Emerging mechanisms and promising approaches in pancreatic cancer metabolism.

Pancreatic cancer is an aggressive cancer with a poor prognosis. Metabolic abnormalities are one of the hallmarks of pancreatic cancer, and pancreatic cancer cells can adapt to biosynthesis, energy intake, and redox needs through metabolic reprogramming to tolerate nutrient deficiency and hypoxic microenvironments. Pancreatic cancer cells can use glucose, amino acids, and lipids as energy to maintain malignant growth. Moreover, they also metabolically interact with cells in the tumour microenvironment to change cell fate, promote tumour progression, and even affect immune responses. Importantly, metabolic changes at the body level deserve more attention. Basic research and clinical trials based on targeted metabolic therapy or in combination with other treatments are in full swing. A more comprehensive and in-depth understanding of the metabolic regulation of pancreatic cancer cells will not only enrich the understanding of the mechanisms of disease progression but also provide inspiration for new diagnostic and therapeutic approaches.

GmNLP1 and GmNLP4 activate nitrate-induced CLE peptides NIC1a/b to mediate nitrate-regulated root nodulation.

Symbiotic nitrogen fixation is an energy-intensive process, to maintain the balance between growth and nitrogen fixation, high concentrations of nitrate inhibit root nodulation. However, the precise mechanism underlying the nitrate inhibition of nodulation in soybean remains elusive. In this study, CRISPR-Cas9-mediated knockout of GmNLP1 and GmNLP4 unveiled a notable nitrate-tolerant nodulation phenotype. GmNLP1b and GmNLP4a play a significant role in the nitrate-triggered inhibition of nodulation, as the expression of nitrate-responsive genes was largely suppressed in Gmnlp1b and Gmnlp4a mutants. Furthermore, we demonstrated that GmNLP1b and GmNLP4a can bind to the promoters of GmNIC1a and GmNIC1b and activate their expression. Manipulations targeting GmNIC1a and GmNIC1b through knockdown or overexpression strategies resulted in either increased or decreased nodule number in response to nitrate. Additionally, transgenic roots that constitutively express GmNIC1a or GmNIC1b rely on both NARK and hydroxyproline O-arabinosyltransferase RDN1 to prevent the inhibitory effects imposed by nitrate on nodulation. In conclusion, this study highlights the crucial role of the GmNLP1/4-GmNIC1a/b module in mediating high nitrate-induced inhibition of nodulation.

Evaluation of the Protection Effectiveness of Natural Protected Areas on the Qinghai-Tibet Plateau Based on Ecosystem Services.

Evaluating the protection effectiveness of natural protected areas is an important step in successful management. Adopting 330 natural protected areas on the Qinghai-Tibet Plateau as research subjects, the regional dominant ecosystem service function was selected, and various temporal and spatial analysis methods were employed to analyze the evolution characteristics and influencing factors of ecosystem service patterns from 2000 to 2020. Our results indicated that (1) the water conservation function stabilized after fluctuation and decline, the soil conservation function fluctuated upward, and the windbreak and sand fixation function exhibited an increase after a decreasing fluctuation. (2) The protection effectiveness of25 protected areas significantly improved, that of 151 protected areas improved, that of 84 protected areas stabilized, that of 56 protected areas worsened, and that of 14 protected areas significantly worsened. (3) The top three influencing factors in descending order were precipitation change > altitude > mining area density. (4) Remarkable protection results were achieved in national protected areas, established management institutions, earlier established areas (before 2000), and areas exhibiting alow built-up area density (<0.75%) and low mining density (<1%). Our study provides technical support for the construction and management of protected areas and improvement in ecosystem service functions on the Qinghai-Tibet Plateau.

The small peptide CEP1 and the NIN-like protein NLP1 regulate NRT2.1 to mediate root nodule formation across nitrate concentrations.

Legumes acquire fixed nitrogen (N) from the soil and through endosymbiotic association with diazotrophic bacteria. However, establishing and maintaining N2-fixing nodules are expensive for the host plant, relative to taking up N from the soil. Therefore, plants suppress symbiosis when N is plentiful and enhance symbiosis when N is sparse. Here, we show that the nitrate transporter MtNRT2.1 is required for optimal nodule establishment in Medicago truncatula under low-nitrate conditions and the repression of nodulation under high-nitrate conditions. The NIN-like protein (NLP) MtNLP1 is required for MtNRT2.1 expression and regulation of nitrate uptake/transport under low- and high-nitrate conditions. Under low nitrate, the gene encoding the C-terminally encoded peptide (CEP) MtCEP1 was more highly expressed, and the exogenous application of MtCEP1 systemically promoted MtNRT2.1 expression in a compact root architecture 2 (MtCRA2)-dependent manner. The enhancement of nodulation by MtCEP1 and nitrate uptake were both impaired in the Mtnrt2.1 mutant under low nitrate. Our study demonstrates that nitrate uptake by MtNRT2.1 differentially affects nodulation at low- and high-nitrate conditions through the actions of MtCEP1 and MtNLP1.

Naples prognostic score, a novel prognostic score for patients with high- and intermediate-risk gastrointestinal stromal tumours after surgical resection.

BACKGROUND: A novel multidimensional inflammatory and nutritional assessment system named the Naples prognostic score could serve as an independent prognostic indicator. However, its significance in patients with high- and intermediate-risk gastrointestinal stromal tumours remains unclear. METHODS: We performed this retrospective cohort study based on a prospectively collected database of gastrointestinal stromal tumours (GISTs) between March 2010 and December 2019. The Kaplan-Meier method and log-rank test were used for survival analyses. Least absolute shrinkage and selection operator (LASSO) and Cox proportional hazards regression analysis was used for univariate and multivariate analyses. Time-dependent receiver operating characteristic curves were generated to evaluate the discriminatory ability of the prognostic scoring systems. Differences in the areas under the curve were further compared. RESULTS: A total of 405 patients with regular follow-up were included and analysed in this study. Significant differences in progression-free survival and overall survival were observed between the groups (P < 0.001). Multivariate analysis demonstrated that the NPS was a significant predictor of poor progression-free survival (1 vs 0, HR = 4.622, P = 0.001; 2 vs 0, HR = 12.770, P < 0.001) and overall survival (2 vs 0, HR = 5.535, P = 0.002). Furthermore, time-dependent AUC analyses showed that the NPS was more accurate than other haematologic prognostic systems. CONCLUSIONS: The present study demonstrates that the NPS could independently predict disease progression and survival among patients with high- and intermediate-risk GISTs. The NPS might be regarded and applied as one of the most convenient and effective preoperative risk stratification tools in the future, which should be validated by large-scale multicentre prospective cohort studies.

Asymmetric redundancy of soybean Nodule Inception (NIN) genes in root nodule symbiosis.

Nodule Inception (NIN) is one of the most important root nodule symbiotic genes as it is required for both infection and nodule organogenesis in legumes. Unlike most legumes with a sole NIN gene, there are four putative orthologous NIN genes in soybean (Glycine max). Whether and how these NIN genes contribute to soybean-rhizobia symbiotic interaction remain unknown. In this study, we found that all four GmNIN genes are induced by rhizobia and that conserved CE and CYC binding motifs in their promoter regions are required for their expression in the nodule formation process. By generation of multiplex Gmnin mutants, we found that the Gmnin1a nin2a nin2b triple mutant and Gmnin1a nin1b nin2a nin2b quadruple mutant displayed similar defects in rhizobia infection and root nodule formation, Gmnin2a nin2b produced fewer nodules but displayed a hyper infection phenotype compared to wild type (WT), while the Gmnin1a nin1b double mutant nodulated similar to WT. Overexpression of GmNIN1a, GmNIN1b, GmNIN2a, and GmNIN2b reduced nodule numbers after rhizobia inoculation, with GmNIN1b overexpression having the weakest effect. In addition, overexpression of GmNIN1a, GmNIN2a, or GmNIN2b, but not GmNIN1b, produced malformed pseudo-nodule-like structures without rhizobia inoculation. In conclusion, GmNIN1a, GmNIN2a, and GmNIN2b play functionally redundant yet complicated roles in soybean nodulation. GmNIN1b, although expressed at a comparable level with the other homologs, plays a minor role in root nodule symbiosis. Our work provides insight into the understanding of the asymmetrically redundant function of GmNIN genes in soybean.

Parallel Loop Binding Compression Suture, a Modified Procedure for Pernicious Placenta Previa Complicated With Placenta Increta.

Objective: To evaluate the efficacy and safety of parallel loop binding compression suture of the lower uterus during cesarean section in pernicious placenta previa complicated with placenta increta. Methods: This retrospective study was performed in patients with pernicious placenta previa complicated with placenta increta or percreta between November 2014 and December 2020 at the Qilu Hospital of Shandong University. Patients underwent parallel loop binding compression suture surgery were defined as study group, and patients underwent traditional surgery with figure-of-eight sutures as the main hemostatic method were defined as control group. Postpartum hemorrhage was evaluated as the primary outcome. The secondary outcomes included age, gestational weeks, operative time, fetal childbirth time, prevention of hysterectomy, blood transfusion, duration of postoperative catheterization, duration of antibiotic treatment, and postoperative hospitalization (days). Additionally, neonatal outcomes were evaluated. Results: A total of 124 patients were enrolled in the study, including 38 patients receiving parallel loop binding compression suture surgery in the study group, and 86 patients in the control group. With parallel loop binding compression suture, the average operation time was significantly reduced (109.0 ± 33.5 vs. 134.4 ± 54.2 min, p = 0.00), and the volume of blood lost were also decreased (2152.6 ± 1169.4 vs. 2960.5 ± 1963.6 ml, p = 0.02), which correspondingly reduced RBC transfusion (7.2 ± 3.5 vs. 10.3 ± 8.7 units, p = 0.03) and FFP transfusion (552.6 ± 350.3 vs. 968.0 ± 799.8 ml, p = 0.00). The fetal childbirth time was extended (14.1 ± 5.6 vs. 11.0 ± 8.0 min, p = 0.03), however, there was no increase in NICU admission rates (36.9 vs. 34.9%, p = 0.83). Except for one premature infant (32 weeks) death in the control group, all infants at our hospital were safely discharged after treatment. Conclusion: Parallel loop binding compression suture is an effective, swift, practical, and safe method to reduce postpartum bleeding in women with pernicious placenta previa, complicated with placenta increta. Besides, it has no adverse effects on newborns.

Surgical Resection Is Still Better Than Endoscopic Resection for Patients With 2-5 cm Gastric Gastrointestinal Stromal Tumours: A Propensity Score Matching Analysis.

BACKGROUND: The management of 2-5 cm gastric gastrointestinal stromal tumours (GISTs) is still debated between surgeons and endoscopists. We aimed to investigate short-term and long-term outcomes between surgical resection (SR) and endoscopic resection (ER). METHODS: This study included 67 and 215 patients between 2010 and 2020 who underwent ER and SR, respectively. After propensity score matching, the clinical outcomes were compared. Individual patient information that requires special instructions is also summarized. RESULTS: After matching, the operation time (P=0.005) and postoperative hospital stay (P=0.005) were significantly longer in the SR group than in the ER group. However, there were no significant differences in blood loss (P=0.741), resection margin (P=1.000) or time to liquid diet (P=0.055). Statistical differences were also seen in en bloc resection (P<0.001) and adverse events (P=0.027). The recurrence rate did not differ significantly between the two techniques, and the mitotic index and ulceration were identified as independent prognostic factors of progression-free survival. CONCLUSIONS: ER might be comparable to SR for the treatment of 2-3 cm gastric GISTs. SR is still considered the standard treatment for 3-5 cm gastric GISTs, while the intraoperative and postoperative information of ER should be recorded in detail and closely evaluated. Surgical resection is recommended if the tumour has a high mitotic index or mucosal ulceration.

Clinicopathological characteristics and longterm survival of patients with synchronous multiple primary gastrointestinal stromal tumors: A propensity score matching analysis.

BACKGROUND: Multiple gastrointestinal stromal tumors (MGISTs) are specific and rare. Little is known about the impact of MGISTs on the survival of patients with gastrointestinal stromal tumors (GIST). The diagnosis, treatment and follow-up strategies of MGISTs is not specifically described in guidelines. AIM: To compare the clinicopathological characteristics and prognosis of MGISTs and solitary GISTs (SGISTs). METHODS: Patients diagnosed with primary GISTs from March 2010 to January 2020 were included. Due to the inhomogeneous distribution of several baseline characteristics and uneven MGIST and SGIST group sizes, propensity score matching was performed according to comorbidities, body mass index, tumor location, mitotic index, sex, age and American Society of Anesthesiologists score. Differences in clinicopathological characteristics and prognosis between patients with MGISTs and patients with SGISTs were compared. RESULTS: Among the entire cohort of 983 patients, the incidence of MGISTs was 4.17%. Before matching, patients with MGISTs and those with SGISTs had disparities in body mass index, surgical approach, tumor size and mitotic index. After 1:4 ratio matching, the clinical baseline data were comparable. The 5-year progression-free survival rate was 52.17% in the MGIST group and 75.00% in the SGIST group (P = 0.031). On multivariate analysis, tumor location, tumor size, mitotic index, imatinib treatment and MGISTs (hazard ratio = 2.431, 95% confidence interval = 1.097-5.386, P = 0.029) were identified as independent prognostic factors of progression-free survival. However, overall survival was similar between the SGIST and MGIST groups. CONCLUSION: Patients with MGISTs had poorer progression-free survival than patients with SGISTs. Risk criteria and diagnostic and treatment strategies should be developed to achieve personalized precision therapy and maximize the survival benefit.

NLP1 reciprocally regulates nitrate inhibition of nodulation through SUNN-CRA2 signaling in Medicago truncatula.

Most legume plants can associate with diazotrophic soil bacteria called rhizobia, resulting in new root organs called nodules that enable N2 fixation. Nodulation is an energy-consuming process, and nodule number is tightly regulated by independent systemic signaling pathways controlled by CLE/SUNN and CEP/CRA2. Moreover, nitrate inhibits legume nodulation via local and systemic regulatory pathways. In Medicago truncatula, NLP1 plays important roles in nitrate-induced inhibition of nodulation, but the relationship between systemic and local pathways in mediating nodulation inhibition by nitrate is poorly understood. In this study, we found that nitrate induces CLE35 expression in an NLP1-dependent manner and that NLP1 binds directly to the CLE35 promoter to activate its expression. Grafting experiments revealed that the systemic control of nodule number involves negative regulation by SUNN and positive regulation by CRA2 in the shoot, and that NLP1's control of the inhibition of rhizobial infection, nodule development, and nitrogenase activity in response to nitrate is determined by the root. Unexpectedly, grafting experiments showed that loss of CRA2 in the root increases nodule number at inhibitory nitrate levels, probably because of CEP1/2 upregulation in the cra2 mutants, suggesting that CRA2 exerts active negative feedback regulation in the root.

The role and application of small extracellular vesicles in gastric cancer.

Gastric cancer (GC) is a common tumour that affects humans worldwide, is highly malignant and has a poor prognosis. Small extracellular vesicles (sEVs), especially exosomes, are nanoscale vesicles released by various cells that deliver bioactive molecules to recipient cells, affecting their biological characteristics, changing the tumour microenvironment and producing long-distance effects. In recent years, many studies have clarified the mechanisms by which sEVs function with regard to the initiation, progression, angiogenesis, metastasis and chemoresistance of GC. These molecules can function as mediators of cell-cell communication in the tumour microenvironment and might affect the efficacy of immunotherapy. Due to their unique physiochemical characteristics, sEVs show potential as effective antitumour vaccines as well as drug carriers. In this review, we summarize the roles of sEVs in GC and highlight the clinical application prospects in the future.

Optimizing livestock carrying capacity for wild ungulate-livestock coexistence in a Qinghai-Tibet Plateau grassland.

Wild ungulates are an important part of terrestrial ecosystems and play a critical role in maintaining ecosystem health and integrity. In many grassland ecosystems that are habituated by wild ungulates, the coexistence of domestic ungulates has created a conflict over grazing resources. Solving this conflict requires a balanced and sustainable policy that satisfies both the needs of wildlife protection and food production. Here, we assess the optimal grassland livestock carrying capacity of an alpine grassland on the Qinghai-Tibet Plateau, given the coexistence of wild populations of kiangs (Equus kiang) and Tibetan gazelles (Procapra picticaudata), two key species grazing in this region. We use kriging and the MaxEnt method to estimate the population sizes of kiangs and Tibetan gazelles in Maduo County, Qinghai Province. We then convert the estimated population size of the two species into sheep units and calculate the residual carrying capacity for livestock grazing. We show that after accounting for the grazing need for kiangs and Tibetan gazelles, grassland in Maduo is capable of supporting 420,641 sheep units, which is slightly more than the current livestock population. However, the residual carrying capacity is highly uneven across the region, and overgrazing is found in many areas of Maduo, especially in northern Maduo. This research provides a useful framework for planning sustainable livestock farming for the Qinghai-Tibet Plateau and other regions facing wildlife-livestock conflict.

Effects of Neoadjuvant Chemotherapy in Ovarian Cancer Patients With Different Germline BRCA1/2 Mutational Status: A Retrospective Cohort Study.

BACKGROUND: Whether neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) against primary debulking surgery (PDS) has a differential effect on prognosis due to Breast Cancer Susceptibility Genes (BRCA)1/2 mutations has not been confirmed by current studies. METHODS: All patients included in this retrospective study were admitted to Qilu Hospital of Shandong University between January 2009 and June 2020, and germline BRCA1/2 mutation were tested. Patients in stage IIIB, IIIC, and IV, re-staged by International Federation of Gynecology and Obstetrics (FIGO) 2014, were selected for analysis. All patients with NAC received 1-5 cycles of platinum-containing (carboplatin, cisplatin, or nedaplatin) chemotherapy. Patients who received maintenance therapy after chemotherapy were not eligible for this study. All relevant medical records were collected. RESULTS: A total of 322 patients were enrolled, including 112 patients with BRCA1/2 mutations (BRCAmut), and 210 patients with BRCA1/2 wild-type (BRCAwt). In the two groups, 40 BRCAmut patients (35.7%) and 69 BRCAwt patients (32.9%) received NAC. The progression-free survival (PFS) of BRCAmut patients was significantly reduced after NAC (median: 14.9 vs. 18.5 months; p=0.023); however, there was no difference in overall survival (OS) (median: 75.1 vs. 72.8 months; p=0.798). Whether BRCAwt patients received NAC had no significant effect on PFS (median: 13.5 vs. 16.0 months; p=0.780) or OS (median: 54.0 vs. 56.4 months; p=0.323). Multivariate analyses in BRCAmut patients showed that the predictors of prolonged PFS were PDS (p=0.001), the absence of residual lesions (p=0.012), and FIGO III stage (p=0.020); Besides, PARP inhibitor was the independent predictor for prolonged OS in BRCAmut patients (p=0.000), for BRCAwt patients, the absence of residual lesions (p=0.041) and history of PARP inhibitors (p=0.000) were beneficial factors for OS prolongation. CONCLUSIONS: For ovarian cancer patients with FIGO IIIB, IIIC, and IV, NAC-IDS did not adversely affect survival outcomes due to different BRCA1/2 germline mutational status.

Transhiatal versus transthoracic surgical approach for Siewert type â ¡ adenocarcinoma of the esophagogastric junction: a meta-analysis.

BACKGROUND: With the increasing prevalence of Siewert type Ⅱ adenocarcinoma of the esophagogastric junction (EGJ), the optimal surgical treatment is not universally agreed. This meta-analysis compares the safety and efficacy between the transhiahtal (TH) approach and the transthoracic (TT) approach. METHODS: A systematic and electronic search of several databases was performed up to June 2020. The Newcastle-Ottawa scale was used to evaluate article quality and funnel plots were created to identify potential publication bias. The random-effects model was used when significant heterogeneity was identified. RESULTS: In total, nine retrospective studies and two randomized controlled trials (RCTs) involving 2331 patients were included. Decreased intraoperative blood loss, shorter hospital stay, lower incidence of pulmonary complications, and longer 3-year overall survival were observed in the TH group. There were no significant differences concerning duration of surgery, R0 resection rate, number of dissected lymph nodes, perioperative mortality and morbidity rate, abdominal complication rate, or anastomotic leak rate. With regard to 5-year overall survival, a potential benefit may be achieved with the TH approach, which requires further confirmation. CONCLUSION: In terms of surgery-related and long-term outcomes, the TH approach may be more appropriate for Siewert type Ⅱ adenocarcinoma of EGJ, especially for esophagus invasion ≤4 cm.

Bifidobacterium and Lactobacillus for preventing necrotizing enterocolitis in very-low-birth-weight preterm infants: a systematic review and meta-analysis.

BACKGROUND: The therapeutic effect of Bifidobacterium and Lactobacillus on necrotizing enterocolitis (NEC) in very-low-birth-weight preterm infants was controversial, and we aimed to explore the exact impact of the two probiotics. METHODS: The PubMed, EMBASE, Web of Science and Cochrane Library were systematically searched for studies published from January 1, 2010 to February 28, 2019. Results were combined with fixed-effect model or random-effect model with specific conditions. Sensitivity analysis was conducted by the trim-and-fill method, and the Begger's and Egger's test were used to measure publication bias. RESULTS: The meta-analysis included 16 original articles with 4632 very-low-birth-weight preterm infants. With respect to the intervention of Bifidobacterium, we estimated non-significant decrease in the morbidity of NEC with a risk ratio (RR) of 0.75 [95% confidence internal (CI) 0.56-1.01, P = 0.06]. Regarding the effect of Lactobacillus, there was no evidence of significant lower risk in the incidence of NEC (RR = 0.67, 95% CI 0.39-1.17, P = 0.16). The use of mixture of probiotics (Bifidobacterium and Lactobacillus) reduced the risk of NEC in the probiotics group (RR = 0.45, 95% CI 0.25-0.80, P = 0.007). CONCLUSION: The mixture of Bifidobacterium and Lactobacillus could prevent the morbidity of NEC in very-low-birth-weight preterm infants. But Bifidobacterium or Lactobacillus alone did not show this effect.

Lamin-like Proteins Negatively Regulate Plant Immunity through NAC WITH TRANSMEMBRANE MOTIF1-LIKE9 and NONEXPRESSOR OF PR GENES1 in Arabidopsis thaliana.

Nuclear lamins are involved in multiple biological processes in metazoan cells. The proteins of the CROWDED NUCLEI (CRWN) family are considered lamin-like candidates in Arabidopsis, although the functions of these proteins are largely unknown. In this article we show that crwn1 crwn2 double mutant displays an enhanced resistance against virulent bacterial pathogens, and both virulent bacteria and salicylic acid (SA) induce transcription of CRWN1 gene as well as proteasome-mediated degradation of CRWN1 protein. We also show that CRWN1 interacts with NAC WITH TRANSMEMBRANE MOTIF1-LIKE9 (NTL9), a NAC transcription factor involved in plant immunity. The interaction between CRWN1 and NTL9 enhances the binding of NTL9 to the promoter of the PATHOGENESIS-RELATED1 (PR1) gene, and inhibits PR1 expression. Further genetic experiments indicated that the defense-related phenotypes of crwn1 crwn2 double mutant are dependent on NONEXPRESSOR OF PR GENES1 (NPR1), a transcriptional cofactor of PR1. These findings revealed a regulatory network composed of lamin-like protein CRWN1, NTL9, and NPR1 for the regulation of PR1 expression.

[Ecological vulnerability of coal mining area: a case study of Shengli Coalfield in Xilinguole of Inner Mongolia, China].

In this paper, an ecological vulnerability evaluation index system for the Shengli Coalfield in Xilinguole of Inner Mongolia was established, which included 16 factors in ecological sensitivity, natural and social pressure, and ecological recovery capacity, respectively. Based on the expert scoring method and analytic hierarchy process (AHP), an ecological vulnerability model was built for the calculation of the regional ecological vulnerability by means of RS and GIS spatial analysis. An analysis of the relationships between land use and ecological vulnerability was also made, and the results were tested by spatial auto-correlation analysis. Overall, the ecological vulnerability of the study area was at medium-high level. The exploitation of four opencast areas in the Coalfield caused a significant increase of ecological vulnerability. Moreover, due to the effects of mine drained water and human activities, the 300 -2000 m around the opencast areas was turning into higher ecologically fragile area. With further exploitation, the whole Coalfield was evolved into moderate and heavy ecological vulnerability area, and the coal resources mining was a key factor in this process. The cluster analysis showed that the spatial distribution of the ecological vulnerability in the study area had reasonable clustering characteristics. To decrease the population density, control the grazing capacity of grassland, and regulate the ratios of construction land and cultivated land could be the optimal ways for resolving the natural and social pressure, and to increase the investment and improve the vegetation recovery coefficient could be the fundamental measures for decreasing the ecological vulnerability of the study area.