdomain Adaptation Capsule Network for Partial Discharge Diagnosis in Gas-Insulated Switchgear.

Deep learning methods, especially convolutional neural networks (CNNs), have achieved good results in the partial discharge (PD) diagnosis of gas-insulated switchgear (GIS) in the laboratory. However, the relationship of features ignored in CNNs and the heavy dependance on the amount of sample data make it difficult for the model developed in the laboratory to achieve high-precision, robust diagnosis of PD in the field. To solve these problems, a subdomain adaptation capsule network (SACN) is adopted for PD diagnosis in GIS. First, the feature information is effectively extracted by using a capsule network, which improves feature representation. Then, subdomain adaptation transfer learning is used to accomplish high diagnosis performance on the field data, which alleviates the confusion of different subdomains and matches the local distribution at the subdomain level. Experimental results demonstrate that the accuracy of the SACN in this study reaches 93.75% on the field data. The SACN has better performance than traditional deep learning methods, indicating that the SACN has potential application value in PD diagnosis of GIS.

A Fused [5]Helicene Dimer with a Figure-Eight Topology: Synthesis, Chiral Resolution, and Electronic Properties.

Chiral shape-persistent molecular nanocarbons are promising chiroptical materials; their synthesis, however, remains a big challenge. Herein, we report the facile synthesis and chiral resolution of a double-stranded figure-eight carbon nanobelt 1 in which two [5]helicene units are fused together. Two synthetic routes were developed, and, in particular, a strategy involving Suzuki coupling-mediated macrocyclization followed by Bi(OTf)3 -catalyzed cyclization of vinyl ether turned out to be the most efficient. The structure of 1 was confirmed by X-ray crystallographic analysis. The isolated (P,P)- and (M,M)- enantiomers show persistent chiroptical properties with relatively large dissymmetric factors (|gabs |=5.4×10-3 and |glum |=1.0×10-2 ), which can be explained by the effective electron delocalization along the fully conjugated belt and the unique D2 symmetry. 1 exhibits local aromatic character with a dominant structure containing eight Clar's aromatic sextet rings.

Histone methyltransferase KMT2D promotes prostate cancer progression through paracrine IL-6 signaling.

Histone methyltransferase KMT2D plays a critical role as a human oncogene in prostate cancer (PCa). Dysregulated inflammatory responses and cytokine signaling are implicated in cancer progression. Furthermore, interleukin 6 (IL-6) is a pleiotropic cytokine that contributes to PCa progression; however, the association between KMT2D and IL-6 in PCa remains unclear. PCa cell proliferative potential, migratory potential, and apoptosis in vitro were determined using cell counting kit-8 (CCK-8), EdU incorporation, wound healing, and apoptosis assays. Proliferation and migratory potential were impaired and apoptosis was induced in PCa cells cultured with the conditioned medium from KMT2D-depleted cells. Cytokine array analysis showed that IL-6 was the most affected cytokine in the conditioned media. KMT2D knockdown significantly downregulated the expression of IL-6 in PCa cells. What's more, proliferation and migration were also impaired and apoptosis was also induced by silencing IL-6R expression. Immunohistochemistry (IHC) and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were performed to validate the positive correlation between KMT2D and IL-6 in PCa tissue samples. Chromatin immunoprecipitation (ChIP)-PCR demonstrated that KMT2D and H3K4me1 occupied IL-6 enhancer regions and therefore, directly regulated IL-6 expression. The present study revealed that the KMT2D knockdown suppressed prostate cancer progression through the downregulation of paracrine IL-6 signaling. These results suggest that KMT2D could be regarded as a potential new target for PCa therapy.

Stable Crystalline Nanohoop Radical and Its Self-Association Promoted by van der Waals Interactions.

A stable nanohoop radical (OR3) combining the structures of cycloparaphenylene and an olympicenyl radical is synthesized and isolated in the crystalline state. X-ray crystallographic analysis reveals that OR3 forms a unique head-to-tail dimer that further aggregates into a one-dimensional chain in the solid state. Variable-temperature NMR and concentration-dependent absorption measurements indicate that the π-dimer is not formed in solution. An energy decomposition analysis indicates that van der Waals interactions are the driving force for the self-association process, in contrast with other olympicenyl derivatives that favor π-dimerization. The physical properties in solution phase have been studied, and the stable cationic species obtained by one-electron chemical oxidation. This study offers a new molecular design to modulate the self-association of organic radicals for overcoming the spin-Peierls transition, and to prepare novel nanohoop compounds with spin-related properties.

Synthesis and structure elucidation of triarylmethyl radicals with anthryl substitution.

Two stable triarylmethyl radicals with one or two anthryl substitutions are synthesized in gram scale, and are isolated in the crystalline state. Detailed structural elucidation with X-ray crystallographic analysis and DFT calculations revealed that the twisted structure is more energetically favorable than the folded structure, and consequently, the spin density is mainly localized at the methyl carbon. The spin distribution leads to unique physical properties, making them promising open-shell organic materials.

Experimental analysis of bladder cancer-associated mutations in EP300 identifies EP300-R1627W as a driver mutation.

BACKGROUND: Bladder cancer (BCa) is the most common malignant tumor of the urinary system, with transitional cell carcinoma (TCC) being the predominant type. EP300 encodes a lysine acetyltransferase that regulates a large subset of genes by acetylating histones and non-histone proteins. We previously identified several bladder cancer-associated mutations in EP300 using high-throughput sequencing; however, the functional consequences of these mutations remain unclear. METHODS: Bladder cancer cells T24 and TCC-SUP were infected with shEP300 lentiviruses to generate stable EP300 knockdown cell lines. The expression levels of EP300, p16 and p21 were detected by real-time PCR and western blots. The transcriptional activity of p16 and p21 were detected by dual luciferase assay. Cell proliferation assay, flow cytometric analyses of cell cycle, invasion assay and xenograft tumor model were used to measure the effect of EP300-R1627W mutation in bladder cancer. Immunoprecipitation was used to explore the relationship between EP300-R1627W mutation and p53. Structural analysis was used to detect the structure of EP300-R1627W protein compared to EP300-wt protein. RESULTS: we screened the mutations of EP300 and found that the EP300-R1627W mutation significantly impairs EP300 transactivation activity. Notably, we demonstrated that the R1627W mutation impairs EP300 acetyltransferase activity, potentially by interfering with substrate binding. Finally, we show that EP300-R1627W is more aggressive in growth and invasion in vitro and in vivo compared to cells expressing EP300-wt. We also found that the EP300-R1627W mutation occurs frequently in seven different types of cancers. CONCLUSION: In summary, our work defines a driver role of EP300-R1627W in bladder cancer development and progression.

Tautomycin and enzalutamide combination yields synergistic effects on castration-resistant prostate cancer.

The androgen receptor (AR) plays an essential role in prostate cancer progression and is a key target for prostate cancer treatment. However, patients with prostate cancer undergoing androgen deprivation therapy eventually experience biochemical relapse, with hormone-sensitive prostate cancer progressing into castration-resistant prostate cancer (CRPC). The widespread application of secondary antiandrogens, such as enzalutamide, indicates that targeting AR remains the most efficient method for CRPC treatment. Unfortunately, neither can block AR signaling thoroughly, leading to AR reactivation within several months. Here, we report an approach for suppressing reactivated AR signaling in the CRPC stage. A combination of the protein phosphatase 1 subunit α (PP1α)-specific inhibitor tautomycin and enzalutamide synergistically inhibited cell proliferation and AR signaling in LNCaP and C4-2 cells, as well as in AR variant-positive 22RV1 cells. Our results revealed that enzalutamide competed with residual androgens in CRPC, enhancing tautomycin-mediated AR degradation. In addition, the remaining competitive inhibitory role of enzalutamide on AR facilitated tautomycin-induced AR degradation in 22RV1 cells, further decreasing ARv7 levels via a full-length AR/ARv7 interaction. Taken together, our findings suggest that the combination of tautomycin and enzalutamide could achieve a more comprehensive inhibition of AR signaling in CRPC. AR degraders combined with AR antagonists may represent a new therapeutic strategy for CRPC.

Case Report: TEMPI syndrome: Report of three cases and treatment follow-up.

The TEMPI syndrome is a novel and rare disease with five distinct clinical features: Telangiectasis, Erythrocytosis, Monoclonal gammopathy, Perinephric fluids collection, and Intrapulmonary shunting. Here, we report three cases of TEMPI syndrome and their treatment response. The three patients were presented to our department with polycythemia, abdominal distension, and dyspnea. On admission, all patients manifested telangiectasis, erythrocytosis, monoclonal gammopathy, and intrapulmonary shunting. Patient 1 and 2 manifested perinephric fluids collection. In addition, all patients had skin pigmentation, patient 1 and 2 had polyserosal effusion, two symptoms that had not been associated with TEMPI syndrome before. The three patients showed various response to plasma cell-directed therapy. We demonstrated their treatment response by measuring erythropoietin, hemoglobin, and M protein levels throughout therapy. This report suggested that TEMPI syndrome is a rare yet treatable disease. The diagnosis and treatment of it remain challenging.

π-Extended Doublet Open-Shell Graphene Fragments Exhibiting One-Dimensional Chain Stacking.

The hitherto elusive benzo[c]anthanthrenyl radical derivatives composed of seven fused six-membered rings are synthesized and isolated in the crystalline form, representing a laterally π-extended doublet open-shell graphene fragment compared to the phenalenyl and olympicenyl radical structures. X-ray crystallographic analysis revealed one-dimensional chain stacking with relatively close intermolecular contacts, which is an important precondition for achieving single-component conductors. The magnetic, optical, and redox properties are investigated in the solution phase. In combination with the good stability, such open-shell molecular systems have potentials as functional electronic materials.

Downregulation of miR-335 exhibited an oncogenic effect via promoting KDM3A/YAP1 networks in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer affecting many people worldwide. Although the 5-year survival rate is 65% in localized disease, after metastasis, the survival rate is <10%. Emerging evidence has shown that microRNAs (miRNAs) play a crucial regulatory role in the progression of ccRCC. Here, we show that miR-335, an anti-onco-miRNA, is downregulation in tumor tissue and inhibited ccRCC cell proliferation, invasion, and migration. Our studies further identify the H3K9me1/2 histone demethylase KDM3A as a new miR-335-regulated gene. We show that KDM3A is overexpressed in ccRCC, and its upregulation contributes to the carcinogenesis and metastasis of ccRCC. Moreover, with the overexpression of KDM3A, YAP1 was increased and identified as a direct downstream target of KDM3A. Enrichment of KDM3A demethylase on YAP1 promoter was confirmed by CHIP-qPCR and YAP1 was also found involved in the cell growth and metastasis inhibitory of miR-335. Together, our study establishes a new miR-335/KDM3A/YAP1 regulation axis, which provided new insight and potential targeting of the metastasized ccRCC.

The impact of pulmonary metastases on therapeutic response and prognosis in malignant gestational trophoblastic neoplasia patients: a retrospective cohort study.

AIM: The lung is the most common site of metastasis for gestational trophoblastic neoplasia (GTN). However, the level of influence of lung metastases on the prognosis of GTN and the degree to which lung metastases are considered in assessments of disease treatment options are unclear. Moreover, it is unclear which characteristics of lung metastases impact the disease. In this study, we evaluated the influence of lung metastases on the clinical course of GTN and identified lung imaging characteristics that impact treatment outcomes. METHODS: A retrospective cohort study was conducted on GTN patients treated at Peking Union Medical College Hospital between 2002 and 2018. The baseline characteristics, first-line treatment outcomes and final outcomes of patients with lung metastases (Group 1) and those without lung metastases (Group 2) were compared. RESULTS: The emergence of resistance occurred significantly more frequently in Group 1 (n = 994) than in Group 2 (n = 570) (19.52% versus 14.56%, p = 0.019), and the death rate was higher in Group 1 (0.91% versus 0%, p = 0.031). Among the patients treated with multi-agent chemotherapy, the rate of resistance and the number of treatment courses were significantly higher in Group 1 than in Group 2 (p = 0.002 and < 0.001, respectively). The lung imaging characteristics that impacted prognosis included the number of nodules, whether there were multiple nodules or a single nodule, and the number of nodules sized >1 cm. Multivariate analysis showed that a nodule measuring ≥1.8 cm was an independent risk factor for first-line treatment resistance and recurrence. CONCLUSION: Although pulmonary metastases do not affect overall survival in GTN patients, the presence of lung metastases before treatment is associated with increased risk of disease recurrence and resistance to first-line multidrug chemotherapy, especially when pulmonary nodules are larger than 1.8 cm. CLINICAL TRIAL REGISTRATION: N.A.

Overcrowded Ethylene-Bridged Nanohoop Dimers: Regioselective Synthesis, Multiconfigurational Electronic States, and Global Hückel/Möbius Aromaticity.

The design and preparation of molecular systems with multiple geometric and electronic configurations are the cornerstones for multifunctional materials with stimuli-responsive behaviors. We describe here the regioselective and facile synthesis of two types of overcrowded ethylene-bridged nanohoop dimers, with folded and twisted geometric structures as well as closed-shell, diradical and dication electronic structures. The strained nanohoop structures have a profound effect on the overall molecular and electronic configurations, which resulted in the destabilized diradical state. X-ray crystallographic analysis revealed the folded molecular geometry for the neutral species and twisted geometry for the dication species. The unique molecular dynamics, optical properties, and dynamic redox properties were disclosed in the solution phase by spectroscopic and electrochemical methods. Furthermore, the global Hückel and Möbius aromaticity were revealed by a combination of experimental and theoretical approaches. Our studies shed light on the design of nanohoop-incorporated multiconfigurational materials with unique topologies and functions.

Long noncoding RNA GAS5 interacts and suppresses androgen receptor activity in prostate cancer cells.

The androgen receptor (AR) plays an important role in the progression of prostate cancer and is the most important therapeutic target. However, androgen deprivation therapy will finally lead patients to progress to castration-resistant prostate cancer (CRPC). Here, we confirmed that GAS5, a long noncoding RNA, could interact and suppress AR transactivation in CRPC C4-2 cells. Knockdown GAS5 by short hairpin RNA would enhance the transcription of AR via promote AR recruitment to the promoter of its downstream target genes. Functionally, GAS5 overexpression inhibits cell proliferation partially through inhibiting AR transactivation in C4-2 cells. Moreover, knocking down GAS5 protects C4-2 cells from the docetaxel-induced cell apoptosis. In return, the suppressed AR was found to downregulate the GAS5 expression, which forms a feedback loop resulted in AR high transcription activity in CRPC. Collectively, our findings revealed the important role of GAS5 in AR axis activity regulation and CRPC progression. Targeting GAS5 to intervene the feedback loop might be a new potential therapeutic approach for the patients at CRPC stage.