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The timing and ecological impacts of the Deccan Traps large igneous province eruption are vigorously debated. Pre–Cretaceous-Paleogene (KPg) boundary impacts of Deccan volcanism have been widely identified in marine sediments, but direct evidence of terrestrial impacts remains rare. We used mercury concentrations and isotopic compositions, a proxy for volcanic activity, to assess impacts on terrestrial environments. We studied two drill cores across the KPg boundary in eastern China that represent two different depositional environments: clastic deposits in the Jiaolai Basin and carbonate deposits in the Pingyi Basin. Both drill cores exhibit strong Hg enrichment prior to the KPg boundary. Near consistent mass-independent fractionation (MIF) of odd-Hg isotopes (odd-MIF) in the Jiaolai Basin likely indicates a volcanogenic source of Hg spikes below the KPg boundary. Odd-MIF isotopes in the Pingyi Basin likewise suggest a volcanogenic Hg source but with a terrestrial Hg signature of lower Δ199Hg values before and after the Hg spike interval. The Hg enrichment level can be stratigraphically correlated to the beginning of the Latest Maastrichtian warming event (LMWE) and is consistent with a strong, negative carbon-isotope excursion (CIE) in both δ13Corg (organic matter) and δ13Ccarb (carbonate), suggesting a disturbance of the global carbon cycle induced by a major pulse of Deccan Traps volcanism. Our discovery of a ter-restrial record of pre-KPg boundary Deccan volcanism provides robust evidence of global influence of the Deccan Traps large igneous province during the LMWE.

Penetrating atherosclerotic ulcer (PAU), an uncommon etiology of acute aortic syndrome (AAS), is a potential cause of chest pain seen in emergency departments. As PAU may lead to electrocardiogram (ECG) changes or rarely, elevated troponin levels, it is most likely misdiagnosed as acute coronary syndrome (ACS). Hence, individuals with PAU may be offered potentially life-threatening treatment. This paper reports a case of a 81-year-old male who presented with intermittent chest pain with a history of old inferior myocardial infarction and stent placement in the left circumflex coronary artery (LCX) three years ago. Initially, he was diagnosed with non-ST-elevation myocardial infarction (NSTEMI) based on abnormal ECG changes and raised troponin I. However, emergency coronary angiography (CAG) showed no restenosis in the left circumflex coronary artery (LCX) but with mild stenosis in the left anterior descending artery (LAD) and right coronary artery (RCA). Computed tomographic angiography (CTA) of the whole aorta showed multiple atherosclerotic plaques with penetrating atherosclerotic ulcer in the aortic arch and descending aorta. Endovascular aortic repair with Ankura II covered stent was performed. This case study reminds us that it is clinically difficult to distinguish PAU from ACS. Upon excluding ACS from the diagnosis, we should take into consideration of PAU, especially in elderly patients with positive cTnI.

Downscaling the anaerobic fermentation in a microtiter plate (MTP) facilitates high throughput screening (HTS) applications. This study investigates the impacts of MTP configurations (scale, shaking, and cover) on the S. pastorianus beer fermentation compared to that in the shaking flask (SF) and European Brewing Convention (EBC) tube regarding fermentation performances and flavor attributes. The lager strains in MTPs accelerated cells reproduction and vitalization, sugar consumption, and glycerol accumulation. The microscale beer fermentation was closer to the SF but differed greatly from EBC tube fermentation depending on the MTP configurations. The downscaling from 2 mL to 0.2 mL in MTP increased the cell growth rate and vitality but did not change the maximum cell density. The shaking MTP did not promote early growth but sustained significantly higher cell numbers at the later fermentation stage. More than 1.5-folds acetaldehyde and higher alcohols, yet less than half esters, were obtained from the MTP and SF fermentations relative to that in the EBC tube. The air-tight MTP cover, as compared to the gas-permeable cover, not only balanced the above volatile flavors but also maintained integrity to the endogenous carbon dioxide pressure during beer fermentation. Additionally, fermentative activities were reduced by excluding air in either the material or the headspace of MTP. Hence, MTP configurations influenced S. pastorianus beer fermentation. These influences were partly attributed to their impacts on air accessibility. Conscious of the impacts, this study helps interpret the minimized fermentation and sheds light on the development of MTP based HTS platform for anaerobic cultivations.

Oceanic Anoxic Event (OAE) 1b is well documented in western Tethys; however, records in Eurasia are still lacking. Here, we carried out high-resolution organic carbon isotope (δ 13 C org ), total organic carbon (TOC) content and mercury (Hg) concentration analysis of the lacustrine sediments from the Xiagou and Zhonggou formations in the Hanxiagou section of the Jiuquan Basin, NW China. The lacustrine δ 13 C org curve presents three stages of negative excursions above the basalt layer dated at 112.4 ± 0.3 Ma in the lowermost Zhonggou Formation. The three negative δ 13 C org excursions correspond well with the three sub-events (Kilian, Paquier and Leenhardt) of the OAE 1b in the Poggio le Guaine (central Italy), Vocontian Basin (SE France) and St Rosa Canyon (NE Mexico) sections, supporting the record of the terrestrial OAE 1b in the Jiuquan Basin. Five mercury enrichment intervals in Hg/TOC ratios were recognized, indicating that the pulsed volcanism from the Southern Kerguelen Plateau likely triggered OAE 1b. However, the decoupling between negative isotopic excursion shifts and mercury enrichments, signifying another carbon reservoir (with no link to mercury), probably contributed to the global carbon cycle perturbation during the OAE 1b period. Our results provide direct evidence to link OAE 1b and the terrestrial ecosystem in Eurasia.

Background and objectives Galectin-3 promotes fibroblast-to-myofibroblast differentiation and facilitates injury repair. Previous studies have shown that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) promote the differentiation of myocardial fibroblasts into myofibroblasts under inflammatory environment. Whether hucMSC-ex derived Galectin-3 (hucMSC-ex-Galectin-3) plays an important role in fibroblast-to-myofibroblast differentiation is the focus of this study. Methods and results Galectin-3 was knocked-down by siRNA in hucMSCs, and then exosomes were extracted. Fibroblasts were treated with LPS, LPS＋hucMSC-ex, LPS＋negative control-siRNA-ex (NC-ex), or LPS＋ Galectin-3-siRNA-ex (si-ex) in vitro. The coronary artery of the left anterior descending (LAD) branch was permanently ligated, followed by intramyocardial injection with phosphate buffered saline(PBS), hucMSC-ex, hucMSC-NC-ex, or hucMSC-si-ex in vivo. Western blot, RT-PCR, and immunohistochemistry were used to detect the expression of markers related to fibroblast-to-myofibroblast differentiation and inflammatory factors. Migration and contraction functions of fibroblasts were evaluated using Transwell migration and collagen contraction assays, respectively. β-catenin expression was detected by western blot and immunofluorescence. The results showed that hucMSC-ex increased the protein expression of myofibroblast markers, anti-inflammatory factors, and β-catenin. HucMSC-ex also reduced the migration and promoted the contractility of fibroblasts. However, hucMSC-si-ex did not show these activities. Conclusions HucMSC-ex-Galectin-3 promoted the differentiation of cardiac fibroblasts into myofibroblasts in an inflammatory environment, which was associated with increased β-catenin levels.

RNA polymerase II (RNAPII) is an essential machinery for catalyzing mRNA synthesis and controlling cell fate in eukaryotes. Although the structure and function of RNAPII have been relatively defined, the molecular mechanism of its assembly process is not clear. The identification and functional analysis of assembly factors will provide new understanding to transcription regulation. In this study, we identify that RTR1, a known transcription regulator, is a new multicopy genetic suppressor of mutants of assembly factors Gpn3, Gpn2, and Rba50. We demonstrate that Rtr1 is directly required to assemble the two largest subunits of RNAPII by coordinating with Gpn3 and Npa3. Deletion of RTR1 leads to cytoplasmic clumping of RNAPII subunit and multiple copies of RTR1 can inhibit the formation of cytoplasmic clump of RNAPII subunit in gpn3-9 mutant, indicating a new layer function of Rtr1 in checking proper assembly of RNAPII. In addition, we find that disrupted activity of Rtr1 phosphatase does not trigger the formation of cytoplasmic clump of RNAPII subunit in a catalytically inactive mutant of RTR1. Based on these results, we conclude that Rtr1 cooperates with Gpn3 and Npa3 to assemble RNAPII core.

Background & Aims Acute liver failure (ALF) is a life-threatening condition with limited treatment alternatives. ALF pathogenesis seemingly involves the complement system. However, no complement-targeted intervention has been clinically applied. In this study, we aimed to investigate the potential of Complement-5 (C5)-targeted ALF treatment. Methods ALF was induced in C5-knockout (KO, B10D2/oSn) mice and their wild-type (WT) counterparts (B10D2/nSn) through intraperitoneal lipopolysaccharide (LPS) and d -galactosamine (D-GalN) administration. Thereafter, monoclonal anti-C5 antibody (Ab) or control immunoglobulin was administered intravenously. Furthermore, a selective C5a-receptor (C5aR) antagonist was administered to WT mice to compare its efficacy with that of anti-C5-Ab-mediated total C5 inhibition. We clarified the therapeutic effect of delayed anti-C5-Ab administration after LPS/D-GalN challenge. We also assessed the efficacy of anti-C5-Ab in another ALF model, using concanavalin-A. Results Liver injury was evident 6 hours after LPS/D-GalN administration. C5-KO and anti-C5-Ab treatment significantly improved overall animal survival and significantly reduced serum transaminase and high-mobility group box-1 release with decreased histological tissue damage. This improvement was characterized by significantly reduced CD41+ platelet aggregation, maintained F4/80+ cells, and less infiltration of CD11+/Ly6-G+ cells with lower cytokine/chemokine expression. Furthermore, C5-KO and anti-C5-Ab downregulated tumor necrosis factor-α production by macrophages before inducing marked liver injury. Moreover, single-stranded-DNA cells and caspase activation were reduced, indicating significant attenuation of apoptosis. Anti-C5-Ab treatment protected the liver more effectively than the C5aR antagonist, and its delayed doses were hepatoprotective. In addition, anti-C5-Ab treatment was effective against concanavalin-A–induced ALF. Conclusions C5 inhibition effectively suppresses progression to ALF in mice models of fulminant hepatitis, serving as a new potential treatment strategy for ALF.

The end-Permian mass extinction (EPME; ca. 252 Ma) led to profound changes in lacustrine ecosystems. However, whether or not post-extinction recovery of lacustrine ecosystems was delayed has remained uncertain, due to the apparent rarity of Early and Middle Triassic deep perennial lakes. Here we report on mid–Middle Triassic lacustrine organic-rich shales with abundant fossils and tuff interlayers in the Ordos Basin of China, dated to ca. 242 Ma (around the Anisian-Ladinian boundary of the Middle Triassic). The organic-rich sediments record the earliest known appearance, after the mass extinction, of a deep perennial lake that developed at least 5 m.y. earlier than the globally distributed lacustrine shales and mudstones dated as Late Triassic. The fossil assemblage in the organic-rich sediments is diverse and includes plants, notostracans, ostracods, insects, fishes, and fish coprolites, and thus documents a Mesozoic-type, trophically multileveled lacustrine ecosystem. The results reveal the earliest known complex lacustrine ecosystem after the EPME and suggest that Triassic lacustrine ecosystems took at most 10 m.y. to recover fully, which is consistent with the termination of the “coal gap” that signifies substantial restoration of peat-forming forests.

Donor-recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990-2020). The primary and secondary endpoints were recipient survival and the incidence of T cell-mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0-10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21-5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11-5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor-recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children.

The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations, such as NF2-deficiency or LATS1/2 mutations leading to hyperactivation of YAP/TAZ and subsequent activation of TEAD, have been reported in many cancers, including mesothelioma, meningioma, soft tissue sarcoma and non-small cell lung cancer. Inhibiting TEAD auto-palmitoylation by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Here we present BPI-460372, a novel small molecule that directly blocks the TEAD auto-palmitoylation. BPI-460372 covalently and irreversibly binds to the cysteine residue in the TEAD palmitoylation pocket, preventing TEAD palmitoylation and inhibiting its biological function. BPI-460372 significantly inhibits the expression of a TEAD-responsive element reporter, as well as the mRNA of downstream target genes such as CTGF and CYR61 in NF2-deficient cells. At the cellular level, BPI-460372 strongly inhibited the proliferation of tumor cells harboring Hippo pathway aberrations. BPI-460372 also significantly suppressed tumor growth in NF2-deficient or LATS1/2 mutation xenograft models. In addition, BPI-460372 exhibited excellent oral bioavailability, high exposure across multiple species, and adequate ADME properties. In conclusion, BPI-460372 is a potent and selective TEAD palmitoylation inhibitor for the treatment of solid tumors harboring Hippo pathway aberrations. It is planned to enter Phase I clinical trial in China in early 2023. Citation Format: Hongling Shen, Xiaofeng Xu, Hongfei Rong, Xizhen Song, Jinheng Gao, Jie Chen, Di Zhu, Xiangdong Zhao, Jun Tong, Zhengyao Zou, Xiaoyun Liu, Jin Guo, Yan Xu, Yabin Li, Xiangyong Liu, Hong Chen, Jiayu Zhao, Yanju Liu, Xuepeng Ju, Haibo Chen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 501.

The end-Permian mass extinction (EPME) led to a severe terrestrial ecosystem collapse. However, the ecological response of insects—the most diverse group of organisms on Earth—to the EPME remains poorly understood. Here, we analyse beetle evolutionary history based on taxonomic diversity, morphological disparity, phylogeny, and ecological shifts from the Early Permian to Middle Triassic, using a comprehensive new data set. Permian beetles were dominated by xylophagous stem groups with a high diversity and disparity, which probably played an underappreciated role in the Permian carbon cycle. Our suite of analyses shows that Permian xylophagous beetles suffered a severe extinction during the EPME largely due to the collapse of forest ecosystems, resulting in an Early Triassic gap of xylophagous beetles. New xylophagous beetles appeared widely in the early Middle Triassic, which is consistent with the restoration of forest ecosystems. Our results highlight the ecological significance of insects in deep-time terrestrial ecosystems.

We consider a quasilinear chemotaxis–consumption system with singular sensitivity $$u_t=(D(u)u_x)_x-\chi (\frac{S(u)}{v} v_x)_x$$ , $$v_t=v_{xx}-uv$$ in a bounded interval $$\Omega \subset {\mathbb {R}}$$ with $$\chi >0$$ . The diffusivity fulfills $$D(u)\ge D_0(u+1)^{m-1}$$ with $$D_0,m>0$$ , and the density-signal governed sensitivity satisfies $$00$$ . It is proved that the system possesses a globally bounded classical solution under one dimension if $$M1$$ .

The Eomeropidae is a species-poor family with only 11 known fossil species from the Early Jurassic to Palaeogene. A new species of fossil eomeropid, Tsuchingothauma gongi sp. nov., is described based on a well-preserved wing from the Middle Jurassic Daohugou deposits of Inner Mongolia, China. Our new species is distinguished from the type species T. shihi mainly in having very numerous crossveins and cells; more longitudinal veins: 13 and 11 terminal branches in radial sector and medial field, CuA with 3 terminal branches and A with 7 terminal branches.

Context: The pathogenesis of cardiomyocyte death is closely associated with mitochondrial homeostasis via poorly understood mechanisms.Objective: The aim of our study is to explore the contribution of large tumor suppressor kinase 2 (LATS2) to the apoptosis of cardiomyocyte H9C2 cells.Materials and Methods: Adenovirus-mediated LATS2 overexpression was carried out in H9C2 cells. The cell viability and apoptosis rate were measured via an MTT assay, TUNEL staining, western blotting, an ELISA, and an LDH release assay. Mitophagy was quantified using immunofluorescence and western blotting.Results: The overexpression of LATS2 in H9C2 cells drastically promoted cell death. Molecular investigations showed that LATS2 overexpression was associated with mitochondrial injury, as evidenced by increased mitochondrial ROS production, reduced antioxidant factor levels, increased cyt-c liberation into the nucleus and activated mitochondrial caspase-9-dependent apoptotic pathway activity. Furthermore, our results demonstrated that LATS2-mediated mitochondrial malfunction by repressing mitophagy and that the reactivation of mitophagy could sustain mitochondrial integrity and homeostasis in response to LATS2 overexpression. Furthermore, we found that LATS2 inhibited mitophagy by inactivating the Prx3-Mfn2 axis. The reactivation of Prx3-Mfn2 pathways abrogated the LATS2-mediated inhibition of mitochondrial apoptosis in H9C2 cells.Conclusions: The overexpression of LATS2 induces mitochondrial stress by repressing protective mitophagy in a manner dependent on Prx3-Mfn2 pathways, thus reducing the survival of H9C2 cells.

The fossil record of the family Corydalidae (Megaloptera) is rare with only six reported species and several undescribed larvae from the Middle Jurassic to Eocene. Little is known about the food habits and digestive system of ancient insects. We report the first corydalid larva preserved with gut contents from the Lower Cretaceous Yixian Formation of northeast China, examining the contents using a scanning electron microscope with energy dispersive X-ray analysis. The results show that the main component of the gut contents is quartz gastroliths ('stomach stones'), providing the first fossil evidence of a gastric mill promoting digestion in a megalopteran larva, extending the record of this behaviour to the Early Cretaceous.

We consider the fully parabolic Keller–Segel system with singular sensitivity and logistic-type source: u t = Δ u − χ ∇ ⋅ ( u v ∇ v ) + r u − μ u k , v t = Δ v − v + u under the non-flux boundary conditions in a smooth bounded convex domain Ω ⊂ R n , χ , r , μ > 0 , k > 1 . A global very weak solution for the system with n ≥ 2 is obtained under one of the following conditions: (i) r > χ 2 4 for 0 χ ≤ 2 , or r > max ⁡ { χ 2 4 ( 1 − p 0 2 ) , χ − 1 } for χ > 2 with p 0 = 4 ( k − 1 ) 4 + ( 2 − k ) k χ 2 if k ∈ ( 2 − 1 n , 2 ] ; (ii) χ 2 min ⁡ { 2 ( r + r 2 ) k , 4 k ( k − 1 ) ( k − 2 ) } if k > 2 . Furthermore, this global very weak solution should be globally bounded in fact provided r μ and the initial data ‖ u 0 ‖ L 2 ( Ω ) , ‖ ∇ v ‖ L 4 ( Ω ) suitably small for n = 2 , 3 . In addition, if k > 3 ( n + 2 ) n + 4 replaces k > 2 in the condition (ii), the system admits globally bounded classical solutions. All these describe the influence of the exponent k > 1 in the logistic-type source r u − μ u k to the behavior of solutions for the considered fully parabolic Keller–Segel system with singular sensitivity.

The fossil record of Gyrinidae is not poor, with 19 species having been reported previously: here, however, we recognize the first whirligig beetle larva in mid-Cretaceous amber from Myanmar. Cretogyrus beuteli gen. et sp. nov. is described based on a well-preserved individual, differing from other gyrinid larvae by a combination of the following characters: mandibles large; neck region wide; two pairs of nasalean teeth present; cardo moderately elongated; series of small hooks on the lacinia absent; labial palpus 2-segmented; maxillary and labial palpomeres elongated and slender.

A new species of caraboid larva (Coleoptera, Adephaga), Carabilarva gongi sp. nov., is described based on a well-preserved specimen from the Middle Jurassic Daohugou deposits (in the upper part of Jiulongshan Formation) of Inner Mongolia, China. It is the fourth caraboid larva from the Mesozoic, and differs from the other three Mesozoic species mainly in having a longer body with shorter mandibles. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) show that this Daohugou fossil is preserved as carbonaceous compressions that lost the micro-structure, such as macrochaetae.

Fossil tiger beetles (Carabidae: Cicindelinae) are extremely rare, and little is known about their early evolutionary history. Here we report the earliest known tiger beetle, Cretotetracha grandis gen. et. sp. nov., from the Lower Cretaceous Yixian Formation (lower Aptian) of China. C. grandis bears several features characteristic of the subtribe Megacephalina, including a large body with total length/width ratio 2.3:1; labium transverse, without median tooth; eyes large; eyes and head together wider than the thorax; prothorax noticeably narrower than elytra; anterior corners of pronotum noticeably more extended anteriorly than anterior margin of prosternum. It represents the second definite Mesozoic record of Cicindelinae, and extends the further lineage back into the Early Cretaceous.

Src homology region 2 domain-containing phosphatase-2 (SHP-2) is a key node in the RAS signaling pathway. Allosteric inhibition of SHP2 phosphatase is a potential therapeutic strategy for cancers harboring oncogenic mutations in the KRAS pathway. SHP2 also participates in the signal transduction downstream of regulatory immunoreceptors, and it has been shown in preclinical models that SHP2 inhibition drives anti-tumor immunity through modulation of both innate and adaptive mechanism. BPI-442096 is a potent, selective, and orally bioavailable small molecule SHP2 inhibitor. It exhibited significant anti-proliferation activities against multiple KRAS mutant cancer cell lines, including those from NSCLC, PDAC, CRPC, etc. BPI-442096 dose-dependently inhibited SHP2 phosphatase and downstream ERK phosphorylation in cancer cells, as well as NFAT reporter gene expression downstream of PD-1/PD-L1 signaling in immune cells. In vivo, BPI-442096 demonstrated strong tumor growth inhibition in KRASG12C, KRASG12D, and KRASG12V mutant xenograft mouse models. BPI-442096 also exhibited anti-tumor immunity in the MC38 syngeneic model, as a single agent or in combination with anti-PD1/PD-L1 drugs. Moreover, BPI-442096 combining with KRASG12C inhibitor may reverse intrinsic and acquired resistance to KRASG12C inhibition. Adequate oral exposure across multiple pre-clinical species and good ADME properties ensured the druggability of BPI-442096. In conclusion, BPI-442096 exhibits a robust anti-tumor effect in multiple KRAS mutant models and enhanced anti-cancer immunity in syngeneic mouse models, and it shows multiple combination potentials to overcome drug resistance. Phase 1 clinical trial is planned in early 2022. Citation Format: Ling Li, Bang Fu, Han Han, Zhongxin Sun, Xiangdong Zhao, Xuepeng Jv, Jun Tong, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Wei Ren, Yinlong Li, Wenmao Wu, Jing Guo, Dan Yan, Xiangyong Liu, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-442096: A potent and selective inhibitor of SHP2 for the treatment of multiple cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5463.

Background and Objectives Galectin-3 promotes fibroblast-to-myofibroblast differentiation and facilitates injury repair. Previous studies have shown that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) promote the differentiation of myocardial fibroblasts into myofibroblasts under inflammatory environment. Whether hucMSC-ex derived Galectin-3 (hucMSC-ex-Galectin-3) plays an important role in fibroblast-to-myofibroblast differentiation is the focus of this study. Methods and Results Galectin-3 was knocked-down by siRNA in hucMSCs, and then exosomes were extracted. Fibroblasts were treated with LPS, LPS＋hucMSC-ex, LPS＋negative control-siRNA-ex (NC-ex), or LPS＋Galectin-3-siRNA-ex (si-ex) in vitro. The coronary artery of the left anterior descending (LAD) branch was permanently ligated, followed by intramyocardial injection with phosphate buffered saline(PBS), hucMSC-ex, hucMSC-NC-ex, or hucMSC-si-ex in vivo. Western blot, RT-PCR, and immunohistochemistry were used to detect the expression of markers related to fibroblast-to-myofibroblast differentiation and inflammatory factors. Migration and contraction functions of fibroblasts were evaluated using Transwell migration and collagen contraction assays, respectively. β-catenin expression was detected by western blot and immunofluorescence. The results showed that hucMSC-ex increased the protein expression of myofibroblast markers, anti-inflammatory factors, and β-catenin. HucMSC-ex also reduced the migration and promoted the contractility of fibroblasts. However, hucMSC-si-ex did not show these activities. Conclusions HucMSC-ex-Galectin-3 promoted the differentiation of cardiac fibroblasts into myofibroblasts in an inflammatory environment, which was associated with increased β-catenin levels.

BackgroundThe phosphatase and tensin homolog gene(PTEN) is a crucial cancersuppressor gene in nasopharyngeal carcinoma(NPC),which encodes the protein i-ncluding lipid phosphatase and protein phosphatase.p-P38 plays a vital role in the development process of cancers.However,whether and how PTEN protein p-hosphatase inhibit p-P38 expression and regulate migration and invasion in nas-opharyngeal carcinoma is still fully elucidated.MethodsThe abilities of migration and invasion were analyzed using Scratch,Transwell,Boyden experiments in NPC cells.Westere Blot was utilized to explo-re the expression of E-caherin,N-caherin and VIMENTIN in Epithelial-mesench-ymal transition(EMT),P38,p-P38(Thr180/Tyr182),AKT,p-AKT(Ser473),PTEN and its mutants.qPCR was done to detect the mRNA expression of PTEN and PTEN mutants.Immunofluorescence localization assay and Co-immunoprecipitatio-n assay was used to explore the mutual combination of PTEN and P38.ResultsWe verified that transforming growth factor-β1(TGF-β1) could induce migration,invasion,and EMT in NPC again,and appropriate concentration was 5ng/ml.Interesting,we demonstrated that 5ng/ml TGF-β1 enhanced the level of p-AKT(Ser473)and p-P38(Thr180/Tyr182).Further more,after overexpression of PTEN WT and various mutants including PTEN-C124S(lacking of both lipid p-hosphatase and protein phosphatase),PTEN-G129E(only lacking of lipid phosph-atase but remaining protein phosphatase),PTEN-Y138L(lacking of protein phosp-hatase but remaining lipid phosphatase),and PTEN 1-353(Lack of c-tail structur-e),we observed that PTEN protein phosphatase reduced the ability of migration,invasion by inhibiting TGF-β1-induced p-P38,but the PTEN c-tail did not invo-lvein this process.At last,we confirmed PTEN could bind to P38 each other.ConclusionsThe asssys in the study indicated that PTEN protein phosphatasemight be anticancer,where it was able to inhibit the ability of TGF-β1 inducingmigration and invasion by reducing p-P38 in NPC cells.