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Well‐differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5‐year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3‐isobutyl‐1‐methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis‐inducing compounds could be used to treat DDLPS patients in a clinical setting. Induction of adipogenesis using four compounds used as medication or possible drug inhibited the tumor potency of DDLPS. Our finding suggests the potential application of drug repositioning in which adipogenic‐inducing compounds can be used to treat DDLPS patients in clinical therapy.

Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P < 0.001). In addition, a TERT promoter mutation was detected in 7/73 (10%) cases, and it showed a significant association with malignant SFTs (P = 0.003). To identify molecular changes during malignant progression, we selected an index patient to obtain parallel tissue samples from the primary and metastatic tumors. In the metastatic tissue, 10 unique molecular alterations, including those in TP53 and APAF1, were detected. In vitro functional experiments showed that APAF1 depletion increased the tumor potency of cells expressing NAB2-STAT6 fusion protein under treatment with staurosporine. We found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.Key messagesWe firstly found that the TERT promoter mutation was strongly associated with malignant SFTs (P = 0.003) and the representative 1b (NAB2ex4-STAT6ex2) or 2a (NAB2ex6-STAT6ex16) fusion variants similarly contribute to tumorigenicity.We also found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs.Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.

Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria for well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that the depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis remains unclear. We examined whether MDM2 and/or CDK4 cause WDLPS/DDLPS, using two types of transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that the co-overexpression of MDM2 and CDK4 plays a key role in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency when compared with the sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that the co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can cause proliferative sarcoma with a DDLPS-like morphology in vivo. Our results suggest that the co-overexpression of MDM2 and CDK4, along with multiple genetic factors, increases the tendency for high-grade sarcoma with a DDLPS-like morphology in transformed human BMSCs by accelerating their growth and migration and blocking their adipogenic potential.

Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria of well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, it remains unclear whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis. We examined whether MDM2 and/or CDK4 produce WDLPS/DDLPS using transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that co-overexpression of MDM2 and CDK4 plays key roles in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency compared to sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can develop proliferative DDLPS in vivo. Our results suggest that co-overexpression of MDM2 and CDK4 induces DDLPS tumour potency in transformed human BMSCs by accelerating cell growth and migration and blocking adipogenetic potential incooperation with multiple genetic factors.

Aim： Stem cells hold great promise for brain and spinal cord injuries （SCI）, but cell survival following transplantation to adult central nervous system has been poor. Salvianolic acid B （Sal B） has been shown to improve functional recovery in braininjured rats. The present study was designed to determine whether Sal B could improve transplanted mesenchymal stem cell （MSC） survival in SCI rats. Methods： SCI rats were treated with Sal B. The Basso-Beatie-Bresnahan （BBB） scale was used to test the functional recovery. Sal B was used to protect MSC from being damaged by TNF-α in vitro. Bromodeoxyuridine-labeled MSC were transplanted into SCI rats with Sal B intraperitoneal injection, simul-taneously. MSC were examined, and the functional recovery of the SCI rats was tested. Results： Sal B treatment significantly reduced the lesion area from 0.26±0.05 mm^2 to 0.15±0.03 mm^2 （P〈0.01） and remarkably raised the BBB scores on d 28, post-injury, from 7.3±0.9 to 10.5± 1.3 （P〈0.05）, compared with the phosphate-buffered saline （PBS） control group. MSC were protected from the damage of TNF-α by Sal B. The number of surviving MSC in the MSC plus Sal B groups were 1143.3±195.6 and 764.0±81.3 on d 7 and 28, post-transplantation, more than those in the MSC group, which was 569.3±72.3 and 237.0±61.3, respectively （P〈0.05）. Rats with MSC transplanted and Sal B injected obtained higher BBB scores than those with MSC transplanted alone （P〈0.05） and PBS （P〈0.01）. Conclusion： Sal B provides neuroprotection to SCI and promotes the survival of MSC in vitro and after cell transplantation to the injured spinal cord in vivo.

Background Using the published survival statistics from cancer registration or population‐based studies, we aimed to describe the global pattern and trend of lung cancer survival. Methods By searching SinoMed, PubMed, Web of Science, EMBASE, and SEER, all survival analyses from cancer registration or population‐based studies of lung cancer were collected by the end of November 2022. The survival rates were extracted by sex, period, and country. The observed, relative, and net survival rates of lung cancer were applied to describe the pattern and time changes from the late 1990s to the early 21st century. Results Age‐standardized 5‐year relative/net survival rate of lung cancer was typically low, with 10%–20% for most regions. The highest age‐standardized relative/net survival rate was observed in Japan (32.9%, 2010–2014), and the lowest was in India (3.7%, 2010–2014). In most countries, the five‐year age‐standardized relative/net survival rates of lung cancer were higher in females and younger people. The patients with adenocarcinoma had a better prognosis than other groups. In China, the highest 5‐year overall relative/net survival rates were 27.90% and 31.62% in men and women in Jiangyin (2012–2013). Conclusion Over the past decades, the prognosis of lung cancer has gradually improved, but significant variations were also observed globally. Worldwide, a better prognosis of lung cancer can be observed in females and younger patients. It is essential to compare and evaluate the histological or stage‐specific survival rates of lung cancer between different regions in the future. This study collected globally published data on observed and relative survival rates of lung cancer from population‐based cancer registration. Over the past decades, the prognosis of lung cancer has gradually improved. However, region, period, sex, and age might affect the survival rate of lung cancer patients. The observed and relative survival rate of lung cancer patients varies greatly among different histological types and stages.

Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of neuronal, metabolic, and inflammatory diseases. However, our understanding of its mechanism of action and the potential of drug discovery targeting this receptor is limited by the lack of structural information of VIP1R. Here we report a cryo-electron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, whose complex assembly is stabilized by a NanoBiT tethering strategy. Comparison with other class B GPCR structures reveals that PACAP27 engages VIP1R with its N-terminus inserting into the ligand binding pocket at the transmembrane bundle of the receptor, which subsequently couples to the G protein in a receptor-specific manner. This structure has provided insights into the molecular basis of PACAP27 binding and VIP receptor activation. The methodology of the NanoBiT tethering may help to provide structural information of unstable complexes. Vasoactive intestinal polypeptide receptor (VIP1R) is a widely expressed class B G protein-coupled receptor and a drug target for the treatment of inflammatory diseases. Here authors report a cryoelectron microscopy structure of human VIP1R bound to PACAP27 and Gs heterotrimer, which provides insights into PACAP27 binding and VIP receptor activation.

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.

Nanotransfer printing of colloidal nanoparticles is a promising technique for the fabrication of functional materials and devices. However, patterning nonplanar nanostructures pose a challenge due to weak adhesion from the extremely small nanostructure‐substrate contact area. Here, the study proposes a thermal‐assisted nonplanar nanostructure transfer printing (NP‐NTP) strategy for multiscale patterning of polystyrene (PS) nanospheres. The printing efficiency is significantly improved from ≈3.1% at low temperatures to ≈97.2% under the glass transition temperature of PS. Additionally, the arrangement of PS nanospheres transitioned from disorder to long‐range order. The mechanism of printing efficiency enhancement is the drastic drop of Young's modulus of nanospheres, giving rise to an increased contact area, self‐adhesive effect, and inter‐particle necking. To demonstrate the versatility of the NP‐NTP strategy, it is combined with the intaglio transfer printing technique, and multiple patterns are created at both micro and macro scales at a 4‐inch scale with a resolution of ≈2757 pixels per inch (PPI). Furthermore, a multi‐modal anti‐counterfeiting concept based on structural patterns at hierarchical length scales is proposed, providing a new paradigm of imparting multiscale nanostructure patterning into macroscale functional devices.

Of the two cultivated species of allopolyploid cotton, Gossypium barbadense produces extra-long fibers for the production of superior textiles. We sequenced its genome (AD) 2 and performed a comparative analysis. We identified three bursts of retrotransposons from 20 million years ago (Mya) and a genome-wide uneven pseudogenization peak at 11–20 Mya, which likely contributed to genomic divergences. Among the 2,483 genes preferentially expressed in fiber, a cell elongation regulator, PRE1 , is strikingly A t biased and fiber specific, echoing the A-genome origin of spinnable fiber. The expansion of the PRE members implies a genetic factor that underlies fiber elongation. Mature cotton fiber consists of nearly pure cellulose. G. barbadense and G. hirsutum contain 29 and 30 cellulose synthase (CesA) genes, respectively; whereas most of these genes (>25) are expressed in fiber, genes for secondary cell wall biosynthesis exhibited a delayed and higher degree of up-regulation in G. barbadense compared with G. hirsutum , conferring an extended elongation stage and highly active secondary wall deposition during extra-long fiber development. The rapid diversification of sesquiterpene synthase genes in the gossypol pathway exemplifies the chemical diversity of lineage-specific secondary metabolites. The G. barbadense genome advances our understanding of allopolyploidy, which will help improve cotton fiber quality.