Development of miRNA-based PROTACs targeting Lin28 for breast cancer therapy.

Lin28, a highly conserved carcinogenic protein, plays an important role in the generation of cancer stem cells, contributing to the unfavorable prognosis of cancer patients. This RNA binding protein specifically binds to pri/pre-microRNA (miRNA) lethal-7 (let-7), impeding its miRNA maturation. The reduced expression of tumor suppressor miRNA let-7 fosters development and progression-related traits such as proliferation, invasion, metastasis, and drug resistance. We report a series of miRNA-based Lin28A-miRNA proteolysis-targeting chimeras (Lin28A-miRNA-PROTACs) designed to efficiently degrade Lin28A through a ubiquitin-proteasome-dependent mechanism, resulting in up-regulation of mature let-7 family. The augmented levels of matured let-7 miRNAs further exert inhibitory effects on cancer cell proliferation and migration, and increase its sensitivity to chemotherapy. In a mouse ectopic tumor model, Lin28A-miRNA-PROTAC demonstrates a substantial efficacy in inhibiting tumor growth. When combined with tamoxifen, the tumors exhibit gradual regression. This study displays an effective miRNA-based PROTACs to degrade Lin28A and inhibit tumor growth, providing a promising therapeutic avenue for cancer treatment with miRNA-based therapy.

The New Roles of traf6 Gene Involved in the Development of Zebrafish Liver and Gonads.

Traf6, an adaptor protein, exhibits non-conventional E3 ubiquitin ligase activity and was well studied as an important factor in immune systems and cancerogenesis. In mice, the traf6-null caused a perinatal death, so that the underlying pathophysiology of traf6-defeciency is still largely unclear in animals. Here, in the present study, a traf6 knockout zebrafish line (traf6-/-) was generated and could survive until adulthood, providing a unique opportunity to demonstrate the functions of traf6 gene in animals' organogenesis beyond the mouse model. The body of traf6-/- fish was found to be significantly shorter than that of the wildtype (WT). Likewise, a comparative transcriptome analysis showed that 866 transcripts were significantly altered in the traf6-/- liver, mainly involved in the immune system, metabolic pathways, and progesterone-mediated oocyte maturation. Especially, the mRNA expression of the pancreas duodenum homeobox protein 1 (pdx1), glucose-6-phosphatase (g6pcb), and the vitellogenesis genes (vtgs) were significantly decreased in the traf6-/- liver. Subsequently, the glucose was found to be accumulated in the traf6-/- liver tissues, and the meiotic germ cell was barely detected in traf6-/- testis or ovary. The findings of this study firstly implied the pivotal functions of traf6 gene in the liver and gonads' development in fish species.

The relationship between gastric microbiome features and responses to neoadjuvant chemotherapy in gastric cancer.

Background: Emerging evidence demonstrates that the gastrointestinal microbiome has the potential to be a biomarker in neoadjuvant chemoradiotherapy for colorectal cancer (CRC). Yet studies on the impact of the gastric microbiome (GM) on the response to neoadjuvant chemotherapy (NACT) are still scarce. Methods: Forty-eight patients with gastric cancer participated in this retrospective study, and 16S rRNA sequencing was performed to evaluate formalin-fixed and paraffin-embedded (FFPE) tissue biospecimens and fresh-frozen tissues. Results: In this study, 16 bacterial taxa at different levels, including Bacillus, Anaerococcus, and Chloroflexi, were identified to be enriched before NACT in response (R) patients in group FFPE. In contrast, 6 bacterial taxa, such as Haemophilus, Veillonellaceae (Veillonella), etc. were enriched after NACT, in which we reported for the first time that the phylum Chloroflexi was enriched before NACT in R patients. Thirty-one bacterial taxa of Coriobacteriaceae, Ruminococcaceae, Veillonellaceae, and Lachnospiraceae were identified in group mucosa as being enriched in R patients. In comparison, 4 bacterial taxa dominated by the phylum Proteobacteria were enriched in NR patients. Notably, the family Veillonellaceae was found in both tissue samples, and the metabolic pathways, including the citrate cycle (TCA cycle) and various amino acids, including alanine, were found to be potentially predictive in both sample species. Conclusion: There are differences in the features of the GM for different NACT response results. The causal relationship deserves to be confirmed by further investigations.

Deep learning-based characterization and redesign of major potato tuber storage protein.

Potato is one of the most important crops worldwide, to feed a fast-growing population. In addition to providing energy, fiber, vitamins, and minerals, potato storage proteins are considered as one of the most valuable sources of non-animal proteins due to their high essential amino acid (EAA) index. However, low tuber protein content and limited knowledge about potato storage proteins restrict their widespread utilization in the food industry. Here, we report a proof-of-concept study, using deep learning-based protein design tools, to characterize the biological and chemical characteristics of patatins, the major potato storage proteins. This knowledge was then employed to design multiple cysteines on the patatin surface to build polymers linked by disulfide bonds, which significantly improved viscidity and nutrient of potato flour dough. Our study shows that deep learning-based protein design strategies are efficient to characterize and to create novel proteins for future food sources.

Short- and long-term outcomes of laparoscopic or robotic radical gastrectomy based on preoperative perigastric artery CTA surgical decision-making: a high-volume center retrospective study with propensity score matching.

BACKGROUND: Some studies have demonstrated the short-term recovery course for patients who underwent laparoscopic gastrectomy according to preoperative computed tomography angiography (CTA) assessment. However, reports of the long-term oncological outcomes are still limited. METHODS: The data of 988 consecutive patients who underwent laparoscopic or robotic radical gastrectomy between January 2014 and September 2018 were analyzed retrospectively at our center, and propensity score matching was used to eliminate bias. Study cohorts were divided into the CTA group (n = 498) and the non-CTA group (n = 490) depending on whether preoperative CTA was available. The primary and secondary endpoints were the 3-year overall survival (OS) and disease-free survival (DFS) rates and the intraoperative course and short-term outcomes, respectively. RESULTS: 431 patients were included in each group after PSM. Compared with the non-CTA group, the CTA group had more harvested lymph nodes and less operative time, blood loss, intraoperative vascular injury and total cost, especially in the subgroup analysis with BMI ≥ 25 kg/m2 patients. There was no difference in the 3 year OS and DFS between the CTA group and the non-CTA group. When further stratified by BMI < 25 or ≥ 25 kg/m2, the 3-year OS and DFS were significantly higher in the CTA group than in the non-CTA group in terms of BMI ≥ 25 kg/m2. CONCLUSIONS: Laparoscopic or robotic radical gastrectomy based on preoperative perigastric artery CTA surgical decision-making has the possibility of improving short-term outcomes. However, there is no difference in the long-term prognosis, except for a subgroup of patients with BMI ≥ 25 kg/m2.

Development and validation of nomograms for predicting overall survival and cancer-specific survival in elderly patients with locally advanced gastric cancer: a population-based study.

OBJECTIVE: To evaluate the multiple factors influencing the survival of elderly patients with locally advanced gastric cancer (LAGC) and develop and validate the novel nomograms for predicting the survival. METHODS: The clinical features of patients treated between 2000 and 2018 were collected and collated from the Surveillance, Epidemiology, and End Results (SEER) database and three medical centres in China, and the patients were randomly divided into a training cohort (3494), internal validation cohort (1497) and external validation cohort (841). Univariate and multivariate analyses of the prognostic values were performed to identify independent prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS), and two nomogram models were developed. Harrell's concordance index (C-index) and calibration curves were employed to assess discrimination and calibration. Decision curve analysis (DCA) and receiver-operating characteristic (ROC) curves were utilized to investigate the clinical usefulness. RESULTS: In the SEER database, the 5-year OS of the patients was 31.08%, while the 5-year CSS of the patients was 44.09%. Furthermore, in the external validation set, the 5-year OS of the patients was 49.58%, and the 5-year CSS of these patients was 53.51%. After statistical analysis, nine independent prognostic factors of OS and CSS were identified, including age, race, tumour size, differentiation, TNM stage, gastrectomy type, lymph node metastasis (LNM), lymph node ratio (LNR) and chemotherapy. The C-index (approximately 0.7) and calibration curve (close to the optimal calibration line) indicated satisfactory discrimination and calibration of the nomogram. DCA and ROC curves showed that the developed nomogram was superior to TNM stage. CONCLUSION: The novel validated nomogram could accurately predict the prognosis of individual elderly patients with LAGC and guide the selection of clinical treatment measures.

Intraoperative performance and outcomes of robotic and laparoscopic total gastrectomy for gastric cancer: A high-volume center retrospective propensity score matching study.

BACKGROUND: Studies on robotic total gastrectomy (RTG) are currently limited. This study aimed to compare the intraoperative performance as well as short- and long-term outcomes of RTG and laparoscopic total gastrectomy (LTG). METHODS: A total of 969 patients underwent robotic (n = 161) or laparoscopic (n = 636) total gastrectomy between October 2014 and October 2021. The two groups of patients were matched 1:3 using the propensity score matching (PSM) method. The intraoperative performance as well as short- and long-term outcomes of the robotic (n = 147) and the laparoscopic (n = 371) groups were compared. RESULTS: After matching, the estimated intraoperative blood loss was lower (80.51 ± 68.77 vs. 89.89 ± 66.12, p = 0.008), and the total number of lymph node dissections was higher (34.74 ± 12.44 vs. 29.83 ± 12.22, p < 0.001) in the RTG group compared with the LTG group. More lymph node dissections at the upper edge of the pancreas were performed in the RTG group than in the LTG (12.59 ± 4.18 vs. 10.33 ± 4.58, p = 0.001). Additionally, postoperative recovery indicators and laboratory data were greater in the RTG group than those in the LTG group, while postoperative complications were comparable between the two groups (19.0% vs. 18.9%, p = 0.962). For overweight or obese patients with body mass indexes (BMIs) ≥25, certain clinical outcomes of the RTG remained advantageous, and no significant differences in three-year overall survival (OS) or relapse-free survival (RFS) were observed. CONCLUSIONS: Robotic total gastrectomy demonstrated better intraoperative performance, could improve the short-term clinical outcomes of patients, and was more conducive to patient recovery. However, the long-term efficacies of the two approaches were similar. Robotic surgical systems may reduce surgical stress responses in patients, allowing them to receive postoperative chemotherapy sooner.

Loss of ALDH2 aggravates mitochondrial biogenesis disorder in cardiac myocytes induced by TAC.

Heart failure is one of the major fatal diseases and mitochondrial biogenesis is an important compensatory mechanism in the process of heart failure. Aldehyde dehydrogenase 2(ALDH2) is an important endogenous cardiac protective factor in mitochondria, but its role in mitochondrial biogenesis of cardiomyocytes remains unknown. In our study, transverse aorta constriction(TAC)-induced heart failure model was established in ALDH2-/- mice and wild-type mice. The cardiac function was examined by echocardiography at 4 weeks after operation. The myocardial tissue was stained by HE. The mitochondria morphology was observed using electron microscope, and the ATP content, Sirt1,PGC-1α and NRF1 expression were measured. Compared with wild-type mice, the cardiac function of ALDH2 -/- mice decreased significantly at 4 weeks after TAC. The proportion of mitochondrial area and mitochondrial crest/mitochondrial ratio decreased in the ALDH2-/- group after TAC. The ATP content decreased in ALDH2 -/- mice at 4 weeks after TAC. In the meantime, the expression of PGC-1α,Sirt 1 and NRF1 decreased in the ALDH2-/- TAC group compared with wild type TAC group.Neonatal rat cardiomyocytes were cultured and stretched. Cardiomyocytes were treated with the activator of ALDH2(Alda-1), Sirt1-SiRNA and PGC-1α-siRNA, respectively. The mitochondrial structure of cardiomyocytes was observed by transmission electron microscopy. The levels of PGC-1α,NRF-1 and Tfam were measured by Western blot.Mitochondrial biogenesis was enhanced in stretch cardiomyocytes treated with Alda-1.When cardiomyocytes were treated with Sirt1-SiRNA or PGC1α-SiRNA, the effect of Alda-1 in promoting mitochondrial biogenesis was attenuated.Therefore, these results suggested that the loss of ALDH2 aggravates mitochondrial biogenesis disorder in cardiac myocytes induced by TAC. Alda-1 could promote mitochondrial biogenesis in stretched cardiomyocytes, and this effect depends on Sirt1/PGC-1α pathway.

Detection Methods and Research Progress of Human Serum Albumin.

Human serum albumin (HSA) is a biological macromolecule with important physiological functions; abnormal HSA levels are associated with coronary heart disease, multiple myeloma, diabetes, nephropathy, neurometabolic disorders, liver cirrhosis and other diseases. Therefore, accurate and quantitative detection of HAS have extremely important research and application value in biological science, molecular biology, clinical medicine and other fields. As for the detection method of HSA, dye-binding method and immune method are the first to be used, and have been applied in clinical detection. In recent years, many new detection technologies have emerged, such as fluorescent probe detection method, nano-materials for HSA detection, biosensor and so on. Although there are many methods developed recently to detect HSA, comprehensive reviews for HSA detection methods are still rare. Thus, writing this review to fill in the blank is in need. In order to highlight the recent progress in the field of HSA detection, in this review, the methods used to detect HSA are summarized and sorted, the advantages and disadvantages of these detection methods are also listed, then the research progress of small molecular fluorescence probe method is emphatically introduced in this paper. Then, we briefly discussed the challenges and future development directions in this field.

Integrin-ß6 Serves as a Potential Prognostic Serum Biomarker for Gastric Cancer.

Discovering novel biomarkers that easily accessed is a key step towards the personalized medicine approach for gastric cancer patients. Integrin-ß6 (ITGB6) is a subtype of integrin that is exclusively expressed on the surface of epithelial cells and is up-regulated in various tumors. In the present study, a retrospective cohort with 135 gastric cancer patients and a prospective cohort with 34 gastric cancer patients were constructed, ITGB6 expression were detected in both the serum specimens and the tissue specimens. Detailed clinicopathological parameters as well as patients' survival were recorded. A nomogram including ITGB6 expression was also constructed and validated to predict the prognosis of gastric cancer patients. Results showed that serum ITGB6 expression was obviously increased and associated with tumor stage in gastric cancer patients, serum ITGB6 expression was relatively high in patients with liver metastasis. High ITGB6 expression indicated a poor prognosis, and nomogram including serum ITGB6 expression could predict the prognosis of gastric cancer patients effectively. Moreover, serum ITGB6 expression was associated with ITGB6 expression in tumor tissues. Furthermore, combined serum ITGB6 and CEA levels contributed to the risk stratification and prognostic prediction for gastric cancer patients. In addition, the serum expression of ITGB6 decreased significantly after radical surgery, and a new rise in serum ITGB6 expression indicated tumor recurrence or progression. The present study identified a novel serum biomarker for the risk stratification, prognostic prediction and surveillance of gastric cancer patients.

A Nomogram for Prediction of Survival in Patients After Gastrectomy Within Enhanced Recovery After Surgery (ERAS): A Single-Center Retrospective Study.

BACKGROUND Enhanced Recovery After Surgery (ERAS) programs can optimize clinical outcomes and have been widely used across multiple specialties, but a personalized prediction model involving ERAS for the prognosis of gastric cancer is lacking. MATERIAL AND METHODS We retrospectively collected clinical data on 725 gastric cancer patients within ERAS who underwent curative gastric resection in the Affiliated Hospital of Qingdao University from 2007 to 2014. Kaplan-Meier method, log-rank test, and Cox proportional risk model were used to determine the independent prognostic factors of patients. The accuracy of model was evaluated by C-index, calibration curve, and Decision Curve Analysis (DCA), and the receiver operator characteristic (ROC) curve was used to compare the nomogram model with the predictive value of TNM staging system. RESULTS The 5-year overall survival (OS) of 725 patients within ERAS was 72.5%. Age at diagnosis, T stage, N stage, and postoperative complications were determined to be independent factors affecting the prognosis of patients within ERAS, and nomogram model was constructed. The C-index of the training group was 0.809 and that of the verification group was 0.804; the calibration curves and DCA of the 2 groups showed good accuracy. Through verification, we found that, compared with the TNM staging assessment method, the nomogram model was more accurate in predicting the prognosis of gastric cancer. CONCLUSIONS This study identified factors affecting the prognosis of patients with gastric cancer, and we constructed the first prognostic nomogram model in ERAS mode to facilitate postoperative personalized prognostic evaluation.

Paracrine HGF promotes EMT and mediates the effects of PSC on chemoresistance by activating c-Met/PI3K/Akt signaling in pancreatic cancer in vitro.

BACKGROUND: Pancreatic stellate cells (PSCs) play key roles in the pancreatic tumor microenvironment and are considered to contribute to chemoresistance. PSCs can participate in malignant behaviors of pancreatic carcinoma (PC) by secreting hepatocyte growth factor (HGF). The objective of this research was to explore the potential molecular mechanism of HGF on gemcitabine (GEM) chemoresistance of PC. MATERIALS AND METHODS: HGF, c-Met, E-Cadherin and Vimentin levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). The changes of HGF level were detected by ELISA. The half maximal inhibitory concentration, the growth inhibitions and apoptosis of pancreatic cancer cells (PCCs) were respectively assayed using CCK-8 and flow cytometry. Associated proteins were measured using western blot and cell immunofluorescence assay. KEY FINDINGS: PSCs strongly expressed HGF, and its receptor c-Met was expressed in PCCs. PCCs exerted a positive regulative effect on HGF production. HGF neutralizing antibody AMG102 could effectively reduce the HGF level in PSC-conditioned medium (PSC-CM). PSC-CM promoted chemoresistance in PCCs. When exposed to PSC-CM, PCCs underwent epithelial-to-mesenchymal transition (EMT), and c-Met was also activated. Recombinant human HGF had the same protective effect. Blocking the HGF/c-Met axis with a c-Met inhibitor PHA665752 and AMG102 reduced the phosphorylation level of c-Met (p-c-Met) and attenuated EMT and chemoresistance. P-c-Met overexpression resulted in activation of the PI3K/Akt pathway, and inhibition of PI3K/Akt signaling with LY294002 reversed chemoresistance and EMT. SIGNIFICANCE: PSCs can activate the c-Met/PI3K/Akt pathway in PCCs via paracrine HGF, induce EMT of PCCs and inhibit cancer cell apoptosis, thus enhance chemoresistance to Gem in PCCs.

2D/1D V2O5 Nanoplates Anchored Carbon Nanofibers as Efficient Separator Interlayer for Highly Stable Lithium-Sulfur Battery.

Quick capacity loss due to the polysulfide shuttle effects is a critical challenge for high-performance lithium-sulfur (Li-S) batteries. Herein, a novel 2D/1D V2O5 nanoplates anchored carbon nanofiber (V-CF) interlayer coated on standard polypropylene (PP) separator is constructed, and a stabilization mechanism derived from a quasi-confined cushion space (QCCS) that can flexibly accommodate the polysulfide utilization is demonstrated. The incorporation of the V-CF interlayer ensures stable electron and ion pathway, and significantly enhanced long-term cycling performances are obtained. A Li-S battery assembled with the V-CF membrane exhibited a high initial capacity of 1140.8 mAh·g-1 and a reversed capacitance of 1110.2 mAh·g-1 after 100 cycles at 0.2 C. A high reversible capacity of 887.2 mAh·g-1 is also maintained after 500 cycles at 1 C, reaching an ultra-low decay rate of 0.0093% per cycle. The excellent electrochemical properties, especially the long-term cycling stability, can offer a promising designer protocol for developing highly stable Li-S batteries by introducing well-designed fine architectures to the separator.

Pancreatic stellate cells increase pancreatic cancer cells invasion through the hepatocyte growth factor /c-Met/survivin regulated by P53/P21.

Pancreatic stellate cells (PSCs) are a key cellular component of the pancreatic tumor microenvironment and are considered to contribute to tumor invasion and metastasis. Multiple cytokines and growth factors derived from PSCs are involved in malignant cancer progression, including hepatocyte growth factor (HGF). However, the molecular mechanisms by which HGF regulates cancer invasion and metastasis have not been completely elucidated. Here, we report that two pancreatic cancer (PC) cell lines, Panc-1 and SW1990, displayed different invasive and migratory abilities after treatment with HGF secreted by PSCs. We found that HGF enhanced the invasive and migratory capacity of Panc-1 cells because of P53 deficiency, leading to overexpression of c-Met, which was regulated through P21. Additionally, our data showed that HGF/c-Met-mediated invasion and migration required the upregulation of survivin expression. In conclusion, PSCs promote PC cells invasion and migration via the HGF/c-Met/survivin pathway, which is negatively regulated by P53/P21.