Anatomic femoral tunnel and satisfactory clinical outcomes achieved with the modified transtibial technique in anterior cruciate ligament reconstruction: A systematic review and meta-analysis.

Background: Anatomic anterior cruciate ligament (ACL) reconstruction is considered the gold standard treatment for ACL injuries because it aims to restore the knee's normal anatomy and stability, while also protecting long-term knee health. Long-term clinical and radiological outcomes after ACL reconstruction using the modified TT technique are unclear. Objective: To assess the clinical and radiological outcomes following ACL reconstruction using modified transtibial (TT) techniques at a minimum 12-month follow-up. Design: A systematic review with meta-analysis. Methods: PubMed, EMBASE, Web of Science, the Cochrane Library, and MEDLINE databases were searched from the inception to December 1, 2022. PICO search strategy was used to identify studies applying modified TT techniques on patients with ACL reconstruction and a minimum follow-up of 12 months. Eligible studies were identified independently by two reviewers. We extracted data on patient demographics, surgical characteristics, patient reported outcomes including subjective evaluations and clinical outcomes. Radiological data including femoral and tibial tunnel position, femoral and tibial tunnel length, and femoral tunnel angle were also extracted. The tunnel position was evaluated using the quadrant method based on three-dimensional computed tomography (3D CT) images. The standardized mean difference (SMD) and 95 % confidence interval (CI) were calculated for clinical and radiological outcomes. Results: Sixteen studies involving 628 patients were finally included. The SMD of Lysholm (90.39; 95 % CI 83.41-97.38), IKDC (86.07; 95 % CI 79.84-92.31), and Tegner (6.15; 95 % CI 3.96-8.33) scores were considered satisfactory. The depth of the femoral tunnel showed a pooled SMD of 30.08 % (95 % CI 28.25-31.91 %), and the height showed a pooled SMD of 37.72 % (95 % CI 35.75-39.70 %). The pooled SMD for the femoral tunnel angle in the coronal plane was 48.27°(95 % CI 43.14-53.40°), and the pooled SMD for the femoral tunnel length was 33.98 mm (95 % CI 29.03-38.93 mm). Conclusions: This investigation has shown that modified TT technique can create an anatomic femoral tunnel and maintain optimal tunnel length and angulation. Most patients had satisfactory subjective outcomes and physical examinations after ACL reconstruction using modified TT technique. This information may assist in guiding expectations of clinicians and patients following ACL reconstruction with modified TT technique.

Cucurbitacin B and Its Derivatives: A Review of Progress in Biological Activities.

The emergence of natural products has provided extremely valuable references for the treatment of various diseases. Cucurbitacin B, a tetracyclic triterpenoid compound isolated from cucurbitaceae and other plants, is the most abundant member of the cucurbitin family and exhibits a wide range of biological activities, including anti-inflammatory, anti-cancer, and even agricultural applications. Due to its high toxicity and narrow therapeutic window, structural modification and dosage form development are necessary to address these issues with cucurbitacin B. This paper reviews recent research progress in the pharmacological action, structural modification, and application of cucurbitacin B. This review aims to enhance understanding of advancements in this field and provide constructive suggestions for further research on cucurbitacin B.

Arabidopsis F-box proteins D5BF1 and D5BF2 negatively regulate Agrobacterium-mediated transformation and tumorigenesis.

The pathogen Agrobacterium tumefaciens is known for causing crown gall tumours in plants. However, it has also been harnessed as a valuable tool for plant genetic transformation. Apart from the T-DNA, Agrobacterium also delivers at least five virulence proteins into the host plant cells, which are required for an efficient infection. One of these virulence proteins is VirD5. F-box proteins, encoded in the host plant genome or the Ti plasmid, and the ubiquitin/26S proteasome system (UPS) also play an important role in facilitating Agrobacterium infection. Our study identified two Arabidopsis F-box proteins, D5BF1 and D5BF2, that bind VirD5 and facilitate its degradation via the UPS. Additionally, we found that Agrobacterium partially suppresses the expression of D5BF1 and D5BF2. Lastly, stable transformation and tumorigenesis efficiency assays revealed that D5BF1 and D5BF2 negatively regulate the Agrobacterium infection process, showing that the plant F-box proteins and UPS play a role in defending against Agrobacterium infection.

Ensemble Algorithm for Risk Prediction of Clinical Failure After Anterior Cruciate Ligament Reconstruction.

Background: Patient-specific risk profiles of clinical failure after anterior cruciate ligament reconstruction (ACLR) are meaningful for preoperative surgical planning and postoperative rehabilitation guidance. Purpose: To create an ensemble algorithm machine learning (ML) model and ML-based web-based tool that can predict the patient-specific risk of clinical failure after ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: Included were 432 patients (mean age, 26.8 ± 8.4 years; 74.1% male) who underwent anatomic double-bundle ACLR with hamstring tendon autograft between January 2010 and February 2019. The primary outcome was the probability of clinical failure at a minimum 2-year follow-up. The authors included 24 independent variables for feature selection and model development. The data set was split randomly into training sets (75%) and test sets (25%). Models were built using 4 ML algorithms: extreme gradient boosting, random forest, light gradient boosting machine, and adaptive boosting. In addition, a weighted-average voting (WAV) ensemble model was constructed using the ensemble-voting technique to predict clinical failure after ACLR. Concordance (area under the receiver operating characteristic curve [AUC]), calibration, and decision curve analysis were used to evaluate predictive performances of the 5 models. Results: Clinical failure occurred in 73 of the 432 patients (16.9%). The 8 most important predictors for clinical failure were follow-up period, high-grade preoperative knee laxity, time from injury to ACLR, participation in competitive sports, posterior tibial slope, graft diameter, age at surgery, and medial meniscus resection. The WAV ensemble algorithm achieved the best predictive performance based on concordance (AUC, 0.9139), calibration (calibration intercept, -0.1806; calibration slope, 1.2794; Brier score, 0.0888), and decision curve analysis (greatest net benefits) and was used to develop an web-based application to predict a patient's clinical failure risk of ACLR. Conclusion: The WAV ensemble algorithm was able to accurately predict patient-specific risk of clinical failure after ACLR. Clinicians and patients can use the web-based application during preoperative consultation to understand individual prediction outcomes.

Independent Risk Factors Associated With Venous Thromboembolism After Knee Arthroscopy: A Retrospective Study of 222 Patients.

Background: A serious complication after knee arthroscopy is venous thromboembolism (VTE), which includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). However, asymptomatic VTE is frequently undetected. Purpose: To (1) report the incidence of VTE after knee arthroscopy using ultrasound examination and computed tomography pulmonary angiography (CTPA) and (2) discover the independent risk factors of VTE after knee arthroscopy and determine the corresponding cutoff values of these indicators. Study Design: Case-control study; Level of evidence, 3. Methods: Included were 222 patients (115 male) who underwent arthroscopic knee procedures between October 2022 and January 2023. Baseline characteristics, blood test results, and VTE assessments were collected. During the 2-week follow-up, routine lower extremity vascular ultrasound was applied for DVT measurement, with CTPA evaluation for suspected PE. Patients were allocated into VTE and no-VTE groups, and descriptive statistics were used to analyze baseline data. Logistic regression analysis was used to determine the correlation between binary variables and the presence of postoperative VTE. Multivariate logistic regression analysis was further performed to determine the independent risk factors of VTE. Results: Of the 222 patients, 37 (16.7%) had DVT and 1 (0.5%) had both DVT and PE. Compared to the no-VTE group, the VTE group was significantly older, with more female patients; higher body mass index (BMI) and postoperative D-dimer level; and higher rates of hypertension, hyperlipidemia, varicose veins of the lower extremity, and abnormal postoperative fibrin degradation product level (P≤ .043 for all). Notably, operative time >20 minutes was not significantly associated with postoperative VTE (P = .513). The independent risk factors for VTE included age >32 years (odds ratio [OR], 20.71 [95% CI, 4.40-97.47]; P < .001), BMI >23 kg/m2 (OR, 3.52 [95% CI, 1.11-11.14]; P = .032), hyperlipidemia (OR, 6.81 [95% CI, 1.86-24.88]; P = .004), and postoperative D-dimer level >0.63 mg/L (OR, 34.01 [95% CI, 7.36-157.07]; P < .001). Conclusion: The incidence of VTE after knee arthroscopy was 16.7% at the 2-week follow-up. Age >32 years, BMI >23 kg/m2, hyperlipidemia, and postoperative D-dimer >0.63 mg/L were independent risk factors of postoperative VTE within 2 weeks after knee arthroscopy. For patients with knee arthroscopy, the cutoff value of postoperative D-dimer for VTE was found to be 0.63 mg/L for timely intervention.

Endogenous capsid-forming protein ARC for self-assembling nanoparticle vaccines.

The application of nanoscale scaffolds has become a promising strategy in vaccine design, with protein-based nanoparticles offering desirable avenues for the biocompatible and efficient delivery of antigens. Here, we presented a novel endogenous capsid-forming protein, activated-regulated cytoskeleton-associated protein (ARC), which could be engineered through the plug-and-play strategy (SpyCatcher3/SpyTag3) for multivalent display of antigens. Combined with the self-assembly capacity and flexible modularity of ARC, ARC-based vaccines elicited robust immune responses against Mpox or SARS-CoV-2, comparable to those induced by ferritin-based vaccines. Additionally, ARC-based nanoparticles functioned as immunostimulants, efficiently stimulating dendritic cells and facilitating germinal center responses. Even without adjuvants, ARC-based vaccines generated protective immune responses in a lethal challenge model. Hence, this study showed the feasibility of ARC as a novel protein-based nanocarrier for multivalent surface display of pathogenic antigens and demonstrated the potential of exploiting recombinant mammalian retrovirus-like protein as a delivery vehicle for bioactive molecules.

Preclinical Efficacy of Cap-Dependent and Independent mRNA Vaccines against Bovine Viral Diarrhea Virus-1.

Bovine viral diarrhea virus (BVDV) is an RNA virus associated with severe economic losses in animal production. Effective vaccination and viral surveillance are urgent for the prevention and control of BVDV infection. However, the application of traditional modified live vaccines and inactivated vaccines is faced with tremendous challenges. In the present study, we describe the preclinical efficacy of two BVDV mRNA vaccines tested in mice and guinea pigs, followed by a field trial in goats, where they were compared to a commercial vaccine (formaldehyde inactivated). The two mRNAs were engineered to express the envelope protein E2 of BVDV-1, the most prevalent subtype across the world, through a 5' cap-dependent or independent fashion. Better titers of neutralizing antibodies against BVDV-1 were achieved using the capped RNA in the sera of mice and guinea pigs, with maximum values reaching 9.4 and 13.7 (by -log2), respectively, on the 35th day post-vaccination. At the same time point, the antibody levels in goats were 9.1 and 10.2 for the capped and capless RNAs, respectively, and there were no significant differences compared to the commercial vaccine. The animals remained healthy throughout the experiment, as reflected by their normal leukogram profiles. Collectively, our findings demonstrate that mRNA vaccines have good safety and immunogenicity, and we laid a strong foundation for the further exploitation of efficient and safe BVDV vaccines.

SARS-CoV-2 spike-induced syncytia are senescent and contribute to exacerbated heart failure.

SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.

Inositol 1,4,5-Trisphosphate Receptors Regulate Vascular Smooth Muscle Cell Proliferation and Neointima Formation in Mice.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation is involved in many types of arterial diseases, including neointima hyperplasia, in which Ca2+ has been recognized as a key player. However, the physiological role of Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3Rs) from endoplasmic reticulum in regulating VSMC proliferation has not been well determined. METHODS AND RESULTS: Both in vitro cell culture models and in vivo mouse models were generated to investigate the role of IP3Rs in regulating VSMC proliferation. Expression of all 3 IP3R subtypes was increased in cultured VSMCs upon platelet-derived growth factor-BB and FBS stimulation as well as in the left carotid artery undergoing intimal thickening after vascular occlusion. Genetic ablation of all 3 IP3R subtypes abolished endoplasmic reticulum Ca2+ release in cultured VSMCs, significantly reduced cell proliferation induced by platelet-derived growth factor-BB and FBS stimulation, and also decreased cell migration of VSMCs. Furthermore, smooth muscle-specific deletion of all IP3R subtypes in adult mice dramatically attenuated neointima formation induced by left carotid artery ligation, accompanied by significant decreases in cell proliferation and matrix metalloproteinase-9 expression in injured vessels. Mechanistically, IP3R-mediated Ca2+ release may activate cAMP response element-binding protein, a key player in controlling VSMC proliferation, via Ca2+/calmodulin-dependent protein kinase II and Akt. Loss of IP3Rs suppressed cAMP response element-binding protein phosphorylation at Ser133 in both cultured VSMCs and injured vessels, whereas application of Ca2+ permeable ionophore, ionomycin, can reverse cAMP response element-binding protein phosphorylation in IP3R triple knockout VSMCs. CONCLUSIONS: Our results demonstrated an essential role of IP3R-mediated Ca2+ release from endoplasmic reticulum in regulating cAMP response element-binding protein activation, VSMC proliferation, and neointima formation in mouse arteries.

Near Ultraviolet-Excitable Cyan-Emissive Hybrid Copper(I) Halides Nonlinear Optical Crystals with Near-Unity Photoluminescence Quantum Yield and High-Efficiency X-ray Scintillation.

Designing and synthesizing multifunctional hybrid copper halides with near ultraviolet (NUV) light-excited high-energy emission (<500 nm) remains challenging. Here, a pair of broadband-excited high-energy emitting isomers, namely, α-/ß-(MePh3P)2CuI3 (MePh3P=methyltriphenylphosphonium), were synthesized. α-(MePh3P)2CuI3 with blue emission peaking at 475 nm is firstly discovered wherein its structure contains regular [CuI3]2- triangles and crystallizes in centrosymmetric space group P21/c. While ß-(MePh3P)2CuI3 featuring distorted [CuI3]2- planar triangles shows inversion symmetry breaking and crystallizes in the noncentrosymmetric space group P21, which exhibits cyan emission peaking at 495 nm with prominent near-unity photoluminescence quantum yield and the excitation band ranging from 200 to 450 nm. Intriguingly, ß-(MePh3P)2CuI3 exhibits phase-matchable second-harmonic generation response of 0.54×KDP and a suitable birefringence of 0.06@1064 nm. Furthermore, ß-(MePh3P)2CuI3 also can be excited by X-ray radioluminescence with a high scintillation light yield of 16193 photon/MeV and an ultra-low detection limit of 47.97 nGy/s, which is only 0.87 % of the standard medical diagnosis (5.5 µGy/s). This work not only promotes the development of solid-state lighting, laser frequency conversion and X-ray imaging, but also provides a reference for constructing multifunctional hybrid metal halides.

Revealing the effect of sea buckthorn oil, fish oil and structured lipid on intestinal microbiota, colonic short chain fatty acid composition and serum lipid profiles in vivo.

In this study, the effects of sea buckthorn oil (SBO), fish oil (FO) and an enzymatically synthesized structured lipid (SL) on serum, short-chain fatty acids (SCFAs) and intestinal microbiota in Sprague-Dawley (SD) rats were investigated. The results demonstrated that FO, SBO, and SL effectively reduced the levels of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in the serum of SD rats. SBO increased serum triglyceride levels, while FO elevated total cholesterol levels. Furthermore, all three dietary lipids decreased short-chain fatty acid production and enhanced intestinal microbiota diversity. FO increased the abundance of intestinal microbiota including Romboutsia, Lactobacillus, Escherichia-Shigella, and Lachnospiraceae_NK4A136_group. Conversely, all three dietary lipids reduced the abundance of Klebsiella and Blautia. These findings provide a foundation for understanding the functionality of SBO and FO as well as their potential application in synthesizing novel SLs to regulate intestinal microbiota.

A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release.

Neurotransmitter release is triggered in microseconds by Ca2+-binding to the Synaptotagmin-1 C2 domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca2+-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C2B domain to SNARE complexes through a 'primary interface' comprising two regions (I and II). The Synaptotagmin-1 Ca2+-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but SNARE complex binding orients the Ca2+-binding loops away from the fusion site, hindering these putative activities. Molecular dynamics simulations now suggest that Synaptotagmin-1 C2 domains near the site of fusion hinder SNARE action, providing an explanation for this paradox and arguing against previous models of Sytnaptotagmin-1 action. NMR experiments reveal that binding of C2B domain arginines to SNARE acidic residues at region II remains after disruption of region I. These results and fluorescence resonance energy transfer assays, together with previous data, suggest that Ca2+ causes reorientation of the C2B domain on the membrane and dissociation from the SNAREs at region I but not region II. Based on these results and molecular modeling, we propose that Synaptotagmin-1 acts as a lever that pulls the SNARE complex when Ca2+ causes reorientation of the C2B domain, facilitating linker zippering and fast membrane fusion. This hypothesis is supported by the electrophysiological data described in the accompanying paper.

Combining GC-MS/MS with a LLE-SPE sample pretreatment step to simultaneously analyse enrofloxacin and ofloxacin residues in chicken tissues and pork.

A widely applicable original gas chromatography-tandem mass spectrometry (GC-MS/MS) method was explored to qualitatively and quantitatively measure enrofloxacin and ofloxacin residues in chicken tissues and pork. The experimental samples were processed based on liquid-liquid extraction (LLE) and solid-phase extraction (SPE). Trimethylsilyl diazomethane (TMSD) was chosen to react derivatively with enrofloxacin and ofloxacin. In total, 78.25% âˆ¼ 90.56% enrofloxacin and 78.43% âˆ¼ 91.86% ofloxacin was recovered from the blank fortified samples. The limits of detection (LODs) were 0.7-1.0 µg/kg and 0.1-0.2 µg/kg, respectively. The limits of quantitation (LOQs) were 1.6-1.9 µg/kg and 0.3-0.4 µg/kg, respectively. It was verified that various experimental data met the requirements of the FAO & WHO (2014) for the detection of veterinary drug residues. Real samples obtained from local markets were analysed using the established method, and no residues of enrofloxacin or ofloxacin were detected in the samples.

Dynamic patterns of carbohydrate metabolism genes in bacterioplankton during marine algal blooms.

Carbohydrates play a pivotal role in nutrient recycling and regulation of algal-bacterial interactions. Despite their ecological significance, the intricate molecular mechanisms governing regulation of phycosphere carbohydrates by bacterial taxa linked with natural algal bloom have yet to be fully elucidated. Here, a comprehensive temporal metagenomic analysis was conducted to explore the carbohydrate-active enzyme (CAZyme) genes in two discrete algal bloom microorganisms (Gymnodinium catenatum and Phaeocystis globosa) across three distinct bloom stages: pre-bloom, peak bloom, and post-bloom. Elevated levels of extracellular carbohydrates, primarily rhamnose, galactose, glucose, and arabinose, were observed during the initial and post-peak stages. The prominent CAZyme families identified-glycoside hydrolases (GH) and carbohydrate-binding modules (CBMs)-were present in both algal bloom occurrences. In the G. catenatum bloom, GH23/24 and CBM13/14 were prevalent during the pre-bloom and peak bloom stages, whereas GH2/3/30 and CBM12/24 exhibited increased prevalence during the post-bloom phase. In contrast, the P. globosa bloom had a dominance of GH13/23 and CBM19 in the initial phase, and this was succeeded by GH3/19/24/30 and CBM54 in the later stages. This gene pool variation-observed distinctly in specific genera-highlighted the dynamic structural shifts in functional resources driven by temporal alterations in available substrates. Additionally, ecological linkage analysis underscored a correlation between carbohydrates (or their related genes) and phycospheric bacteria, hinting at a pattern of bottom-up control. These findings contribute to understanding of the dynamic nature of CAZymes, emphasizing the substantial influence of substrate availability on the metabolic capabilities of algal symbiotic bacteria, especially in terms of carbohydrates.

Optimal tibial tunnel angulation for anatomical anterior cruciate ligament reconstruction using transtibial technique.

Numerous studies have suggested that the primary cause of failure in transtibial anterior cruciate ligament reconstruction (ACLR) is often attributed to non-anatomical placement of the bone tunnels, typically resulting from improper tibial guidance. We aimed to establish the optimal tibial tunnel angle for anatomical ACLR by adapting the transtibial (TT) technique. Additionally, we aimed to assess graft bending angle (GBA) and length changes during in vivo dynamic flexion of the knee. Twenty knee joints underwent a CT scan and dual fluoroscopic imaging system (DFIS) to reproduce relative knee position during dynamic flexion. For the single-legged lunge, subjects began in a natural standing position and flexed the right knee beyond 90° When performing the lunge task, the subject supported the body weight on the right leg, while the left leg was used to keep the balance. The tibial and femoral tunnels were established on each knee using a modified TT technique for single-bundle ACLR. The tibial tunnel angulation to the tibial axis and the sagittal plane were measured. Considering that ACL injuries tend to occur at low knee flexion angles, GBA and graft length were measured between 0° and 90° of flexion in this study. The tibial tunnel angulated the sagittal plane at 42.8° ± 3.4°, and angulated the tibial axis at 45.3° ± 5.1° The GBA was 0° at 90° flexion of the knee and increased substantially to 76.4 ± 5.5° at 0° flexion. The GBA significantly increased with the knee extending from 90° to 0° (p < 0.001). The ACL length was 30.2mm±3.0 mm at 0° flexion and decreased to 27.5mm ± 2.8 mm at 90° flexion (p = 0.072). To achieve anatomic single-bundle ACLR, the optimal tibial tunnel should be angulated at approximately 43° to the sagittal plane and approximately 45° to the tibial axis using the modified TT technique. What's more, anatomical TT ACLR resulted in comparable GBA and a relatively constant ACL length from 0° to 90° of flexion. These findings provide theoretical support for the clinical application and the promotion of the current modified TT technique with the assistance of a robot to achieve anatomical ACLR.

Signaling pathways in liver cancer: pathogenesis and targeted therapy.

Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.

Intra-Articular Platelet-Rich Plasma Injection After Anterior Cruciate Ligament Reconstruction: A Randomized Clinical Trial.

Importance: Platelet-rich plasma (PRP) has been considered a promising treatment for musculoskeletal disorders. The effects of PRP on clinical outcomes of anterior cruciate ligament reconstruction (ACLR) are controversial. Objective: To compare subjective outcomes and graft maturity in patients undergoing ACLR with and without postoperative intra-articular PRP injection. Design, Setting, and Participants: This surgeon- and investigator-masked randomized clinical trial included patients treated at a national medical center in China who were aged 16 to 45 years and scheduled to undergo ACLR. Participants were enrolled between March 21, 2021, and August 18, 2022, and followed up for 12 months, with the last participant completing follow-up on August 28, 2023. Interventions: Participants were randomized 1:1 to the PRP group (n = 60), which received 3 doses of postoperative intra-articular PRP injection at monthly intervals, or to the control group (n = 60), which did not receive postoperative PRP injection. Both groups had the same follow-up schedule. Main Outcomes and Measures: The primary outcome was the mean score for 4 subscales of the Knee Injury and Osteoarthritis Outcome Score (KOOS4) (range, 0-100, with higher scores indicating better knee function and fewer symptoms) at 12 months postoperatively. Secondary outcomes were patient-reported outcomes, graft maturity (on magnetic resonance imaging), and physical examinations at 3, 6, and 12 months. Results: Among the 120 randomized participants (mean [SD] age, 29.0 [8.0] years; 84 males [70%]), 114 (95%) were available for the primary outcome analysis. The mean KOOS4 scores at 12 months were 78.3 (SD, 12.0; 95% CI, 75.2-81.4) in the PRP group and 76.8 (SD, 11.9; 95% CI, 73.7-79.9) in the control group (adjusted mean between-group difference, 2.0; 95% CI, -2.3 to 6.3; P = .36). Secondary outcomes were not statistically significantly different between the 2 groups except for sports and recreation level and graft maturity at 6 months. Intervention-related adverse events included pain at the injection site and knee swelling after injection. Conclusions and Relevance: In this randomized clinical trial among patients undergoing ACLR, the addition of postoperative intra-articular PRP injection did not result in superior improvement of knee symptoms and function at 12 months compared with no postoperative injection. Further studies are required to determine appropriate indications for PRP in musculoskeletal disorders. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000040262.

Melatonin ameliorates 10-hydroxycamptothecin-induced oxidative stress and apoptosis via autophagy-regulated p62/Keap1/Nrf2 pathway in mouse testicular cells.

10-Hydroxycamptothecin (HCPT) is a widely used clinical anticancer drug but has a significant side effect profile. Melatonin has a beneficial impact on the chemotherapy of different cancer cells and reproductive processes, but the effect and underlying molecular mechanism of melatonin's involvement in the HCPT-induced side effects in cells, especially in the testicular cells, are poorly understood. In this study, we found that melatonin therapy significantly restored HCPT-induced testicular cell damage and did not affect the antitumor effect of HCPT. Further analysis found that melatonin therapy suppressed HCPT-induced DNA damage associated with ataxia-telangiectasia mutated- and Rad3-related and CHK1 phosphorylation levels in the testis. Changes in apoptosis-associated protein levels (Bax, Bcl-2, p53, and Cleaved caspase-3) and in reactive oxygen species-associated proteins (Nrf2 and Keap1) and index (malondialdehyde and glutathione) suggested that melatonin treatment relieved HCPT-induced cell apoptosis and oxidative damage, respectively. Mechanistically, melatonin-activated autophagy proteins (ATG7, Beclin1, and LC3bII/I) may induce p62-dependent autophagy to degrade Keap1, eliciting Nrf2 from Keap1-Nrf2 interaction to promote antioxidant enzyme expression such as HO-1, which would salvage HCPT-induced ROS production and mitochondrial dysfunction. Collectively, this study reveals that melatonin therapy may protect testicular cells from HCPT-induced damage via the activation of autophagy, which alleviates oxidative stress, mitochondrial dysfunction, and cell apoptosis.