Assessment of multi-source observation merged 1 km-grid precipitation product during the disastrous rainstorms in Guangdong

This paper aims to assess the latest 1 km-grid Analysis Real Time (ART_1 km) precipitation product developed by the National Meteorological Information Center of China Meteorological Administration (CMA), which can provide great support for disaster weather monitoring and warning, intelligent grid forecasting and weather services. Observed precipitation data from the independent stations (including non-uploaded regional meteorological stations and hydrometric stations) that were not integrated into the ART_1 km precipitation product as well as precipitation classification inspection are used to assess the quality of this product during twenty disastrous rainstorm cases from May to August during 2019-2022 in Guangdong. The results show that the ART_1 km precipitation product successfully reproduces the precipitation location, strength, and trends in these cases, with the best performance in the Pearl River Delta, the east of eastern Guangdong, and the north of northern Guangdong. The stronger the precipitation, the greater the correlation as well as the root mean square error (RMSE) and mean error (ME) between the ART_1 km precipitation and the observed precipitation. When the hourly precipitation is not classified, about 60% of these independent stations present a correlation efficient ≥ 0.8, more than 90% of the stations present an RMSE within the range of [1.0, 5.0) mm, and more than 60% of the stations present a ME within ±0.1 mm. When the hourly precipitation is < 5 mm, most of the stations have a correlation efficient < 0.5, an RMSE within the range of [1.0, 5.0) mm, and a ME within [0.0, 0.5] mm. When the hourly precipitation is ≥ 20 mm, 42%~56% of the stations have a correlation efficient ≥ 0.5, and most of the stations have an RMSE ≥ 10 mm and a ME < 0 mm, even when the hourly precipitation is ≥ 50 mm, most of the stations have a ME < -10 mm. Overall, ART_1 km precipitation is usually underestimated at the independent stations, and integrating observations from more sites into producing ART_1 km precipitation is helpful to improve the quality of the products

Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma

Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis. SIGNIFICANCE: Increased splicing-mediated biogenesis of circARFGEF2 in KRAS-mutant pancreatic ductal adenocarcinoma activates JAK2–STAT3 signaling and triggers lymph node metastasis, suggesting circARFGEF2 could be a therapeutic target to inhibit pancreatic cancer progression

Extracellular vesicle-packaged circBIRC6 from cancer-associated fibroblasts induce platinum resistance via SUMOylation modulation in pancreatic cancer

Abstract Background Cancer-associated fibroblasts (CAFs) play pivotal roles in chemoresistance of pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanisms are poorly understood. Revealing the cross-talk network between tumor stroma and pancreatic cancer and developing effective strategies against oxaliplatin resistance are highly desired in the clinic. Methods High-throughput sequence was used to screened the key circRNAs transmitted by extracellular vesicles (EVs) from CAFs to pancreatic cancer cells. The associations between EV-packaged circBIRC6 and chemotherapy responsiveness were validated in a cohort of 82 cases of advanced PDAC patients. Then, the effects of EV-packaged circBIRC6 on CAF-induced oxaliplatin resistance were investigated by flow cytometry, colony formation, viability of pancreatic cancer organoids in vitro and by xenograft models in vivo. RNA pulldown, RNA immunoprecipitation, and sites mutation assays were used to reveal the underlying mechanism. Results We identified a circRNA, circBIRC6, is significantly upregulated in CAF-derived EVs and is positively associated with oxaliplatin-based chemoresistance. In vitro and in vivo functional assays showed that CAF-derived EV-packaged circBIRC6 enhance oxaliplatin resistance of pancreatic cancer cells and organoids via regulating the non-homologous end joining (NHEJ) dependent DNA repair. Mechanistically, circBIRC6 directly binds with XRCC4 and enhanced the interaction of XRCC4 with SUMO1 at the lysine 115 residue, which facilitated XRCC4 chromatin localization. XRCC4K115R mutation dramatically abrogated the EV-packaged circBIRC6 induced effect. Moreover, combination of antisense oligonucleotide inhibitors against circBIRC6 with Olaparib dramatically suppressed chemoresistance in patient-derived xenograft models. Conclusions Our study revealed that EV-packaged circBIRC6 confer oxaliplatin resistance in PDAC by mediating SUMOylation of XRCC4, introducing a promising predictive and therapeutic target for PDAC on oxaliplatin resistance