Unveiling HOXB7 as a novel diagnostic and prognostic biomarker through pan-cancer computer screening.

We attempted to investigate the role of HOXB7 in tumor progression and evolution by means of an extensive computer screening analysis of various cancer types. We performed univariate Cox regression and Kaplan-Meier survival analyses to assess the impact of HOXB7 on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in different types of cancer. Furthermore, we examined the relationship between HOXB7 and several clinical features: tumor microenvironment, immune regulatory genes, immune checkpoints, tumor mutational burden (TMB), and microsatellite instability (MSI). We performed gene set enrichment analysis to gain deeper insights into the potential molecular mechanisms of HOXB7, and validated our findings through functional assays in cells, including methyl thiazolyl tetrazolium cytotoxicity and Transwell invasion assays. HOXB7 expression was associated with different clinical characteristics in numerous malignancies. Higher HOXB7 expression was associated with worse OS, DSS, and PFI in some cancer types. In particular, HOXB7 expression was favorably associated with immune cell infiltration, immune regulatory genes, immunological checkpoints, TMB, and MSI in malignancies. Furthermore, we identified a strong link between copper death-associated gene expression and HOXB7 expression. According to the findings of this study, HOXB7 might serve as an appealing focus for tumor diagnosis and immunotherapy and a prospective indicator of prognosis.

Microsatellite instability in mismatch repair proficient colorectal cancer: clinical features and underlying molecular mechanisms.

BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

Overcoming neutrophil-induced immunosuppression in postoperative cancer therapy: Combined sialic acid-modified liposomes with scaffold-based vaccines.

Immunotherapy is a promising approach for preventing postoperative tumor recurrence and metastasis. However, inflammatory neutrophils, recruited to the postoperative tumor site, have been shown to exacerbate tumor regeneration and limit the efficacy of cancer vaccines. Consequently, addressing postoperative immunosuppression caused by neutrophils is crucial for improving treatment outcomes. This study presents a combined chemoimmunotherapeutic strategy that employs a biocompatible macroporous scaffold-based cancer vaccine (S-CV) and a sialic acid (SA)-modified, doxorubicin (DOX)-loaded liposomal platform (DOX@SAL). The S-CV contains whole tumor lysates as antigens and imiquimod (R837, Toll-like receptor 7 activator)-loaded PLGA nanoparticles as immune adjuvants for cancer, which enhance dendritic cell activation and cytotoxic T cell proliferation upon localized implantation. When administered intravenously, DOX@SAL specifically targets and delivers drugs to activated neutrophils in vivo, mitigating neutrophil infiltration and suppressing postoperative inflammatory responses. In vivo and vitro experiments have demonstrated that S-CV plus DOX@SAL, a combined chemo-immunotherapeutic strategy, has a remarkable potential to inhibit postoperative local tumor recurrence and distant tumor progression, with minimal systemic toxicity, providing a new concept for postoperative treatment of tumors.

CA1 Modulates the Osteogenic Differentiation of Dental Follicle Stem Cells by Activating the BMP Signaling Pathway In Vitro.

BACKGROUND: Carbonic anhydrase 1 (CA1) has been found to be involved in osteogenesis and osteoclast in various human diseases, but the molecular mechanisms are not completely understood. In this study, we aim to use siRNA and lentivirus to reduce or increase the expression of CA1 in Dental follicle stem cells (DFSCs), in order to further elucidate the role and mechanism of CA1 in osteogenesis, and provide better osteogenic growth factors and stem cell selection for the application of bone tissue engineering in alveolar bone fracture transplantation. METHODS: The study used RNA interference and lentiviral vectors to manipulate the expression of the CA1 gene in DFSCs during in vitro osteogenic induction. The expression of osteogenic marker genes was evaluated and changes in CA1, alkaline phosphatase (ALP), Runt-related transcription factor 2 (RUNX2), and Bone morphogenetic proteins (BMP2) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB). The osteogenic effect was assessed through Alizarin Red staining. RESULTS: The mRNA and protein expression levels of CA1, ALP, RUNX2, and BMP2 decreased distinctly in the si-CA1 group than other groups (p < 0.05). In the Lentivirus-CA1 (LV-CA1) group, the mRNA and protein expressions of CA1, ALP, RUNX2, and BMP2 were amplified to varying degrees than other groups (p < 0.05). Apart from CA1, BMP2 (43.01%) and ALP (36.69%) showed significant upregulation (p < 0.05). Alizarin red staining indicated that the LV-CA1 group produced more calcified nodules than other groups, with a higher optical density (p < 0.05), and the osteogenic effect was superior. CONCLUSIONS: CA1 can impact osteogenic differentiation via BMP related signaling pathways, positioning itself upstream in osteogenic signaling pathways, and closely linked to osteoblast calcification and ossification processes.

Dynamic transcriptome profiling revealed a key gene ZmJMJ20 and pathways associated with cadmium stress in maize.

Cadmium (Cd) pollution in soil poses a global concern due to its serious impacts on human health and ecological security. In plants, tremendous efforts have been made to identify some key genes and pathways in Cd stress responses. However, studies on the roles of epigenetic factors in response to Cd stress were still limited. In the study, we first gain insight into the gene expression dynamics for maize seedlings under 0 h, 12 h, and 72 h Cd stress. As a result, six distinct groups of genes were identified by hierarchical clustering and principal component analysis. The key pathways associated with 12 h Cd stress were protein modifications including protein ubiquitination, signal transduction by protein phosphorylation, and histone modification. Whereas, under 72 h stress, main pathways were involved in biological processes including phenylalanine metabolism, response to oxygen-containing compounds and metal ions. Then to be noted, one of the most highly expressed genes at 12 h under Cd treatment is annotated as histone demethylases (ZmJMJ20). The evolutionary tree analysis and domain analysis showed that ZmJMJ20 belonged to the JmjC-only subfamily of the Jumonji-C (JmjC) family, and ZmJMJ20 was conserved in rice and Arabidopsis. After 72 h of Cd treatment, the zmjmj20 mutant created by EMS treatment manifested less severe chlorosis/leaf yellowing symptoms compared with wild-type plants, and there was no significant difference in Fv/Fm and φPSII value before and after Cd treatment. Moreover, the expression levels of several photosynthesis-related down-regulated genes in EMS mutant plants were dramatically increased compared with those in wild-type plants at 12 h under Cd treatment. Our results suggested that ZmJMJ20 plays an important role in the Cd tolerance response pathway and will facilitate the development of cultivars with improved Cd stress tolerance.

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.

Fusobacterium nucleatum induces chemoresistance in colorectal cancer by inhibiting pyroptosis via the Hippo pathway.

Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.

An in silico scheme for optimizing the enzymatic acquisition of natural biologically active peptides based on machine learning and virtual digestion.

BACKGROUND: As a potential natural active substance, natural biologically active peptides (NBAPs) are recently attracting increasing attention. The traditional proteolysis methods of obtaining effective NBAPs are considerably vexing, especially since multiple proteases can be used, which blocks the exploration of available NBAPs. Although the development of virtual digesting brings some degree of convenience, the activity of the obtained peptides remains unclear, which would still not allow efficient access to the NBAPs. It is necessary to develop an efficient and accurate strategy for acquiring NBAPs. RESULTS: A new in silico scheme named SSA-LSTM-VD, which combines a sparrow search algorithm-long short-term memory (SSA-LSTM) deep learning and virtually digested, was presented to optimize the proteolysis acquisition of NBAPs. Therein, SSA-LSTM reached the highest Efficiency value reached 98.00 % compared to traditional machine learning algorithms, and basic LSTM algorithm. SSA-LSTM was trained to predict the activity of peptides in the proteins virtually digested results, obtain the percentage of target active peptide, and select the appropriate protease for the actual experiment. As an application, SSA-LSTM was employed to predict the percentage of neuroprotective peptides in the virtual digested result of walnut protein, and trypsin was ultimately found to possess the highest value (85.29 %). The walnut protein was digested by trypsin (WPTrH) and the peptide sequence obtained was analyzed closely matches the theoretical neuroprotective peptide. More importantly, the neuroprotective effects of WPTrH had been demonstrated in nerve damage mouse models. SIGNIFICANCE: The proposed SSA-LSTM-VD in this paper makes the acquisition of NBAPs efficient and accurate. The approach combines deep learning and virtually digested skillfully. Utilizing the SSA-LSTM-VD based strategy holds promise for discovering and developing peptides with neuroprotective properties or other desired biological activities.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

SOX4 regulates proliferation and apoptosis of human ovarian granulosa-like tumor cell line KGN through the Hippo pathway.

The proliferation and apoptosis of ovarian granulosa cells are important for folliculogenesis. As a transcription factor, SRY-box transcription factor 4 (SOX4) has important roles in regulating cellular proliferation and apoptosis. Nonetheless, the regulatory mechanisms of SOX4 on proliferation and apoptosis of granulosa cells remain elusive. Therefore, a stably overexpressed SOX4 ovarian granulosa cell line KGN was generated by lentivirus encapsulation. We observed that overexpression of SOX4 inhibits apoptosis, promotes proliferation and migration of KGN cells. Comparative analysis of the transcriptome revealed 868 upregulated and 696 downregulated DEGs in LV-SOX4 in comparison with LV-CON KGN cell lines. Afterward, further assessments were performed to explore the possible functions about these DEGs. The data showed their involvement in many biological processes, particularly the Hippo signaling pathway. Moreover, the expression levels of YAP1, WWTR1, WTIP, DLG3, CCN2, and AMOT, which were associated with the Hippo signaling pathway, were further validated by qRT-PCR. In addition, the protein expression levels of YAP1 were markedly elevated, while p-YAP1 were notably reduced after overexpression of SOX4 in KGN cells. Thus, these results suggested that SOX4 regulates apoptosis, proliferation and migration of KGN cells, at least partly, through activation of the Hippo signaling pathway, which might be implicated in mammalian follicle development.

Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response.

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors.

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

RPGR is a guanine nucleotide exchange factor for the small GTPase RAB37 required for retinal function via autophagy regulation.

Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, the upstream regulatory mechanism of autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa GTPase regulator (RPGR) is a guanine nucleotide exchange factor that activates RAB37 by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain to promote autophagy through stimulating exchange. Rpgr knockout (KO) in mice leads to photoreceptor degeneration owing to autophagy impairment in the retina. Notably, the retinopathy phenotypes of Rpgr KO retinas are rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas. This rescue upregulates autophagy through the re-expression of RPGR in KO retinas to accelerate GDP-to-GTP exchange; thus, retinal homeostasis reverts to normal. Taken together, these findings provide an important missing link for coordinating RAB37 GDP-GTP exchange via the RPGR and retinal homeostasis by autophagy regulation.

The Origin and Course of the Blood Supply to the Lower Eyelid Orbital Fat: Anatomical Study and Clinical Significance.

PURPOSE: The aim of this study is to investigate the origin and course of the orbital fat arterial supply in the lower eyelid using traditional anatomy and three-dimensional computed tomography (CT). METHODS: Twenty-seven cadaver heads were infused with mercury sulfide contrast media through the ophthalmic artery, maxillary artery, transverse facial artery, and facial artery. CT images were obtained after contrast agent injection, three-dimensional CT scans were reconstructed, and the cadaver heads were dissected. RESULTS: Forty-five qualified hemifaces showed that the orbital fat arterial supply in the lower eyelid originates primarily from the inferomedial muscular trunk (IMT) of the ophthalmic artery and the orbital branch of the infraorbital artery. The medial branch of the IMT terminated at the medial fat pad (35.6%) or the orbital floor (64.4%). The lateral branch terminated at the inferior oblique (IO) muscle (28.9%) or the central and lateral fat pads (17.8%). In 53.3%, the lateral branch extended to the anterior part of the lateral fat pad and terminated in the orbital wall or the zygomaticoorbital foramina. The orbital branch of the infraorbital artery coursed between the orbital floor and the orbital fat, providing supply to the IO muscle, inferior rectus (IR) muscle, nasolacrimal duct, and orbital fat. CONCLUSION: This study elucidated the origin and course of the orbital fat arterial supply in the lower eyelid, which may help to avoid reducing the blood supply of the orbital fat pedicles during surgery. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Accumulation mechanism of metabolite markers identified by machine learning between Qingyuan and Xiushui counties in Polygonatum cyrtonema Hua.

Polygonatum cyrtonema Hua is a traditional Chinese medicinal plant acclaimed for its therapeutic potential in diabetes and various chronic diseases. Its rhizomes are the main functional parts rich in secondary metabolites, such as flavonoids and saponins. But their quality varies by region, posing challenges for industrial and medicinal application of P. cyrtonema. In this study, 482 metabolites were identified in P. cyrtonema rhizome from Qingyuan and Xiushui counties. Cluster analysis showed that samples between these two regions had distinct secondary metabolite profiles. Machine learning methods, specifically support vector machine-recursive feature elimination and random forest, were utilized to further identify metabolite markers including flavonoids, phenolic acids, and lignans. Comparative transcriptomics and weighted gene co-expression analysis were performed to uncover potential candidate genes including CHI, UGT1, and PcOMT10/11/12/13 associated with these compounds. Functional assays using tobacco transient expression system revealed that PcOMT10/11/12/13 indeed impacted metabolic fluxes of the phenylpropanoid pathway and phenylpropanoid-related metabolites such as chrysoeriol-6,8-di-C-glucoside, syringaresinol-4'-O-glucopyranosid, and 1-O-Sinapoyl-D-glucose. These findings identified metabolite markers between these two regions and provided valuable genetic insights for engineering the biosynthesis of these compounds.

Pseudomonas weihenstephanensis through the iron metabolism pathway promotes in situ spoilage capacity of prepared beef steaks during cold storage.

In this study, we evaluated the histomorphology, reactive oxygen species (ROS), protein degradation, and iron metabolism characteristics and differential expression analysis of genes for siderophores synthesis and protease secretion in prepared beef steaks inoculated alone or co-inoculated with P. weihenstephanensis, B. thermotrichothrix and M. caseolyticus at 4 °C for 12 days. The results showed that the P. weihenstephanensis was the key bacteria that degraded protein in the process of prepared beef steaks spoilage, which led to protein oxidation by promoting ferritin degradation to release free iron and inducing ROS accumulation. The highest expression of FpvA and AprE was detected in the P. weihenstephanensis group by comparing qRT-PCR of the different inoculation groups. Both qRT-PCR and Western blot revealed that ferritin heavy polypeptide and ferritin light chain polypeptide gene and protein expressions were significantly higher in the P. weihenstephanensis inoculation group compared to the other inoculation groups. Results suggested that FpvA and AprE might play roles in meat spoilage and were potential positional, physiological and functional candidate genes for improving the quality traits of prepared beef steaks. This work may provide insights on controlling food quality and safety by intervening in spoilage pathways targeting iron carrier biosynthesis or protease secretion genes.

Global burden of all cause-specific injuries among children and adolescents from 1990 to 2019: a prospective cohort study.

BACKGROUND: To assess the burden and change in incidence, death, and disability-adjusted life years (DALYs) for all-cause-specific injuries among children and adolescents in 204 countries and territories between 1990 and 2019. MATERIALS AND METHODS: Data were extracted from the Global Burden of Disease, Injury, and Risk Factor Study 2019 (GBD 2019). Global, regional, and country-level age-standardized rate (per 100 000) of incidence (ASRI), mortality (ASRM), and DALYs (ASRD) with 95% uncertainty interval (95% UI) of injuries were estimated by age, sex, socio-demographic index (SDI), and all-cause-specific injuries from 1990 to 2019. RESULTS: Overall, the ASRI, ASRM, and ASRD of injury were 9006.18 (95% UI: 7459.74-10 918.04), 23.04 (20.00-26.50), and 2020.19 (1759.47-2318.64) among children and adolescents worldwide in 2019, respectively. All the above indicators showed a downward trend from 1990 to 2019. In level 2 cause of injury, both the global transport injury and unintentional injury declined during the study years, while self-harm and interpersonal violence-related injury showed an increasing trend. High SDI regions had higher ASRI of injuries, but low SDI regions had higher ASRM and ASRD of injuries globally in 2019. Males had a higher burden of injuries than those in females. The ASRI of injuries is higher in adolescents aged 15-19 years, whereas the mortality and DALYs rate are higher among children under 5 years old. Moreover, adolescents aged 15-19 years and individuals living in Central Asia, Middle East, and Africa had higher ASRI, ASRM, and ASRD of injuries owing to self-harm and interpersonal violence. Generally, falls and road traffic injuries are the leading cause of injury among the population aged 0-19 years worldwide, but self-harm, interpersonal violence, and conflict and terrorism are also leading types of injuries in some regions, particularly in Low-Income Countries and Middle-Income Countries. CONCLUSIONS: Injury remains a major global public health problem among children and adolescents, although its burden at the worldwide level showed a decreasing trend from 1990 to 2019. Of concern, the burden of injuries caused by transport injuries, and unintentional injuries has shown a downward trend in most countries, while the burden caused by self-harm and interpersonal violence has shown an upward trend in most countries. These findings suggest that more targeted and specific strategies to prevent the burden of injuries should be reoriented, and our study provides important findings for decision-makers and healthcare providers to reduce injury burden among children and adolescents.

Paeoniflorin alleviated muscle atrophy in cancer cachexia through inhibiting TLR4/NF-κB signaling and activating AKT/mTOR signaling.

Cancer cachexia is a progressive wasting syndrome, which is mainly characterized by systemic inflammatory response, weight loss, muscle atrophy, and fat loss. Paeoniflorin (Pae) is a natural compound extracted from the dried root of Paeonia lactiflora Pallas, which is featured in anti-inflammatory, antioxidant, and immunoregulatory pharmacological activities. While, the effects of Pae on cancer cachexia had not been reported before. In the present study, the effects of Pae on muscle atrophy in cancer cachexia were observed both in vitro and in vivo using C2C12 myotube atrophy cell model and C26 tumor-bearing cancer cachexia mice model. In the in vitro study, Pae could alleviate myotubes atrophy induced by conditioned medium of C26 colon cancer cells or LLC Lewis lung cancer cells by decreasing the expression of Atrogin-1 and inhibited the decrease of MHC and MyoD. In the in vivo study, Pae ameliorated weight loss and improved the decrease in cross-sectional area of muscle fibers and the impairment of muscle function in C26 tumor-bearing mice. The inhibition of TLR4/NF-κB pathway and the activation of AKT/mTOR pathway was observed both in C2C12 myotubes and C26 tumor-bearing mice treated by Pae, which might be the main basis of its ameliorating effects on muscle atrophy. In addition, Pae could inhibit the release of IL-6 from C26 tumor cells, which might also contribute to its ameliorating effects on muscle atrophy. Overall, Pae might be a promising candidate for the therapy of cancer cachexia.

Combination Immunotherapy of Oncolytic Flu-Vectored Virus and Programmed Cell Death 1 Blockade Enhances Antitumor Activity in Hepatocellular Carcinoma.

Oncolytic viruses (OVs) are appealing anti-tumor agents. But it is limited in its effectiveness. In this study, we used combination therapy with immune checkpoint inhibitor to enhance the antitumor efficacy of OVs. Using reverse genetics technology, we rescued an oncolytic influenza virus with the name delNS1-GM-CSF from the virus. After identifying the hemagglutination and 50% tissue culture infectivedose (TCID50) of delNS1-GM-CSF, it was purified, and the viral morphology was observed under electron microscopy. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was used to identify the level of GM-CSF expression in delNS1-GM-CSF, and the GM-CSF expression level was determined after infection with delNS1-GM-CSF by enzyme linked immunosorbent assay (ELISA). To study the tumor-killing effect of delNS1-GM-CSF, we utilized the hepatocellular carcinoma (HCC) tumor-bearing mouse model. To examine signaling pathways, we performed transcriptome sequencing on mouse tumor tissue and applied western blotting to confirm the results. Changes in T-cell infiltration in HCC tumors following treatment were analyzed using flow cytometry and immunohistochemistry. DelNS1-GM-CSF can target and kill HCCs without damaging normal hepatocytes. DelNS1-GM-CSF combined with programmed cell death 1 blockade therapy enhanced anti-tumor effects and significantly improved mouse survival. Further, we found that combination therapy had an antitumor impact via the janus kinase-signal transducer and activator of transcription (JAK2-STAT3) pathway as well as activated CD4+ and CD8+T cells. Interestingly, combined therapy also showed promising efficacy in distant tumors. DelNS1-GM-CSF is well targeted. Mechanistic investigation revealed that it functions through the JAK2-STAT3 pathway. Combination immunotherapies expected to be a novel strategy for HCC immunotherapy.

Er:YAG Laser Therapy on Alveolar Osteitis After Mandibular Third Molar Surgery: A Randomized Controlled Clinical Study.

Background: Alveolar osteitis (AO) or "dry socket" affects the quality of life of patients, and there is a high clinical demand for its effective treatment. Objective: To evaluate the effect of Er:YAG laser therapy (ErLT) on AO after mandibular third molar surgery. Methods: Eighty-three patients were randomly divided into Er (n = 43) and control groups (n = 40). In the Er group, the Er:YAG laser (2940 nm; AT Fidelis Fotona, Ljubljana, Slovenia) was used to irradiate the AO site directly in micro short-pulsed mode (pulse duration 0.1 ms, pulse energy 100 mJ, frequency 40 Hz, water 4, and air 2) until all debris and necrotic material had been removed, exposing fresh bone and soft tissue surfaces with blood exudation. The control group received mechanical therapy until the treated lesions resembled those in the Er group. Pain assessment was performed at baseline and on days 1-7 post-intervention using the visual analog scale (VAS). Wound healing was assessed using the wound healing index (WHI). The operating times of the two therapies were also recorded. Results: Group Er had lower VAS scores than the control group on days 1-3 (p = 0.00). There was no significant difference between the two groups on days 4-7 (p = 0.15). The WHI scores were better in the Er group than those in the control group (t = 2.65, p = 0.01), especially in terms of redness (t = 2.70, p = 0.01). There was no significant difference in the operating time between the two groups (t = 0.76, p = 0.45). Conclusions: Compared with mechanical therapy, ErLT for AO provides rapid pain relief and improved wound healing.