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Background Systemic conversion therapy provides patients with initially unresectable hepatocellular carcinoma (HCC) the chance to salvage radical liver resection and superior survival outcomes, but the optimal conversion strategy is unclear. Methods A systematic literature search was conducted on PubMed, EMBASE, Web of Science, Scopus, and the Cochrane Library between 2007 and 2024 focusing on studies reporting conversion therapy for HCC. The treatment groups were divided into Tyrosine kinase inhibitors (TKI), TKI plus loco-regional therapy (LRT), TKI plus anti-PD-1 therapy (TKI + PD-1), TKI + PD-1 + LRT, immune checkpoint inhibitors (ICI) plus LRT, and Atezolizumab plus bevacizumab (A + T) groups. The conversion to surgery rate (CSR), objective response rate (ORR), grade ≥ 3 treatment-related adverse events (AEs), overall survival (OS) and progression-free survival (PFS) were analyzed. Results 38 studies and 4,042 patients were included. The pooled CSR were 8% (95% CI, 5-12%) in TKI group, 13% (95% CI, 8-19%) in TKI + LRT group, 28% (95% CI, 19-37%) in TKI + PD-1 group, 33% (95% CI, 25-41%) in TKI + PD-1 + LRT group, 23% (95% CI, 1-46%) in ICI + LRT group, and 5% (95% CI, 3-8%) in A + T group, respectively. The pooled HR for OS (0.45, 95% CI, 0.35–0.60) and PFS (0.49, 95% CI, 0.35–0.70) favored survival benefit of conversion surgery. Subgroup analysis revealed that lenvatinib + PD-1 + LRT conferred higher CSR of 35% (95% CI, 26-44%) and increased ORR of 70% (95% CI, 56-83%). Conclusions The current study indicates that TKI + PD-1 + LRT, especially lenvatinib + PD-1 + LRT, may be the superior conversion therapy with a manageable safety profile for patients with initially unresectable HCC. The successful conversion therapy favors the superior OS and PFS compared with systemic treatment alone. Trial registration International prospective register of systematic reviews (PROSPERO) (registration code: CRD 42024495289).

Background and aim The association between gallstones/cholecystectomy and cancer remains inconclusive in the current literature. This study aimed to explore the causal connections between gallstones/cholecystectomy and cancer risk by utilizing a bidirectional two-sample multivariable Mendelian randomization approach with Genome-Wide Association Studies data. Methods Utilizing Genome-Wide Association Studies data from the UK Biobank and FinnGen, this research employed multivariable Mendelian randomization analyses to explore the impact of gallstones and cholecystectomy on the risk of 33 distinct cancer types. Instrumental variables for gallstones and cholecystectomy were carefully selected to ensure robust analyses, and sensitivity and heterogeneity tests were conducted to verify the findings’ validity. Results Multivariable Mendelian randomization analysis, incorporating data from more than 450,000 individuals for gallstones and cholecystectomy, revealed nuanced associations with cancer risk. Cholecystectomy was associated with a significantly increased risk of nonmelanoma skin cancer (OR = 1.59, 95% CI: 1.21 to 2.10, P  = 0.001), while gallstones were linked to a decreased risk of the same cancer type (OR = 0.63, 95% CI: 0.47 to 0.84, P  = 0.002). Interestingly, the analysis also suggested that cholecystectomy may lower the risk of small intestine tumors (OR = 0.18, 95% CI: 0.043 to 0.71, P  = 0.015), with gallstones showing an inverse relationship, indicating an increased risk (OR = 6.41, 95% CI: 1.48 to 27.80, P  = 0.013). Conclusions The multivariable Mendelian randomization analysis highlights the differential impact of gallstones and cholecystectomy on cancer risk, specifically for nonmelanoma skin cancer and small intestine tumors. These results underscore the importance of nuanced clinical management strategies and further research to understand the underlying mechanisms and potential clinical implications of gallstone disease and cholecystectomy on cancer risk. Study Highlights What is known 1. Gallstone disease is a prevalent disorder of the gastrointestinal system that contributes significantly to healthcare expenditures annually. 2. Previous studies have reported inconsistent findings regarding the association between gallstones/cholecystectomy and various extrabiliary malignancies. What is new here 1. In this study, multivariate Mendelian analysis revealed intricate and nuanced causal relationships between gallstones/cholecystectomy and pan-cancers, particularly extrabiliary tumors. 2. The study demonstrated that gallstone diseases were associated with a reduced risk of nonmelanoma (OR = 0.63, 95% CI: 0.47 to 0.84, P  = 0.002), while cholecystectomy increased the risk (OR = 1.59, 95% CI: 1.21 to 2.10, P  = 0.001). 3.The findings indicated that gallstone disease increased the risk of small intestinal neoplasms (OR = 6.41, 95% CI: 1.48 to 27.80, P  = 0.013), whereas cholecystectomy decreased the risk (OR = 0.18, 95% CI: 0.043 to 0.71, P  = 0.015).

Gut microbiota can regulate the metabolic and immunological aspects of ischemic stroke and modulate the treatment effects. The present study aimed to identify specific changes in gut microbiota in patients with large vessel occlusion (LVO) ischemic stroke and assess the potential association between gut microbiota and clinical features of ischemic stroke. A total of 63 CSVD patients, 64 cerebral small vessel disease (CSVD) patients, and 36 matching normal controls (NCs) were included in this study. The fecal samples were collected for all participants and analyzed for gut microbiota using 16S rRNA gene sequencing technology. The abundances of five gut microbiota, including genera Bifidobacterium, Butyricimonas, Blautia, and Dorea and species Bifidobacterium_longum, showed significant changes with high specificity in the LVO patients as compared to the NCs and CSVD patients. In LVO patients, the genera Bifidobacterium and Blautia and species Bifidobacterium_longum were significantly correlated with the National Institutes of Health Stroke Scale (NIHSS) scores at the admission and discharge of the patients. Serum triglyceride levels could significantly affect the association of the abundance of genus Bifidobacterium and species Bifidobacterium_longum with the NIHSS scores at admission and modified Rankin Scale (mRS) at discharge in LVO patients. The identification of five gut microbiota with high specificity were identified in the early stage of LVO stroke, which contributed to performed an effective clinical management for LVO ischemic stroke.

Anxiety is one of the most common psychiatric symptoms of Parkinson's disease (PD), and brain iron deposition is considered to be one of the pathological mechanisms of PD. The objective of this study was to explore alterations in brain iron deposition in PD patients with anxiety compared to PD patients without anxiety, especially in the fear circuit. Sixteen PD patients with anxiety, 23 PD patients without anxiety, and 26 healthy elderly controls were enrolled prospectively. All subjects underwent neuropsychological assessments and brain magnetic resonance imaging (MRI) examinations. Voxel-based morphometry (VBM) was used to study morphological brain differences between the groups. Quantitative susceptibility mapping (QSM), an MRI technique capable of quantifying susceptibility changes in brain tissue, was used to compare susceptibility changes in the whole brain among the three groups. The correlations between brain susceptibility changes and anxiety scores quantified using the Hamilton Anxiety Rating Scale (HAMA) were compared and analyzed. PD patients with anxiety had a longer duration of PD and higher HAMA scores than PD patients without anxiety. No morphological brain differences were observed between the groups. In contrast, voxel-based and ROI-based QSM analyses showed that PD patients with anxiety had significantly increased QSM values in the medial prefrontal cortex, anterior cingulate cortex, hippocampus, precuneus, and angular cortex. Furthermore, the QSM values of some of these brain regions were positively correlated with the HAMA scores (medial prefrontal cortex:  = 0.255,  = 0.04; anterior cingulate cortex:  = 0.381,  < 0.01; hippocampus:  = 0.496,  < 0.01). Our findings support the idea that anxiety in PD is associated with iron burden in the brain fear circuit, providing a possible new approach to explaining the potential neural mechanism of anxiety in PD.

Hepatocellular carcinoma (HCC) is the sixth most common primary cancer with an unsatisfactory long-term survival. Gain of function mutations of PIK3CA occur in a subset of human HCC. Alpelisib, a selective PIK3CA inhibitor, has been approved by the FDA to treat PIK3CA mutant breast cancers. In this manuscript, we evaluated the therapeutic efficacy of alpelisib, either alone or in combination, for the treatment of HCC. We tested alpelisib in mouse HCC induced by hydrodynamic injection of c-Met/PIK3CA(H1047R) (c-Met/H1047R), c-Met/PIK3CA(E545K) (c-Met/E545K), and c-Met/sgPten gene combinations. Alpelisib slowed down the growth of c-Met/H1047R and c-Met/E545K HCC but was ineffective in c-Met/sgPten HCC. Mechanistically, alpelisib inhibited p-ERK and p-AKT in c-Met/H1047R and c-Met/E545K HCC progression but did not affect the mTOR pathway or genes involved in cell proliferation. In human HCC cell lines transfected with PIK3CA(H1047R), alpelisib synergized with the mTOR inhibitor MLN0128 or the CDK4/6 inhibitor palbociclib to suppress HCC cell growth. In c-Met/H1047R mice, alpelisib/MLN0128 or alpelisib/palbociclib combination therapy caused tumor regression. Our study demonstrates that alpelisib is effective for treating PIK3CA- mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA -mutated HCC, providing novel opportunities for precision medicine against HCC.

Heat stress is a primary constraint to Australia's barley production. In addition to impacting grain yield, it adversely affects physical grain quality (weight and plumpness) and market value. The incidence of heat stress during grain filling is rising with global warming. However, breeding for new superior heat-tolerant genotypes has been challenging due to the narrow window of sensitivity, the unpredictable nature of heat stress, and its frequent co-occurrence with drought stress. Greater scientific knowledge regarding traits and mechanisms associated with heat tolerance would help develop more efficient selection methods. Our objective was to assess 157 barley varieties of contrasting genetic backgrounds for various developmental, agro-morphological, and physiological traits to examine the effects of heat stress on physical grain quality. Delayed sowing (i.e., July and August) increased the likelihood of daytime temperatures above 30°C during grain-filling. Supplementary irrigation of field trials ensured a reduced impact of drought stress. Heat tolerance appeared to be the primary factor determining grain plumpness. A wide variation was observed for heat tolerance, particularly among the Australian varieties. Genotypic variation was also observed for grain weight, plumpness, grain growth components, stay-green and stem water-soluble carbohydrates (WSC) content, and mobilisation under normal and delayed sown conditions. Compared to normal sowing, delayed sowing reduced duration of developmental phases, plant height, leaf size, head length, head weight, grain number, plumpness, grain width and thickness, stem WSC content, green leaf area retention, and harvest index (HI), and increased screenings, grain length, grain-filling rate (GFR), WSC mobilisation efficiency (WSCME), and grain protein content. Overall, genotypes with heavier and plumper grains under high temperatures had higher GFR, longer grain-filling duration, longer green leaf area retention, higher WSCME, taller stature, smaller leaf size, greater HI, higher grain weight/plumpness potentials, and earlier flowering. GFR played a significant role in determining barley grain weight and plumpness under heat-stress conditions. Enhancing GFR may provide a new avenue for improving heat tolerance in barley.

During the development of multi-layer tight sandstone gas reservoirs in Ordos Basin, China, it has not been easy to calculate accurately the production of each individual layer in gas wells. However, production allocation provides a vital basis for evaluating dynamic reserves and drainage areas of gas wells and remaining gas distributions of gas layers. To improve the accuracy and reliability of production allocation of gas wells, a new model was constructed based on the seepage equation, material balance equation, and pipe string pressure equation. In particular, this new model introduced the seepage equation with an elliptical boundary to accurately capture the fluid flow characteristics within a lenticular tight gas reservoir. The new model can accurately calculate the production and reservoir pressure of each individual layer in gas wells. In addition, the new model was validated and applied in the Sulige gas field, Ordos Basin. The following conclusions were drawn: First, The gas production contribution rates of pay zones based on the new model are fairly close to the measurements of the production profile logging, with errors less than 10%. Second, The overall drainage area of a gas well lies among those of each pay zone, and the total dynamic reserves of the well are close to the sum of the dynamic reserves of pay zones. Third, Higher permeability may lead to higher initial gas production of the pay zone, but the ultimate gas production contributions of pay zones are affected jointly by permeability and dynamic reserves. Finally, The new model has been successfully applied to the SZ block of the Sulige gas field, in which the fine evaluation of dynamic reserves, drainage areas, gas production, recovery factors, and remaining gas distributions of different layers was delivered, and the application results provide technical support for the future well placement and enhanced gas recovery of the block.

With the development of the wireless communication technology and the popularity of mobile devices, the mobile wireless network（MWN） has been widely used in our daily life. Through the access point（AP）, users could access the Internet anytime and anywhere using their mobile devices. Therefore, MWNs can bring much convenience to us. Due to the limitation of AP＇s coverage, the seamless handover frequently occurs in practical applications. How to guarantee the user＇s privacy and security and identify the real identity when he/she brings harm to the system becomes very challenging. To achieve such goals, many anonymous handover authentication（AHA） protocols have been proposed in the last several years. However, most of them have high computation costs because mobile nodes need to carry out the bilinear pairing operations or the hash-to-point operations. Besides, most of them cannot satisfy some critical requirements, such as non-traceability and perfect forward secrecy. In this paper, we first outline the security requirements of AHA protocols, and then propose a new AHA protocol to eliminate weaknesses existing in previous AHA protocols. Based on the hardness of two famous mathematical problems, we demonstrate that the proposed AHA protocol is secure against different kinds of attacks and can meet a variety of security requirements. It can be seen from the details of implementations that the proposed AHA protocol also has much less computation cost than three latest AHA protocols.

Nitrogen (N) fertilizer is largely responsible for barley grain yield potential and quality, yet excessive application leads to environmental pollution and high production costs. Therefore, efficient use of N is fundamental for sustainable agriculture. In the present study, we investigated the performance of 282 barley accessions through hydroponic screening using optimal and low NH NO treatments. Low-N treatment led to an average shoot dry weight reduction of 50%, but there were significant genotypic differences among the accessions. Approximately 20% of the genotypes showed high (>75%) relative shoot dry weight under low-N treatment and were classified as low-N tolerant, whereas 20% were low-N sensitive (≤55%). Low-N tolerant accessions exhibited well-developed root systems with an average increase of 60% in relative root dry weight to facilitate more N absorption. A genome-wide association study (GWAS) identified 66 significant marker trait associations (MTAs) conferring high nitrogen use efficiency, four of which were stable across experiments. These four MTAs were located on chromosomes 1H(1), 3H(1), and 7H(2) and were associated with relative shoot length, relative shoot and root dry weight. Genes corresponding to the significant MTAs were retrieved as candidate genes, including members of the asparagine synthetase gene family, several transcription factor families, protein kinases, and nitrate transporters. Most importantly, the ( ) was identified as a promising candidate on 7H for root and shoot dry weight. The identified candidate genes provide new insights into our understanding of the molecular mechanisms driving nitrogen use efficiency in barley and represent potential targets for genetic improvement.

Dear editor, As certificateless public key cryptography （CL- PKC） [1] is proposed, a number of certificateless public key signature （CL-PKS） schemes [2 6] have been proposed. According to various construction methods,