Pyroptosis and mitochondrial function participated in miR-654-3p-protected against myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of heart failure with highly complicated pathogeneses. miR-654-3p has been recognized as a pivotal regulator of controlling cell survival. However, the function of miR-654-3p in cardiomyocytes and MI has yet to be reported. This study aimed to identify the role of miR-654-3p in the regulation of myocardial infarction. To understand the contribution of miR-654-3p on heart function, we generated cardiac-specific knockdown and overexpression mice using AAV9 technology in MI injury. Mechanically, we combined cellular and molecular techniques, pharmaceutical treatment, RNA sequencing, and functional testing to elucidate the potential pathological mechanisms. We identified that mice subjected to MI decreased the expression of miR-654-3p in the border and infarcted area. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. Furthermore, we found a deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death but not other programmed cell death. Intriguingly, miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Cardiac elevating miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Using RNA sequence and molecular biological approaches, we found overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function. Our finding identified the character of miR-654-3p in protecting against MI damage by mediating pyroptosis and mitochondrial metabolism. These findings provide a new mechanism for miR-654-3p involvement in the pathogenesis of MI and reveal novel therapeutic targets. miR-654-3p expression was decreased after MI. Mice lacking miR-654-3p in the heart showed some inflammation infiltration and myocardial fibrosis, resulting in a mild cardiac injury. The deficiency of miR-654-3p in cardiomyocytes resulted in pyroptotic cell death. miR-654-3p deficiency aggravated MI-induced cardiac dysfunction, accompanied by higher myocardial fibrosis and cardiac enzymes and augmented pyroptosis activation. Overexpression of miR-654-3p prevented myocardial fibrosis and inflammation infiltration and decreased pyroptosis profile, thereby attenuating MI-induced cardiac damage. Overexpression of miR-654-3p in the heart promoted the metabolic ability of the cardiomyocytes by promoting mitochondrial metabolism and mitochondrial respiration function.

Pt─O Bond Accelerated Cu0/Cu+ Activity for Boosting Low-Energy Bipolar Hydrogen Production.

To address the imperative challenge of producing hydrogen in a low-energy consumption electrocatalytic system, this study emphasizes the utilization of thermodynamically favorable biomass oxidation for achieving energy-efficient hydrogen generation. This research integrates ultralow PtO2-loaded flower-like nanosheets (denoted as PtO2@Cu2O/Cu FNs) with Cu0/Cu+ pairs and Pt─O bonds, thereby yielding substantial enhancement in both hydrogen evolution reaction (HER, -0.042 VRHE at 10 mA cm-2) and furfural oxidation reaction (FFOR, 0.09 VRHE at 10 mA cm-2). As validated by DFT calculations, the dual built-in electric field (BIEF) is elucidated as the driving force behind the enhanced activities, in which Pt─O bonds expedite the HER, while Cu+/Cu0 promotes low-potential FFOR. By coupling the FFOR and HER together, the resulting bipolar-hydrogen production system requires a low power input (0.5072 kWh per m3) for producing H2. The system can generate bipolar hydrogen and high value-added furoic acid, significantly enhancing hydrogen production efficiency and concurrently mitigating energy consumption.

Two-dimensional ice-like water adlayers on a mica surface with and without a graphene coating under ambient conditions.

Water tends to wet all hydrophilic surfaces under ambient conditions, and the first water adlayers on solids are important for a broad range of physicochemical phenomena and technological processes, including corrosion, wetting, lubrication, anti-icing, catalysis, and electrochemistry. Unfortunately, challenges in characterizing the first water adlayer in the laboratory have hampered molecular-level understanding of the contact water structure. Herein, we present the first ab initio molecular dynamics simulation evidence of a previously unreported ice-like adlayer structure (named as Ice-AL-II) on a prototype mica surface under ambient conditions. Calculation showed that the newly identified Ice-AL-II structure is more stable than the widely recognized ice-adlayer structure on mica surfaces (named as Ice-AL-I). Ice-AL-II exhibited a face-centered corner-cut tetragon (or a face-centered irregular pentagon) pattern of a hydrogen-bonded network. The center of the corner-cut tetragon was occupied by either a K+ cation or a water molecule with two H atoms pinned by the mica (100) via double hydrogen bonds. Our simulation also suggested that bilayer Ice-AL-II favors AA stacking rather than AB stacking. Interestingly, when a graphene sheet was coated on top of the ice-like adlayer, the stability of Ice-AL-II was further enhanced. In contrast, due to its strongly puckered structure, the Ice-AL-I structure could be crushed into a near-Ice-AL-II structure by the graphene coating. Ice-AL-II is thus proposed as a promising candidate for the ice-like structure on a mica surface detected by scanning polarization force microscopy and by atomic force microscopy between a graphene coating and a mica surface.

Highly Efficient and Scalable p-i-n Perovskite Solar Cells Enabled by Poly-metallocene Interfaces.

Inverted p-i-n perovskite solar cells (PSCs) are easy to process but need improved interface characteristics with reduced energy loss to prevent efficiency drops when increasing the active photovoltaic area. Here, we report a series of poly ferrocenyl molecules that can modulate the perovskite surface enabling the construction of small- and large-area PSCs. We found that the perovskite-ferrocenyl interaction forms a hybrid complex with enhanced surface coordination strength and activated electronic states, leading to lower interfacial nonradiative recombination and charge transport resistance losses. The resulting PSCs achieve an enhanced efficiency of up to 26.08% for small-area devices and 24.51% for large-area devices (1.0208 cm2). Moreover, the large-area PSCs maintain >92% of the initial efficiency after 2000 h of continuous operation at the maximum power point under 1-sun illumination and 65 °C.

A general descriptor for single-atom catalysts decorated with axial ligand.

Decoration of an axial coordination ligand (ACL) on the active metal site is a highly effective and versatile strategy to tune activity of single-atom catalysts (SACs). However, the regulation mechanism of ACLs on SACs is still incompletely known. Herein, we investigate diversified combinations of ACL-SACs, including all 3d-5d transition metals and ten prototype ACLs. We identify that ACLs can weaken the adsorption capability of the metal atom (M) by raising the bonding energy levels of the M-O bond while enhancing dispersity of the d orbital of M. Through examination of various local configurations and intrinsic parameters of ACL-SACs, a general structure descriptor σ is constructed to quantify the structure-activity relationship of ACL-SACs which solely based on a few key intrinsic features. Importantly, we also identified the axial ligand descriptor σACL, as a part of σ, which can serve as a potential descriptor to determine the rate-limiting steps (RLS) of ACL-SACs in experiment. And we predicted several ACL-SACs, namely, CrN4-, FeN4-, CoN4-, RuN4-, RhN4-, OsN4-, IrN4- and PtN4-ACLs, that entail markedly higher activities than the benchmark catalysts of Pt and IrO2, thereby supporting that the general descriptor σ can provide a simple and cost-effective method to assess efficient electrocatalysts.

Construction of a stable radical hydrogen-bonded metal-organic framework with functionalized tetrathiafulvalene linkers.

A stable two-dimensional radical hydrogen-bonded metal-organic framework, constructed using a modified tetrathiafulvalene-tetrabenzoate ((2-Me)-H4TTFTB) linker and Cd2+ ions, exhibits a high electrical conductivity of 4.1 × 10-4 S m-1 and excellent photothermal conversion with a temperature increase of 137 °C in 15 s under the irradiation of a 0.7 W cm-2 808 nm laser.

Formation of compounds with diverse polyelectrolyte morphologies and nonlinear ion conductance in a two-dimensional nanofluidic channel.

Aqueous electrolytes subjected to angstrom-scale confinement have recently attracted increasing interest because of their distinctive structural and transport properties, as well as their promising applicability in bioinspired nanofluidic iontronics and ion batteries. Here, we performed microsecond-scale molecular dynamics simulations, which provided evidence of nonlinear ionic conductance under an external lateral electric field due to the self-assembly of cations and anions with diverse polyelectrolyte morphologies (e.g., extremely large ion clusters) in aqueous solutions within angstrom-scale slits. Specifically, we found that the cations and anions of Li2SO4 and CaSO4 formed chain-like polyelectrolyte structures, whereas those of Na2SO4 and MgSO4 predominantly formed a monolayer of hydrated salt. Additionally, the cations and anions of K2SO4 assembled into a hexagonal anhydrous ionic crystal. These ion-dependent diverse polyelectrolyte morphologies stemmed from the enhanced Coulomb interactions, weakened hydration and steric constraints within the angstrom-scale slits. More importantly, once the monolayer hydrated salt or ionic crystal structure was formed, the field-induced ion current exhibited an intriguing gating effect at a low field strength. This abnormal ion transport was attributed to the concerted movement of cations and anions within the solid polyelectrolytes, leading to the suppression of ion currents. When the electric field exceeded a critical strength, however, the ion current surged rapidly due to the dissolution of many cations and anions within a few nanoseconds in the aqueous solution.

Inhibition of cIAP1/2 reduces RIPK1 phosphorylation in pulmonary endothelial cells and alleviate sepsis-induced lung injury and inflammatory response.

Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination. Additionally, cIAP1/2 inhibition led to the up-regulation of programmed cell death, including apoptosis, necroptosis, and pyroptosis, and inhibiting these three cell death pathways can further reduce the inflammatory response, which is similar to the recently discovered programmed cell death pathway PANoptosis. Our findings suggest that cIAP1/2 and PANoptosis inhibition may be a new strategy for treating sepsis-induced lung injury and provide important references for further exploring the mechanism of sepsis-induced lung injury and identifying new therapeutic targets.

Highly Dispersed Ni Atoms and O3 Promote Room-Temperature Catalytic Oxidation.

Transition metal oxides are promising catalysts for catalytic oxidation reactions but are hampered by low room-temperature activities. Such low activities are normally caused by sparse reactive sites and insufficient capacity for molecular oxygen (O2) activation. Here, we present a dual-stimulation strategy to tackle these two issues. Specifically, we import highly dispersed nickel (Ni) atoms onto MnO2 to enrich its oxygen vacancies (reactive sites). Then, we use molecular ozone (O3) with a lower activation energy as an oxidant instead of molecular O2. With such dual stimulations, the constructed O3-Ni/MnO2 catalytic system shows boosted room-temperature activity for toluene oxidation with a toluene conversion of up to 98%, compared with the O3-MnO2 (Ni-free) system with only 50% conversion and the inactive O2-Ni/MnO2 (O3-free) system. This leap realizes efficient room-temperature catalytic oxidation of transition metal oxides, which is constantly pursued but has always been difficult to truly achieve.

Mixed response to the first-line treatment of KRAS G12C inhibitor, sotorasib, in non-small cell lung cancer: A brief report.

Key Clinical Message: One Kirsten Ras (KRAS) G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line KRAS-targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract: KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8-month median progress-free survival (PFS) and 12.5-month overall survival (OS) in previously treated KRAS G12C-mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next-generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG-PS) with metastatic KRAS G12C-mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first-line treatment. Although 5-month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG-PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first-line treatment with sotorasib for the advance untreated KRAS G12C-mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C-mutated patient may favor the immunotherapy.

First report of Botrytis cinerea causing grey mold on Corydalis yanhusuo in Panan, China.

Yanhusuo (Corydalis yanhusuo (Y. H. Chou & Chun C. Hsu) W. T. Wang ex Z.Y. Su & C.Y. Wu), a perennial herbaceous plant of the Papaveraceae family and genus Corydalis, is also known as Yuanhu and used as medicine by its tuberous roots. It is mainly planted in Zhejiang, Jiangsu and Anhui provinces of China, with the best quality produced in Panan County of Zhejiang province. Yanhusuo has the effects of promoting blood circulation, invigorating the flow of qi and relieving pain, and is widely used in Chinese traditional medicines. In surveys carried out in summer of 2020-2023, grey mold disease was found occurred on C. yanhusuo in Panan County. This disease begins at April, and lasts to July, with incidence of 20% to 70%. The diseased plants showed a large number of gray mold layers adhere to the leaves. When the disease infects from the leaf tips, it form V-shaped lesions; when the leaves are severely infected, the entire leaves die, shrink, curl, and have a large number of gray mold layers on the surface. To identify the causal agent of this leaf disease, diseased leaves were collected from Yanhusuo field at Panan County of Zhejiang province in China since 2020, and tissues at the junction of the healthy and diseased areas were cut off, disinfected with 75% ethanol for 30 seconds, rinsed with sterile water for 3 times for 1 minute each time, air-dried under sterile conditions, and then were inoculated in PDA medium and cultured in a 25℃ incubator. After 2-3 days, picked the edge hyphae of the fungi that grew on the PDA plate and cultured them on a new PDA plate. After 5 days, picked the single spore and inoculated on a new PDA plate for continuous cultivation until pure culture strains were obtained. Thirty strains were isolated from 30 samples that collected from 3 Yanhusuo fields in Panan County. One of the thirty purified strains was named "YH8" for further identification. When cultured on PDA medium, mycelia were initially whitish and turned gray with age. The hyphae accumulate into clusters, and no sclerotia are produced during the cultivation. The conidiophores are slender, septate. The base of the conidiophore is enlarged or slightly enlarged. The conidiophore often has branches and produces a large number of conidia, which are similar to grape clusters. The conidia are monosporous, ovoid, and colorless, 6.08 µm-12.76 µm×8.42 µm-19.34 µm, with an average size of 9.55 µm×14.50 µm. To further identify the species, YH8 genomic DNA was extracted, and the internal transcribed spacer (ITS), heat shock protein (HSP60), and glyceraldehyde-3-phosphate dehydrogenase (G3PDH) genes were amplified with the primers ITS1/4 (White et al. 1990), HSP60-F/HSP60-R, and G3PDH-F/G3PDH-R (Staats et al. 2005), respectively. A multilocus phylogenetic tree was constructed with the ITS, HSP60, and G3PDH reference sequences, and the sequences of PCR amplicons (Genbank number: PP388281, PP376066 and PP376067) were 100% (518 bp out of 518 bp), 99% (994 bp out of 995 bp) and 100% (880 bp out of 880 bp) identical to the Botrytis cinerea strain 5-3, respectively, and the grouping of strain YH8 was supported by 99% bootstrap value. To fulfill the Koch's postulates, spore suspension (approximately 103 CFU/mL) of YH8 was sprayed onto leaves of 3-week Yanhusuo seedlings, and sterile water was sprayed as negative control, 15 seedlings for each treatment, and the experiments was repeated for times. The seedlings were incubated in a growth chamber under 28℃ and 80% humidity. Seven days after inoculation, leaves of noninoculated controls were green and healthy, while the seedlings inoculated with spore suspension of YH8 showed lesions and molds, which were same with field symptoms. The causal pathogen was then reisolated from the lesions, and the gained pathogen showed same colony and spore morphology with YH8, which suggested the confirmation of Koch's postulates. Based on the morphological characteristics and molecular identification, the strain YH8 was identified as B. cinerea. To our knowledge, this is the first report of B. cinerea causing gray mold on the Corydalis yanhusuo in China. This report will provide guide to growers and local technicians for diagnostic and controlling grey mold disease of Yanhusuo.

Superdiffusive Rotation of Interfacial Water on Noble Metal Surface.

Interfacial water on a metal surface acts as an active layer through the reorientation of water, thereby facilitating the energy transfer and chemical reaction across the metal surface in various physicochemical and industrial processes. However, how this active interfacial water collectively behaves on flat noble metal substrates remains largely unknown due to the experimental limitation in capturing librational vibrational motion of interfacial water and prohibitive computational costs at the first-principles level. Herein, by implementing a machine-learning approach to train neural network potentials, we enable performing advanced molecular dynamics simulations with ab initio accuracy at a nanosecond scale to map the distinct rotational motion of water molecules on a metal surface at room temperature. The vibrational density of states of the interfacial water with two-layer profiles reveals that the rotation and vibration of water within the strong adsorption layer on the metal surface behave as if the water molecules in the bulk ice, wherein the O-H stretching frequency is well consistent with the experimental results. Unexpectedly, the water molecules within the adjacent weak adsorption layer exhibit superdiffusive rotation, contrary to the conventional diffusive rotation of bulk water, while the vibrational motion maintains the characteristic of bulk water. The mechanism underlying this abnormal superdiffusive rotation is attributed to the translation-rotation decoupling of water, in which the translation is restrained by the strong hydrogen bonding within the bilayer interfacial water, whereas the rotation is accelerated freely by the asymmetric water environment. This superdiffusive rotation dynamics may elucidate the experimentally observed large fluctuation of the potential of zero charge on Pt and thereby the conventional Helmholtz layer model revised by including the contribution of interfacial water orientation. The surprising superdiffusive rotation of vicinal water next to noble metals will shed new light on the physicochemical processes and the activity of water molecules near metal electrodes or catalysts.

An exosomal strategy for targeting cancer-associated fibroblasts mediated tumors desmoplastic microenvironments.

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.

A dual dynamically cross-linked hydrogel promotes rheumatoid arthritis repair through ROS initiative regulation and microenvironment modulation-independent triptolide release.

High oxidative stress and inflammatory cell infiltration are major causes of the persistent bone erosion and difficult tissue regeneration in rheumatoid arthritis (RA). Triptolide (TPL) has become a highly anticipated anti-rheumatic drug due to its excellent immunomodulatory and anti-inflammatory effects. However, the sudden drug accumulation caused by the binding of "stimulus-response" and "drug release" in a general smart delivery system is difficult to meet the shortcoming of extreme toxicity and the demand for long-term administration of TPL. Herein, we developed a dual dynamically cross-linked hydrogel (SPT@TPL), which demonstrated sensitive RA microenvironment regulation and microenvironment modulation-independent TPL release for 30 days. The abundant borate ester/tea polyphenol units in SPT@TPL possessed the capability to respond and regulate high reactive oxygen species (ROS) levels on-demand. Meanwhile, based on its dense dual crosslinked structure as well as the spontaneous healing behavior of numerous intermolecular hydrogen bonds formed after the breakage of borate ester, TPL could remain stable and slowly release under high ROS environments of RA, which dramatically reduced the risk of TPL exerting toxicity while maximized its long-term efficacy. Through the dual effects of ROS regulation and TPL sustained-release, SPT@TPL alleviated oxidative stress and reprogrammed macrophages into M2 phenotype, showing marked inhibition of inflammation and optimal regeneration of articular cartilage in RA rat model. In conclusion, this hydrogel platform with both microenvironment initiative regulation and TPL long-term sustained release provides a potential scheme for rheumatoid arthritis.

Topological wetting states of microdroplets on closed-loop structured surfaces: Breakdown of the Gibbs equation at the microscale.

Microdroplets are a class of soft matter that has been extensively employed for chemical, biochemical, and industrial applications. However, fabricating microdroplets with largely controllable contact-area shape and apparent contact angle, a key prerequisite for their applications, is still a challenge. Here, by engineering a type of surface with homocentric closed-loop microwalls/microchannels, we can achieve facile size, shape, and contact-angle tunability of microdroplets on the textured surfaces by design. More importantly, this class of surface topologies (with universal genus value = 1) allows us to reveal that the conventional Gibbs equation (widely used for assessing the edge effect on the apparent contact angle of macrodroplets) seems no longer applicable for water microdroplets or nanodroplets (evidenced by independent molecular dynamics simulations). Notably, for the flat surface with the intrinsic contact angle ~0°, we find that the critical contact angle on the microtextured counterparts (at edge angle 90°) can be as large as >130°, rather than 90° according to the Gibbs equation. Experiments show that the breakdown of the Gibbs equation occurs for microdroplets of different types of liquids including alcohol and hydrocarbon oils. Overall, the microtextured surface design and topological wetting states not only offer opportunities for diverse applications of microdroplets such as controllable chemical reactions and low-cost circuit fabrications but also provide testbeds for advancing the fundamental surface science of wetting beyond the Gibbs equation.

Formation of a two-dimensional helical square tube ice in hydrophobic nanoslit using the TIP5P water model.

In extreme and nanoconfinement conditions, the tetrahedral arrangement of water molecules is challenged, resulting in a rich and new phase behavior unseen in bulk phases. The unique phase behavior of water confined in hydrophobic nanoslits has been previously observed, such as the formation of a variety of two-dimensional (2D) ices below the freezing temperature. The primary identified 2D ice phase, termed square tube ice (STI), represents a unique arrangement of water molecules in 2D ice, which can be viewed as an array of 1D ice nanotubes stacked in the direction parallel to the confinement plane. In this study, we report the molecular dynamics (MD) simulations evidence of a novel 2D ice phase, namely, helical square tube ice (H-STI). H-STI is characterized by the stacking of helical ice nanotubes in the direction parallel to the confinement plane. Its structural specificity is evident in the presence of helical square ice nanotubes, a configuration unseen in both STI and single-walled ice nanotubes. A detailed analysis of the hydrogen bonding strength showed that H-STI is a 2D ice phase diverging from the Bernal-Fowler-Pauling ice rules by forming only two strong hydrogen bonds between adjacent molecules along its helical ice chain. This arrangement of strong hydrogen bonds along ice nanotube and weak bonds between the ice nanotube shows a similarity to quasi-one-dimensional van der Waals materials. Ab initio molecular dynamics simulations (over a 30 ps) were employed to further verify H-STI's stability at 1 GPa and temperature up to 200 K.

Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

H4K20me3, H3K4me2 and H3K9me2 mediate the effect of ER on prognosis in breast cancer.

Previous studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.

The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.