Changes in planta K nutrient content altered the interaction pattern between Nicotiana benthamiana and Alternaria longipes.

Potassium (K) fertilisation has frequently been shown to enhance plant resistance against pathogens, though the mechanisms remain elusive. This study investigates the interaction dynamics between Nicotiana benthamiana and the pathogen Alternaria longipes under different planta K levels. On the host side, adding K activated the expressions of three NLR (nucleotide-binding domain and leucine-rich repeat-containing proteins) resistance genes, including NbRPM1, NbR1B23 and NbNBS12. Silencing these NLRs attenuated resistance in high-K (HK, 40.8 g/kg) plant, whereas their overexpression strengthened resistance in low-K (LK, 23.9 g/kg) plant. Typically, these NLRs mainly strengthened plant resistance via promoting the expression of pathogenesis-related genes (PRs), ROS burst and synthesis of antifungal metabolites in HK plant. On the pathogen side, the expression of effectors HKCSP1, HKCSP2 and LKCSP were shown to be related to planta K content. A. longipes mainly expressed effectors HKCSP1 and HKCSP2 in HK plant to interfere host resistance. HKCSP1 physically interacted with NbRPM1 to promote the degradation of NbRPM1, then attenuated related resistance in HK N. benthamiana. Meanwhile, HKCSP2 directly interacted with NbPR5 to suppress resistance in HK plant. In LK plant, A. longipes mainly deployed LKCSP that interacted with NbR1B23 to interfere reduce resistance in N. benthamiana. Overall, our research insights that both pathogen and host mobilise distinct strategies to outcompete each other during interactions in different K nutrient environments.

Enhancing multiple myeloma staging: a novel cell death risk model approach.

The prognostication of survival trajectories in multiple myeloma (MM) patients presents a substantial clinical challenge. Leveraging transcriptomic and clinical profiles from an expansive cohort of 2,088 MM patients, sourced from the Gene Expression Omnibus and The Cancer Genome Atlas repositories, we applied a sophisticated nested lasso regression technique to construct a prognostic model predicated on 28 gene pairings intrinsic to cell death pathways, thereby deriving a quantifiable risk stratification metric. Employing a threshold of 0.15, we dichotomized the MM samples into discrete high-risk and low-risk categories. Notably, the delineated high-risk cohort exhibited a statistically significant diminution in survival duration, a finding which consistently replicated across both training and external validation datasets. The prognostic acumen of our cell death signature was further corroborated by TIME ROC analyses, with the model demonstrating robust performance, evidenced by AUC metrics consistently surpassing the 0.6 benchmark across the evaluated arrays. Further analytical rigor was applied through multivariate COX regression analyses, which ratified the cell death risk model as an independent prognostic determinant. In an innovative stratagem, we amalgamated this risk stratification with the established International Staging System (ISS), culminating in the genesis of a novel, refined ISS categorization. This tripartite classification system was subjected to comparative analysis against extant prognostic models, whereupon it manifested superior predictive precision, as reflected by an elevated C-index. In summation, our endeavors have yielded a clinically viable gene pairing model predicated on cellular mortality, which, when synthesized with the ISS, engenders an augmented prognostic tool that exhibits pronounced predictive prowess in the context of multiple myeloma.

MAP7 drives EMT and cisplatin resistance in ovarian cancer via wnt/ß-catenin signaling.

Methods: Our approach encompasses analyzing MAP7's expression levels across various datasets and clinical specimens, evaluating its association with patient outcomes, and probing its influence on ovarian cancer cell dynamics such as proliferation, migration, invasion, and apoptosis. Results: We have identified significant upregulation of MAP7 in ovarian cancer tissues, which correlates with advanced disease stages, higher pathological grades, and unfavorable prognoses. Functionally, the inhibition of MAP7 suppresses cancer cell proliferation, migration, and invasion while promoting apoptosis. Notably, the silencing of MAP7 attenuates the epithelial-mesenchymal transition (EMT) and disrupts Wnt/ß-catenin pathway signaling-two critical processes implicated in metastasis and chemoresistance. In cisplatin-resistant A2780-DDP cells, the downregulation of MAP7 effectively reverses their resistance to cisplatin. Furthermore, the nuclear localization of MAP7 in these cells underscores its pivotal role in driving cisplatin resistance by modulating the transcriptional regulation and interaction dynamics of ß-catenin. Conclusion: Our findings position MAP7 as a pivotal element in ovarian cancer advancement and cisplatin resistance, primarily through its modulation of EMT and the Wnt/ß-catenin pathway. Its association with poor clinical outcomes underscores its potential as both a prognostic marker and a therapeutic target. Strategies aimed at MAP7 could represent a new frontier in combating chemotherapy resistance in ovarian cancer, emphasizing its significance in crafting complementary treatments for this disease.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Phosphorylation of FOXK2 at Thr13 and Ser30 by PDK2 sustains glycolysis through a positive feedback manner in ovarian cancer.

Ovarian cancer is one of the most common gynecological malignant tumors with insidious onset, strong invasiveness, and poor prognosis. Metabolic alteration, particularly aerobic glycolysis, which is tightly regulated by transcription factors, is associated with the malignant behavior of OC. We screened FOXK2 in this study as a key transcription factor that regulates glycolysis in OC. FOXK2 is overly expressed in OC, and poor prognosis is predicted by overexpression. FOXK2 promotes OC cell proliferation both in vitro and in vivo and cell migration in vitro. Further studies showed that PDK2 directly binds to the forkhead-associated (FHA) domain of FOXK2 to phosphorylate FOXK2 at Thr13 and Ser30, thereby enhancing the transcriptional activity of FOXK2. FOXK2 transcriptionally regulates the expression of PDK2, thus forming positive feedback to sustain glycolysis in OC cells.

Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial.

OBJECTIVE: To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. METHODS: In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1. RESULTS: 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%). CONCLUSIONS: The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety. TRIAL REGISTRATION NUMBER: NCT05180851.

Salvia miltiorrhiza inhibited lung cancer through aerobic glycolysis suppression.

Lung cancer causes the most cancer deaths and needs new treatment strategies urgently. Salvia miltiorrhiza is a classical Chinese herb and a strong candidate for tumor treatment. The study found that the aqueous extract of Salvia miltiorrhiza (DSAE), ethanol extract of Salvia miltiorrhiza (DSEE), and its active components danshensu (DSS) and dihydrotanshinone I (DHI), exhibited antineoplastic effects in vivo and in vitro. Meanwhile, DSAE, DSEE, DSS, and DHI reduced glycolysis metabolites (ATP, lactate, and pyruvate contents) production, decreased aerobic glycolysis enzymes, and inhibited Seahorse indexes (OCR and ECAR) in Lewis lung cancer cells (LLC). Data suggests that aerobic glycolysis could be inhibited by Salvia miltiorrhiza and its components. The administration of DSS and DHI further reduced the level of HKII in lung cancer cell lines that had been inhibited with HK-II antagonists (2-deoxyglucose, 2-DG; 3-bromo-pyruvate, 3-BP) or knocked down with siRNA, thereby exerting an anti-lung cancer effect. Although DSS and DHI decreased the level of HKII in HKII-Knock-In lung cancer cell line, their anti-lung cancer efficacy remained limited due to the persistent overexpression of HKII in these cells. Reiterating the main points, we have discovered that the anti-lung cancer effects of Salvia miltiorrhiza may be attributed to its ability to regulate HKII expression levels, thereby inhibiting aerobic glycolysis. This study not only provides a new research paradigm for the treatment of cancer by Salvia miltiorrhiza, but also highlights the important link between glucose metabolism and the effect of Salvia Miltiorrhiza.

The Contribution and Mechanism of Hypoxia /USP19/Beclin-1 Feed-Forward Loop in Cervical Cancer.

Cervical cancer ranks fourth in female mortality. Since the mechanisms for pathogenesis of cervical cancer are still poorly understood and the effective treatment options are lacking. Beclin-1 exhibits an inhibitory role in cervical cancer via suppressing the proliferation, invasion, and migration of cervical cancer cells. It is reported that the USP19 removes the K11-linked ubiquitination of Beclin-1 to protect Beclin-1 from proteasomal degradation. Interestingly, we found that hypoxia induced significant decrease of both Beclin-1 and USP19, suggesting that hypoxia could dually inhibit the protein level of Beclin-1 through a type 2 coherent feed-forward loop (C2-FFL, hypoxia ⊸ Beclin-1 integrating with hypoxia ⊸ USP19 → Beclin-1) to promote the occurrence and development of cervical cancer. Furthermore, mathematical modeling revealed that under the hypoxic environment of solid tumor, the hypoxia/ USP19/ Beclin-1 coherent feed-forward loop could significantly reduce the protein level of Beclin-1, greatly enhance the sensitivity of Beclin-1 to hypoxia, strikingly restrict the heterogeneity of Beclin-1, and contribute to the low positive rate of Beclin-1 in cervical cancer. It is expected to have significance for elucidating the underlying mechanisms of the occurrence and development of cervical cancer, and provide novel targets and strategies for prevention and treatment of cervical cancer.

New α-Glucosidase Inhibitors from the Whole Plant of Hypericum beanii Based on Ligand Fishing and Molecular Networking Analysis.

In this work, a new rapid and targeted method for screening α-glucosidase inhibitors from Hypericum beanii was developed and verified. Ten new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperlagarol A-J (1-10), and nine known PPAPs (11-19) were obtained from H. beanii. Their structures were identified by using comprehensive analyses involving mass spectrometry, ultraviolet spectroscopy, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and electron capture dissociation calculations. 1 and 2 are two new rare 2,3-seco-spirocyclic PPAPs, 3 and 4 are two novel 12,13-seco-spirocyclic PPAPs, 5 and 6 are two novel spirocyclic PPAPs, 7 and 8 are two new unusual spirocyclic PPAPs with complex bridged ring systems, and 9 and 10 are two novel nonspirocyclic PPAPs. α-GC inhibitory activities of all isolated compounds were tested. Most of them displayed inhibitory activities against α-glucosidase, with the IC50 values ranging from 6.85 ± 0.65 to 112.5 ± 9.03 µM. Moreover, the inhibitory type and mechanism of the active compounds were further analyzed using kinetic studies and molecular docking.

Spontaneous intestinal perforation among very preterm infants in China: a multicenter cohort study.

Background: Spontaneous intestinal perforation (SIP) is one of the most serious surgical bowel conditions affecting preterm infants. There are limited data on the mortality and morbidities of very preterm infants [VPIs, <32 weeks' gestational age (GA)] with SIP in China. The study aimed to describe the prevalence, treatment, and outcomes of SIP among VPIs in China. Methods: This retrospective cohort study included all infants born at 24+0-31+6 weeks GA from January 1, 2019, to December 31, 2020, and admitted within seven days after birth to the neonatal intensive care units in the Chinese Neonatal Network. The primary outcome was survival without major morbidities. The association between SIP and neonatal outcomes was evaluated using multivariate logistic regression controlling for possible confounders. Results: Out of the 15,814 enrolled infants, 150 (1.0%) developed SIP with a median onset age of four (IQR 2-6) days. Infants with GA 24+0-25+6 weeks had the highest incidence of SIP (13/532, 2.4%), followed by those with GA 26+0-27+6 weeks (22/2,005, 1.1%), 28+0-29+6 weeks (44/5,269, 0.8%) and 30+0-31+6 weeks (71/8,008, 0.9%). Ten SIP cases were lost to follow-up with unknown survival status and 41 (29.3%) of the remaining 140 infants with SIP died during hospitalization. Only 29.3% of infants with SIP survived without major morbidities, significantly lower than those without SIP (59.2%; P<0.01). Multivariate analysis revealed SIP was associated with a higher risk of overall death (adjusted OR 3.36; 95% CI: 1.85 to 6.08), late-onset sepsis (adjusted OR 2.10; 95% CI: 1.02 to 4.31), and bronchopulmonary dysplasia (adjusted OR 2.49; 95% CI: 1.44 to 4.30). Among all infants with SIP, 28 (18.7%) did not receive any surgical intervention. Laparotomy was provided to 113 (92.6%) of the remaining 122 infants, solely (84/122, 68.9%) or following peritoneal drainage (29/122, 23.8%), while nine (7.4%) infants underwent peritoneal drainage only. Conclusions: Around 1% of VPIs in China developed SIP, associated with increased risk of mortality and morbidities. Over 90% of VPIs with SIP underwent laparotomy as initial or subsequent surgical treatment. Effective and evidence-based strategies are needed for the prevention and management of SIP.

Nitrogen-Doped Graphene-Supported Nickel Nanoparticles Reveal Low Dehydrogenation Temperature and Long Cyclic Life of Magnesium Hydrides.

Magnesium hydride (MgH2) is a promising hydrogen storage candidate due to its large capacity; however, high dehydrogenation temperature and slow kinetic rates are the main bottlenecks. Herein, we proposed a strategy for designing nitrogen-doped graphene-supported Ni nanoparticles (NPs) (Ni@NC) to tackle these problems. The results showed that the MgH2 + 15 wt % Ni@NC nanocomposite reduced the on-set dehydrogenation temperature to 195 °C, which was 175 °C lower than pristine MgH2. In addition, MgH2 + 15 wt % Ni@NC achieved 1.7 and 6.5 wt % desorption capacities at 225 and 300 °C, respectively, while absorbing 5.5 wt % hydrogen at 100 °C. The MgH2 + 15 wt % Ni@NC nanocomposite showed high cyclic stability, achieving 98.0% capacity retention after 100 cycles at 270 °C with negligible loss in capacity. This remarkable hydrogen storage performance can be attributed to the homogeneous distribution of Ni NPs on N-doped graphene layers, in situ formed Mg2NiH2 NPs, and multiphasic regions, promoting the nucleation and growth process during hydrogenation/dehydrogenation, which stabilized and improved the cyclic stability. This strategy paves the way to developing high-performance MgH2 for large-scale applications.

TGF ß1 promotes the polarization of M2-type macrophages and activates PI3K/mTOR signaling pathway by inhibiting ISG20 to sensitize ovarian cancer to cisplatin.

The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-ß1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-ß1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-ß1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-ß1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-ß1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-ß1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.

Interior decorative volatile organic compounds exposure induces sleep disorders through aberrant branched chain amino acid transaminase 2 mediated glutamatergic signaling resulting from a neuroinflammatory cascade.

Air pollution has been recognized as a contributing factor to sleep disorders (SD), which have been correlated with an elevated susceptibility to a variety of human diseases. Nevertheless, research has not definitively established a connection between SD and interior decorative volatile organic compounds (ID-VOCs), a significant indoor air pollutant. In this study, we employed a mouse model exposed to ID-VOCs to explore the impacts of ID-VOCs exposure on sleep patterns and the potential underlying mechanism. Of the 23 key compositions of ID-VOCs identified, aromatic hydrocarbons were found to be the most prevalent. Exposure to ID-VOCs in mice resulted in SD, characterized by prolonged wake fullness and decreased sleep during the light period. ID-VOCs exposure triggered neuroinflammatory responses in the suprachiasmatic nucleus (SCN), with microglia activation leading to the overproduction of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α), and complement component 1q (C1q), ultimately inducing A1 astrocytes. Consequently, the upregulation of branched chain amino acid transaminase 2 (BCAT2) in A1 astrocytes resulted in elevated extracellular glutamate and disruption of the wake-sleep transition mechanism, which might be the toxicological mechanism of SD caused by ID-VOCs.

ROS-mediated lysosomal membrane permeabilization and autophagy inhibition regulate bleomycin-induced cellular senescence.

Bleomycin exhibits effective chemotherapeutic activity against multiple types of tumors, and also induces various side effects, such as pulmonary fibrosis and neuronal defects, which limit the clinical application of this drug. Macroautophagy/autophagy has been recently reported to be involved in the functions of bleomycin, and yet the mechanisms of their crosstalk remain insufficiently understood. Here, we demonstrated that reactive oxygen species (ROS) produced during bleomycin activation hampered autophagy flux by inducing lysosomal membrane permeabilization (LMP) and obstructing lysosomal degradation. Exhaustion of ROS with N-acetylcysteine relieved LMP and autophagy defects. Notably, we observed that LMP and autophagy blockage preceded the emergence of cellular senescence during bleomycin treatment. In addition, promoting or inhibiting autophagy-lysosome degradation alleviated or exacerbated the phenotypes of senescence, respectively. This suggests the alternation of autophagy activity is more a regulatory mechanism than a consequence of bleomycin-induced cellular senescence. Taken together, we reveal a specific role of bleomycin-induced ROS in mediating defects of autophagic degradation and further regulating cellular senescence in vitro and in vivo. Our findings, conversely, indicate the autophagy-lysosome degradation pathway as a target for modulating the functions of bleomycin. These provide a new perspective for optimizing bleomycin as a clinically applicable chemotherapeutics devoid of severe side-effects.Abbreviations: AT2 cells: type II alveolar epithelial cells; ATG7: autophagy related 7; bEnd.3: mouse brain microvascular endothelial cells; BNIP3L: BCL2/adenovirus E1B interacting protein 3-like; CCL2: C-C motif chemokine ligand 2; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; FTH1: ferritin heavy polypeptide 1; γ-H2AX: phosphorylated H2A.X variant histone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HUVEC: human umbilical vein endothelial cells; HT22: hippocampal neuronal cell lines; Il: interleukin; LAMP: lysosomal-associated membrane protein; LMP: lysosome membrane permeabilization; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NCOA4: nuclear receptor coactivator 4; PI3K: phosphoinositide 3-kinase; ROS: reactive oxygen species; RPS6KB/S6K: ribosomal protein S6 kinase; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SAHF: senescence-associated heterochromatic foci; SASP: senescence-associated secretory phenotype; SEC62: SEC62 homolog, preprotein translocation; SEP: superecliptic pHluorin; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB.

The immunosuppressive landscape in tumor microenvironment.

Recent advances in cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have revolutionized the clinical outcome of many cancer patients. Despite the fact that impressive progress has been made in recent decades, the response rate remains unsatisfactory, and many patients do not benefit from ICIs. Herein, we summarized advanced studies and the latest insights on immune inhibitory factors in the tumor microenvironment. Our in-depth discussion and updated landscape of tumor immunosuppressive microenvironment may provide new strategies for reversing tumor immune evasion, enhancing the efficacy of ICIs therapy, and ultimately achieving a better clinical outcome.

Enhanced protein-metabolite correlation analysis: To investigate the association between Staphylococcus aureus mastitis and metabolic immune pathways.

Mastitis is a disease characterized by congestion, swelling, and inflammation of the mammary gland and usually caused by infection with pathogenic microorganisms. Furthermore, the development of mastitis is closely linked to the exogenous pathway of the gastrointestinal tract. However, the regulatory mechanisms governing the gut-metabolism-mammary axis remain incompletely understood. The present study revealed alterations in the gut microbiota of mastitis rats characterized by an increased abundance of the Proteobacteria phylum. Plasma analysis revealed significantly higher levels of L-isoleucine and cholic acid along with 7-ketodeoxycholic acid. Mammary tissue showed elevated levels of arachidonic acid metabolites and norlithocholic acid. Proteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which suggests that mastitis triggers an inflammatory response and immune stress. Follistatin (Fst) and progesterone receptor (Pgr) were significantly downregulated, raising the risk of breast cancer. Extracellular matrix (ECM) receptors and focal adhesion signaling pathways were downregulated, while blood-milk barrier integrity was disrupted. Analysis of protein-metabolic network regulation revealed that necroptosis, protein digestion and absorption, and arachidonic acid metabolism were the principal regulatory pathways involved in the development of mastitis. In short, the onset of mastitis leads to changes in the microbiota and alterations in the metabolic profiles of various biological samples, including colonic contents, plasma, and mammary tissue. Key manifestations include disturbances in bile acid metabolism, amino acid metabolism, and arachidonic acid metabolism. At the same time, the integrity of the blood-milk barrier is compromised while inflammation is promoted, thereby reducing cell adhesion in the mammary glands. These findings contribute to a more comprehensive understanding of the metabolic status of mastitis and provide new insights into its impact on the immune system.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Genome comparisons reveal accessory genes crucial for the evolution of apple Glomerella leaf spot pathogenicity in Colletotrichum fungi.

Apple Glomerella leaf spot (GLS) is an emerging fungal disease caused by Colletotrichum fructicola and other Colletotrichum species. These species are polyphyletic and it is currently unknown how these pathogens convergently evolved to infect apple. We generated chromosome-level genome assemblies of a GLS-adapted isolate and a non-adapted isolate in C. fructicola using long-read sequencing. Additionally, we resequenced 17 C. fructicola and C. aenigma isolates varying in GLS pathogenicity using short-read sequencing. Genome comparisons revealed a conserved bipartite genome architecture involving minichromosomes (accessory chromosomes) shared by C. fructicola and other closely related species within the C. gloeosporioides species complex. Moreover, two repeat-rich genomic regions (1.61 Mb in total) were specifically conserved among GLS-pathogenic isolates in C. fructicola and C. aenigma. Single-gene deletion of 10 accessory genes within the GLS-specific regions of C. fructicola identified three that were essential for GLS pathogenicity. These genes encoded a putative non-ribosomal peptide synthetase, a flavin-binding monooxygenase and a small protein with unknown function. These results highlight the crucial role accessory genes play in the evolution of Colletotrichum pathogenicity and imply the significance of an unidentified secondary metabolite in GLS pathogenesis.

Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

Risk factors for severe bronchopulmonary dysplasia in a Chinese cohort of very preterm infants.

OBJECTIVES: To examine the risk factors for severe bronchopulmonary dysplasia (BPD) in a cohort of very preterm infants (VPIs) in China, as BPD is common among VPIs and associated with a high mortality rate. METHODS: In this multicenter retrospective study, medical records from infants with BPD born at gestation age (GA) of <32 weeks with birth weight (BW) of <1,500 grams (g) in 7 regions of China were included. The cohort was stratified into different BPD severity groups based on their fraction of inspired oxygen requirement at a modified GA of 36 weeks or post discharge. Risk factors were identified using logistic regression analysis. RESULTS: A significant inverse correlation was revealed between BPD severity and both GA and BW (p<0.001). Independent risk factors for severe BPD (sBPD) were identified as invasive mechanical ventilation (≥7d), multiple blood transfusion (≥3), nosocomial infection (NI), hemodynamically significant patent ductus arteriosus (hsPDA), delayed initiation of enteral nutrition, and longer time to achieve total caloric intake of 110 kcal/kg. Conversely, administration of antenatal steroids was associated with reduced risk of sBPD. CONCLUSION: Our study not only reaffirmed the established risk factors of low GA and BW for sBPD in VPIs, but also identified additional, potentially modifiable risk factors. Further research is warranted to explore whether intervention in these modifiable factors might reduce the risk of sBPD.Clinical Trial Reg. No.: ChiCTR1900023418.