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This paper investigates two accelerated primal-dual mirror dynamical approaches for smooth and nonsmooth convex optimization problems with affine and closed, convex set constraints. In the smooth case, an accelerated primal-dual mirror dynamical approach (APDMD) based on accelerated mirror descent and primal-dual framework is proposed and accelerated convergence properties of primal-dual gap, feasibility measure and the objective function value along with trajectories of APDMD are derived by the Lyapunov analysis method. Then, we extend APDMD into two distributed dynamical approaches to deal with two types of distributed smooth optimization problems, i.e., distributed constrained consensus problem (DCCP) and distributed extended monotropic optimization (DEMO) with accelerated convergence guarantees. Moreover, in the nonsmooth case, we propose a smoothing accelerated primal-dual mirror dynamical approach (SAPDMD) with the help of smoothing approximation technique and the above APDMD. We further also prove that primal-dual gap, objective function value and feasibility measure of SAPDMD have the same accelerated convergence properties as APDMD by choosing the appropriate smooth approximation parameters. Later, we propose two smoothing accelerated distributed dynamical approaches to deal with nonsmooth DEMO and DCCP to obtain accelerated and efficient solutions. Finally, numerical experiments are given to demonstrate the effectiveness of the proposed accelerated mirror dynamical approaches.

Typhoon-related precipitation over land can result in severe disasters such as floods and landslides, and satellites are a valuable tool to estimate surface precipitation with high spatial-temporal resolutions. This study develops a high-resolution surface precipitation integration framework to combine observations from geostationary Fengyun-4A/ Himawari-8 (F4/H8) satellite radiometers, high-density rain-gauge observations (or Integrated Multisatellite Retrievals for GPM (IMERG) data) and atmospheric reanalysis (ERA5) based on a random forest (RF) algorithm. The RF methods fuse cloud and atmospheric features from radiometric observations and reanalysis information, and the intensity and spatial distribution of rainfall can be revealed by high-density rain-gauge or IMERGE observations. We take three typhoons made landfall in South China in 2018 as examples. Both F4- and H8-based results using rain-gauge data as the predictand show excellent results with correlation coefficients (R) with the references ~0.75 and probabilities of detection (POD) as large as 0.98, higher than current satellite-only results. However, if the IMERG data are used as the predictand, the corresponding R and POD drop to ~0.5 and 0.93, respectively, due to the uncertainties related to IMERG retrievals. By carefully choosing the predictors, the RF algorithm can clearly summarize the information from satellite observations, surface observations and atmospheric reanalysis, resulting in precipitation results that are highly consistent with the actual ground observations. Our proposed integration framework can not only reconstruct hourly surface precipitation estimation datasets at high-spatial resolution for historical typhoon studies but also potentially monitor the fine- resolution surface precipitation of frequent typhoons in near-real time.

As important drug targets, G protein-coupled receptors (GPCRs) play pivotal roles in a wide range of physiological processes. Extensive efforts of structural biology have been made on the study of GPCRs. However, a large portion of GPCR structures remain unsolved due to structural instability. Recently, AlphaFold2 has been developed to predict structure models of many functionally important proteins including all members of the GPCR family. Herein we evaluated the accuracy of GPCR structure models predicted by AlphaFold2. We revealed that AlphaFold2 could capture the overall backbone features of the receptors. However, the predicted models and experimental structures were different in many aspects including the assembly of the extracellular and transmembrane domains, the shape of the ligand-binding pockets, and the conformation of the transducer-binding interfaces. These differences impeded the use of predicted structure models in the functional study and structure-based drug design of GPCRs, which required reliable high-resolution structural information.

Background: Combined therapy with tyrosine kinase inhibitors (TKIs) and anti-PD-1 antibodies has shown high tumor response rates for patients with unresectable hepatocellular carcinoma (HCC). However, using this treatment strategy to convert initially unresectable HCC to resectable HCC was not reported. Methods: Consecutive patients with unresectable HCC who received first-line therapy with combined TKI/anti-PD-1 antibodies were analyzed. Tumor response and resectability were evaluated via imaging every 2 months (±2 weeks) using RECIST v1.1. Resectability criteria were (1) R0 resection could be achieved with sufficient remnant liver volume and function; (2) intrahepatic lesions were evaluated as partial responses or stable disease for at least 2 months; (3) no severe or persistent adverse effects occurred; and (4) hepatectomy was not contraindicated. Results: Sixty-three consecutive patients were enrolled. Of them, 10 (15.9%) underwent R0 resection in 3.2 months (range: 2.4–8.3 months) after the initiation of combination therapy. At baseline, these 10 patients had a median largest tumor diameter of 9.3 cm, 7 had Barcelona Clinic Liver Cancer stage C (vascular invasion) disease, 2 had stage B, and 1 had stage A. Before surgery, 6 patients were evaluated as a partial response, 3 stable disease, and 1 partial response in the intrahepatic lesion but a new metastatic lesion in the right adrenal gland. Six patients (60%) achieved a pathological complete response. One patient died from immune-related adverse effects 2.4 months after hepatectomy. After a median follow-up of 11.2 months (range: 7.8–15.9 months) for other 9 patients, 8 survived without disease recurrence, and 1 experienced tumor recurrence. Conclusions: Combination of TKI/anti-PD-1 antibodies is a feasible conversion therapy for patients with unresectable HCC to become resectable. This study represents the largest patient cohort on downstaging role of combinational systemic therapy on TKI and PD-1 antibody for HCC.

Specific cytotoxicity for catalytic nanomedicine triggered by the tumor microenvironment (TME) has attracted increasing interest. In this work, we prepared AgBiS2 hollow nanospheres with narrow bandgaps via rapid precipitation in a weakly polar solvent, which lowered the intrinsic energy gap for the active production of highly reactive hydroxyl radicals (•OH), especially in the TME. The as-prepared AgBiS2 hollow nanospheres exhibited enhanced optical absorption and high photothermal conversion efficiency (44.2%). In addition, the hollow structured AgBiS2 nanospheres were found to have a peroxidase-mimicking feature to induce cancer cell-specific cytotoxicity while exhibiting negligible cytotoxicity toward normal cells, which might be attributed to the efficient production of highly reactive •OH originating from the overexpression H2O2 in the TME caused by surface catalysis. In particular, the cancer cell-specific cytotoxicity of the nanospheres was greatly enhanced both in vitro and in vivo upon irradiation with a near-infrared (NIR) laser (808 nm). The above-mentioned features of the hollow structured AgBiS2 will make it a promising candidate for tumor therapy.

Circulating factors associated with aging have been shown to be involved in the development of age-related chronic and acute brain diseases. Here, we aimed to investigate the roles and mechanisms of CCL12, a circulating factor that is highly expressed in the plasma of aged rodents after intracerebral hemorrhage (ICH) using parabiosis and ICH models. Neurological deficit score (NDS), mortality rate, brain water content (BWC), and levels of inflammatory factors were determined to assess the degree of ICH-induced brain injury. Peripheral inflammatory cell infiltration was examined using immunofluorescence and flow cytometry. After confirming that acute brain injury after ICH was aggravated with age, we found that brain and plasma CCL12 levels were markedly higher in old mice than in young mice after ICH, and that plasma CCL12 was able to enter the brain. Using CCL12-/- mice, we showed that the degree of damage in the brain-as determined by NDS, mortality rate, BWC, levels of inflammatory factors, and numbers of degenerative and apoptotic neural cells and surviving neurons was significantly attenuated compared to that observed in old wild-type (WT) mice. These effects were reversed in CCL12-treated old mice. The detrimental effects caused by CCL12 may involve its ability to recruit macrophages and T cells. Finally, the administration of an anti-CCL12 antibody markedly improved the outcomes of ICH mice. Our results are the first to indicate that elevated peripheral CCL12 levels in old mice aggravates ICH-induced brain injury by recruiting macrophages and T cells. Thus, CCL12 may be a new target for ICH treatment.

The phenomenon of enhanced invasion and metastasis of residual tumor cells has been observed in an increasing number of patients receiving chemoradiotherapy recently, and tumor metastasis will undoubtedly limit patient prognosis. However, the key mechanism by which chemoradiotherapy affects the invasion and metastasis of tumor cells remains unclear. Studies have shown that chemoradiotherapy may directly act on tumor cells and alter the tumor microenvironment, or induce cell apoptosis and autophagy to promote tumor cell survival and metastasis. In this review, we summarize the potential mechanisms by which chemoradiotherapy may affect the biological behavior of tumor cells and open up new avenues for reducing tumor recurrence and metastasis after treatment. These insights will improve the efficacy of chemoradiotherapy.

Liver cancer, mostly hepatocellular carcinoma (HCC), is the second leading cause of cancer mortality globally. Most patients were diagnosed at an advanced stage, and systemic therapy is the standard of care. All the approved systemic therapies for HCC are molecular targeted therapies with anti-angiogenic effects targeting the vascular endothelial growth factor signaling pathway. Sorafenib and lenvatinib are the first-line treatment, and regorafenib, ramucirumab, and cabozantinib are second-line treatment options. Although anti-PD-1 antibodies, including nivolumab and pembrolizumab, demonstrated promising anti-tumor effects as monotherapy for advanced HCC in phase II clinical trials, both failed in phase III studies. Anti-angiogenic treatment remains the backbone of systemic therapy for HCC. In this review, we summarized the approved anti-angiogenic medicines and discussed the potential strategies to improve the efficacy of anti-angiogenic therapy, including combination therapy with other treatments, and discussed the approaches to overcome the drawbacks of anti-angiogenic therapies.

Additional file 2: Table S1. Distribution of selected physical activities in the active group

Additional file 3: Table S2. Univariate analysis of the association between baseline factors and treatment outcomes. AFP alpha-fetoprotein, ALB albumin, ALT alanine transaminase, AST aspartate transaminase, BCLC Barcelona Clinic Liver Cancer, CI confidence interval, CNLC China Liver Cancer, DCP des-γ-carboxy prothrombin, GGT gamma-glutamyl transpeptidase, HBV hepatitis B virus, HBsAg hepatitis B surface antigen, HR hazard ratio, INR international normalized ratio, NLR neutrophil–lymphocyte ratio, OR odds ratio, PS performance status, TB total bilirubin WBC white blood count.

Additional file 1: Figure S1. Immunohistochemical staining and analysis of subcutaneous tumors. Immunohistochemical staining was conducted on subcutaneous tumor tissue microarray. H-score were calculated to quantify the expression levels of marker proteins. Representative images captured at 40X. *P