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Rockfall events are a common geological hazard in the mountain areas of western China and frequently occur on unstable slopes. The purpose of this study was to establish a statistical model of random rockfall–slope collision using the impulse moment theorem considering that the impacted stones are moving. The rebound velocity of rockfall is random because the microstructure of the ground and slope can be described with statistical properties. The analytical solutions of the rebound particles are obtained as formulas for the incident velocity, incident angle, impacted rock movement, slope angle, and ground surface microstructure. The means and standard deviations of rebound velocity are fitted with slope angle to calculate formulas based on probability theory, which agrees with the previous results. The probability distribution functions of the horizontal distance and vertical distance follow a Gaussian distribution and a negative exponential distribution under the given slope angle, respectively. A formula of trajectory is also given.

Background：The diagnosis of myelodysplastic syndrome （MDS）,especially hypoplastic MDS,and MDS with low blast counts or normal karyotype may be problematic.This study characterized ID4 gene methylation in patients with MDS and aplastic anemia （AA）.Methods：The methylation status ofID4 was analyzed by bisulfite sequencing polymerase chain reaction （PCR） and quantitative real-time methylation-specific PCR （MethyLight PCR） in 100 patients with MDS and 31 patients with AA.Results：The MDS group had a higher ID4 gene methylation positivity rate （22.22%） and higher methylation levels （0.21 [0-3.79]） than the AA group （P 〈 0.05）.Furthermore,there were significant differences between the hypoplastic MDS and AA groups,the MDS with low blast count and the AA groups,and the MDS with normal karyotype and the AA groups.The combination of genetic and epigenetic markers was used in much more patients with MDS （62.5% [35/56]） than the use of genetic markers only （51.79% [29/56]）.Conclusions：These results showed that the detection ofID4 methylation positivity rates and levels could be a useful biomarker for MDS diagnosis.

The AMP-activated protein kinase （AMPK） is the key energy sensor in response to various stresses that decrease cellular ATP levels, including low glucose, hy- poxia, ischemia and heat shock. Recently, evidence has suggested that AMPK also plays critical roles in coupling the cellular bio-energetic state to various physiological processes, such as tumor suppression, cell polarity, life span, circadian clock, gene transcription and autophagy. Thus, AMPK represents a potential drug target for meta- bolic disorders and cancer treatment [1, 2].

As the heart and kidneys are closely connected by the circulatory system, primary dysfunction of either organ usually leads to secondary dysfunction or damage to the other organ. These interactions play a major role in the pathogenesis of a clinical entity named cardiorenal syndrome (CRS). The pathophysiology of CRS is complicated and involves multiple body systems. In early studies, CRS was classified into five subtypes according to the organs associated with the vicious cycle and the acuteness and chronicity of CRS. Increasing evidence shows that CRS is associated with a variety of pathological mechanisms, such as haemodynamics, neurohormonal changes, hypervolemia, hypertension, hyperuraemia and hyperuricaemia. In this review, we summarize the classification and currently available diagnostic biomarkers of CRS. We highlight the recently revealed molecular pathogenesis of CRS, such as oxidative stress and inflammation, hyperactive renin‒angiotensin‒aldosterone system, maladaptive Wnt/β-catenin signalling pathway and profibrotic TGF‒β1/Smad signalling pathway, as well as other pathogeneses, such as dysbiosis of the gut microbiota and dysregulation of noncoding RNAs. Targeting these CRS-associated signalling pathways has new therapeutic potential for treating CRS. In addition, various chemical drugs, natural products, complementary therapies, blockers, and agonists that protect against CRS are summarized. Since the molecular mechanisms of CRS remain to be elucidated, no single intervention has been shown to be effective in treating CRS. Pharmacologic therapies designed to block CRS are urgently needed. This review presents a critical therapeutic avenue for targeting CRS and concurrently illuminates challenges and opportunities for discovering novel treatment strategies for CRS.

PD-1 blockade is highly efficacious for mismatch repair-deficient colorectal cancer in both metastatic and neoadjuvant settings. We aimed to explore the activity and safety of neoadjuvant therapy with PD-1 blockade plus an angiogenesis inhibitor and the feasibility of organ preservation in patients with locally advanced mismatch repair-deficient colorectal cancer. We initiated a single-arm, open-label, phase 2 trial (NEOCAP) at Sun Yat-sen University Cancer Center and the Provincial Hospital of Traditional Chinese Medicine, Guangzhou, China. Patients aged 18–75 years with untreated mismatch repair-deficient or microsatellite instability-high or POLE/POLD1-mutated locally advanced colorectal cancer (cT3 or N+ for rectal cancer, and T3 with invasion ≥5mm or T4, with or without N+ for colon cancer) and an Eastern Cooperative Oncology Group performance score of 0–1 were enrolled and given 200 mg camrelizumab intravenously on day 1 and 250 mg apatinib orally from day 1–14, every 3 weeks for 3 months followed by surgery or 6 months if patients did not have surgery. Patients who had a clinical complete response did not undergo surgery and proceeded with a watch-and-wait approach. The primary endpoint was the proportion of patients with a pathological or clinical complete response. Eligible enrolled patients who received at least one cycle of neoadjuvant treatment and had at least one tumour response assessment following the baseline assessment were included in the activity analysis, and patients who received at least one dose of study drug were included in the safety analysis. The study is registered with ClinicalTrials.gov (NCT04715633) and is ongoing. Between Sept 29, 2020, and Dec 15, 2022, 53 patients were enrolled; one patient was excluded from the activity analysis because they were found to be mismatch repair-proficient and microsatellite-stable. 23 (44%) patients were female and 29 (56%) were male. The median follow-up was 16·4 (IQR 10·5–23·5) months. 28 (54%; 95% CI 35–68) patients had a clinical complete response and 24 of these patients were managed with a watch-and-wait approach, including 20 patients with colon cancer and multiple primary colorectal cancer. 23 (44%) of 52 patients underwent surgery for the primary tumour, and 14 (61%; 95% CI 39–80) had a pathological complete response. 38 (73%; 95% CI 59–84) of 52 patients had a complete response. Grade 3–5 adverse events occurred in 20 (38%) of 53 patients; the most common were increased aminotransferase (six [11%]), bowel obstruction (four [8%]), and hypertension (four [8%]). Drug-related serious adverse events occurred in six (11%) of 53 patients. One patient died from treatment-related immune-related hepatitis. Neoadjuvant camrelizumab plus apatinib show promising antitumour activity in patients with locally advanced mismatch repair-deficient or microsatellite instability-high colorectal cancer. Immune-related adverse events should be monitored with the utmost vigilance. Organ preservation seems promising not only in patients with rectal cancer, but also in those with colon cancer who have a clinical complete response. Longer follow-up is needed to assess the oncological outcomes of the watch-and-wait approach. The National Natural Science Foundation of China, Guangdong Basic and Applied Basic Research Foundation, and the Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. For the Chinese translation of the abstract see Supplementary Materials section.

Background Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide because of rapid progression and high incidence of metastasis or recurrence. Accumulating evidence shows that CD73-expressing tumor cell is implicated in development of several types of cancer. However, the role of CD73 in HCC cell has not been systematically investigated and its underlying mechanism remains elusive. Methods CD73 expression in HCC cell was determined by RT-PCR, Western blot, and immunohistochemistry staining. Clinical significance of CD73 was evaluated by Cox regression analysis. Cell counting kit-8 and colony formation assays were used for proliferation evaluation. Transwell assays were used for motility evaluations. Co-immunoprecipitation, cytosolic and plasma membrane fractionation separation, and ELISA were applied for evaluating membrane localization of P110β and its catalytic activity. NOD/SCID/γc(null) (NOG) mice model was used to investigate the in vivo functions of CD73. Results In the present study, we demonstrate that CD73 was crucial for epithelial-mesenchymal transition (EMT), progression and metastasis in HCC. CD73 expression is increased in HCC cells and correlated with aggressive clinicopathological characteristics. Clinically, CD73 is identified as an independent poor prognostic indicator for both time to recurrence and overall survival. CD73 knockdown dramatically inhibits HCC cells proliferation, migration, invasion, and EMT in vitro and hinders tumor growth and metastasis in vivo. Opposite results could be observed when CD73 is overexpressed. Mechanistically, adenosine produced by CD73 binds to adenosine A2A receptor (A2AR) and activates Rap1, which recruits P110β to the plasma membrane and triggers PIP3 production, thereby promoting AKT phosphorylation in HCC cells. Notably, a combination of anti-CD73 and anti-A2AR achieves synergistic depression effects on HCC growth and metastasis than single agent alone. Conclusions CD73 promotes progression and metastasis through activating PI3K/AKT signaling, indicating a novel prognostic biomarker for HCC. Our data demonstrate the importance of CD73 in HCC in addition to its immunosuppressive functions and revealed that co-targeting CD73 and A2AR strategy may be a promising novel therapeutic strategy for future HCC management.

Objective While PD-L1 expression serves as a predictive biomarker for programmed cell death 1 and its ligand (PD-1/PD-L1) inhibitor efficacy in patients with non-small cell lung cancer (NSCLC), its association with treatment-related adverse events (TRAEs) has yet to be fully elucidated. This study systematically evaluated the correlation between PD-L1 expression status and TRAEs in patients with NSCLC. Methods We systematically searched the Cochrane Library, Embase, and PubMed databases from inception to June 30, 2024, to identify prospective clinical trials examining PD-1/PD-L1 inhibitors among NSCLC patients that reported treatment-related toxicity data stratified by PD-L1 expression. Results Twenty-six prospective trials ( N  = 5,453) were analyzed. At the 1%, 25%, and 50% PD-L1 cutoffs, PD-L1-negative patients presented significantly reduced risks of grade 3–4 TRAEs (OR = 0.37, 0.53, 0.41; 95% CI = 0.18–0.77, 0.31–0.90, 0.19–0.97; P  < 0.01, 0.02, 0.04). Similarly, PD-L1-negative patients had significantly reduced risks of AEs leading to treatment discontinuation at the 1% and 25% PD-L1 cutoffs (OR = 0.25, 0.38; 95% CI = 0.08–0.76, 0.16–0.89; P  = 0.01, 0.03) but not at the 50% PD-L1 cutoff (OR 0.28, 95% CI 0.07–1.12, P  = 0.07). Subgroup analyses revealed elevated all-grade TRAEs with the 22C3 immunohistochemistry assay ( P  < 0.001), whereas first-line therapy recipients ( P  = 0.006) and open-label trial participants ( P  = 0.002) presented increased grade 3–4 TRAEs. Conclusions PD-L1 positivity may predict increased risks of grade 3–4 TRAEs and AEs leading to treatment discontinuation in NSCLC patients receiving PD-1/PD-L1 blockade. Furthermore, PD-L1 expression might be a useful biomarker for toxicity management in patients with NSCLC after PD-1/PD-L1 inhibitor treatment.

Objective We aim to explore the prevalence and temporal trends of the burden of kidney dysfunction (KD) in global, regional and national level, since a lack of related studies. Design Cross-sectional study. Materials The data of this research was obtained from Global Burden of Diseases Study 2019. The estimation of the prevalence, which was measured by the summary exposure value (SEV), and attributable burden of KD was performed by DisMod-MR 2.1, a Bayesian meta-regression tool. The Spearman rank order correlation method was adopted to perform correlation analysis. The temporal trends were represented by the estimated annual percentage change (EAPC). Results In 2019, there were total 3.16 million deaths and 76.5 million disability-adjusted life years (DALYs) attributable to KD, increased by 101.1% and 81.7% compared with that in 1990, respectively. From 1990 to 2019, the prevalence of KD has increased in worldwide, but decreased in High-income Asia Pacific. Nearly 48.5% of countries globally, such as South Africa, Egypt and Mexico had increased mortality rates of KD from 1990 to 2019 while 44.6% for disability rate. Countries with lower socio-demographic index (SDI) are facing a higher prevalence as well as mortality and disability rate compared with those with higher SDI. Compared with females, the prevalence of KD was lower in males, however the attributable mortality and disability rate were higher in all years from 1990 to 2019. Conclusion With the progress of senescent, we will face more severe challenges of reducing the prevalence and attributable burden of KD, especially in regions with lower SDI. Effective measures are urgently required to alleviate the prevalence and burden of KD.

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging owing to the fragile nature of fear extinction, for which the ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low-gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed for fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhanced the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low-gamma-band oscillations that facilitate fear extinction. Finally, application of low-gamma DBS and tACS to a mouse model with persistent PTSD showed potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be stimulated for therapy to remove traumatic memory trace.

Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor derived from bile duct epithelium. Its characteristics include an insidious onset and frequent recurrence or metastasis after surgery. Current chemotherapies and molecular target therapies provide only modest survival benefits to patients with ICC. Anlotinib is a novel multi-target tyrosine kinase inhibitor that has good antitumor effects in a variety of solid tumors. However, there are few studies of anlotinib-associated mechanisms and use as a treatment in ICC. In this study using in vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration and invasion restraint, and cell-cycle arrestment. Anlotinib treatment affected induction of apoptosis and the mesenchymal–epithelial transition. Patient-derived xenograft models generated directly from patients with ICC revealed that anlotinib treatment dramatically hindered in vivo tumor growth. We also examined anlotinib’s mechanism of action using transcriptional profiling. We found that anlotinib treatment might mainly inhibit tumor cell proliferation and invasion and promote apoptosis via cell-cycle arrestment by inactivating the VEGF/PI3K/AKT signaling pathway, as evidenced by significantly decreased phosphorylation levels of these kinases. The activation of vascular endothelial growth factor receptor 2 (VEGFR2) can subsequently activate PI3K/AKT signaling. We identified VEGRF2 as the main target of anlotinib. High VEGFR2 expression might serve as a promising indicator when used to predict a favorable therapeutic response. Taken together, these results indicated that anlotinib had excellent antitumor activity in ICC, mainly via inhibiting the phosphorylation level of VEGFR2 and subsequent inactivation of PIK3/AKT signaling. This work provides evidence and a rationale for using anlotinib to treat patients with ICC in the future.