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Abstract Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N-acyl groups play a decisive role in the reaction activity.

ObjectiveThis study aimed to investigate the characteristics of positional nystagmus in patients with cupulolithiasis of the posterior semicircular canal-benign paroxysmal positional vertigo (PC-BPPV-cu) to improve clinical diagnostic accuracy.MethodsThis study retrospectively analyzed 128 cases of PC-BPPV-cu and 128 cases of canalolithiasis of BPPV (PC-BPPV-ca). General data, intensity, distribution, and the correlation of positional nystagmus were compared between the two groups.ResultsCompared to the PC-BPPV-ca group, more cases from the PC-BPPV-cu group initially presented in the emergency department (P < 0.05). The most frequent positional nystagmus induced by PC-BPPV-cu was torsional-upbeat nystagmus, characterized by the upper pole of the affected eye beating toward the lower ear and vertically upward (387 cases, 59.7%). It was followed by torsional-downbeat nystagmus, characterized by the upper pole of the unaffected eye beating toward the lower ear and vertically downward (164 cases, 25.3%). The former represented posterior canal excitatory nystagmus (PC-EN), while the latter represented posterior canal inhibitory nystagmus (PC-IN). In the PC-BPPV-cu group, PC-EN was most easily caused by the Half Dix–Hallpike (HH) maneuver on the affected side, while PC-IN was most easily induced by a face-down position (FDP) on the unaffected side at approximately 45° angle (45° FDP). The vertical slow phase velocity (v-SPV) of positional nystagmus was more potent in the affected HH than in other positions with PC-EN (all P < 0.05); the v-SPV of positional nystagmus was greater in the 45° FDP than in different positions with PC-IN (all P < 0.05); the v-SPV of the affected Dix–Hallpike (DH) maneuver in the PC-BPPV-ca group was significantly greater than that of the affected HH maneuver in the PC-BPPV-cu group (P < 0.05). The a priori analysis showed that the strongest correlation with HH positional nystagmus was observed in the affected side roll test, followed by the DH maneuver.ConclusionIn the PC-BPPV-cu group, the HH maneuver most easily induced PC-EN on the affected side, and PC-IN was most easily induced by the 45° FDP. In some cases of PC-BPPV-cu, significant nystagmus was not observed to be induced in the DH position on the affected side; however, vertical rotation nystagmus was induced in the roll-test position on the affected side. In such cases, PC-BPPV-cu diagnosis should be considered, and HH and 45° FDP tests should be conducted to support the diagnosis.

Abstract Background There is no evidence supporting the feasibility of laparoscopic pancreaticoduodenectomy (LPD) compared to open pancreatoduodenectomy (OPD) following neoadjuvant chemotherapy (NACT) for pancreatic ductal adenocarcinoma (PDAC). Methods The clinical data of consecutive patients with borderline resectable PDAC who received NACT and underwent either LPD or OPD between January 2020 and December 2022 at Fudan University Shanghai Cancer Center was prospectively collected and retrospectively analyzed. Results The analysis included 57 patients in the OPD group and 20 in the LPD group. Following NACT, the LPD group exhibited a higher median CA19-9 decrease rate compared to the OPD group (85.3% vs. 66.9%, P = 0.042). Furthermore, 3 anatomically borderline PDACs in the LPD group and 5 in the OPD group were downstaged into resectable status (30.0% vs. 12.3%, P = 0.069). According to RECIST criteria, 51 (66.2%) patients in the entire cohort were evaluated as having stable disease. The median operation time for the LPD group was longer than the OPD group (419 vs. 325 min, P 3 cm before NACT (HR 2.185) and poor tumor differentiation (HR 1.805) were independent risk factors for recurrence-free survival, and a decrease rate of CA19-9 > 70% (OR 0.309) was a protective factor for early tumor recurrence and overall survival. Conclusions LPD for PDAC following NACT is feasible and oncologically equivalent to OPD. Effective control of CA19-9 levels is beneficial in reducing early tumor recurrence and improving overall survival.

Abstract Background The defect of B cell self-tolerance and the continuous antigen presentation by T cells (TCs) mediated by autoreactive B cells (BCs) play a key role in the occurrence and development of systemic lupus erythematosus (SLE). PD-1/PD-L1 signaling axis negatively regulates the immune response of TCs after activation and maintains immune tolerance. However, the effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B/CD4+TCs in the peripheral blood of patients with SLE has not been studied in detail. Methods PD-1/PD-L1 and Ki-67 levels in peripheral blood (PB) of 50 SLE patients and 41 healthy controls (HCs) were detected through flow cytometry, and then the expression of PD-1+/−cells and PD-L1+/−cells Ki-67 was further analyzed. CD19+B/CD4+TCs were separated for cell culture and the supernatant was collected to determine proliferation and differentiation of TCs. IL-10 and IFN-γ secretion in the supernatant was also determined using ELISA. Results The PD-1, PD-L1, and Ki-67 levels on CD19+B/CD4+TCs in patients with SLE were higher than HCs. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ cells was higher than that of PD-L1− cells, and the proliferative activity of PD-1+ cells was higher than that of PD-1− cells. In the system co-culturing CD19+B/CD4+TCs from HCs/SLE patients, activated BCs promoted TCs proliferation and PD-L1 expression among TCs. Addition of anti-PD-L1 to co-culture system restored the proliferation of TCs, and inhibited IL-10/IFN-γ level. The addition of anti-PD-L1 to co-culture system also restored Tfh and downregulated Treg in HCs. Conclusions Axis of PD-1/PD-L1 on CD19+B/CD4+TCs in PB of SLE patients is abnormal, and cell proliferation is abnormal. In CD19+B/CD4+TCs of SLE patients, the proliferative activity of PD-L1+ and PD-1+ cells compared with PD-L1− and PD-1− cells in SLE patients, respectively. CD19+B/CD4+TCs in SLE patients can interact through PD-1/PD-L1.

BackgroundOne of the biggest challenges facing older adults is cognitive decline and social participation has always been considered a protective factor. However, it is not clear whether social participation predicts cognitive function in this population, rather than depressive symptoms, self-reported health, and activities of daily life, with sufficient capacity to detect unique effects.MethodsThis study included adults aged 45 and above in China (N = 5,258) who participated in a large national older adult health survey and provided data from 2011, 2013, 2015, and 2018. The unique associations between the predictors of social participation and cognitive function over time and context were evaluated in the Latent Growth Model (LGM).ResultsAmong the 5,258 participants in our study, an overall cognitive decline was observed. Social participation predicts two dimensions of cognitive function, with a degree of impact comparable to depressive symptoms, self-reported health, and activities of daily life. Among them, social participation exhibits a noteworthy prognostic impact on episodic memory during the same period. The regression coefficient is approximately 0.1 (p

Background: Tumors involving the main pancreatic duct (MPD) used to be a contraindication for enucleation. Methods: Clinical data of consecutive patients with pancreatic tumors who received laparoscopic or robotic enucleation (LEN or REN) between January 2019 and December 2021 at Fudan University Shanghai Cancer Center were analyzed. Results: Ninety-six patients were included in the analysis, with 55 in the LEN group and 41 in the REN group, and no conversion to laparotomy. Most tumors were located in the head of pancreas (71.9 %). The tumor diameter (3.1 vs. 1.9 cm) was larger, and more cystic tumors (92.7 % vs. 56.4 %) and more tumors involving the MPD (34.1 % vs. 3.6 %) were observed in the REN group. MPD support tube insertion was performed in 15 cases, with 11 in the REN group and 4 in the LEN group. The incidence of biochemical and grade B postoperative pancreatic fistula (POPF) was both 46.9 %, and no grade C POPF occurred. Among the 45 patients with grade B POPF, 28 cases (62.2 %) were due to carrying drainage tube >3 weeks without additional treatment, and only 4 cases required invasive treatment. For patients with MPD support tube implantation (n = 15), support tube fall-offs were observed in 12 cases, 2 patients had MPD dilatation, and no MPD stricture, stone formation or pancreatic atrophy was observed during follow-up. Conclusions: The incidence of POPF was high but still controllable without serious complications after minimally invasive enucleation. The MPD is no longer a restricted area, and the robotic system has advantages in handling complex enucleations.

Summary: Tumor-suppressive cell competition (TSCC) is a conserved surveillance mechanism in which neighboring cells actively eliminate oncogenic cells. Despite overwhelming studies showing that the unfolded protein response (UPR) is dysregulated in various tumors, it remains debatable whether the UPR restrains or promotes tumorigenesis. Here, using Drosophila eye epithelium as a model, we uncover a surprising decisive role of the Ire1 branch of the UPR in regulating cell polarity gene scribble (scrib) loss-induced TSCC. Both mutation and hyperactivation of Ire1 accelerate elimination of scrib clones via inducing apoptosis and autophagy, respectively. Unexpectedly, relative Ire1 activity is also crucial for determining loser cell fate, as dysregulating Ire1 signaling in the surrounding healthy cells reversed the “loser” status of scrib clones by decreasing their apoptosis. Furthermore, we show that Ire1 is required for cell competition in mammalian cells. Together, these findings provide molecular insights into scrib-mediated TSCC and highlight Ire1 as a key determinant of loser cell fate.

Abstract Gene therapy has emerged as a potential approach for lung cancer therapy. However, the application of gene therapy is still limited by their properties, such as low specificity to the cancer cells, negatively charged groups, short systemic circulation time, and rapid degradation by nucleases. The progression of lung adenocarcinoma (LUAD) can be promoted through the methylation process of miR‐148a‐3p promoter, as confirmed by our previous research. In the current study, we are the first to design a mirrored Arg‐Gly‐Asp (RGD)‐modified cationic peptide (RD24) as a microRNA (miRNA) vehicle, which enabled to pack the miRNA (miR‐148a‐3p) efficiently and generate RD24/miR‐148a‐3p nanoparticles (RPRIN) by self‐assembling. RPRIN exhibited a high transfection efficiency in lung cancer cells via the conjugation between RGD and integrins on the surface of lung cancer cells. Furthermore, RD24 showed matrix metallopeptidase 2 (MMP2) responsiveness, which improved lung cancer cell inhibition induced by the miRNA intracellularly. In addition, RPRIN exhibits several advantages, such as prolonged circulation duration, reduced toxicity, and immune escape. Experiments conducted both in vitro and in vivo revealed that RPRIN effectively suppressed the growth and progression of lung cancer. Thus, the mirrored RGD‐modified cationic peptide showed great potential in transducing miRNA for lung cancer therapy.

Abstract The balance of M1/M2 macrophage polarization plays an important role in regulating inflammation during acute lung injury (ALI). Yes‐associated protein (YAP1) is a key protein in the Hippo–YAP1 signaling pathway and is involved in macrophage polarization. We aimed to determine the role of YAP1 in pulmonary inflammation following ALI and regulation of M1/M2 polarization. Pulmonary inflammation and injury with upregulation of YAP1 were observed in lipopolysaccharide (LPS)‐induced ALI. The YAP1 inhibitor, verteporfin, attenuated pulmonary inflammation and improved lung function in ALI mice. Moreover, verteporfin promoted M2 polarization and inhibited M1 polarization in the lung tissues of ALI mice and LPS‐treated bone marrow‐derived macrophages (BMMs). Additionally, siRNA knockdown confirmed that silencing Yap1 decreased chemokine ligand 2 (CCL2) expression and promoted M2 polarization, whereas silencing large tumor suppressor 1 (Lats1) increased CCL2 expression and induced M1 polarization in LPS‐treated BMMs. To investigate the role of inflammatory macrophages in ALI mice, we performed single‐cell RNA sequencing of macrophages isolated from the lungs. Thus, verteporfin could activate the immune‐inflammatory response, promote the potential of M2 macrophages, and alleviate LPS‐induced ALI. Our results reveal a novel mechanism where YAP1‐mediated M2 polarization alleviates ALI. Therefore, inhibition of YAP1 may be a target for the treatment of ALI.

DNA–Protein cross-links (DPCs) are cytotoxic DNA lesions with a protein covalently bound to the DNA. Although much has been learned about the formation, repair, and biological consequences of DPCs in the nucleus, little is known regarding mitochondrial DPCs. This is due in part to the lack of robust and specific methods to measure mitochondrial DPCs. Herein, we reported an enzyme-linked immunosorbent assay (ELISA)-based method for detecting mitochondrial DPCs formed between DNA and mitochondrial transcription factor A (TFAM) in cultured human cells. To optimize the purification and detection workflow, we prepared model TFAM-DPCs via Schiff base chemistry using recombinant human TFAM and a DNA substrate containing an abasic (AP) lesion. We optimized the isolation of TFAM-DPCs using commercial silica gel-based columns to achieve a high recovery yield for DPCs. We evaluated the microplate, DNA-coating solution, and HRP substrate for specific and sensitive detection of TFAM-DPCs. Additionally, we optimized the mtDNA isolation procedure to eliminate almost all nuclear DNA contaminants. For proof of concept, we detected the different levels of TFAM-DPCs in mtDNA from HEK293 cells under different biological conditions. The method is based on commercially available materials and can be amended to detect other types of DPCs in mitochondria.

This study demonstrated Da Vinci robot assisted pancreaticoduodenectomy with superior mesenteric vein (SMV) resection and reconstruction. The patient was diagnosed with pancreatic head cancer preoperatively. After anesthesia, trocars were placed by “six-hole method”, and then constant pressure pneumoperitoneum was established. The first step was to remove the gallbladder, open the gastrocolonic ligament, and expose the pancreas and surrounding tissues. After making a Kocher incision, we dissected duodenum, inferior vena cava and uncinate process of pancreas, and then cleaned lymph nodes in groups 13 and 16A. After the stomach was severed using linear stapler, the right gastric artery was dissected and ligated. In this case, the adhesion around the pancreas and common hepatic artery was serious, so the pancreas was transected firstly. The gastroduodenal artery was dissected from the upper edge of the pancreas, and the lymph nodes in groups 7, 8, 9 and 12 were cleaned to expose the common bile duct and portal vein. The common bile duct was transected above the confluence plane of the cystic duct. After opening the colonic mesentery on the left side of the superior mesenteric artery (SMA), the jejunum was severed with a linear cutting obturator. The uncinate process was treated through the middle artery approach; the inferior pancreaticoduodenal artery was severed and lymph nodes were cleaned to the root of SMA and celiac trunk. The tumor and part of the invaded SMV were removed and end-to-end SMV anastomosis was performed. The proper hepatic artery was wrapped with the round hepatic ligament. To protect the stump of gastroduodenal artery, we padded the round hepatic ligament below the pancreaticoduodenal anastomosis. The modified Blumgart method was used for pancreaticointestinal duct to mucosal anastomosis. 4-0 ​V-Lock suture was used for continuous suture of posterior wall and anterior wall respectively, and finally gastrointestinal side-to-side anastomosis was performed. The operation time was 360 ​min and the intraoperative bleeding was 200 ​mL. The patient was discharged 7 days after operation.

Abstract Background Lung cancer is one of the fatal cancers worldwide, and over 60% of patients are lung adenocarcinoma (LUAD). Our clinical data demonstrated that DNA methylation of the promoter region of miR-126-3p was upregulated, which led to the decreased expression of miR-126-3p in 67 cases of lung cancer tissues, implying that miR-126-3p acted as a tumor suppressor. Transduction of miR-126-3p is a potential therapeutic strategy for treating LUAD, yet the physiological environment and properties of miRNA challenge current transduction approaches. Methods We evaluated the expression of miR-126-3p in 67 pairs of lung cancer tissues and the corresponding adjacent non-tumorous tissues by Reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The relationship between the overall survival of lung cancer patients and miR-126-3p was analyzed by the Cancer Genome Atlas cohort database (Oncolnc, http://www.oncolnc.org ). We analyzed DNA methylation Methylation-specific PCR (MSP) analysis. To determine whether ADAM9 is the direct target of miR-126-3p, we performed the 3′-UTR luciferase reporter assay. The protein levels in the cells or tissues were evaluated with western blotting (WB) analysis. The biodistribution of nanoparticles were monitored by in vivo tracking system. Results We describe the development of novel stealth and matrix metalloproteinase 2 (MMP2)-activated biomimetic nanoparticles, which are constructed using MMP2-responsive peptides to bind the miR-126-3p (known as MAIN), and further camouflaged with red blood cell (RBC) membranes (hence named REMAIN). REMAIN was able to effectively transduce miRNA into lung cancer cells and release them via MMP2 responsiveness. Additionally, REMAIN possessed the advantages of the natural RBC membrane, including extended circulation time, lower toxicity, better biocompatibility, and immune escape. Moreover, in vitro and in vivo results demonstrated that REMAIN effectively induced apoptosis of lung cancer cells and inhibited LUAD development and progression by targeting ADAM9. Conclusion The novel style of stealth and MMP2-activated biomimetic nanoparticles show great potential in miRNA delivery.

Nephronophthisis (NPHP) is a ciliopathy characterized by renal fibrosis and cyst formation, and accounts for a significant portion of end stage renal disease in children and young adults. Currently, no targeted therapy is available for this disease. INVS/NPHP2 is one of the over 25 NPHP genes identified to date. In mouse, global knockout of Invs leads to renal fibrosis and cysts. However, the precise contribution of different cell types and the relationship between epithelial cysts and interstitial fibrosis remains undefined. Here, we generated and characterized cell-type-specific knockout mouse models of Invs, investigated the impact of removing cilia genetically on phenotype severity in Invs mutants and evaluated the impact of the histone deacetylase inhibitor valproic acid (VPA) on Invs mutants. Epithelial-specific knockout of Invs in Invsflox/flox;Cdh16-Cre mutant mice resulted in renal cyst formation and severe stromal fibrosis, while Invsflox/flox;Foxd1-Cre mice, where Invs is deleted in stromal cells, displayed no observable phenotypes up to the young adult stage, highlighting a significant role of epithelial-stromal crosstalk. Further, increased cell proliferation and myofibroblast activation occurred early during disease progression and preceded detectable cyst formation in the Invsflox/flox;Cdh16-Cre kidney. Moreover, concomitant removal of cilia partially suppressed the phenotypes of the Invsflox/flox;Cdh16-Cre mutant kidney, supporting a significant interaction of cilia and Invs function in vivo. Finally, VPA reduced cyst burden, decreased cell proliferation and ameliorated kidney function decline in Invs mutant mice. Our results reveal the critical role of renal epithelial cilia in NPHP and suggest the possibility of repurposing VPA for NPHP treatment.

Abstract Background Although some factors that predict the prognosis in pancreatic neuroendocrine tumor (pNET) have been confirmed, the predictive value of lymph node metastasis (LNM) in the prognosis of pNETs remains conflicting and it is not clear whether regional lymphadenectomy should be performed in all grades of tumors. Methods We included pNET patients undergoing surgery in Shanghai pancreatic cancer institute (SHPCI). The risk factors for survival were investigated by the Kaplan–Meier method and Cox regression model. We evaluated the predictors of LNM using Logistic regression. Results For 206 patients in the SHPCI series, LNM was an independent prognostic factor for entire cohort suggested by multivariate Cox regression analysis. LNM (P = 0.002) predicted poorer overall survival (OS) in grade 2/3 cohort, but there is no significant association between LNM and OS in grade 1 cohort. Grade (P 4 cm tumors. On the other way, LNM was seems to be not associated with prognosis in patients with grade 1 tumors less than 4 cm. Moreover, tumor grade and tumor size seem to act as independent predictors of LNM. Thus, regional lymphadenectomy should be performed in grade 2/3 patients but was not mandatory in grade 1 tumors

Abstract Background The relationship between online media exposure and disordered eating symptoms has been reported in western regions. Though the prevalence of eating disorders and access to the Internet increased substantially in recent years, relevant evidence is rare in mainland China. This study aims to evaluate the association between online media exposure or weight and fitness management app use and disordered eating symptoms in Chinese mainland young adults, and the mediation effect of disordered eating cognition. Methods 353 Chinese mainland female and 142 male young adults completed online questionnaires consisting of demographic information, Eating Disorder Examination-Questionnaire 6.0 (EDE-Q 6.0), and items relating to online media exposure and weight and fitness management app use. Through correlation analysis, the relationship between online media exposure or weight and fitness management app use and disordered eating symptoms was examined, separately by sex. The mediation effect of disordered eating cognition on the relationship between online media exposure or weight and fitness management app use on disordered eating behaviors was investigated with two moderated mediation models. Results Young female adults in the Chinese mainland presented higher disordered eating symptoms and were more engaged in online media and weight and fitness management app use than males. Online media exposure and weight and fitness management app use showed a significant correlation with disordered eating behaviors in males and females. Disordered eating cognition mediated the relationship between online media exposure or weight and fitness management app use and disordered eating behaviors. This effect was significantly higher in females. Conclusion Online media exposure and weight and fitness management app use play a crucial role in the generation of disordered eating symptoms in Chinese mainland young adults, especially in females. The mediation analysis suggested the importance of prevention and intervention of disordered eating cognition. Monitoring and scientific guidance of online media are necessary.

Abstract Background ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. Methods IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. Results To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. Conclusions Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development.

In order to encourage residents to go to primary care facilities, China has set up differentiated basic medical insurance reimbursement ratios. The study aims to use the dynamic point of view of longitudinal data to examine the changes in the impact of basic medical insurance on primary care. The data for this study comes from the Chinese Family Panel Study (CFPS) in 2010, 2012, 2014, 2016, and 2018. We adopted Hierarchal Age-period-cohort-Cross-Classified Random Effects Models (HAPC-CCREM) to examine the changes in the impact of basic medical insurance on primary care. Compared with non-insured groups, participants of the New Rural Cooperative Medical System (coefficient = 0.730) have a relatively high incidence of primary care seeks, while Urban Residents' Basic Medical Insurance (coefficient = −0.482) and Urban Employees' Basic Medical Insurance (coefficient = −0.663) are lower, respectively. Age, period over time and cohort have a more obvious moderating effect on primary care seeks. The study of primary care behavior is an important direction for the construction of a hierarchical medical system. As basic medical insurance is the source of power for the hierarchical medical system, we can provide certain direction for policy formulation on the changes of basic medical insurance in primary care behavior.

The diagnostic value of procalcitonin and the prognostic role of PCT clearance remain unclear in neutropenic period after allogeneic hematopoietic stem cell transplantation introduction. This study evaluated 219 febrile neutropenic patients (116, retrospectively; 103, prospectively) who underwent allo-HSCT from April 2014 to March 2016. The area under the receiver operator characteristic curve (AUC) of PCT for detecting documented infection (DI) was 0.637, and that of bloodstream infection (BSI) was 0.811. In multivariate analysis, the inability to decrease PCT by more than 80% within 5–7 days after the onset of fever independently predicted poor 100-day survival following allo-HSCT (P = 0.036). Furthermore, the prognostic nomogram combining PCTc and clinical parameters showed a stable predictive performance, supported by the C-index of 0.808 and AUC of 0.813 in the primary cohort, and C-index of 0.691 and AUC of 0.697 in the validation cohort. This study demonstrated the diagnostic role of PCT in documented and bloodstream infection during the neutropenic period after allo-HSCT. PCTc might serve as a predictive indicator of post-HSCT 100-day mortality. A nomogram based on PCTc and several clinical factors effectively predicted the 100-day survival of febrile patients and may help physicians identify high-risk patients in the post-HSCT neutropenic period.

Hemophagocytic lymphohistiocytosis is a rare and almost universally fatal disease in adults. A 60-year-old female patient presented to our hospital with a 3-day history of weakness and anorexia. Physical examination revealed severe pallor without lymphadenopathy or hepatosplenomegaly. The initial blood test showed a hemoglobin level of 2.6 g/dL and a platelet count of 76 × 10 9 /L. Later the patient experienced persistent high fever for 1 week without any obvious infective symptoms. Biochemical examination revealed hyperferritinemia and low natural killer cell viability. The bone marrow morphology showed hemophagocytosis and infiltration with metastatic small-cell lung cancer. The patient was diagnosed as small-cell lung cancer-related hemophagocytic lymphohistiocytosis. Subsequently, she underwent chemotherapy with dexamethasone and etoposide. However, the patient succumbed within 2 weeks of presentation due to rapidly progressive disease. In conclusion, we reported the first hemophagocytic lymphohistiocytosis case with small-cell lung cancer. It is critical to have early identification of hemophagocytic lymphohistiocytosis in patients with small-cell lung cancer.

In order to achieve the vision of seamless wireless communication coverage, a space–air–ground integrated network is proposed as a key component of the sixth-generation (6G) mobile communication system. However, the spectrum used by aerial networks has become gradually crowded with the increase in wireless devices. Space networks are also in dire need of developing new bands to address spectrum shortages. As an effective way to solve the spectrum shortage problem, spectrum sharing between aerial/space networks and ground networks has been extensively studied. This article summarizes state-of-the-art studies on spectrum sharing between aerial/space networks and ground networks. First, this article provides an overview of aerial networks and space networks and introduces the main application scenarios of aerial networks and space networks. Then, this article summarizes the spectrum sharing techniques between aerial/space networks and ground networks, including existing spectrum utilization rules, spectrum sharing modes and key technologies. Finally, we summarize the challenges of spectrum sharing between aerial/space networks and ground networks. This article provides guidance for spectrum allocation and spectrum sharing of space–air–ground integrated networks.

BackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression.MethodsWe evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment.ResultsWe found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21.ConclusionsOur results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.

Arabidopsis mitochondrial-localized heat shock protein 70-1 (mtHSC70-1) modulates vegetative growth by assisting mitochondrial complex IV assembly and maintaining reactive oxygen species (ROS) homeostasis. In addition, mtHSC70-1 affects embryo development, and this effect is mediated by auxin. However, whether mtHSC70-1 regulates vegetative growth through auxin and knowledge of the link between ROS homeostasis and auxin distribution remain unclear. Here, we found that mtHSC70-1 knockout seedlings (mthsc70-1a) displayed shortened roots, decreased fresh root weight and lateral root number, increased root width and abnormal root morphology. The introduction of the mtHSC70-1 gene into mthsc70-1a restored the growth and development of roots to the level of the wild type. However, sugar and auxin supplementation could not help the mutant roots restore to normal. Moreover, mthsc70-1a seedlings showed a decrease in meristem length and activity, auxin transport carrier (PINs and AUX1) and auxin abundances in root tips. The application of exogenous reducing agents upregulated the levels of PINs in the mutant roots. The introduction of antioxidant enzyme genes (MSD1 or CAT1) into the mthsc70-1a mutant rescued the PIN and local auxin abundances and root growth and development. Taken together, our data suggest that mtHSC70-1 regulates polar auxin transport through ROS homeostasis in Arabidopsis roots.

There is striking racial disparity in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates in the United States. We hypothesize that the disparity is significantly smaller in areas with a higher ratio of green spaces. County level data on the SARS-CoV-2 infection rates of black and white individuals in 135 of the most urbanized counties across the United States were collected. The total population in these counties is 132,350,027, comprising 40.3% of the U.S. population. The ratio of green spaces by land-cover type in each county was extracted from satellite imagery. A hierarchical regression analysis measured cross-sectional associations between racial disparity in infection rates and green spaces, after controlling for socioeconomic, demographic, pre-existing chronic disease, and built-up area factors. We found a higher ratio of green spaces at the county level is significantly associated with a lower racial disparity in infection rates. Four types of green space have significant negative associations with the racial disparity in SARS-CoV-2 infection rates. A theoretical model with five core mechanisms and one circumstantial mechanism is presented to interpret the findings.

Both Hippo signaling pathways and cell polarity regulation are critical for cell proliferation and the maintenance of tissue homeostasis, despite the well-established connections between cell polarity disruption and Hippo inactivation, the molecular mechanism by which aberrant cell polarity induces Hippo-mediated overgrowth remains underexplored. Here we use Drosophila wing discs as a model and identify the Wnd-Nmo axis as an important molecular link that bridges loss-of-cell polarity-triggered Hippo inactivation and overgrowth. We show that Wallenda (Wnd), a MAPKKK (mitogen-activated protein kinase kinase kinase) family member, is a novel regulator of Hippo pathways in Drosophila and that overexpression of Wnd promotes growth via Nemo (Nmo)- mediated Hippo pathway inactivation. We further demonstrate that both Wnd and Nmo are required for loss-of-cell polarity-induced overgrowth and Hippo inactivation. In summary, our findings provide a novel insight on how cell polarity loss contributes to overgrowth and uncover the Wnd-Nmo axis as an essential additional branch that regulates Hippo pathways in Drosophila.

Abstract Background The introduction of laparoscopic technology has greatly promoted the development of surgery, and the trend of minimally invasive surgery is becoming more and more obvious. However, there is no consensus as to whether laparoscopic pancreaticoduodenectomy (LPD) should be performed routinely. Main body We summarized the development of laparoscopic pancreaticoduodenectomy (LPD) in recent years by comparing with open pancreaticoduodenectomy (OPD) and robotic pancreaticoduodenectomy (RPD) and evaluated its feasibility, perioperative, and long-term outcomes including operation time, length of hospital stay, estimated blood loss, and overall survival. Then, several relevant issues and challenges were discussed in depth. Conclusion The perioperative and long-term outcomes of LPD are no worse and even better in length of hospital stay and estimated blood loss than OPD and RPD except for a few reports. Though with strict control of indications, standardized training, and learning, ensuring safety and reducing cost are still and will always the keys to the healthy development of LPD; the best times for it are coming.

Abstract Background The epigenetic factor protein arginine methyltransferase 5 (PRMT5) has been reported to play vital roles in a wide range of cellular processes, such as gene transcription, genomic organization, differentiation and cell cycle control. However, its role in pancreatic cancer remains unclear. Our study aimed to investigate the roles of PRMT5 in pancreatic cancer prognosis and progression and to explore the underlying molecular mechanism. Methods Real-time PCR, immunohistochemistry and analysis of a dataset from The Cancer Genome Atlas (TCGA) were performed to study the expression of PRMT5 at the mRNA and protein levels in pancreatic cancer. Cell proliferation assays, including cell viability, colony formation ability and subcutaneous mouse model assays, were utilized to confirm the role of PRMT5 in cell proliferation and tumorigenesis. A Seahorse extracellular flux analyzer, a glucose uptake kit, a lactate level measurement kit and the measurement of 18F-FDG (fluorodeoxyglucose) uptake by PET/CT (positron emission tomography/computed tomography) imaging were used to verify the role of PRMT5 in aerobic glycolysis, which sustains cell proliferation. The regulatory effect of PRMT5 on cMyc, a master regulator of oncogenesis and aerobic glycolysis, was explored by quantitative PCR and protein stability measurements. Results PRMT5 expression was significantly upregulated in pancreatic cancer tissues compared with that in adjacent normal tissues. Clinically, elevated expression of PRMT5 was positively correlated with worse overall survival in pancreatic cancer patients. Silencing PRMT5 expression inhibited the proliferation of pancreatic cancer cells both in vitro and in vivo. Moreover, PRMT5 regulated aerobic glycolysis in vitro in cell lines, in vivo in pancreatic cancer patients and in a xenograft mouse model used to measure 18F-FDG uptake. We found that mechanistically, PRMT5 posttranslationally regulated cMyc stability via F-box/WD repeat-containing protein 7 (FBW7), an E3 ubiquitin ligase that controls cMyc degradation. Moreover, PRMT5 epigenetically regulated the expression of FBW7 in pancreatic cancer cells. Conclusions The present study demonstrated that PRMT5 epigenetically silenced the expression of the tumor suppressor FBW7, leading to increased cMyc levels and the subsequent enhancement of the proliferation of and aerobic glycolysis in pancreatic cancer cells. The PRMT5/FBW7/cMyc axis could be a potential therapeutic target for the treatment of pancreatic cancer.

Abstract Background Hepatocyte nuclear factor 4α (HNF4α) is a tissue-specific transcription factor that regulates the expression of numerous genes in hepatocytes and pancreatic β cells. HNF4α has been reported to affect cell proliferation and chemoresistance in several cancers. However, the role of HNF4α in pancreatic adenocarcinoma (PDAC) has not been studied extensively and remains unclear. Methods By utilizing immunohistochemical (IHC) staining, we measured the expression of HNF4α in PDAC tissues. By silencing HNF4α in PDAC cell lines, we assessed the impact of HNF4α on pancreatic cancer cell proliferation and gemcitabine sensitivity. We used CCK8 and colony formation assays to examine the effect of HNF4α on cell proliferation. A flow cytometry assay was used to assess cell apoptosis. The expression of gemcitabine-related genes was detected by quantitative real‑time PCR (qRT-PCR) and Western blotting. IHC was utilized to assess the correlation between HNF4α and human equilibrative nucleoside transporter 1 (hENT1) expression in PDAC patients. Chromatin immunoprecipitation (ChIP) and dual‑luciferase reporter assays were used to confirm that hENT1 is a target gene of HNF4α. Results Increased HNF4α expression was detected in PDAC tissues; patients with higher HNF4α expression displayed worse prognosis. To elucidate the function of HNF4α, we examined its role in pancreatic cancer cell proliferation, apoptosis and gemcitabine resistance. In HNF4α-silenced Capan-1 and MiaPaCa-2 cells, we observed decreased cell proliferation and increased sensitivity to gemcitabine compared to those of controls. The mechanism of HNF4α in gemcitabine-related chemosensitivity was then explored. In response to HNF4α silencing, the expression levels of gemcitabine-related proteins, hENT1 and deoxycytidine kinase (dCK) were significantly increased. Additionally, hENT1 was negatively correlated with HNF4α in PDAC tissue samples. Moreover, we identified hENT1 as a downstream target of HNF4α. Conclusion HNF4α is a prognostic marker for overall survival, is required for pancreatic cancer cell proliferation and promotes resistance to gemcitabine by downregulating hENT1. Therefore, targeting HNF4α might reverse gemcitabine resistance and provide novel treatment strategies for PDAC.

FBW7 functions as a tumor suppressor by targeting oncoproteins for degradation. Our previous study found FBW7 was low expressed in pancreatic cancer due to sustained activation of Ras-Raf-MEK-ERK pathway, which destabilized FBW7 by phosphorylating at Thr205. MicroPET/CT imaging results revealed that FBW7 substantially decreased 18F-fluorodeoxyglucose uptake in xenograft tumors. Mechanistically, FBW7 inhibited glucose metabolism via c-Myc/TXNIP axis. But in these studies, we observed FBW7 down-regulated genes were widely involved in redox reaction and lipid metabolism. Here we reanalyzed previous gene expression profiling and conducted targeted cell metabolites analysis. Results revealed that FBW7 regulated lipid peroxidation and promoted ferroptosis, a non-apoptotic form of cell death. Mechanistically, we found FBW7 inhibited the expression of stearoyl-CoA desaturase (SCD1) via inhibiting nuclear receptor subfamily 4 group A member 1 (NR4A1). SCD1 was reported to inhibit both ferroptosis and apoptosis, which was consistent with the function of FBW7 and NR4A1, another FBW7 down-regulated gene in the gene expression profiling. Moreover, FBW7 potentiated cytotoxic effect of gemcitabine via activating ferroptosis and apoptosis. Combination ferroptosis inducers and apoptosis activators could also significantly potentiated cytotoxic effect of gemcitabine in pancreatic cancer. Therefore, our findings might provide new strategies for the comprehensive treatment of pancreatic cancer.

Background During the outbreak of COVID-19, the national policy of home quarantine may affect the mental health of parents. However, few studies have investigated the mental health of parents during the COVID-19 pandemic.Aims To investigate the depression, anxiety and stress of the students’ parents during the COVID-19 pandemic, and to explore the influence factors, especially the influence of social support and family-related factors.Methods The Generalised Anxiety Disorder-7, Patient Health Questionnaire-9, Perceived Stress Scale-10 and Social Support Rating Scale were applied to 1163 parents to measure the parents’ depression, anxiety, stress and social support.Results (1) The detection rates of depression and anxiety in parents were 6.1% and 4.0%. The depression, anxiety and perceived stress of parents in central China were significantly higher than those in non-central China. The anxiety of college students’ parents was lower than that of parents of the primary, middle and high school students. The depression, anxiety and perceived stress of parents with conflicts in the family were significantly higher than those with a harmonious family. Other factors that influence parents’ depression, anxiety and perceived stress include marital satisfaction, social support, parents’ history of mental illness and parenting style, etc. (2) The regression analysis results showed that perceived stress, social support, marital satisfaction, family conflicts, child’s learning stage as well as parents’ history of mental illness had significant effects on parents’ anxiety and depression.Conclusion During the COVID-19 pandemic, the mental health of parents was affected by a variety of factors. Good marital relationships, good social support, family harmony and parents without a history of mental illness may be protective factors for parents’ mental health, while perceived stress and child in middle or high school are risk factors for parents’ mental health.