Oncogenic KRAS drives immunosuppression of colorectal cancer by impairing DDX60-mediated dsRNA accumulation and viral mimicry.

The interferon (IFN) response is vital for the effectiveness of immune checkpoint inhibition (ICI) therapy. Our previous research showed that KRAS (Kirsten rat sarcoma viral) mutation impairs the IFN response in colorectal cancer (CRC), with an unclear mechanism. Here, we demonstrate that KRAS accelerates double-stranded RNA (dsRNA) degradation, impairing dsRNA sensing and IFN response by down-regulating DExD/H-box helicase 6 (DDX60). DDX60 was identified as a KRAS target here and could bind to dsRNAs to protect against RNA-induced silencing complex (RISC)-mediated degradation. Overexpressing DDX60 induced dsRNA accumulation, reactivated IFN signaling, and increased CRC sensitivity to ICI therapy. Mechanistically, KRAS engaged the AKT (also known as protein kinase B)-GSK3ß (glycogen synthase kinase-3 beta) pathway to suppress STAT3 phosphorylation, thereby inhibiting STAT3-driven DDX60 transcription. Our findings reveal a role for KRAS in dsRNA homeostasis, suggesting potential strategies to convert "cold" tumors to "hot" and to overcome ICI resistance in CRC with KRAS mutations.

Controllable Synthesis of Hollow Dodecahedral Si@C Core-Shell Structures for Ultrastable Lithium-Ion Batteries.

Silicon (Si) has attracted considerable attention as a promising alternative to graphite in lithium-ion batteries (LIBs) because of its high theoretical capacity and voltage. However, the durability and cycling stability of Si-based composites have emerged as major obstacles to their widespread adoption as LIBs anode materials. To tackle these challenges, a hollow core-shell dodecahedra structure of a Si-based composite (HD-Si@C) is developed through a novel double-layer in situ growth approach. This innovative design ensures that the nano-sized Si particles are evenly distributed within a hollow carbon shell, effectively addressing issues like Si fragmentation, volume expansion, and detachment from the carbon layer during cycles. The HD-Si@C composite demonstrates remarkable structural integrity as a LIBs anode, resulting in exceptional electrochemical performance and promising practical applications, as evidenced by tests in pouch-type full cells. Notably, the composite shows outstanding cycling stability, retaining 85% of its initial capacity (713 mAh g-1) even after 3000 cycles at a high current rate of 5000 mA g-1. Additionally, the material achieves a gravimetric energy density of 369 W h kg-1, showcasing its potential for efficient energy storage solutions. This research signifies a significant step toward realizing the practical utilization of Si-based materials in the next generation of LIBs.

The efficacy of suprapatellar, parapatellar and infrapatellar intramedullary nailing in the treatment of tibial fractures: a systematic review and meta-analysis.

BACKGROUND: Tibial fractures are common and challenging orthopedic injuries that are commonly treated with intramedullary nailing techniques via suprapatellar (SP), parapatellar (PP), and infrapatellar (IP) approaches. This study aimed to provide a comprehensive comparative analysis of the efficacy of different treatment approaches based on clinical outcomes. METHODS: We conducted a detailed search in PubMed, Cochrane Library, Embase, and Web of Science for clinical studies comparing suprapatellar, parapatellar, and infrapatellar approaches in intramedullary nailing of tibial fractures. Inclusion criteria included randomized controlled trials and retrospective cohort studies involving patients aged 18 and older, comparing outcomes of these surgical techniques. Exclusion criteria included studies with insufficient data, non-English publications, and those focusing on non-tibial fractures. RESULTS: A total of 15 studies involving 1396 patients were included in meta-analysis. Pooled results indicated that, compared to IP nailing, the SP approach significantly reduced fluoroscopy time (MD = - 35.63, 95% CI - 39.37 to - 31.89, p < 0.001), operative time (MD = - 10.72, 95% CI - 17.30 to - 4.15, p = 0.001), pain scores (SMD = - 1.49, 95% CI - 2.36 to - 0.62, p < 0.001), and improved Lysholm scores (MD = 5.74, 95% CI 3.29 to 8.19, p < 0.001) and malalignment rate (RR = 0.24, 95% CI 0.08 to 0.68, p = 0.008). Quality of life assessments also indicated higher physical component scores for the SP group (MD = 6.68, 95% CI 5.19 to 8.17, p < 0.001). CONCLUSION: The SP approach provides significant intraoperative and postoperative benefits, reducing surgery time and improving patient outcomes in pain management and knee joint function. These findings support the SP approach as a preferred option for surgical treatment of tibial fractures.

Smart delivery vehicles for cancer: categories, unique roles and therapeutic strategies.

Chemotherapy and surgery remain the primary treatment modalities for cancers; however, these techniques have drawbacks, such as cancer recurrence and toxic side effects, necessitating more efficient cancer treatment strategies. Recent advancements in research and medical technology have provided novel insights and expanded our understanding of cancer development; consequently, scholars have investigated several delivery vehicles for cancer therapy to improve the efficiency of cancer treatment and patient outcomes. Herein, we summarize several types of smart therapeutic carriers and elaborate on the mechanism underlying drug delivery. We reveal the advantages of smart therapeutic carriers for cancer treatment, focus on their effectiveness in cancer immunotherapy, and discuss the application of smart cancer therapy vehicles in combination with other emerging therapeutic strategies for cancer treatment. Finally, we summarize the bottlenecks encountered in the development of smart cancer therapeutic vehicles and suggest directions for future research. This review will promote progress in smart cancer therapy and facilitate related research.

Silk Fibroin Microneedles Loaded with Lipopolysaccharide-Pretreated Bone Marrow Mesenchymal Stem Cell-Derived Exosomes for Oral Ulcer Treatment.

Oral ulcers, superficial lesions on the surface of the oral mucosa, have a high incidence rate, and their main symptoms include local pain and erosion. Lipopolysaccharide (LPS)-preconditioned bone marrow mesenchymal stem cells and their secreted exosomes (LPS-pre-Exos) have been shown to promote recovery in various inflammatory conditions and wounds. However, studies documenting LPS-pre-Exos as a therapeutic intervention for oral mucosal-like diseases are lacking. In this study, we prepared a silk fibroin microneedle (MN) patch consisting of LPS-pre-Exos and zeolitic imidazolate framework-8 (ZIF-8) that localized at the tip and base, respectively, and used this MN patch for oral ulcer treatment. Upon insertion into the oral mucosa, continuous LPS-pre-Exos release was observed, which promoted macrophage polarization and tissue healing. Additionally, the ZIF-8 framework in the MN patch facilitated the controlled release of Zn2+, which demonstrated potent antimicrobial properties via synergistic effects. The in vitro experimental results showed that the silk fibroin MN patch can continuously release LPS-pre-Exos and Zn2+ for more than 7 days. Thus, the LPS-pre-Exos and ZIF-8-loaded silk fibroin MN patch exhibited good anti-inflammatory and antibacterial properties, promoting oral ulcer healing, and showed good histocompatibility. Hence, it may represent a potentially valuable strategy for facilitating oral ulcer healing.

Structure Evolution of 2D Covalent Organic Frameworks Unveiled by Single-Crystal X-ray Diffraction.

We report 9 crystal structures of a two-dimensional (2D) covalent organic framework (COF), including the parent Py-1P, 5 derivatives formed by chemical reactions, and 3 dynamic states by solvent exchange/loss. Structure details of these porous crystals, including stacking mode, interlayer distance, pore aperture, and incline angle, before, during, and after conversion processes in solution, were unveiled by single-crystal X-ray diffraction with resolutions up to 0.85 Å. The structure evolution is triggered by stepwise conformational transformation of the molecular building blocks in 2D COF, while their long-range ordering remained unsacrificed.

A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

THOC6 is a novel biomarker of glioma and a target of anti-glioma drugs: An analysis based on bioinformatics and molecular docking.

Glioma is a typical malignant tumor of the nervous system. It is of great significance to identify new biomarkers for accurate diagnosis of glioma. In this context, THOC6 has been studied as a highly diagnostic prognostic biomarker, which contributes to improve the dilemma in diagnosing gliomas. We used online databases and a variety of statistical methods, such as Wilcoxon rank sum test, Dunn test and t test. We analyzed the mutation, location and expression profile of THOC6, revealing the network of THOC6 interaction with disease. Wilcoxon rank sum test showed that THOC6 is highly expressed in gliomas (P < 0.001). Dunn test, Wilcoxon rank sum test and t test showed that THOC6 expression was correlated with multiple clinical features. Logistic regression analysis further confirmed that THOC6 gene expression was a categorical dependent variable related to clinical features of poor prognosis. Kaplan-Meier survival analysis showed that the overall survival (OS) of glioma patients with high expression of THOC6 was poor (P < 0.001). Both univariate (P < 0.001) and multivariate (P = 0.04) Cox analysis confirmed that THOC6 gene expression was an independent risk factor for OS in patients with glioma. ROC curve analysis showed that THOC6 had a high diagnostic value in glioma (AUC = 0.915). Based on this, we constructed a nomogram to predict patient survival. Enrichment analysis showed that THOC6 expression was associated with multiple signal pathways. Immuno-infiltration analysis showed that the expression of THOC6 in glioma was closely related to the infiltration level of multiple immune cells. Molecular docking results showed that THOC6 might be the target of anti-glioma drugs. THOC6 is a novel diagnostic factor and prognostic biomarker of glioma.

Pt-Ru bimetallic nanoclusters with peroxidase-like activity for antibacterial therapy.

Drug-resistant bacteria arising from antibiotic abuse infections have always been a serious threat to human health. Killing bacteria with toxic reactive oxygen species (ROS) is an ideal antibacterial method for treating drug-resistant bacterial infections. Here, we prepared Pt-Ru bimetallic nanoclusters (Pt-Ru NCs) with higher peroxidase (POD)-like activity than Pt monometallic nanoclusters. Pt-Ru can easily catalyze the decomposition of H2O2 to produce ·OH, thereby catalyzing the transformation of 3,3',5,5'-tetramethylbiphenylamine (TMB) to blue oxidized TMB (oxTMB). We utilized the POD-like activity of the Pt-Ru NCs for antibacterial therapy. The results showed that at doses of 40 µg/mL and 16 µg/mL, the Pt-Ru NCs exhibited extraordinary antibacterial activity against E. coli and S. aureus, demonstrating the enormous potential of Pt-Ru NCs as antibacterial agents.

Actinomyces as a rare cause of appendicitis: a case report.

Actinomycosis remains a rare and often underdiagnosed cause of appendicitis with only 10% of cases diagnosed prior to surgery. It is an important cause to consider particularly in the setting of an indolent infection with nonspecific symptoms. We present a 22 years old male who presented with 3 weeks history of lower abdominal pain who underwent laboratory investigations and imaging studies suggestive of acute appendicitis. He underwent an emergency laparoscopic caecectomy with histopathology of the specimen suggestive of actinomycosis. He recovered well postoperatively and was discharged home with a prolonged course of oral penicillins. Preoperative diagnosis of actinomycosis is uncommon and accounts for ~10% of cases. Definitive diagnosis is usually through histopathology or tissue/fluid culture. Treatment usually involves a combination of surgical resection and antibiotic therapy with a success rate of >90%.

Developing Chinese herbal-based functional biomaterials for tissue engineering.

The role of traditional Chinese medicine (TCM) in treating diseases is receiving increasing attention. Chinese herbal medicine is an important part of TCM with various applications and the active ingredients extracted from Chinese herbal medicines have physiological and pathological effects. Tissue engineering combines cell biology and materials science to construct tissues or organs in vitro or in vivo. TCM has been proposed by the World Health Organization as an effective treatment modality. In recent years, the potential use of TCM in tissue engineering has been demonstrated. In this review, the classification and efficacy of TCM active ingredients and delivery systems are discussed based on the TCM theory. We also summarized the current application status and broad prospects of Chinese herbal active ingredients in different specialized biomaterials in the field of tissue engineering. This review provides novel insights into the integration of TCM and modern Western medicine through the application of Chinese medicine in tissue engineering and regenerative medicine.

Multi-omics insights into biogeochemical responses to organic matter addition in an acidic pit lake: Implications for bioremediation.

Acidic pit lakes (APLs) emerge as reservoirs of acid mine drainage in flooded open-pit mines, representing extreme ecosystems and environmental challenges worldwide. The bioremediation of these oligotrophic waters necessitates the addition of organic matter, but the biogeochemical response of APLs to exogenous organic matter remains inadequately comprehended. This study delves into the biogeochemical impacts and remediation effects of digestate-derived organic matter within an APL, employing a multi-omics approach encompassing geochemical analyses, amplicon and metagenome sequencing, and ultra-high resolution mass spectrometry. The results indicated that digestate addition first stimulated fungal proliferation, particularly Ascomycetes and Basidiomycetes, which generated organic acids through lignocellulosic hydrolysis and fermentation. These simple compounds further supported heterotrophic growth, including Acidiphilium, Acidithrix, and Clostridium, thereby facilitating nitrate, iron, and sulfate reduction linked with acidity consumption. Nutrients derived from digestate also promoted the macroscopic development of acidophilic algae. Notably, the increased sulfate reduction-related genes primarily originated from assimilatory metabolism, thus connecting sulfate decrease to organosulfur increase. Assimilatory and dissimilatory sulfate reduction collectively contributed to sulfate removal and metal fixation. These findings yield multi-omics insights into APL biogeochemical responses to organic matter addition, enhancing the understanding of carbon-centered biogeochemical cycling in extreme ecosystems and guiding organic amendment-based bioremediation in oligotrophic polluted environments.

Multifunctional hyaluronic acid/gelatin methacryloyl core-shell microneedle for comprehensively treating oral mucosal ulcers.

Oral ulceration is the most common oral mucosal disease. Oral mucosal ulcers are extremely painful, may interfere with eating and speaking, and potentially complicate systemic symptoms in severe cases. The humid and highly dynamic environment of the oral cavity makes local drug administration for treating oral mucosal ulcers challenging. To overcome these challenges, we designed and prepared a novel dissolving microneedle (MN) patch containing multiple drugs in a core-shell to promote oral ulcer healing. The MNs contained a methacrylate gelatin shell layer of basic fibroblast growth factor (bFGF), a hyaluronic acid (HA) core loaded with dexamethasone (DXMS), and zeolite imidazoline framework-8 (ZIF-8) encapsulated in the HA-based backplane. Progressive degradation of gelatin methacryloyl (GelMA) from the tip of the MN patch in the oral mucosa resulted in sustained bFGF release at the lesion site, significantly promoting cell migration, proliferation, and angiogenesis. Moreover, the rapid release of HA and, subsequently, DXMS inhibited inflammation, and the remaining MN backing after the tip dissolved behaved as a dressing, releasing ZIF-8 for its antimicrobial effects. This novel, multifunctional, transmucosal core-shell MN patch exhibited excellent anti-inflammatory, antimicrobial, and pro-healing effects in vivo and in vitro, suggesting that it can promote oral ulcer healing.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

DNA Image Cytometry for Screening the Carcinogenetic Risk of Oral Potential Malignant Disorders.

Background: Oral Submucosal Fibrosis (OSF) and Oral Leukoplakia (OLK) are well-known oral potentially malignant disorders, and cases of Oral Submucosal Fibrosis concomitant Oral Leukoplakia (OSF+OLK) are now being reported clinically. DNA image cytometry is an objective and non-invasive method for monitoring the risk of precancerous lesions in the oral cavity. Methods: A total of 111 patients with clinically characterized oral mucosal lesions underwent simultaneous and independent histopathological and DNA imaging cytometry assessments. Clinical data were also collected for each patient. Results: The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.003) for OLK. The frequency of DNA content abnormality was higher in the tongue than in other oral sites (P = 0.035) for OSF+OLK. The differences of DNA content abnormality in age, sex, dietary habit, smoking, and alcohol intake were not observed in OLK and OSF+OLK. The study indicates an association between DNA content abnormality and pathological examination in OSF+OLK ( χ2 test, P = 0.007). OLK showed higher sensitivity and specificity than OSF, while the sensitivity and specificity of OSF+OLK are higher than OLK only and OSF only. Conclusion: DNA image cytometry can be utilized as an adjunctive device for the initial detection of oral potentially malignant disorders that require further clinical management.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

Pelvic arteriovenous malformation causing per rectal haemorrhage - A case report.

INTRODUCTION AND IMPORTANCE: We present the case of a 17 years old girl with per rectal haemorrhage secondary to pelvic arteriovenous malformations (AVM) and potentially haemorrhoids. Pelvic AVMs are rare and extremely variable in their clinical presentation, size and location and pose a therapeutic challenge. Focus has turned towards interventional radiological procedures with angioembolisation as the main treatment form for pelvic AVMs. CASE PRESENTATION: A 17 years old girl presented to a rural hospital with significant per rectal bleeding requiring transfer to a tertiary centre with interventional radiology capabilities. Diagnostic imaging determined the presence of a pelvic AVM as well as haemorrhoid. She had no prior history of haemorrhoids, per rectal bleeding or per vaginal bleeding. Further diagnostic imaging including a digital subtraction angiography and MRI pelvis was performed and her case was discussed at a multidisciplinary meeting where the decision was made for angioembolisation of a large right rectal AVM as well as precautionary banding of haemorrhoids that had developed secondary to outflow obstruction. A repeat CT mesenteric angiogram a month later demonstrated diminished appearances of the rectal AVM. CLINICAL DISCUSSION: Pelvic AVMs are a rare entity and are not a common cause for per rectal bleeding. There is currently no direct consensus on the optimum management of complex pelvic AVMs particularly those that present with a second pathology such as haemorrhoids. Surgical management often results in recurrence or rapid progression of the AVM lesion and recruitment of new blood supply further complicates the problem. Selective embolisation allows for control of haemorrhage and utilises chemical agents as well as detachable coils and balloons. However, postoperative pain and swelling can still be expected and multiple transcatheter embolisations may be required. CONCLUSION: The treatment of symptomatic pelvic AVMs is complex and requires a multidisciplinary approach with careful radiological planning prior to embolisation. Angioembolisation is becoming increasingly prevalent and multiple embolisation procedures may be required to reach the desired therapeutic effect.

Multifunctional polysaccharide composited microneedle for oral ulcers healing.

Oral ulcers have periodicity and recurrence, and the etiology and causative mechanisms remain unclear; therefore, it is difficult to treat oral ulcers effectively. Current clinical treatment methods mainly include pain relief and administration of anti-inflammatories to prevent secondary infections and a prolonged recurrence cycle. However, these traditional treatment methods are administered independently and are susceptible to muscle movements and constant salivary secretion in the mouth, resulting in ineffective drug functioning. Therefore, development of a novel treatment to reduce wound infection and accelerate wound healing for oral ulcers is required for effective treatment. Herein, we report a multifunctional polysaccharide composite microneedle patch based on hyaluronic acid (HA) and hydroxypropyl trimethyl ammonium chloride chitosan (HACC) loaded with dexamethasone (DXMS) and basic fibroblast growth factor (bFGF) for oral ulcer healing. DXMS and bFGF encapsulated the HA tip portion of the microneedle patch, endowing the microneedle patches with anti-inflammatory and angiogenic properties. HACC was applied to the back of the microneedle patch, adding antibacterial properties. The experimental results indicated that the prepared dressings exhibited good antibacterial activity and effectively promoted cell migration growth and angiogenesis. More importantly, animal experiments have shown that multifunctional microneedle patches can effectively promote oral ulcer healing. Thus, these novel multifunctional polysaccharide composite microneedle patches have great potential for oral ulcers treatment.

Recent Advances in Anti-Atherosclerosis and Potential Therapeutic Targets for Nanomaterial-Derived Drug Formulations.

Atherosclerosis, the leading cause of death worldwide, is responsible for ≈17.6 million deaths globally each year. Most therapeutic drugs for atherosclerosis have low delivery efficiencies and significant side effects, and this has hampered the development of effective treatment strategies. Diversified nanomaterials can improve drug properties and are considered to be key for the development of improved treatment strategies for atherosclerosis. The pathological mechanisms underlying atherosclerosis is summarized, rationally designed nanoparticle-mediated therapeutic strategies, and potential future therapeutic targets for nanodelivery. The content of this study reveals the potential and challenges of nanoparticle use for the treatment of atherosclerosis and highlights new effective design ideas.