Integrated bulk and single-cell transcriptomes reveal pyroptotic signature in prognosis and therapeutic options of hepatocellular carcinoma by combining deep learning.

Although some pyroptosis-related (PR) prognostic models for cancers have been reported, pyroptosis-based features have not been fully discovered at the single-cell level in hepatocellular carcinoma (HCC). In this study, by deeply integrating single-cell and bulk transcriptome data, we systematically investigated significance of the shared pyroptotic signature at both single-cell and bulk levels in HCC prognosis. Based on the pyroptotic signature, a robust PR risk system was constructed to quantify the prognostic risk of individual patient. To further verify capacity of the pyroptotic signature on predicting patients' prognosis, an attention mechanism-based deep neural network classification model was constructed. The mechanisms of prognostic difference in the patients with distinct PR risk were dissected on tumor stemness, cancer pathways, transcriptional regulation, immune infiltration and cell communications. A nomogram model combining PR risk with clinicopathologic data was constructed to evaluate the prognosis of individual patients in clinic. The PR risk could also evaluate therapeutic response to neoadjuvant therapies in HCC patients. In conclusion, the constructed PR risk system enables a comprehensive assessment of tumor microenvironment characteristics, accurate prognosis prediction and rational therapeutic options in HCC.

Multiplex Assay of Cytokines with Tunable Detection Ranges for the Precise Diagnosis of Breast Cancer.

Precise profiling of the cytokine panel consisting of different levels of cytokines can provide personalized information about several diseases at certain stages. In this study, we have designed and fabricated an "all-in-one" diagnostic tool kit to bioassay multiple inflammatory cytokines ranging from picograms per milliliter to µg/mL in a small cytokine panel. Taking advantage of the kit fabricated by the DNA-encoded assembly of nanocatalysts in dynamic regulation and signal amplification, we have demonstrated the multiplex, visual, and quantitative detection of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) with limits of detection of 1.6 ng/mL (61.54 pM), 20 pg/mL (1.57 pM), and 4 pg/mL (0.19 pM), respectively. This diagnostic tool kit can work well with commercial kits for detecting serum cytokines from breast cancer patients treated with immunotherapies. Furthermore, a small cytokine panel composed of CRP, PCT, and IL-6 is revealed to be significantly heterogeneous in each patient and highly dynamic for different treatment courses, showing promise as a panel of quantitative biomarker candidates for individual treatments. So, our work may provide a versatile diagnostic tool kit for the visual detection of clinical biomarkers with an adjustable broad detection range.

Optical multiple-image authentication based on computational ghost imaging and hybrid non-convex second-order total variation.

An optical security method for multiple-image authentication is proposed based on computational ghost imaging and hybrid non-convex second-order total variation. Firstly, each original image to be authenticated is encoded to the sparse information using computational ghost imaging, where illumination patterns are generated based on Hadamard matrix. In the same time, the cover image is divided into four sub-images with wavelet transform. Secondly, one of sub-images with low-frequency coefficients is decomposed using singular value decomposition (SVD), and all sparse data are embedded into the diagonal matrix with the help of binary masks. To enhance the security, the generalized Arnold transform is used to scramble the modified diagonal matrix. After using SVD again, the marked cover image carrying the information of multiple original images is obtained using the inverse wavelet transform. In the authentication process, the quality of each reconstructed image can be greatly improved based on hybrid non-convex second-order total variation. Even at a very low sampling ratio (i.e., 6%), the existence of original images can be efficiently verified using the nonlinear correlation maps. To our knowledge, it is first to embed sparse data into the high-frequency sub-image using two cascaded SVDs, which can guarantee high robustness against the Gaussian filter and sharpen filter. The optical experiments demonstrate the feasibility of the proposed mechanism, which can provide an effective alternative for the multiple-image authentication.

Molecular Characterization of Exosomes for Subtype-Based Diagnosis of Breast Cancer.

Breast cancer is very heterogeneous and the most frequently diagnosed cancer worldwide, and precise therapy targeting specific subtypes may improve the survival rates of breast cancer patients. In this study, we designed a biomimetic vesicle by camouflaging catalytic DNA machinery with a breast cancer cell membrane, which enabled the molecular classification of circulating exosomes for subtype-based diagnosis through homotypic recognition. In addition, the vesicles specifically targeted and fused with breast cancer exosomes with phenotypic homology and manipulated the DNA machinery to amplify electrochemical signaling using exosomal RNA as an endogenous trigger. The biomimetic vesicles prepared with MCF-7 cancer cell-derived membranes were shown to recognize estrogen receptor-positive breast cancer exosomes and exhibited a low detection limit of 557 particles mL-1 with microRNA-375 used as the endogenous biomarker. Furthermore, the biomimetic vesicles prepared with MDA-MB-231 cancer cell-derived membranes displayed satisfactory performance in a homotypic analysis of triple-negative breast cancer exosomes with a potential therapeutic target, PD-L1 mRNA, used as the endogenous biomarker. Most importantly, cross-validation experiments confirmed the high accuracy and selectivity of this homotypic recognition-driven analysis for molecular subtyping of breast cancer. When applied to clinical samples of breast cancer patients, the vesicles demonstrated feasibility and reliability for evaluating the molecular features of cancer cell-derived exosomes and enabled stage-specific monitoring of breast cancer patients because the electrochemical signals showed a positive correlation with disease progression. Therefore, this work may provide new ideas for the precise diagnosis and personalized treatment of breast cancer patients throughout the whole disease process.

Quantification of Joint Space Width Difference on Radiography Via Phase-Only Correlation (POC) Analysis: a Phantom Study Comparing with Various Tomographical Modalities Using Conventional Margin-Contouring.

Several visual scoring methods are currently used to assess progression of rheumatoid arthritis (RA) on radiography. However, they are limited by its subjectivity and insufficient sensitivity. We have developed an original measurement system which uses a technique called phase-only correlation (POC). The purpose of this study is to validate the system by using a phantom simulating the joint of RA patients.A micrometer measurement apparatus that can adjust arbitrary joint space width (JSW) in a phantom joint was developed to define true JSW. The phantom was scanned with radiography, 320 multi detector CT (MDCT), high-resolution peripheral quantitative CT (HR-pQCT), cone beam CT (CBCT), and tomosynthesis. The width was adjusted to the average size of a women's metacarpophalangeal joint, from 1.2 to 2.2 mm with increments of 0.1 mm and 0.01 mm. Radiographical images were analyzed by the POC-based system and manual method, and images from various tomographical modalities were measured via the automatic margin detection method. Correlation coefficients between true JSW difference and measured JSW difference were all strong at 0.1 mm intervals with radiography (POC-based system and manual method), CBCT, 320MDCT, HR-pQCT, and tomosynthesis. At 0.01 mm intervals, radiography (POC-based system), 320MDCT, and HR-pQCT had strong correlations, while radiography (manual method) and CBCT had low correlations, and tomosynthesis had no statistically significant correlation. The smallest detectable changes for radiography (POC-based system), radiography (manual method), 320MDCT, HR-pQCT, CBCT, and tomosynthesis were 0.020 mm, 0.041 mm, 0.076 mm, 0.077 mm, 0.057 mm, and 0.087 mm, respectively. We conclude that radiography analyzed with the POC-based system might sensitively detect minute joint space changes of the finger joint.

Relationship between tRNA-derived fragments and human cancers.

tRNA-derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA-derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA-derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA-derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA-derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA-derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA-derived fragments, the distinct expression and function of tRNA-derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments.

Lapatinib in combination with capecitabine versus continued use of trastuzumab in breast cancer patients with trastuzumab-resistance: a retrospective study of a Chinese population.

BACKGROUND: The efficacy and safety of lapatinib plus capecitabine (LC or LX) versus trastuzumab plus chemotherapy in patients with HER-positive metastatic breast cancer who are resistant to trastuzumab is unknown. METHODS: We retrospectively analyzed data from breast cancer patients who began treatment with regimens of lapatinib plus capecitabine (LC or LX) or trastuzumab beyond progression (TBP) at eight hospitals between May 2010 and October 2017. RESULTS: Among 554 patients who had developed resistance to trastuzumab, the median PFS (progression free survival) was 6.77 months in the LX group compared with 5.6 months in the TBP group (hazard ratio 0.804; 95% CI, 0.67 to 0.96; P = 0.019). The central nervous system progression rate during treatment was 5.9% in the LX group and 12.5% in the TBP group (P = 0.018). CONCLUSION: The combination of lapatinib and capecitabine showed a prolonged PFS relative to TBP in patients who had progressed on trastuzumab.

The Trauma of Birth or Parenting a Child: Effect on Parents' Negative Emotion in China.

The present study assessed negative emotions associated with the traumas of infertility and child rearing (child's disability or death) and the correlates of duration of trauma. The widely used Chinese Mental Health Scale was used to assess negative emotions in 294 individuals who experienced the aforementioned traumas and 124 who did not (control group). Results showed that individuals with infertility exhibited greater anxiety, depression, and solitude than the control group; bereaved parents and had greater solitude and fear than control group; and parents of children with disabilities had greater solitude than the control group. Parents who experienced the death of a child had more fear and physiological maladjustment than parents of a child with disabilities. In addition, individuals without parenting experience had higher scores on solitude, fear, and physiological disease than those with parenting experience. After controlling for demographic variables, the duration of trauma significantly negatively predicted depression in the infertile group and for bereaved parents. The results suggest that in order to prevent psychological and physiological health problems among infertile couples, parents of a disabled child, and parents who experience the death of child, family and community-based strategies should be developed and implemented.

Enhanced performance of enzymes confined in biocatalytic hydrogen-bonded organic frameworks for sensing of glutamate in the central nervous system.

Glutamate (Glu) is a key excitatory neurotransmitter associated with various neurological disorders in the central nervous system, so its measurement is vital to both basic research and biomedical application. In this work, we propose the first example of using biocatalytic hydrogen-bonded organic frameworks (HOFs) as the hosting matrix to encapsulate glutamate oxidase (GLOD) via a de novo approach, fabricating a cascaded-enzyme nanoreactor for Glu biosensing. In this design, the ferriporphyrin ligands can assemble to form Fe-HOFs with high catalase-like activity, while offering a scaffold for the in-situ immobilization of GLOD. Moreover, the formed GLOD@Fe-HOFs are favorable for the efficient diffusion of Glu into the active sites of GLOD via the porous channels, accelerating the cascade reaction with neighboring Fe-HOFs. Consequently, the constructed nanoreactor can offer superior activity and operational stability in the catalytic cascade for Glu biosensing. More importantly, rapid and selective detection can be achieved in the cerebrospinal fluid (CSF) collected from mice in a low sample consumption. Therefore, the successful fabrication of enzyme@HOFs may offer promise to develop high-performance biosensor for further biomedical applications.

The war between the immune system and the tumor - using immune biomarkers as tracers.

Nowadays, immunotherapy is one of the most promising anti-tumor therapeutic strategy. Specifically, immune-related targets can be used to predict the efficacy and side effects of immunotherapy and monitor the tumor immune response. In the past few decades, increasing numbers of novel immune biomarkers have been found to participate in certain links of the tumor immunity to contribute to the formation of immunosuppression and have entered clinical trials. Here, we systematically reviewed the oncogenesis and progression of cancer in the view of anti-tumor immunity, particularly in terms of tumor antigen expression (related to tumor immunogenicity) and tumor innate immunity to complement the cancer-immune cycle. From the perspective of integrated management of chronic cancer, we also appraised emerging factors affecting tumor immunity (including metabolic, microbial, and exercise-related markers). We finally summarized the clinical studies and applications based on immune biomarkers. Overall, immune biomarkers participate in promoting the development of more precise and individualized immunotherapy by predicting, monitoring, and regulating tumor immune response. Therefore, targeting immune biomarkers may lead to the development of innovative clinical applications.

Corrections to "A Sub-Pixel Accurate Quantification of Joint Space Narrowing Progression in Rheumatoid Arthritis".

Presents corrections to the article "A Sub-Pixel Accurate Quantification of Joint Space Narrowing Progression in Rheumatoid Arthritis".

An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer.

tRNA-derived fragments (tRFs) play crucial roles in cancer progression. Among them, tRF-27 has been identified as a key factor in promoting naïve trastuzumab resistance in HER2-positive breast cancer. However, the origin of tRF-27 remains uncertain. In this study, we propose that the upregulated expression of specific cysteine tRNAs may lead to the increased accumulation of tRF-27 in trastuzumab-resistant JIMT1 cells. Mechanistically, the reduced inhibitory H3K27me3 modification at the promoter regions of tRF-27-related tRNA genes in JIMT1 cells, potentially resulting from decreased EZH2 and increased KDM6A activity, may be a critical factor stimulating the transcriptional activity of these tRNA genes. Our research offers fresh insights into the mechanisms underlying elevated tRF-27 levels in trastuzumab-resistant breast cancer cells and suggests potential strategies to mitigate trastuzumab resistance in clinical treatments.

Unveiling Alterations of Epigenetic Modifications and Chromatin Architecture Leading to Lipid Metabolic Reprogramming during the Evolutionary Trastuzumab Adaptation of HER2-Positive Breast Cancer.

Secondary trastuzumab resistance represents an evolutionary adaptation of HER2-positive breast cancer during anti-HER2 treatment. Most current studies have tended to prioritize HER2 and its associated signaling pathways, often overlooking broader but seemingly less relevant cellular processes, along with their associated genetic and epigenetic mechanisms. Here, transcriptome data is not only characterized but also examined epigenomic and 3D genome architecture information in both trastuzumab-sensitive and secondary-resistant breast cancer cells. The findings reveal that the global metabolic reprogramming associated with trastuzumab resistance may stem from genome-wide alterations in both histone modifications and chromatin structure. Specifically, the transcriptional activities of key genes involved in lipid metabolism appear to be regulated by variant promoter H3K27me3 and H3K4me3 modifications, as well as promoter-enhancer interactions. These discoveries offer valuable insights into how cancer cells adapt to anti-tumor drugs and have the potential to impact future diagnostic and treatment strategies.

Tyrosine kinase inhibitors in HER2-positive metastatic breast cancer with trastuzumab emtansine resistance: insights from a multicenter retrospective real-world study.

The use of trastuzumab emtansine (T-DM1) has revealed significant efficacy in HER2-positive metastatic breast cancer (MBC). However, optimal therapeutic strategies following T-DM1 failure remain a subject of debate in clinical practice. In this multicenter, retrospective, real-world study, we sought to examine the effectiveness and safety of tyrosine kinase inhibitors (TKIs) as a therapeutic strategy in HER2-positive MBC who developed T-DM1 resistance. Between September 2018 and December 2022, 66 patients were enrolled. The median progression-free survival of TKIs-based therapy was 10.1 months (95% CI, 4.7-15.6). Objective response rate and clinical benefit rate were 18.2 and 66.7%, respectively. TKIs-based therapy demonstrated better effectiveness in patients who had previously derived benefit from T-DM1 and featured acquired resistance to trastuzumab. The most common adverse events were diarrhea (36, 54.5%), hand-foot syndrome (31, 47.0%), and leucopenia (30, 45.5%). In conclusion, TKIs-based therapy showed promising effectiveness and safety in HER2-positive MBC patients after T-DM1 failure.

A Sub-Pixel Accurate Quantification of Joint Space Narrowing Progression in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects peripheral synovial joints, like fingers, wrists and feet. Radiology plays a critical role in the diagnosis and monitoring of RA. Limited by the current spatial resolution of radiographic imaging, joint space narrowing (JSN) progression of RA for the same reason above can be less than one pixel per year with universal spatial resolution. Insensitive monitoring of JSN can hinder the radiologist/rheumatologist from making a proper and timely clinical judgment. In this paper, we propose a novel and sensitive method that we call partial image phase-only correlation which aims to automatically quantify JSN progression in the early RA. The majority of the current literature utilizes the mean error, root-mean-square deviation and standard deviation to report the accuracy at pixel level. Our work measures JSN progression between a baseline and its follow-up finger joint images by using the phase spectrum in the frequency domain. Using this study, the mean error can be reduced to 0.0130 mm when applied to phantom radiographs with ground truth, and 0.0519 mm standard deviation for clinical radiography. With the sub-pixel accuracy far beyond usual manual measurements, we are optimistic that the proposed work is a promising scheme for automatically quantifying JSN progression.

Exosome-Transmitted tRF-16-K8J7K1B Promotes Tamoxifen Resistance by Reducing Drug-Induced Cell Apoptosis in Breast Cancer.

Tamoxifen resistance remains a challenge in hormone receptor-positive (HR+) breast cancer. Recent evidence suggests that transfer ribonucleic acid (tRNA)-derived fragments play pivotal roles in the occurrence and development of various tumors. However, the relationship between tRNA-derived fragments and tamoxifen resistance remains unclear. In this study, we found that the expression of tRF-16-K8J7K1B was upregulated in tamoxifen-resistant cells in comparison with tamoxifen-sensitive cells. Higher levels of tRF-16-K8J7K1B were associated with shorter disease-free survival in HR+ breast cancer. Overexpression of tRF-16-K8J7K1B promotes tamoxifen resistance. Moreover, extracellular tRF-16-K8J7K1B could be packaged into exosomes and could disseminate tamoxifen resistance to recipient cells. Mechanistically, exosomal tRF-16-K8J7K1B downregulates the expression of apoptosis-related proteins, such as caspase 3 and poly (ADP-ribose) polymerase, by targeting tumor necrosis factor-related apoptosis-inducing ligand in receptor cells, thereby reducing drug-induced cell apoptosis. Therapeutically, the inhibition of exosomal tRF-16-K8J7K1B increases the sensitivity of breast cancer cells to tamoxifen in vivo. These data demonstrate that exosomal tRF-16-K8J7K1B may be a novel therapeutic target to overcome tamoxifen resistance in HR+ breast cancer.

Alterations in factors associated with diabetic retinopathy combined with thrombosis: A review.

Diabetic retinopathy (DR) is one of the most common and serious microvascular complications of diabetes mellitus, the incidence of which has been increasing annually, and it is the main cause of vision loss in diabetic patients and a common cause of blindness. It is now found that thrombosis plays a crucial role in the disease progression in DR patients, and the final vision loss in DR may be related to the occurrence of thrombosis in the retinal vessels, which is dominated by abnormal endothelial cell function, together with platelet dysfunction, imbalance of coagulation and fibrinolytic function, and related alterations of inflammatory factors leading to the main cause of thrombotic disease in DR patients. In this review, we examine the role between DR and thrombosis and the association of each factor, including endothelial dysfunction; platelet dysfunction; coagulation-fibrinolytic imbalance; and alterations in inflammatory factors.

Dexmedetomidine relieves inflammatory pain by enhancing GABAergic synaptic activity in pyramidal neurons of the anterior cingulate cortex.

Pyramidal neuron (Pyn) hyperactivity in the anterior cingulate cortex (ACC) is involved in the modulation of pain. Previous studies indicate that the activation of α2 adrenoceptors (α2-ARs) by dexmedetomidine (DEX) is a safe and effective means of alleviating multiple types of pain. Here, we showed that systemically administered DEX can ameliorate the inflammatory pain induced by hindpaw injection of formalin (FA) and further examined the molecular and synaptic mechanisms of this DEX-elicited antinociceptive effect. We found that FA caused an increase in c-Fos expression in contralateral layer 2/3 (L2/3) ACC, and that intra-ACC infusion of DEX could also relieve phase 2 inflammatory pain behavior. DEX elicited an increase in the amplitude and frequency of miniature inhibitory post-synaptic currents (mIPSCs) and evoked IPSC amplitude, as well as a reduction in the hyperexcitability and both paired-pulse and excitation/inhibition ratios in contralateral L2/3 ACC Pyns of FA mice. These electrophysiological effects were associated with the upregulation of GABA A receptor (GABAAR) subunits. The interaction of phosphorylated Akt (p-Akt) with GABAAR subunits increased in the ACC following administration of DEX. These results suggest that DEX treatment reduces hyperactivity and enhances GABAergic inhibitory synaptic transmission in ACC Pyns, which produces analgesic effects by increasing GABAAR levels and activating the Akt signaling pathway.

Passivation of multiple heavy metals in lead-zinc tailings facilitated by straw biochar-loaded N-doped carbon aerogel nanoparticles: Mechanisms and microbial community evolution.

Heavy metal (HM) soil pollution has become an increasingly serious problem with the development of industries. Application of biochar in HMs remediation from contaminated environment has attracted considerable research attention during the past decade. Although the mechanism of HMs passivation with biochar has been investigated, effects and mechanisms of interaction among soil-indigenous microbes and novel carbon matrix composites for HMs adsorption and passivation are still unclear. Four different biochar-loaded aerogels, namely, BNCA-1-600, BNCA-1-900, BNCA-2-600, and BNCA-2-900, were synthesized in this study. Adsorption capacity of four kinds of synthetic materials and two types of contrast biochars (BC600 and BC900) to HMs in aqueous solution, passivation capacity of HMs in soil, and effects on soil organic matter and microbial community were explored. Results showed that BNCA-2-900 exhibits excellent adsorption property and a maximum removal capacity of 205.07 mg·g-1 at 25 °C for Pb(II), 105.56 mg·g-1 for Cd(II), and 137.89 mg·g-1 for Zn(II). Leaching concentration of HMs in contaminated soil can meet the national standard of China (GB/T 5085.3-2007) within 120 days. Results of this study confirmed that the additive BNCA-2-900 and coexistence of indigenous microorganisms can effectively reduce bioavailability of HMs. Another potential mechanism may be to remove the passivation of HMs by porous structure and surface functional groups as well as improve the content of organic matter and microbial abundance. The research results may provide a novel perceptive for the development of functional materials and strategies for eco-friendly and sustainable multiple HMs remediation in contaminated soil and water by using a combination of carbon matrix composites and soil-indigenous microorganisms.

A Real-World Multicentre Retrospective Study of Low-Dose Apatinib for Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy.