Electrochemical synthesis of peptide aldehydes via C‒N bond cleavage of cyclic amines.

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.

Evaluating the efficacy of laparoscopic radical antegrade modular pancreatosplenectomy in selected early-stage left-sided pancreatic cancer: a propensity score matching study.

BACKGROUND: Laparoscopic radical pancreatectomy is safe and beneficial for recectable pancreatic cancer, but the extent of resection for early-stage tumors remains controversial. METHODS: Consecutive patients with left-sided pancreatic cancer who underwent either laparoscopic radical antegrade modular pancreatosplenectomy (LRAMPS, n = 54) or laparoscopic distal pancreatosplecnectomy (LDP, n = 131) between October 2020 and December 2022 were reviewed. The preoperative radiological selection criteria were as follows: (1) tumor diameter ≤ 4 cm; (2) located ≥ 1 cm from the celiac trunk; (3) didn't invade the fascial layer behind the pancreas. RESULTS: After 1:1 propensity score matching (LRAMPS, n = 54; LDP, n = 54), baseline data were well-balanced with no differences. LRAMPS resulted in longer operation time (240.5 vs. 219.0 min, P = 0.020) and higher intraoperative bleeding volume (200 vs. 150 mL, P = 0.001) compared to LDP. Although LRAMPS harvested more lymph nodes (16 vs. 13, P = 0.008), there were no statistically significant differences in lymph node positivity rate (35.2% vs. 33.3%), R0 pancreatic transection margin (94.4% vs. 96.3%), and retroperitoneal margin (83.3% vs. 87.0%) rate. Postoperative complications did not significantly differ between the two groups. However, LRAMPS was associated with increased drainage volume (85.0 vs. 40.0 mL, P = 0.001), longer time to recover semi-liquid diet compared to LDP (5 vs. 4 days, P < 0.001) and increased daily bowel movement frequency. Tumor recurrence pattern and recurrence-free survival were comparable between the two groups, but the adjuvant chemotherapy regimens varied, and the completion rate of the 6-month intravenous chemotherapy was lower in the LRAMPS group compared to the LDP group (51.9% vs. 75.9%, P = 0.016). CONCLUSIONS: LRAMPS did not provide oncological benefits over LDP for left-sided pancreatic cancer within the selection criteria, but it increased operation time, intraoperative bleeding, and postoperative bowel movement frequency. These factors impacted the regimen selection and completion of adjuvant chemotherapy, consequently compromising the potential benefits of LRAMPS in achieving better local control.

L-tryptophan anaerobic fermentation for indole acetic acid production: Bacterial enrichment and effects of zero valent iron.

Indole acetic acid (IAA) as a plant hormone, was one of the valuable products of anaerobic fermentation. However, the enriching method remained unknown. Moreover, whether zero valent iron (ZVI) could enhance IAA production was unexplored. In this work, IAA producing bacteria Klebsiella (63 %) was enriched successfully. IAA average production rate and concentration were up to 3 mg/L/h and 56 mg/L. With addition of 1 g/L ZVI, IAA average production rate and concentration was increased for 2 and 3 folds. Mechanisms indicated ZVI increased Na+K+-ATP activity and electron transport activity for 2 folds and 1 fold. Moreover, macro transcription determined indole pyruvate pathway activity like primary-amine oxidase, indole pyruvate decarboxylase and aldehyde dehydrogenase were increased for 146 %, 187 %, and 557 %, respectively. Therefore, ZVI was suitable for enhancement IAA production from mixed culture anaerobic fermentation.

Feasibility of laparoscopic versus open pancreatoduodenectomy following neoadjuvant chemotherapy for borderline resectable pancreatic cancer: a retrospective cohort study.

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 < 0.001), while the venous resection rate was 35.0% vs. 43.9%, respectively (P = 0.489). There was no difference in the number of retrieved lymph nodes, with a median number of 18.5 in the LPD group and 22 in the OPD group, and the R1 margin rate (15.0% vs. 12.3%) was also comparable. The incidence of Clavien-Dindo complications (35.0% vs. 66.7%, P = 0.018) was lower in the LPD group compared to the OPD group. Multivariable regression analysis revealed that a tumor diameter > 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.

Differential Ire1 determines loser cell fate in tumor-suppressive cell competition.

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.

Minimally invasive enucleation of pancreatic tumors: The main pancreatic duct is no longer a restricted area.

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.

Application of split pancreatic duct stent in laparoscopic pancreaticoduodenectomy.

Laparoscopic pancreaticoduodenectomy (LPD) is a classic surgical method for diseases, such as tumors at the lower end of the common bile duct, pancreatic head, and benign and malignant tumors of the duodenum. Postoperative pancreatic fistula (POPF) is one of the most serious complications of LPD. To reduce the incidence of grade B or C POPF and other complications after LPD, we applied a split pancreatic duct stent combined with the characteristics of internal and external stent drainage. Between September 2020 and September 2022,12 patients underwent placement of the Split pancreatic duct stent during LPD. Data on basic characteristics of patients, surgical related indicators and postoperative POPF incidence were collected and analyzed. The results showed that the average operation time was 294.2 ± 36 minutes, average time for pancreaticojejunostomy was 35.9 ± 4.1 minutes, and average estimated blood loss was 204.2 ± 58.2 mL. Biochemical leakage occurred in 2 patients (16.7%), whereas no grade B or C POPF, 1 case (8.3%) had postoperative bleeding, and no death occurred within 30 days after the operation. Preliminary experience shows that the split pancreatic duct stent can effectively reduce the incidence of complications after LPD, especially grade B or C POPF.

The mirrored cationic peptide as miRNA vehicle for efficient lung cancer therapy.

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.

Inhibition of YAP1 activity ameliorates acute lung injury through promotion of M2 macrophage polarization.

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.

Inactivation of Invs/Nphp2 in renal epithelial cells drives infantile nephronophthisis like phenotypes in mouse.

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.

One of the most common causes of kidney failure in children and young adults is nephronophthisis. This genetic disease causes cysts and tissue scarring in the kidneys, leading to excessive urine production and extreme tiredness. Unfortunately, there is no targeted therapy available for this condition. Scientists do not fully understand how genetic mutations lead to these symptoms. Previous research in mice showed that blocking the gene for a protein called INVS recreated signs similar to nephronophthisis. However, it is not clear how the different cell types in the kidneys are involved. Previous results suggest that cilia, the hair-like projections on the surface of cells, could be involved in developing cysts in nephronophthisis. To understand how the disease is driven, Li, Xu et al. created a range of genetically modified mice with INVS missing in different cell types. When INVS was removed from cells that line the kidney tubules, the mice developed scarring and cysts. By contrast, there were no symptoms when connective tissue cells were lacking INVS. When Li, Xu et al. removed the cilia from the cells, it helped to reduce the negative impact of the loss of INVS. In addition, a drug called valproic acid reduced the cysts and tissue scarring, and slowed kidney decline in the mutant mice, suggesting the possibility of repurposing this drug for nephronophthisis treatment. These results could help researchers to study other conditions that are influenced by the health of cilia. Future work on nephronophthisis will be needed to understand how INVS causes the disease and the mechanism for the benefits of valproic acid.

The effect of PD-1/PD-L1 signaling axis on the interaction between CD19+B cells and CD4+T cells in peripheral blood of patients with systemic lupus erythematosus

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.

Ptp61F integrates Hippo, TOR, and actomyosin pathways to control three-dimensional organ size.

Precise organ size control is fundamental for all metazoans, but how organ size is controlled in a three-dimensional (3D) way remains largely unexplored at the molecular level. Here, we screen and identify Drosophila Ptp61F as a pivotal regulator of organ size that integrates the Hippo pathway, TOR pathway, and actomyosin machinery. Pathologically, Ptp61F loss synergizes with RasV12 to induce tumorigenesis. Physiologically, Ptp61F depletion increases body size and drives neoplastic intestinal tumor formation and stem cell proliferation. Ptp61F also regulates cell contractility and myosin activation and controls 3D cell shape by reducing cell height and horizontal cell size. Mechanistically, Ptp61F forms a complex with Expanded (Ex) and increases endosomal localization of Ex and Yki. Furthermore, we demonstrate that PTPN2, the conserved human ortholog of Ptp61F, can functionally substitute for Ptp61F in Drosophila. Our work defines Ptp61F as an essential determinant that controls 3D organ size under both physiological and pathological conditions.

Health Risk Assessment during In Situ Remediation of Cr(VI)-Contaminated Groundwater by Permeable Reactive Barriers: A Field-Scale Study.

The presence of residual Cr(VI) in soils causes groundwater contamination in aquifers, affecting the health of exposed populations. Initially, permeable reactive barriers(PRB) effectively removed Cr(VI) from groundwater. However, as PRB clogging increased and Cr(VI) was released from upstream soils, the contamination plume continued to spread downstream. By 2020, the level of contamination in the downstream was nearly identical to that in the upstream. The study results show that during normal operation, the PRB can successfully remove Cr(VI) from contaminated groundwater and reduce the carcinogenic and non-carcinogenic risks to humans from the downstream side of groundwater. However, the remediated groundwater still poses an unacceptable risk to human health. The sensitivity analysis revealed that the concentration of the pollutant was the most sensitive parameter and interacted significantly with other factors. Ultimately, it was determined that the residual Cr(VI) in the soil of the study region continues to contaminate the groundwater and constitutes a serious health danger to residents in the vicinity. As remediated groundwater still poses a severe threat to human health, PRB may not be as effective as people believe.

Bip-Yorkie interaction determines oncogenic and tumor-suppressive roles of Ire1/Xbp1s activation.

Unfolded protein response (UPR) is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. ER proteostasis is essential to adapt to cell proliferation and regeneration in development and tumorigenesis, but mechanisms linking UPR, growth control, and cancer progression remain unclear. Here, we report that the Ire1/Xbp1s pathway has surprisingly oncogenic and tumor-suppressive roles in a context-dependent manner. Activation of Ire1/Xbp1s up-regulates their downstream target Bip, which sequesters Yorkie (Yki), a Hippo pathway transducer, in the cytoplasm to restrict Yki transcriptional output. This regulation provides an endogenous defensive mechanism in organ size control, intestinal homeostasis, and regeneration. Unexpectedly, Xbp1 ablation promotes tumor overgrowth but suppresses invasiveness in a Drosophila cancer model. Mechanistically, hyperactivated Ire1/Xbp1s signaling in turn induces JNK-dependent developmental and oncogenic cell migration and epithelial-mesenchymal transition (EMT) via repression of Yki. In humans, a negative correlation between XBP1 and YAP (Yki ortholog) target gene expression specifically exists in triple-negative breast cancers (TNBCs), and those with high XBP1 or HSPA5 (Bip ortholog) expression have better clinical outcomes. In human TNBC cell lines and xenograft models, ectopic XBP1s or HSPA5 expression alleviates tumor growth but aggravates cell migration and invasion. These findings uncover a conserved crosstalk between the Ire1/Xbp1s and Hippo signaling pathways under physiological settings, as well as a crucial role of Bip-Yki interaction in tumorigenesis that is shared from Drosophila to humans.

[Clinical Analysis of Elderly Patients with AML/High-Risk MDS].

OBJECTIVE: To analyze the clinical features of acute myeloid leukemia (AML)/high-risk myelodysplastic syndrome (MDS) patients aged over 60 years old. METHODS: The clinical data of 61 elderly newly diagnosed patients with AML and high-risk MDS who submitted to the Department of Hematology/Oncology of the First Affiliated Hospital of Tsinghua University from January 2009 to April 16, 2021 were retrospectively analyzed. These patients were divided into chemotherapy group (45 cases) and supportive treatment group (16 cases). The overall survival (OS) was analyzed by Kaplan-Meier method, and the prognostic factors of survival were analyzed by multivariate Cox regression. RESULTS: After 2 cycles of induction chemotherapy, the complete remission (CR) rate was 37.8% (17/45), and overall response rate was 62.2% (28/45) in the chemotherapy group. The median OS in the chemotherapy group and supportive treatment group was 11.3 (0.07-43) and 1.6 (0.33-7.72) months, respectively (P<0.001). The median OS in patients who reached CR or did not reach after 1 cycle of induction chemotherapy was 19.8 (10-30.63) and 8.17 (0.07-43) months, respectively (P<0.05), while after 2 cycles was 22.7 (4.2-43) and 7.26 (0.07-26) months, respectively (P<0.001). Univariate analysis showed that age > 80 years old, CCI score > 2, PS score > 2 and supportive treatment were the adverse prognostic factors for OS. Further multivariate analysis suggested that chemotherapy was the only independent prognostic factor for OS (HR=0.140, 95%CI: 0.048-0.409, P<0.001). In the chemotherapy group, univariate analysis showed that CCI score > 2 and failure to reach CR after induction chemotherapy were poor prognostic factors. Multivariate analysis showed that CCI score > 2 (HR=0.139, 95%CI: 0.050-0.384, P<0.001) and failure to achieve CR after induction chemotherapy (HR=0.103, 95%CI: 0.041-0.259, P<0.001) were the adverse prognostic factors for OS. The patients were tolerant to side-effect of chemotherapy. CONCLUSION: Appropriate chemotherapy can prolong the survival of elderly patients with AML and high-risk MDS.

The reversion of DNA methylation-induced miRNA silence via biomimetic nanoparticles-mediated gene delivery for efficient lung adenocarcinoma therapy.

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.

Fat body-derived Spz5 remotely facilitates tumor-suppressive cell competition through Toll-6-α-Spectrin axis-mediated Hippo activation.

Tumor-suppressive cell competition is an evolutionarily conserved process that selectively removes precancerous cells to maintain tissue homeostasis. Using the polarity-deficiency-induced cell competition model in Drosophila, we identify Toll-6, a Toll-like receptor family member, as a driver of tension-mediated cell competition through α-Spectrin (α-Spec)-Yorkie (Yki) cascade. Toll-6 aggregates along the boundary between wild-type and polarity-deficient clones, where Toll-6 physically interacts with the cytoskeleton network protein α-Spec to increase mechanical tension, resulting in actomyosin-dependent Hippo pathway activation and the elimination of scrib mutant cells. Furthermore, we show that Spz5 secreted from fat body, the key innate organ in fly, facilitates the elimination of scrib clones by binding to Toll-6. These findings uncover mechanisms by which fat bodies remotely regulate tumor-suppressive cell competition of polarity-deficient tumors through inter-organ crosstalk and identified the Toll-6-α-Spec axis as an essential guardian that prevents tumorigenesis via tension-mediated cell elimination.

The Clinical Value of Procalcitonin in the Neutropenic Period After Allogeneic Hematopoietic Stem Cell Transplantation.

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.