Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal ...transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways.
Direct methane oxidation to methanol is ideal for replacing the oxygen evolution reaction (OER) in artificial photosynthesis. This reaction requires less electricity and generates more valuable ...products than the OER. Moreover, it provides a better way to utilize abundant but inert methane. In this study, we have used density functional theory combined with a constant electrode potential model to evaluate the possibility of using abundant and low-cost N-doped graphene to catalyze this reaction. The active oxygen (*O) for rate-determining C–H activation is generated during the OER process. The results from our calculations show that this catalysis could be realized when graphene is doped with two nitrogen atoms in the vicinity of the reaction center so that long-lived *O is present and reacts to break strong methane C–H bonds. The minimum overall kinetic barrier is 0.91 eV at a potential of U = 1.10 VSHE, which is 0.82 eV lower than that in the absence of Us. The significant barrier reduction indicates that anodic potentials play essential roles in increasing the reactivity of N-doped graphene. During C–H activation, hydrogen is transferred from methane to *O. Analyzing this step using the Intrinsic Atomic Orbitals approach, we find that it follows a hydrogen atom transfer mechanism where the proton and electron travel together. Importantly, our analysis reveals that this transfer starts with the excitation of one electron from the *O lone pair to a surface π-orbital. This excitation increases the radical character on *O, rendering it reactive to couple with the transferred hydrogen atom. Easing this excitation is expected to further improve the reactivity of *O, as demonstrated by our calculations.
The increasing emergence of multidrug-resistant (MDR) bacteria has been recognized as a public health threat worldwide. Hospitalized patients and outpatients are commonly infected by non-fermenting ...Gram-negative bacilli (NFGNB), particularly the
-
complex (ACB) and
. Antimicrobial agents are critical for treating the nosocomial infections caused by NFGNB. The aim of this study was to assess antimicrobial resistance and the use of antimicrobial agents. The bacterial isolates of 638,152 specimens from both inpatients and outpatients, retrieved from 2001 to 2008 at a medical center in central Taiwan, were examined for their susceptibility to various antimicrobial agents, including cefepime, imipenem, ciprofloxacin, gentamicin, amikacin, meropenem, and levofloxacin. Administrated prescriptions of the monitored antibiotics were analyzed using the Taiwan National Health Insurance Research Database (NHIRD). Our results show that the defined daily doses (DDDs) for cefepime, imipenem, and ciprofloxacin increased with time, and a trend toward reduced antimicrobial sensitivities of both ACB and
was noticeable. In conclusion, the antimicrobial sensitivities of ACB and
were reduced with the increased use of antibiotics. Continuous surveillance of antibiotic prescriptions and the prevalence of emerging resistance in nosocomial infections is warranted.
To gain a better understanding of the trophic ecology of Pacific blue marlin Makaira nigricans off eastern Taiwan, nitrogen and carbon stable isotopes (δ15N and δ13C) and Bayesian mixing models were ...used to explore trophic dynamics and potential ontogenetic feeding shifts across M. nigricans of different size classes. Makaira nigricans samples from east of Taiwan (n = 213) and Palau (n = 37), as well as their prey (n = 70), were collected during 2012 and 2013. Results indicated increases in δ15N with size, with values of larger size classes (> 200 cm eye‐to‐fork length; LEF) significantly higher than those < 200 cm LEF. Values of δ13C were negatively correlated with size. Makaira nigricans > 200 cm LEF had the highest estimated trophic position (4.44) and also exhibited ontogenetic changes in trophic position. Large M. nigricans fed more on dolphinfish Coryphaena hippurus and hairtail Trichiurus lepturus, while smaller M. nigricans consumed smaller forage fish (e.g., moonfish Mene maculata) and cephalopods. These changes may relate to greater swimming speeds and vertical habitat use in larger M. nigricans, allowing capture and consumption of larger prey items at higher trophic positions. The high trophic level of M. nigricans east of Taiwan confirms its important role as an apex predator in marine food webs and how ecological role changes with size.
The major cause of death in colorectal cancer (CRC) patients is metastasis. Moreover, lots of studies have emphasized that the epithelial-mesenchymal transition (EMT) is a pivotal step in metastasis. ...Both transforming growth factor beta (TGF-β) and dysregulation of microRNAs (miRNAs) can induce or regulate EMT, promoting the loss of intercellular adhesion and increased motility of cancer cells. Therefore, it is necessary to prevent or inhibit the metastasis of colorectal cancer. Relatively little is known about the anti-metastatic effect of oxyresveratrol (OXY), a natural derivative of resveratrol (RES), compared to RES. Accordingly, RES was used as the positive control to investigate the effects of OXY on colon cancer cell migration. The results showed that OXY could significantly inhibit cell migration (67.17% ± 0.04, 64.89% ± 0.04) compared to RES (84.6% ± 0.07, 76.34% ± 0.08) in HCT116 cells and TGF-β-induced HT-29 cells, respectively,
Snail/E-cadherin expression. In addition, OXY improved EMT-related miRNA expression through, for example, lowering the levels of miR-3687 and miR-301a-3p while upregulating miR-3612 in TGF-β-induced HT-29 cells. In conclusion, OXY inhibits human colon cancer cell migration by regulating EMT and miRNAs. Based on these findings, it can be stated that OXY promotes anti-metastatic properties in CRC.
Background
Long-term exposure to PM
2.5
(particulate matter with an aerodynamic diameter of ≤ 2.5 μm) is associated with pulmonary injury and emphysema in patients with chronic obstructive pulmonary ...disease (COPD). We investigated mechanisms through which the long noncoding RNA lnc-IL7R contributes to cellular damage by inducing oxidative stress in COPD patients exposed to PM
2.5
.
Methods
Associations of serum lnc-IL7R levels with lung function, emphysema, and previous PM
2.5
exposure in COPD patients were analyzed. Reactive oxygen species and lnc-IL7R levels were measured in PM
2.5
-treated cells. The levels of lnc-IL7R and cellular senescence–associated genes, namely
p16
INK4a
and
p21
CIP1/WAF1
, were determined through lung tissue section staining. The effects of
p16
INK4a
or
p21
CIP1/WAF1
regulation were examined by performing lnc-IL7R overexpression and knockdown assays. The functions of lnc-IL7R-mediated cell proliferation, cell cycle, senescence, colony formation, and apoptosis were examined in cells treated with PM
2.5
. Chromatin immunoprecipitation assays were conducted to investigate the epigenetic regulation of
p21
CIP1/WAF1
.
Results
Lnc-IL7R levels decreased in COPD patients and were negatively correlated with emphysema or PM
2.5
exposure. Lnc-IL7R levels were upregulated in normal lung epithelial cells but not in COPD cells exposed to PM
2.5
. Lower lnc-IL7R expression in PM
2.5
-treated cells induced p16
INK4a
and p21
CIP1/WAF1
expression by increasing oxidative stress. Higher lnc-IL7R expression protected against cellular senescence and apoptosis, whereas lower lnc-IL7R expression augmented injury in PM
2.5
-treated cells. Lnc-IL7R and the enhancer of zeste homolog 2 (EZH2) synergistically suppressed
p21
CIP1/WAF1
expression through epigenetic modulation.
Conclusion
Lnc-IL7R attenuates PM
2.5
-mediated
p21
CIP1/WAF1
expression through EZH2 recruitment, and its dysfunction may augment cellular injury in COPD.
Graphical abstract
CPT-11 is one of the drugs employed in colorectal cancer treatment and has faced challenges in the form of resistance. The insulin-like growth factor 1 receptor is a tyrosine kinase receptor that ...mediates cancer cell survival and drug resistance. It is frequently overexpressed in colorectal cancer and has previously been identified as a microRNA target. MicroRNAs are non-coding RNA molecules that regulate gene function by suppressing messenger RNA translation. Studies have demonstrated that natural compounds can regulate microRNA function and their target genes. Therefore, combining natural compounds with existing cancer drugs can enhance the therapeutic efficacy. We investigated a natural compound, Aloin, for the potential sensitization of colorectal cancer to CPT-11. We used western blot, MTT cell viability assay, flow cytometry, and microRNA/gene knockdown and overexpression experiments, as well as an in vivo mouse model. Our investigation revealed that combining Aloin with CPT-11 exerts an enhanced anti-tumor effect in colorectal cancer. This combination reduced cell viability and induced apoptosis, both in vivo and in vitro. Furthermore, this combination upregulated miRNA-133b, while downregulating the IGF1R and its downstream MEK/ERK, and PI3K/AKT/mTOR pathways. Our findings suggests that CPT-11 and Aloin are potential combination treatment partners against colorectal cancer. MicroRNA-133b may serve as a co-therapeutic target with IGF1R against colorectal cancer, which might overcome the existing treatment limitations.
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•A natural anthraquinone glycoside, Aloin, sensitized colorectal cancer to CPT-11, including CPT-11 resistant cells.•MicroRNA-133b was upregulated after Aloin and CPT-11 treatment.•Overexpression of miRNA-133b reversed IGF1R overexpression.•Downregulation of IGF1R by Aloin and CPT-11 combination treatment induced apoptosis.
T cells play a crucial role in the regulation of immune response and are integral to the efficacy of cancer immunotherapy. Because immunotherapy has emerged as a promising treatment for cancer, ...increasing attention has been focused on the differentiation and function of T cells in immune response. In this review, we describe the research progress on T-cell exhaustion and stemness in the field of cancer immunotherapy and summarize advances in potential strategies to intervene and treat chronic infection and cancer by reversing T-cell exhaustion and maintaining and increasing T-cell stemness. Moreover, we discuss therapeutic strategies to overcome T-cell immunodeficiency in the tumor microenvironment and promote continuous breakthroughs in the anticancer activity of T cells.
Background
Current esophageal treatment guidelines suggest that, when more than 15 lymph nodes are detected, dissection should be done as the minimum requirement for staging in esophageal squamous ...cell carcinoma (ESCC) patients undergoing esophagectomy without induction chemoradiotherapy (CRT). However, for neoadjuvant CRT, there is limited information. We sought to clarify the role of lymphadenectomy in ESCC patients with and without neoadjuvant CRT.
Patients and Methods
Data on 3156 ESCC patients receiving esophagectomy with (group 1,
n
= 1399) and without (group 2,
n
= 1757) neoadjuvant CRT between 2008 and 2014 were collected from a national cancer registry in Taiwan. The impact of the resected lymph nodes on overall survival was assessed according to pathologic stages. A Cox regression model was used to identify prognostic factors for overall survival.
Results
Five-year overall survival rates were 35.6% for the entire group, 30.32% for group 1, and 39.55% for group 2 (
p
< 0.0001 for group 1 vs group 2). The best cutoff value was 21 lymph nodes in both group 1 and group 2. In group 1, the independent prognostic factors included age ≥ 54 years, clinical N status, y-pathologic T, y-pathologic N, y-pathologic stage, grade, location, margin status, esophagectomy (thoracoscopic vs open), and number of total resected lymph nodes (≤ 21 vs > 21). For group 2, the independent prognostic factors were gender, clinical stage, pathologic T, pathologic N, tumor length, grade, and margin status.
Conclusions
Extent of lymphadenectomy was associated with survival in patients with neoadjuvant CRT followed by esophagectomy. The optimum lymphadenectomy should be modulated by pathologic stage.
Positive fluid balance and tissue fluid accumulation are associated with adverse outcomes in sepsis. Vascular endothelial growth factor (VEGF) increases in sepsis, promotes vascular permeability, and ...may affect tissue fluid accumulation and oxygenation. We used near-infrared spectroscopy (NIRS) to estimate tissue hemoglobin (Hb) oxygenation and water (H
O) levels to investigate their relationship with serum VEGF levels.
New-onset severe sepsis patients admitted to the intensive care unit were enrolled. Relative tissue concentrations of oxy-Hb (HbO
), deoxy-Hb (HbR), total Hb (HbT), and H
O (H
O) were estimated by near-infrared spectroscopy (NIRS) for three consecutive days and serum VEGF levels were measured. Comparisons between oliguric and non-oliguric patients were conducted and the correlations between variables were analyzed.
Among 75 eligible patients, compared with non-oliguric patients, oliguric patients were administrated more intravascular fluids (median IQR, 1926.00 1348.50-3092.00 mL/day vs. 1069.00 722.00-1486.75 mL/day, p < 0.001) and had more positive daily net intake and output (mean SD, 1,235.06 1303.14 mL/day vs. 313.17 744.75 mL/day, p = 0.012), lower HbO
and HbT over the three-day measurement (analyzed by GEE p = 0.01 and 0.043, respectively) and significantly higher H
O on the third day than on the first two days (analyzed by GEE p = 0.034 and 0.018, respectively). Overall, serum VEGF levels were significantly negatively correlated with HbO
and HbT (rho = - 0.246 and - 0.266, p = 0.042 and 0.027, respectively) but positively correlated with H
O (rho = 0.449, p < 0.001). Subgroup analysis revealed a significant correlation between serum VEGF and H2O in oliguric patients (rho = 0.532, p = 0.003). Multiple regression analysis determined the independent effect of serum VEGF on H
O (standardized coefficient = 0.281, p = 0.038).
In severe sepsis, oliguria relates to higher positive fluid balance, lower tissue perfusion and oxygenation, and progressive tissue fluid accumulation. Elevated serum VEGF is associated with worsening tissue perfusion and oxygenation and independently affects tissue fluid accumulation.
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