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The FIGO 2018 staging of cervix cancer recognizes a total of 11 categories of loco-regionally advanced cervix cancer (LRACC). Whilst incorporating imaging is an improvement over clinical staging (FIGO 2009), this had led to more categories of disease which are not prognostically discrete groups. We aimed to analyze survival according to 2018 FIGO stages of cervix cancer and identify isoprognostic groups of patients based on primary tumor volume and nodal status.Patients referred for radiotherapy with curative intent between 1996 and 2014 were eligible. Baseline clinico-pathological and follow up information was retrieved from an ethics-approved institutional prospective database. Patients were classified according to FIGO 2018 staging based on histo-pathology, MRI (tumor volume and local compartmental spread assessment) and PET results (nodal spread). Kaplan-Meier method was used to estimate survival at five years. Following survival analysis using recognized prognostic factors, isoprognostic categories were identified and merged to form 5 isoprognostic groups.Seven hundred and forty-four LRACC patients were included. The median (IQR) follow-up was 5.1 (2.6-8.4) yrs. Stage migration occurred in most patients, showing heterogeneous 5 years survival according to 2018 FIGO stages. In contrast progressively worsening prognosis could be demonstrated in the 5 observed isoprognostic clusters (p0.002).Prognosis in LRACC depends on the interplay between primary tumor characteristics, type of local spread and nodal disease. A prospective study of survival and patterns of failure according to isoprognostic clusters would be useful to determine the most appropriate treatment modality and estimate survival as well as better patient selection for clinical trials.

Previous research has shown the relationship between loneliness and affect, as well as the relationship between trait loneliness and state loneliness. However, none has investigated how social context affects the association between loneliness and affect. The current study aims to examine the association between trait loneliness, state loneliness and momentary affects in different social contexts.Participants aged 15-24 were randomly recruited from a Hong Kong epidemiological study to participate in an Experience Sampling Method (ESM) study. The group was divided in two based on the mean trait loneliness score (UCLA Loneliness Scale) at baseline. State loneliness, momentary positive (PA) and negative affect (NA) and social context were assessed using ESM. Multilevel logistic regression was used to analyze the association between momentary affect, state loneliness and trait loneliness in various social contexts.HL (high lonely) and LL (low lonely) groups consisted of 79 participants (44.6%) and 98 participants (55.4%) respectively. HL group had lower PA and higher NA, as well as a higher state loneliness than LL group. HL group had a lower state loneliness when being with intimate company compared to alone. LL group only had a higher PA when being with intimate company compared to non-intimate company and alone respectively.Adolescents with high level of trait loneliness experienced higher PA, momentary loneliness and lower NA compared to those with low level of trait loneliness. The quality of social company is crucial in allowing one to experience different degrees of PA and momentary loneliness.

Background Enzalutamide is an important drug in the treatment of prostate cancer. Standard dosing often requires dose reduction because of side effects. There is no information on survival outcomes with lower doses. We investigated the impact of starting enzalutamide at ≤ 50% dose on metastatic prostate cancer outcomes including patients' longevity. Patients and Methods Records of metastatic prostate cancer patients treated with enzalutamide at one center were retrospectively reviewed. Low-dose enzalutamide (≤80 mg/day) was compared with standard-dose (160 mg/day). The primary objective was to compute the restricted mean survival time (RMST - time scale) and restricted mean attained age (RMAA - age scale) using the Irwin method. Secondary objectives included overall survival (OS), progression-free survival (PFS), and PSA progression per PCWG3 criteria (PSA PFS). We used the logrank test and the ∆ difference between RMSTs for comparison. Results Of 111 patients treated, 32 received a low-dose and 79 the standard-dose. Low-dose patients had less prior abiraterone or chemotherapy (28.1% vs. 65.8%, P < .001); more testosterone assessment (65.6% vs. 40.5%, P = .016); poorer ECOG performance status (48.3% score ≥2 vs. 26.6%; P = .040), more comorbidities (75.9% vs. 46.3%; P = .010)) including increased cardiovascular disease (51.7% vs. 21.4%, P = .004). Baseline PSA value and doubling time at start of enzalutamide and distribution of metastases were similar between the groups. OS and PFS did not differ between low-dose and standard-dose. Patients on low-dose had a better longevity with significantly longer RMAA, 89.1 years, versus standard-dose RMAA of 83.8 years (∆ = 5.3 years, P = .003, logrank P = .025). In a subgroup analysis by age at start of enzalutamide

Tup1, a conserved transcriptional repressor, plays a critical role in the growth and development of fungi. Here, we identified a BsTup1 gene from the plant pathogenic fungus Bipolaris sorokiniana. The expression of BsTup1 showed a more than three-fold increase during the conidial stage compared with mycelium stage. Deletion of BsTup1 led to decrease hyphal growth and defect in conidia formation. A significant difference was detected in osmotic, oxidative, or cell wall stress responses between the WT and ΔBsTup1 strains. Pathogenicity assays showed that virulence of the ΔBsTup1 mutant was dramatically decreased on wheat and barely leaves. Moreover, it was observed that hyphal tips of the mutants could not form appressorium-like structures on the inner epidermis of onion and barley coleoptile. Yeast two-hybrid assays indicated that BsTup1 could interact with the BsSsn6. RNAseq revealed significant transcriptional changes in the ΔBsTup1 mutant with 2369 genes down-regulated and 2962 genes up-regulated. In these genes, we found that a subset of genes involved in fungal growth, sporulation, cell wall integrity, osmotic stress, oxidation stress, and pathogenicity, which were misregulated in the ΔBsTup1 mutant. These data revealed that BsTup1 has multiple functions in fungal growth, development, stress response and pathogenesis in B. sorokiniana.

Extracellular vesicles (EVs) are generated by cells in the form of exosomes, microvesicles, and apoptotic bodies. They can be taken up by neighboring cells, and their contents can have functional impact on the cells that engulf them. As the mediators of intercellular communication, EVs can play important roles in both physiological and pathologic contexts. In addition, early detection of EVs in different body fluids may offer a sensitive diagnostic tool for certain diseases, such as cancer. Furthermore, targeting specific EVs may also become a promising therapeutic approach. This review summarizes the latest findings of EVs in the field of liver research, with a focus on the different contents of the EVs and their impact on liver function and on the development of inflammation, fibrosis, and tumor in the liver. The goal of this review is to provide a succinct account of the various molecules that can mediate the function of EVs so the readers may apply this knowledge to their own research.

In this study, a plasmon-semiconductor nanotheranostic system comprising Au nanostars/graphene quantum dots (AuS/QD) hybrid nanoparticles loaded with BNN6 and surface modified with PEG-pyrene was developed for the photo-triggered hyperthermia effect and NO production as the dual modality treatment against orthotopic triple-negative breast cancer. The structure and morphology of the hybrid nanodevice was characterized and the NIR-II induced thermal response and NO production was determined. The hybrid nanodevice has shown enhanced plasmonic energy transfer from localized surface plasmonic resonance of Au nanostars to QD semiconductor that activates the BNN6 species loaded on QD surfaces, leading to the effective NO production and the gas therapy in addition to the photothermal response. The increased accumulation of the NIR-II-responsive hybrid nanotheranostic in tumor via the enhanced permeation and retention effects was confirmed by both in vivo fluorescence and photoacoustic imaging. The prominent therapeutic efficacy of the photothermal/NO combination therapy from the BNN6-loaded AuS@QD nanodevice with the NIR-II laser irradiation at 1064 nm against 4T1 breast cancer was observed both in vitro and in vivo. The NO therapy for the cancer treatment was evidenced with the increased cellular nitrosative and oxidative stress, nitration of tyrosine residues of mitochondrial proteins, vessel eradication and cell apoptosis. The efficacy of the photothermal treatment was corroborated directly by severe tissue thermal ablation and tumor growth inhibition. The NIR-II triggered thermal/NO combination therapy along with the photoacoustic imaging-guided therapeutic accumulation in tumor shows prominent effect to fully inhibit tumor growth and validates the promising strategy developed in this study.

Stressors at the population level affect women more than men. The influence of prolonged stressors on mental disorders in women is yet unknown, especially when social movements and pandemics coexist.This study analysed data from an online mental health self-help service for women in Hong Kong between May and September 2020. We collected demographic data, PTSD symptoms, and exposure to social unrest-related traumatic events (TEs), pandemic-related traumatic events (PEs), and personal stressful life experiences (SLEs). Multiple logistic regression was performed to examine the links between TEs, PEs, and SLEs and PTSD.The study found that 38.4% of 751 women had moderate-to-severe depressive symptoms and 23.8% had probable PTSD. The most common TEs, PEs, and SLEs were violence via media, major physical health concerns, and plans thwarted due to COVID-19, respectively. Younger age, less education, unemployment, and more stressors (individually or collectively, except for high TEs and PEs) were linked to increased odds of moderate-to-severe depressive symptoms. TEs and PEs increased the risk of probable PTSD only when SLEs were present.The non-random samplinging procedure reduced the generalisability to the entire women population.Exposure to social conflicts and pandemics may increase depressive and PTSD symptoms in women. Developing mental health services for women should consider the impact of concurrent major events.

In this study, Fe2+:ZnSe transparent ceramics with different doping concentrations were prepared from annealed FeSe and ZnSe powders by hot pressing. The as-prepared ceramics consisted of a cubic ZnSe phase and compact microstructures. Doping concentrations of Fe2+ ions in the range 0.66–3.05 at.% were accurately realised, which could influence the absorption intensity of Fe2+:ZnSe transparent ceramics. An absorption peak was observed at ∼3 μm, and its intensity could be controlled by the concentration of Fe2+ ions. FexZn1-xSe (0.0066 ≤ x ≤ 0.0305) ceramics with Fe2+ ions concentrations in the range 0.66–3.05 at.% exhibited significant absorption cross sections from 0.6676 × 10−19 to 0.1075 × 10−18 cm2. The specimen doped with 1.55 at.% Fe2+ ions displayed the highest transmittance of 67% at a wavelength of 14 μm and a carbonate absorption peak at 9 μm. The proposed transparent ceramic technique appears promising for preparing Fe2+:ZnSe laser gain media because of its advantage of allowing control over Fe2+ concentration.

Cellular senescence frequently is present in injured livers. The induction mechanism and the pathologic role are not always clear. We aimed to understand the dynamics of senescence induction and progression, and the mechanism responsible for the pathology using a mouse model that disables the essential process of autophagy.Mice deficient in key autophagy genes Atg7 or Atg5 in the liver were used. Senescence was measured using established cellular and molecular signatures. The mechanistic roles of nuclear factor erythroid 2 (NRF2), forkhead box K1, and C-C motif chemokine receptor 2 (CCR2) were assessed using mouse genetic models. Liver functions, pathology, and tumor development were measured using biochemical and histologic approaches.Inducible deletion of Atg7 rapidly up-regulated cyclin-dependent kinase inhibitors independently of injury and induced senescence-associated β-galactosidase activities and senescence-associated secretory phenotype (SASP). Sustained activation of NRF2 was the major factor causing senescence by mediating oxidative DNA damage and up-regulating C-C motif chemokine ligand 2, a key component of autophagy-related SASP, via the NRF2-forkhead box K1 axis. Senescence was responsible for hepatic inflammation through CCR2-mediated recruitment of CD11bThese results provide the insight that hepatic senescence can occur early in the disease process, triggers inflammation and is enhanced by inflammation, and has long-term effects on liver injury and tumor progression.

Recently, atrous spatial pyramid module and encoder-decoder structure are widely investigated for many computer vision tasks to address the scale variation challenge in deep convolutional networks. The atrous spatial pyramid module aims at capturing local and global cues together with various sampling rates in convolutional or pooling layers. At the same time, encoder-decoder structure propagates context features from low-resolution, strong-semantic features to high-resolution, weak-semantic ones, while maintaining the detail object boundaries. However, the aforementioned two strategies have their own drawbacks, and the previous object detectors only employ one of them to handle scale variation. In this work, we propose to cooperate atrous spatial pyramid convolution (ASPC) with encoder-decoder structure (ED) for object detection, termed ASPC-ED, which combines the complementary advantages from both modules in an end-to-endfashion. Specifically, the proposed method is consist of three components: encoder, ASPC and decoder. The extensive experiments on PASCAL VOC and MS COCO benchmarks demonstrate that our method with various backbone achieves the state-of-the-art results for object detection, instance segmentation and panoptic segmentation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and has caused significant medical/socioeconomic impacts. Other than vaccination, effective public health measures, including contact tracing, isolation, and quarantine, is critical for deterring viral transmission, preventing infection progression and resuming normal activities. Viral transmission is affected by many factors, but the viral load and vitality could be among the most important ones. Although in vitro studies have indicated that the amount of virus isolated from infected individuals affects the successful rate of virus isolation, whether the viral load carried at the individual level would determine the transmissibility was unknown. We examined whether the cycle threshold (Ct) value, a measurement of viral load by RT-PCR assay, could differentiate the spreaders from the non-spreaders in a population of college students. Our results indicate that while at the population level the Ct value is lower, suggesting a higher viral load, in the symptomatic spreaders than that in the asymptomatic non-spreaders, there is a significant overlap in the Ct values between the two groups. Thus, Ct value, or the viral load, at the individual level could not predict the transmissibility. Instead, a sensitive method to detect the presence of virus is needed to identify asymptomatic individuals who may carry a low viral load but can still be infectious.

An increasing amount of evidence has shown critical roles of gut microbiome in host pathophysiology. The gut and the liver are anatomically and physiologically connected. Given the critical role of gut-liver axis in the homeostasis of the liver, gut microbiome interplays with a diverse spectrum of hepatic changes, including steatosis, inflammation, fibrosis, cholestasis, and tumorigenesis. In clinic, cholestasis manifests with fatigue, pruritus, and jaundice, caused by the impairment in bile formation or flow. Studies have shown that the gut microbiome is altered in cholestatic liver disease. In this review, we will explore the interaction between the gut microbiome and the liver with a focus on the alteration and the role of gut microbiome in cholestatic liver disease. We will also discuss the prospect of exploiting the gut microbiome in the development of novel therapies for cholestatic liver disease.

Sparse subspace clustering (SSC) method has gained considerable attention in recent decades owing to its advantages in the fields of clustering. In essence, SSC is to learn a sparse affinity matrix followed by striving for a low-dimensional representation of data. However, the SSC and its variants mainly focus on building high-quality affinity matrix while ignoring the importance of low-dimensional feature derived from the affinity matrix. Moreover, due to their intrinsic linearity of models, they cannot efficiently handle data with the nonlinear distribution. In this paper, we propose a stacked independent subspace analysis (ISA) with sparse prior information called stacked-ISASP to deal with these two issues. Powered by handling data with nonlinear structure, our method aims at seeking a low-dimensional feature from the image data. Concretely, the model can stack the modified independent subspace analysis networks by incorporating the prior subspace information from the original data. To validate the efficiency of the proposed method, we compare our proposed stacked-ISASP method with the state-of-the-art methods on real datasets. Experimental results show that our approach can not only learn a better low-dimensional structure from the data but also achieve better performance for the classification task.

With the rapid emergence of data that can be described by different feature sets or different “views”, multi-view subspace clustering has attracted considerable research attention. To uncover the common latent structure shared by multiple views, existing models usually impose the sparse or/and low-rank constraint on the coefficients of each view data, and use Frobenius norm or l 1 -norm based metric to measure the residuals of multi-view data. However, the intuition behind the sparse or low-rank regularization is implicit. Besides, the Frobenius norm or l 1 -norm based metric is suitable to handle either Gaussian noise or sparse noise, which are very sensitive to larger noise or outliers. When the data is contaminated by large noise or densely corrupted, performance of existing models is degraded dramatically. In this article, we propose a novel multi-view subspace clustering method to provide superior robustness against large noise or outliers embedded in multi-view data. Our method adopts a more direct and intuitive block diagonal regularization to preserve the underlying structure of each view, and meantime introduces the cauchy loss function to deal with large noise. The derived consensus representation matrix can effectively preserve the underlying common structure of multi-view data and be robust to large noise and data corruptions. Experimental results show that our method outperforms the state-of-the-arts on both synthetic and real-world benchmark datasets.

Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but most patients will require additional treatment. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equal low nM potency.To evaluate pirtobrutinib safety and efficacy in patients with MCL.BRUIN is an ongoing multicenter phase 1/2 study (NCT03740529) of pirtobrutinib monotherapy.Global; community hospitals, academic medical centers.Patients with advanced B-cell malignancies.Oral pirtobrutinib, phase 1 dose-escalated in a standard 3+3 design, phase 2 continuous therapy, 28-day cycles.The primary phase 1 objective was to determine the recommended phase 2 dose (RP2D) and the primary phase 2 objective was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety/tolerability, and pharmacokinetics.As of 27 September 2020, 323 patients (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL) were treated on 7 dose levels (25-300mg QD). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in10% of patients. The most common adverse event of grade ≥3 was neutropenia (10%). Five (1%) patients discontinued due to treatment-related adverse events. 52 prior BTKi treated MCL patients were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%]), 11 PD [21%] and 5 [10%] discontinued prior to first response assessment). Median follow-up was 6 months (0.7-18.3+). Responses were observed in 9/14 patients (64%) with prior autologous or allogeneic stem cell transplant, and 2/2 with prior CAR-T cell therapy.Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new patients with MCL and an additional 10 months since the prior data-cut will be presented.

In the traditional raw materials used for preparing Sialon ceramics, hydrolytic AlN, cannot easily be used for aqueous gelcasting. To overcome this problem, a new type of gelcasting technique was developed. By introducing 1-methyl-2-pyrrolidinone (NMP) as a solvent, Sialon ceramics were formed using a low-viscosity non-aqueous gel system based on the 2-hydroxyethyl methacrylate (HEMA) gelling agent in this work. Based on this gel system, the rheological properties of the slurry and the solidification and sintering properties of Sialon ceramics were studied. The results show that the best rheological properties of slurry can be obtained with the dispersant dosage of 6 vol%. As the HEMA content increases, the flexural strength of the green bodies increase. When the ratio of HEMA to TMPTA (trimethylolpropane triacrylate) is 10:1 and the HEMA content is 15 wt%, the flexural strength of the green body reaches a maximum of 13.07 MPa. β′-Sialon ceramic has the best comprehensive mechanical properties at the sintering temperature of 1700 °C. Its bulk density, Vickers hardness, fracture toughness and flexural strength were 3.207 g/cm3, 1484 HV, 7.11 MPa m1/2 and 351 MPa, respectively.

The lignin amine (LA) was exploited to prepare dually N/S-doped carbon (NSC), which was endowed with intriguing porous structure by Fe3O4 template. N and S elements, originating from LA, are doped into the materials. NSC possesses diverse-scale 3D pores. The macropores are made by Fe3O4, which facilitate to produce meso and micro pores on their walls by KOH activation. The sample prepared at 700 °C (NSC-700) is found to have the largest specific surface area (1199 cm2 g−1) and specific capacity (241 F g−1 at current density of 1 A g−1). Its capacity is 260% as high as that of lignin amine carbon (LAC) prepared without adding Fe3O4. Excellent rate performance is unraveled because of possessing 82% specific capacity at 20 A g−1 and 27.2 Wh kg−1 energy density at 10000 W kg−1 power density. Moreover, the specific capacity maintains 95.0% after 3000 cycles, indicating good electrochemical stability. The good electrical performance of NSC-700 is attributed to its interesting electronic properties that are induced by special pore structure. Because of having merits such as high rate performance, long life, large specific capacity and low cost, our NSC is anticipated to be a promising capacitor as electrode material.

Subspace clustering groups a set of data into their underlying subspaces according to the low-dimensional subspace structure of data. The performance of spectral clustering-based approaches heavily depends on the learned block diagonal structure of the affinity matrix. However, this structure is fragile in the presence of noise within data. As such, the clustering performance is degraded significantly. On the other hand, in practice, we often do not have a prior knowledge of error distribution at all, which results in that we cannot model the error with suitable norms. To this end, in this paper, we propose a robust block diagonal representation learning for subspace clustering. Specifically, a non-convex regularizer is directly utilized to constrain the affinity matrix for exploiting the block diagonal structure. Furthermore, we use a penalty matrix to adaptively weight the reconstruction error so that we can handle noise without prior knowledge. We also devise an effective method to compute the parameters related to this matrix, reducing the complexity of the parameter trains. Experimental results show that our method outperformed the state-of-the-art methods on both synthetic data and real-world datasets.

Hydrolyzed AlN in traditional raw materials is not suitable for aqueous gel casting using DMAA (N,N-dimethylacrylamide) gelling agents. Therefore, a new hydrolysis-resistant AlCN was studied to replace hydrolyzed AlN. By adding the low toxicity organic monomers DMAA and MBAM (methylenebisacrylamide), the rheological properties of the slurry obtained under different conditions and the solidification and sintering properties of Sialon ceramics were studied. The results show that the best rheological properties can be obtained when the ball milling time is between 8 and 10 h and when the dispersant dose is 2%. When the ratio of DMAA to MBAM is 14:1, the flexural strength of the green body reaches a maximum of 15.29 MPa. When the sintering temperature increases from 1600 °C to 1750 °C, the density, Vickers hardness and fracture toughness of the sintered body gradually increase, reaching 3.195 g/cm3, 1549 HV, and 9.29 MPa m1/2, respectively. The flexural strength of the sintered body first increases and then decreases, reaching a maximum of 415 MPa at 1650 °C and a minimum of 303 MPa at 1750 °C.