Anoikis-related genes in breast cancer patients: reliable biomarker of prognosis.

BACKGROUND: Breast cancer (BC) is the most common cancer in women, and its progression is closely related to the phenomenon of anoikis. Anoikis, the specific programmed death resulting from a lack of contact between cells and the extracellular matrix, has recently been recognized as playing a critical role in tumor initiation, maintenance, and treatment. The ability of cancer cells to resist anoikis leads to cancer progression and metastatic colonization. However, the impact of anoikis on the prognosis of BC patients remains unclear. METHOD: This study utilized data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to collect transcriptome and clinical data of BC patients. Anoikis-related genes (ARGs) were classified into subtypes A and B through consensus clustering. Subsequently, survival prognosis analysis, immune cell infiltration analysis, and functional enrichment analysis were performed for both subtypes. Using the Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a set of 10 ARGs related to prognosis was identified. Immune cell infiltration and tumor microenvironment analyses were conducted on these 10 ARGs to develop a prognostic model. Furthermore, single-cell data analysis and real-time polymerase chain reaction (RT-PCR) analysis were employed to study the expression of the 10 identified prognostic ARGs in BC cells. RESULTS: One hundred thirty-five ARGs were identified as differentially expressed genes in the TCGA and GEO databases, with 42 of them associated with the survival prognosis of BC patients. Analyses involving Principal Component Analysis (PCA), t-Distributed Stochastic Neighbor Embedding (t-SNE), and Uniform Manifold Approximation and Projection (UMAP) revealed distinct expression patterns of ARGs between types A and B. Patients in type A exhibited worse survival prognosis and lower immune cell infiltration compared to type B. Subsequent analyses identified 10 key ARGs (YAP1, PIK3R1, BAK1, PHLDA2, EDA2R, LAMB3, CD24, SLC2A1, CDC25C, and SLC39A6) relevant to BC prognosis. Kaplan-Meier analysis indicated that high-risk patients based on these ARGs had a poorer BC prognosis. Additionally, Cox regression analysis established gender, age, T (tumor), N (nodes), and risk score as predictive factors in a nomogram model for BC. The model demonstrated diagnostic value for BC patients at 1, 3, and 5 years. Decision curve analysis (DCA) verified the risk score as a reliable predictor of BC patient survival rates. Moreover, RT-PCR results confirmed differential expressions of YAP1, PIK3R1, BAK1, PHLDA2, CD24, SLC2A1, and CDC25C in BC cells, with SLC39A6, EDA2R, and LAMB3 showing low expression levels. CONCLUSION: ARGs markers can be used as BC biomarkers for risk stratification and survival prediction in BC patients. Besides, ARGs can be used as stratification factors for individualized and precise treatment of BC patients.

Human Defensin 5 Inhibits Plasmodium yoelii Development in Anopheles stephensi by Promoting Innate Immune Response.

Malaria poses a serious threat to human health. Existing vector-based interventions have shortcomings, such as environmental pollution, strong resistance to chemical insecticides, and the slow effects of biological insecticides. Therefore, the need to develop novel strategies for controlling malaria, such as reducing mosquito vector competence, is escalating. Human defensin 5 (HD5) has broad-spectrum antimicrobial activity. To determine its effect on Plasmodium development in mosquitoes, HD5 was injected into Anopheles stephensi at various time points. The infection density of Plasmodium yoelii in An. stephensi was substantially reduced by HD5 treatment administered 24 h prior to infection or 6, 12, or 24 h post-infection (hpi). We found that HD5 treatment upregulated the expression of the innate immune effectors TEP1, MyD88, and Rel1 at 24 and 72 hpi. Furthermore, the RNA interference of MyD88, a key upstream molecule in the Toll signaling pathway, decreased the HD5-induced resistance of mosquitoes against Plasmodium infection. These results suggest that HD5 microinjection inhibits the development of malaria parasites in An. stephensi by activating the Toll signaling pathway.

Y-90 Radioembolization and PD-1 Inhibitor as Neoadjuvant Treatment in Hepatocellular Carcinoma.

This study showcases a comprehensive treatment protocol for high-risk hepatocellular carcinoma (HCC) patients, focusing on the combined use of Y-90 transarterial radioembolization (TARE) and Programmed Cell Death-1 (PD-1) inhibitors as neoadjuvant therapy. Highlighted through a case report, it offers a step-by-step reference for similar therapeutic interventions. A retrospective analysis was conducted on a patient who underwent hepatectomy following Y-90 TARE and PD-1 inhibitor treatment. Key demographic and clinical details were recorded at admission to guide therapy selection. Y-90 TARE suitability and dosage calculation were based on Technetium-99m (Tc-99m) macroaggregated albumin (MAA) perfusion mapping tests. Lesion coverage by Y-90 microspheres was confirmed through single photon emission computed tomography/computed tomography (SPECT/CT) fusion imaging, and adverse reactions and follow-up outcomes were meticulously documented. The patient, with a 7.2 cm HCC in the right hepatic lobe (T1bN0M0, BCLC A, CNLC Ib) and an initial alpha-fetoprotein (AFP) level of 66,840 ng/mL, opted for Y-90 TARE due to high recurrence risk and initial surgery refusal. The therapy's parameters, including the lung shunting fraction (LSF) and non-tumor ratio (TNR), were within therapeutic limits. A total of 1.36 GBq Y-90 was administered. At 1 month post-therapy, the tumor shrank to 6 cm with partial necrosis, and AFP levels dropped to 21,155 ng/mL, remaining stable for 3 months. After 3 months, PD-1 inhibitor treatment led to further tumor reduction to 4 cm and AFP decrease to 1.84 ng/mL. The patient then underwent hepatectomy; histopathology confirmed complete tumor necrosis. At 12 months post-surgery, no tumor recurrence or metastasis was observed in follow-up sessions. This protocol demonstrates the effective combination of Y-90 TARE and PD-1 inhibitor as a bridging strategy to surgery for HCC patients at high recurrence risk, providing a practical guide for implementing this approach.

Multi-omics analysis of renal vein serum with Ischemia-Reperfusion injury.

BACKGROUND: Acute kidney injury (AKI) is frequently caused by renal ischemia-reperfusion injury (IRI). Identifying potential renal IRI disease biomarkers would be useful for evaluating AKI severity. OBJECTIVE: We used proteomics and metabolomics to investigate the differences in renal venous blood between ischemic and healthy kidneys in an animal model by identifying differentially expressed proteins (DEPs) and differentially expressed protein metabolites (DEMs). METHODS: Nine pairs of renal venous blood samples were collected before and at 20, 40, and 60 min post ischemia. The ischemia time of Group A, B and C was 20,40 and 60 min. The proteome and metabolome of renal venous blood were evaluated to establish the differences between renal venous blood before and after ischemia. RESULTS: We identified 79 common DEPs in all samples of Group A, 80 in Group B, and 131 in Group C. Further common DEPs among all three groups were Tyrosineprotein kinase, GPR15LG, KAZALD1, ADH1B. We also identified 81, 64, and 83 common DEMs in each group respectively, in which 30 DEMs were further common to all groups. Bioinformatic analysis of the DEPs and DEMs was conducted. CONCLUSION: This study demonstrated that different pathological processes occur during short- and long-term renal IRI. Tyrosine protein kinase, GPR15LG, Kazal-type serine peptidase inhibitor domain 1, and all-trans-retinol dehydrogenase are potential biomarkers of renal IRI.

One-step sintering construction of electromagnetic synergistic Co7Fe3/Co@CBC nanocomposites for enhanced microwave absorption properties.

Based on the synergistic modulation of electromagnetic parameters and microstructure design, multidimensional porous magnetic carbon-based nanocomposites have become ideal materials with efficient absorption properties. What's more, a carbon-magnetic alloy composite is a commonly used and efficient microwave absorber. In this paper, Co7Fe3/Co@CBC (CFCC) nanocomposites with strong magnetism, a three-phase composition, and a three-dimensional porous structure were synthesized by reducing Fe2+ and Co2+ using chestnut-shell biomass carbon (CBC). Biomass carbon with a higher specific surface area provides numerous active sites for Co7Fe3 nanosheets and Co nanospheres to form three-dimensional ping-pong chrysanthemum-like nanocomposites, which generate rich heterogeneous interfaces and conductive network structures. By adjusting the amount of added biomass, the electromagnetic parameters can be effectively regulated to achieve efficient microwave absorption properties. When the amount of biomass added varies within the range of 1.0 to 2.5 g, all samples exhibit a favorable effective absorption bandwidth (EAB) of over 5.88 GHz. In particular, the CFCC-2.0 composite exhibits optimal microwave absorption properties, with a minimum reflection loss (RLmin) value of -59.25 dB and an EAB of 6.34 GHz at a thickness of 2.8 mm. The simulation and modeling analysis results of radar cross section (RCS) further confirm the exceptional attenuation capability of composite materials at multiple incident angles. The exceptional microwave absorption properties and stability of EAB for the Co7Fe3/Co@CBC nanocomposite make it a promising candidate in the field of absorbing materials. This work also provides some feasible ideas for designing stable broadband wave-absorbing materials.

Regulating the spatial arrangement of CuO and MgO within activated carbon matrix to maximize their room temperature H2S removal.

Adsorbents with dual-component active phases have attracted much attention owing to their potential application in synergistic H2S removal. The influence of spatial arrangements of two components within a support matrix on their desulfurization performance was investigated through regulating the mutual arrangements of CuO and MgO on an activated carbon surface. Their spatial locations were found to remarkably affect interfacial interactions, local pH, the conductivity of adsorbents, and electronic structure of copper oxide. A close contact of CuO with the carbon surface led to strong interactions of both components, inhibiting the reduction of CuO and decreasing its reactivity with H2S. On the other hand, a proximity of MgO to the carbon surface increased local pH, promoting the oxidation of H2S into elemental S, instead of sulfates. Cu+ in the copper oxide phase increased the desulfurization performance due to its ability to activate oxygen and to accelerate a lattice diffusion. Enhanced surface conductivity due to the interfacial interactions improved the desulfurization efficiency and favored the formation of elemental S through promoting an electron transfer in redox reactions.

SENP3 Promotes Mantle Cell Lymphoma Development through Regulating Wnt10a Expression.

OBJECTIVE: SUMO-specific protease 3 (SENP3), a member of the SUMO-specific protease family, reverses the SUMOylation of SUMO-2/3 conjugates. Dysregulation of SENP3 has been proven to be involved in the development of various tumors. However, its role in mantle cell lymphoma (MCL), a highly aggressive lymphoma, remains unclear. This study was aimed to elucidate the effect of SENP3 in MCL. METHODS: The expression of SENP3 in MCL cells and tissue samples was detected by RT-qPCR, Western blotting or immunohistochemistry. MCL cells with stable SENP3 knockdown were constructed using short hairpin RNAs. Cell proliferation was assessed by CCK-8 assay, and cell apoptosis was determined by flow cytometry. mRNA sequencing (mRNA-seq) was used to investigate the underlying mechanism of SENP3 knockdown on MCL development. A xenograft nude mouse model was established to evaluate the effect of SENP3 on MCL growth in vivo. RESULTS: SENP3 was upregulated in MCL patient samples and cells. Knockdown of SENP3 in MCL cells inhibited cell proliferation and promoted cell apoptosis. Meanwhile, the canonical Wnt signaling pathway and the expression of Wnt10a were suppressed after SENP3 knockdown. Furthermore, the growth of MCL cells in vivo was significantly inhibited after SENP3 knockdown in a xenograft nude mouse model. CONCLUSION: SENP3 participants in the development of MCL and may serve as a therapeutic target for MCL.

Apply Anticoagulants after Discharge not Benefit to the Incidence of Symptomatic Thrombus in High-Altitude Areas: A Retrospective Study.

OBJECTIVE: Many guidelines indicate that continuous use of anticoagulant drugs reduces the incidence of venous thrombus (VT), but no studies show the effect on the incidence of symptomatic venous thrombus (SVT) in total knee arthroplasty (TKA) patients after discharge. This study aimed to investigate whether it is necessary to apply anticoagulants to TKA patients after discharge. METHODS: Patients who met the exclusion criteria requirement, underwent TKA by the same surgical team and received anticoagulant therapy after the operation were eligible for the study. Finally, a total of 567 TKA patients were recruited as participants. The patients were divided into two groups. The patients in group A were taken low molecular heparin for 5-10 days after surgery, which included but was not limited to low molecular weight heparin calcium injection (0.4 mL, ih, Qd), calcium dioxin injection (0.6 mL, ih, Qd), or enoxaparin sodium injection (0.4 mL, ih, Qd), and the patients needed to continue oral anticoagulant drug (10 mg, po, Qd) for 7-21 days after discharge. The patients in group B only took low molecular heparin 5-10 days after surgery and no treatment after discharge. The baseline characteristics of patients, total complications of SVT include lower limb vascular pain (LLVP), lower limb vascular pain no fester (LLVPNF), lower limbs swelling (LLS), lower limb fester (LLF), and death by thrombosis (DT), bleeding and mortality following discharged were compared between two groups. RESULTS: The study showed that the incidence of SVT patients had no significant difference between the two groups (p = 0.489). Moreover, the incidence of LLVP (p = 0.265), LLS (p = 0.84), LLVPNF (p = 0.213), LLF (p = 0.907), DT (p = 0.907), death from other causes, and bleeding (p = 0.323) had no significant differences between the two groups. However, the incidence of SVT in patients with smoking (p = 0.0001 or 0.0011) or drinking (p = 0.0002 or 0.0001) was significantly increased. CONCLUSION: There is not enough evidence showing that the TKA patients given anticoagulants after discharge had benefits in decreasing the risk of SVT. Furthermore, smoking and drinking would significantly increase the risk of SVT in TKA patients.

Acteoside protects podocyte against apoptosis through regulating AKT/GSK-3ß signaling pathway in db/db mice.

BACKGROUND: Podocyte apoptosis is one of the important pathological mechanisms of diabetic kidney disease (DKD). Acteoside (Act), a major active component of Rehmannia glutinosa leaves total glycoside, has a strong renoprotective action. Our study aims to demonstrate Act's renoprotective actions in db/db mice. METHODS: We adopted C57BLKS/J db/db mice as DKD animal models. After 8 weeks of Act administration, the 24-hour urine albumin, renal function index, and blood lipid levels were quantified using matching kits. Renal pathology was evaluated by HE and PAS staining. The podocyte damage and apoptosis-related signaling pathway were observed by using immunohistochemistry, western blot, and TUNEL staining. RESULTS: The albuminuria of db/db mice was reduced from 391 ug/24 h to 152 ug/24 h, and renal pathology changes were alleviated after Act administration. The western blot and immunohistochemistry showed that Act treatment upregulated the synaptopodin and podocin expression compared with db/db mice, while the TUNEL staining indicated podocyte apoptosis was inhibited. The B-cell lymphoma-2 (Bcl-2) level was upregulated in the Act group, but cleaved caspase-3 and Bcl-2 associated X protein (Bax) expression declined, while the protein kinase B/glycogen synthase kinase-3ß (AKT/GSK-3ß) signaling pathway was repressed. CONCLUSIONS: By inhibiting the AKT/GSK-3ß signaling pathway, Act protected podocytes from apoptosis, decreasing the urine albumin of db/db mice and delaying the course of DKD.

Alkbh5 plays indispensable roles in maintaining self-renewal of hematopoietic stem cells.

Alkbh5 is one of the primary demethylases responsible for reversing N6-methyladenosine (m6A) modifications on mRNAs, and it plays a crucial role in many physiological and pathological processes. Previous studies have shown that Alkbh5 is required for maintaining the function of leukemia stem cells but is dispensable for normal hematopoiesis. In this study, we found that Alkbh5 deletion led to a moderate increase in the number of multiple progenitor cell populations while compromising the long-term self-renewal capacity of hematopoietic stem cells (HSCs). Here, we used RNA-seq and m6A-seq strategies to explore the underlying molecular mechanism. At the molecular level, Alkbh5 may regulate hematopoiesis by reducing m6A modification of Cebpa and maintaining gene expression levels. Overall, our study unveiled an essential role for Alkbh5 in regulating HSC homeostasis and provides a reference for future research in this area.

Characteristics of aerosols from swine farms: A review of the past two-decade progress.

With the rapid development of large-scale and intensive swine production, the emission of aerosols from swine farms has become a growing concern, attracting extensive attention. While aerosols are found in various environments, those from swine farms are distinguished from human habitats, such as residential, suburban, and urban areas. In order to gain a comprehensive understanding of aerosols from swine farms, this paper reviewed relevant studies conducted between 2000 and 2022. The main components, concentrations, and size distribution of the aerosols were systematically reviewed. The differences between aerosols from swine farms and human living and working environments were compared. Finally, the sources, influencing factors, and reduction technologies for aerosols from swine farms were thoroughly elucidated. The results demonstrated that the concentrations of aerosols inside swine farms varied considerably, and most exceeded safety thresholds. However, further exploration is needed to fully understand the difference in airborne microorganism community structure and particles with small sizes (<1 µm) between swine farms and human living and working environments. More airborne bacterial and viruses were adhered to large particles in swine houses, while the proportion of airborne fungi in the respirable fraction was similar to that of human living and working environments. In addition, swine farms have a higher abundance and diversity of potential pathogens, airborne resistant microorganisms and resistant genes compared to the human living and working environments. The aerosols of swine farms mainly originated from sources such as manure, feed, swine hair and skin, secondary production, and waste treatment. According to the source analysis and factors influencing aerosols in swine farms, various technologies could be employed to mitigate aerosol emissions, and some end-of-pipe technologies need to be further improved before they are widely applied. Swine farms are advised not to increase aerosol concentration in human living and working environments, in order to decrease the impact of aerosols from swine farms on human health and restrain the spread of airborne potential pathogens. This review provides critical insights into aerosols of swine farms, offering guidance for taking appropriate measures to enhance air quality inside and surrounding swine farms.

PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with an alarming mortality rate. The development of novel therapeutic targets or drugs for AML is urgently needed. Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation. Recently, ferroptosis has emerged as a novel method for targeting cancer, including AML. Epigenetic dysregulation is a hallmark of AML, and a growing body of evidence suggests that ferroptosis is subject to epigenetic regulation. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a ferroptosis regulator in AML. The type I PRMT inhibitor GSK3368715 promoted ferroptosis sensitivity in vitro and in vivo. Moreover, PRMT1-knockout cells exhibited significantly increased sensitivity to ferroptosis, suggesting that PRMT1 is the primary target of GSK3368715 in AML. Mechanistically, both GSK3368715 and PRMT1 knockout upregulated acyl-CoA synthetase long-chain family member 1 (ACSL1), which acts as a ferroptosis promoter by increasing lipid peroxidation. Knockout ACSL1 reduced the ferroptosis sensitivity of AML cells following GSK3368715 treatment. Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome-wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.

Identification of Terpenoid Compounds and Toxicity Assays of Essential Oil Microcapsules from Artemisia stechmanniana.

Plant essential oils, as biological pesticides, have been reviewed from several perspectives and play a key role in chemical ecology. However, plant essential oils show rapid degradation and vulnerability during actual usage. In this study, we conducted a detailed analysis of the compounds present in the essential oils of A. stechmanniana using gas chromatography-mass spectrometry (GC-MS). The results showed seventeen terpenoid compounds in the A. stechmanniana oil, with four major terpenoid compounds, i.e., eucalyptol (15.84%), (+)-2-Bornanone (16.92%), 1-(1,2,3-Trimethyl-cyclopent-2-enyl)-ethanone (25.63%), and (-)-Spathulenol (16.38%), in addition to an amount of the other terpenoid compounds (25.26%). Indoor toxicity assays were used to evaluate the insecticidal activity of Artemisia stechmanniana essential oil against Aphis gossypii, Frankliniella occidentalis, and Bactericera gobica in Lycium barbarum. The LC50/LD50 values of A. stechmanniana essential oils against A. gossypii, F. occidentalis, and B. gobica were 5.39 mg/mL, 0.34 mg/L, and 1.40 µg/insect, respectively, all of which were highly efficient compared with azadirachtin essential oil. Interestingly, A. stechmanniana essential oil embedded in ß-cyclodextrin (microencapsule) remained for only 21 days, whereas pure essential oils remained for only 5 days. A field efficacy assay with the A. stechmanniana microencapsule (AM) and doses at three concentrations was conducted in Lycium barbarum, revealing that the insecticidal activities of AM showed high efficiency, maintained a significant control efficacy at all concentrations tested, and remained for 21 days. Our study identified terpenoid compounds from untapped Artemisia plants and designed a novel method against pests using a new biopesticide on L. barbarum.

Alternating chimera states in complex networks with modular structures.

Chimera, the coexistence state of synchronization and non-synchronization, widely exists in complex networks. It has a great potentially explanatory power for the unihemispheric sleep of birds and some mammals, in which the synchronizations of the hemispheres of the cerebral cortex are evolving alternately. In this study, a coupled nonlinear oscillator system with a topology of the modular complex network was constructed to simulate the left and right hemispheres of the brain. The results showed that a stable chimera, an alternating chimera, and a breathing chimera were produced when the coupling strength and connection probability of the left and right hemispheres were changed. Further, we studied the effect of noise on rich synchronous patterns and found that the alternating chimera was robust to Gaussian white noise when the strength was not very large. Finally, our study was extended to a complex network with three sub-networks, and an alternating chimera could exist in two or three sub-networks. Our research provides a deeper insight into the mechanism of brain function like unihemispheric sleep.

Laparoscopic Common Bile Duct Exploration in Patients with a Previous History of Biliary Tract Surgery.

For recurrent choledocholithiasis, abdominal adhesions in previous surgeries lead to changes in anatomical structures, and a secondary injury occurs easily when performing another operation for laparoscopic common bile duct exploration (LCBDE), which was once considered a relative contraindication. In view of the limitations of the current surgical technique, this study summarized the surgical approaches and crucial anatomical landmarks for reoperation for LCBDE. Four general surgical approaches were proposed to expose the common bile duct, including the ligamentum teres hepatis approach, the anterior hepatic duodenal ligament approach, the right hepatic duodenal ligament approach, and the hybrid approach. Additionally, this study highlighted seven crucial anatomical landmarks: the parietal peritoneum, the gastrointestinal serosa, the ligamentum teres hepatis, the inferior margin of the liver, the gastric antrum, the duodenum, and the hepatic flexure of the colon, which were helpful to safely separate abdominal adhesions and expose the common bile duct. Moreover, to shorten the time of choledocholithotomy, a sequential method was innovatively applied for the removal of the stones in common bile duct. Mastering the above surgical approaches, including identifying crucial anatomical landmarks and adopting the sequential method will improve the safety of reoperation for LCBDE, shorten the operation time, promote the fast recovery of patients, reduce postoperative complications, and contribute to the popularization and application of this technique.

Aberrant JAK-STAT signaling-mediated chromatin remodeling impairs the sensitivity of NK/T-cell lymphoma to chidamide.

BACKGROUND: Natural killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with a poor prognosis and limited therapeutic options. Therefore, there is an urgent need to exploit potential novel therapeutic targets for the treatment of NKTL. Histone deacetylase (HDAC) inhibitor chidamide was recently approved for treating relapsed/refractory peripheral T-cell lymphoma (PTCL) patients. However, its therapeutic efficacy in NKTL remains unclear. METHODS: We performed a phase II clinical trial to evaluate the efficacy of chidamide in 28 relapsed/refractory NKTL patients. Integrative transcriptomic, chromatin profiling analysis and functional studies were performed to identify potential predictive biomarkers and unravel the mechanisms of resistance to chidamide. Immunohistochemistry (IHC) was used to validate the predictive biomarkers in tumors from the clinical trial. RESULTS: We demonstrated that chidamide is effective in treating relapsed/refractory NKTL patients, achieving an overall response and complete response rate of 39 and 18%, respectively. In vitro studies showed that hyperactivity of JAK-STAT signaling in NKTL cell lines was associated with the resistance to chidamide. Mechanistically, our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect in vitro and in vivo. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of the JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. CONCLUSIONS: Our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02878278. Registered 25 August 2016, https://clinicaltrials.gov/ct2/show/NCT02878278.

Laparoscopic Posterior Radical Antegrade Modular Pancreatosplenectomy for Distal Pancreatic Carcinoma.

Distal pancreatic carcinoma is a highly malignant tumor with strong invasiveness, often growing to the edge of the pancreas and penetrating the pancreatic capsule to infiltrate surrounding tissues. In conventional distal pancreatosplenectomy (DPS), tumor cells are prone to spread along the direction of blood and lymphatic reflux due to surgical compression. Additionally, inflammation makes it challenging to achieve R0 resection, leading to a lower patient survival rate. To address these limitations, radical antegrade modular pancreatosplenectomy (RAMPS) was developed, emphasizing deeper excision, including the left anterior renal fascia, the left anterior renal adipose sac, and even the left adrenal gland, to improve the R0 resection rate. With the advancement of minimally invasive surgical techniques, laparoscopic RAMPS (L-RAMPS) is being considered technically safe and feasible in oncology. However, due to technical difficulties and a lack of supporting evidence for clinical application, only a few institutions are currently conducting L-RAMPS. In this context, this article presents detailed techniques for laparoscopic posterior radical antegrade modular pancreatosplenectomy (L-pRAMPS), offering promise for future clinical applications.

Biphasic amplitude oscillator characterized by distinct dynamics of trough and crest.

Biphasic amplitude dynamics (BAD) of oscillation have been observed in many biological systems. However, the specific topology structure and regulatory mechanisms underlying these biphasic amplitude dynamics remain elusive. Here, we searched all possible two-node circuit topologies and identified the core oscillator that enables robust oscillation. This core oscillator consists of a negative feedback loop between two nodes and a self-positive feedback loop of the input node, which result in the fast and slow dynamics of the two nodes, thereby achieving relaxation oscillation. Landscape theory was employed to study the stochastic dynamics and global stability of the system, allowing us to quantitatively describe the diverse positions and sizes of the Mexican hat. With increasing input strength, the size of the Mexican hat exhibits a gradual increase followed by a subsequent decrease. The self-activation of input node and the negative feedback on input node, which dominate the fast dynamics of the input node, were observed to regulate BAD in a bell-shaped manner. Both deterministic and statistical analysis results reveal that BAD is characterized by the linear and nonlinear dependence of the oscillation trough and crest on the input strength. In addition, combining with computational and theoretical analysis, we addressed that the linear response of trough to input is predominantly governed by the negative feedback, while the nonlinear response of crest is jointly regulated by the negative feedback loop and the self-positive feedback loop within the oscillator. Overall, this study provides a natural and physical basis for comprehending the occurrence of BAD in oscillatory systems, yielding guidance for the design of BAD in synthetic biology applications.

Network modeling-based identification of the switching targets between pyroptosis and secondary pyroptosis.

The newly identified cell death type, pyroptosis plays crucial roles in various diseases. Most recently, mounting evidence accumulates that pyroptotic signaling is highly correlated with coronavirus disease 2019 (COVID-19). Thus, understanding the induction of the pyroptotic signaling and dissecting the detail molecular control mechanisms are urgently needed. Based on recent experimental studies, a core regulatory model of the pyroptotic signaling is constructed to investigate the intricate crosstalk dynamics between the two cell death types, i.e., pyroptosis and secondary pyroptosis. The model well reproduces the experimental observations under different conditions. Sensitivity analysis determines that only the expression level of caspase-1 or GSDMD has the potential to individually change death modes. The decrease of caspase-1 or GSDMD level switches cell death from pyroptosis to secondary pyroptosis. Besides, eight biochemical reactions are identified that can efficiently switch death modes. While from the viewpoint of bifurcation analysis, the expression level of caspase-3 is further identified and twelve biochemical reactions are obtained. The coexistence of pyroptosis and secondary pyroptosis is predicted to be observed not only within the bistable range, but also within proper monostable range, presenting two potential different control mechanisms. Combined with the landscape theory, we further explore the stochastic dynamic and global stability of the pyroptotic system, accurately quantifying how each component mediates the individual occurrence probability of pyroptosis and secondary pyroptosis. Overall, this study sheds new light on the intricate crosstalk of the pyroptotic signaling and uncovers the regulatory mechanisms of various stable state transitions, providing potential clues to guide the development for prevention and treatment of pyroptosis-related diseases.