Anti-angiogenesis in colorectal cancer therapy.

The morbidity of colorectal cancer (CRC) has risen to third place among malignant tumors worldwide. In addition, CRC is a common cancer in China whose incidence increases annually. Angiogenesis plays an important role in the development of tumors because it can bring the nutrients that cancer cells need and take away metabolic waste. Various mechanisms are involved in the formation of neovascularization, and vascular endothelial growth factor is a key mediator. Meanwhile, angiogenesis inhibitors and drug resistance (DR) are challenges to consider when formulating treatment strategies for patients with different conditions. Thus, this review will discuss the molecules, signaling pathways, microenvironment, treatment, and DR of angiogenesis in CRC.

PTK7 is a novel oncogenic target for esophageal squamous cell carcinoma.

BACKGROUND: Overexpression of PTK7 has been found in multiple cancers and has been proposed to serve as a prognostic marker for intrahepatic cholangiocarcinoma. Its role in esophageal cancer, however, remains to be clarified. We hypothesize that PTK7 positively regulates tumorigenesis of esophageal cancer. METHODS: We examined PTK7 expression pattern in human esophageal squamous carcinoma by Oncomine expression analysis and by immunohistochemistry (IHC) staining. We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells. Expressions of major apoptotic regulators and effectors were also determined by quantitative real-time PCR in PTK7-defective cells. We further overexpressed PTK7 in the cell to evaluate its effects on cell proliferation, apoptosis, and migration. RESULTS: Both Oncomine expression and IHC analyses showed that PTK7 is overexpressed in clinical esophageal squamous cell carcinoma tumors. PTK7 siRNA suppressed cell growth and promoted apoptosis of TE-5 and TE-9. PTK7-defective cells further displayed reduced cellular migration that was concomitant with upregulation of E-cadherin. Conversely, overexpression of PTK7 promotes cell proliferation and invasion, while apoptosis of the PTK7-overexpressing cells is repressed. Notably, major apoptotic regulators, such as p53 and caspases, are significantly upregulated in siPTK7 cells. CONCLUSIONS: PTK7 plays an oncogenic role in tumorigenesis and metastasis of esophageal squamous carcinoma. PTK7 achieves its oncogenic function in esophageal squamous cell carcinoma partially through the negative regulation of apoptosis.

Brachytherapy Using Elastin-Like Polypeptides with (131)I Inhibit Tumor Growth in Rabbits with VX2 Liver Tumor.

BACKGROUND: Brachytherapy is a targeted type of radiotherapy utilized in the treatment of cancers. Elastin-like polypeptides are a unique class of genetically engineered peptide polymers that have several attractive properties for brachytherapy. AIMS: To explore the feasibility and application of brachytherapy for VX2 liver tumor using elastin-like polypeptides with (131)I so as to provide reliable experimental evidence for a new promising treatment of liver cancer. METHODS: Elastin-like polypeptide as carrier was labeled with (131)I using the iodogen method. Ten eligible rabbits with VX2 liver tumor were randomly divided into the treatment group (n = 5) and control group (n = 5). The treatment group received brachytherapy using elastin-like polypeptide with (131)I, and in the control group, elastin-like polypeptide was injected into the VX2 liver tumor as a control. Periodic biochemical and imaging surveillances were required to assess treatment efficacy. RESULTS: The stability of elastin-like polypeptide with (131)I in vitro was maintained at over 96.8 % for 96 h. Biochemistry and imaging indicated brachytherapy using elastin-like polypeptide with (131)I for liver tumor can improve liver function and inhibit tumor growth (P < 0.05). CONCLUSIONS: Elastin-like polypeptide can be an ideal carrier of (131)I and have high labeling efficiency, radiochemical purity and stability. Brachytherapy using elastin-like polypeptide with (131)I for liver tumor is a useful therapy that possesses high antitumor efficacy advantages.

A feasibility study of a thermally sensitive elastin-like polypeptide for submucosal injection application in endoscopic resection in 3 animal models.

BACKGROUND AND AIMS: Endoscopic submucosal dissection (ESD) can successfully resect large lesions en bloc by using a submucosal injection solution, but the cost of currently available submucosal injection solutions is not satisfactory. The authors' aim was to evaluate the feasibility and effectiveness of a thermally sensitive elastin-like polypeptide (ELP) used as submucosal injection solution in ESD. METHODS: We conducted an ex vivo study to determine the optimal concentration of ELPs in rabbits, an in vivo study to evaluate the effectiveness of mucosal elevation in rats, and a large animal study to confirm the feasibility of preclinical application by using conventional clinical procedure in pigs. RESULTS: ELP (500 µM) was proved to be the optimal injectable submucosal injection solution and elevated mucosa more efficiently than any control. The same concentration of ELP exhibited an equivalent effectiveness of mucosal elevation, the retention of the elevation, and minimal bleeding with sodium hyaluronate. The ESD procedure time with 500 µM ELP in a preclinical study with pigs was significantly shorter than with any other concentration of ELP and normal saline solution. CONCLUSIONS: Use of ELP as submucosal injection solution was feasible, with higher and longer-lasting elevation and fewer adverse events.

Low serum manganese as a noninvasive marker predicting the presence of myosteatosis among hospitalized patients with cirrhosis.

Emerging evidence expands on a close connection between trace elements and muscular abnormalities, mostly focusing on sarcopenia. We hypothesized an association between concentrations of serum trace elements and myosteatosis, given that myosteatosis has a more pronounced clinical implication relative to sarcopenia, but there is a paucity of data in patients with cirrhosis. Consecutive patients were hospitalized for cirrhosis-associated complications. Serum trace elements (zinc, copper, manganese [Mn], magnesium, calcium, and iron) were measured by inductively coupled plasma mass spectrometry. The presence of myosteatosis was defined according to computed tomography-demarcated intramuscular adipose tissue content. In total, the 295 patients with cirrhosis analyzed had a median age of 63 years and 53.6% were male. Among them, 42 patients presented with myosteatosis (14.2%) and concomitant higher Model for End-stage Liver Disease-Sodium and triglyceride concentrations and lower neutrophil counts and serum Mn concentrations (all P < .05). No differences were found regarding other 5 trace elements in patients with versus without myosteatosis. The median serum Mn concentrations were 1.16 µg/L, and this population was categorized into high-Mn and low-Mn groups. The proportion of myosteatosis was significantly lower in high-Mn group than that in low-Mn group (8.1% vs 20.4%, P < .001). Univariable binary logistic regression indicated that low Mn was associated with myosteatosis (odds ratio, 2.906; 95% confidence interval, 1.424-5.932; P = .003) in the context of cirrhosis. This result was validated according to multivariable analysis by adjusting for confounding factors. In conclusion, low serum Mn can be predictive of myosteatosis, a novel muscular abnormality representing more clinical relevance and close relation to inferior outcomes among cirrhosis.

Risk factors and major adverse cardiovascular events of isolated coronary artery ectasia: An observational study.

To evaluate the cardiac index and major adverse cardiovascular events (MACE) events between isolated coronary artery ectasia (CAE) and control groups over 1 year period from diagnosis. A total of 18 patients who were diagnosed with isolated CAE in the Second Hospital of Hebei Medical University from December 2020 to December 2021 were included in CAE group. About 36 patients with non-obstructive coronary artery lesions were included in the control group. All patients in 2 groups completed dobutamine stress echocardiography (DSE) during hospitalization. The chamber size, wall thickness, left ventricular ejection fraction, and left ventricular diastolic function indicators (including E/A ratio, e', and E/e' ratio) were measured. MACE and all-cause death were measured during follow-up after discharge. Interventricular septum thickness (IVSd), left ventricular posterior wall (LVPW) thickness in diastole and E/e' in CAE group were significantly higher than control group (P < .05). No significant differences were found in prognosis including angina, myocardial ischemia (MI), patient readmission and cardiovascular death (P > .05). In CAE group, coronary angiography showed dilation of left anterior descending (LAD) in 1 case, left circumflex (LCX) in 3 cases and right coronary artery (RCA) in 14 cases. Multivariate logistic regression analysis showed that BMI and IVSd were independent risk factors for CAE. IVSd, LVPW thickness in diastole and E/e' in CAE group were significantly higher than control group. BMI and IVSd were independent risk factors for isolated CAE, and had a good predictive value for isolated CAE.

Global Leadership Initiative on Malnutrition-defined malnutrition coexisting with visceral adiposity predicted worse long-term all-cause mortality among inpatients with decompensated cirrhosis.

BACKGROUND/OBJECTIVES: Malnutrition coexisting with abdominal adipose tissue accumulation bring a double burden on prognosis. More recently, the Global Leadership Initiative on Malnutrition (GLIM) has reached a novel consensus concerning the diagnostic criteria, that is, a two-step modality combining nutritional risk screening and subsequent phenotypic/etiologic parameters for comprehensive evaluation in hopes of harmonizing the malnutrition diagnosis. We aimed to elucidate their synergistic impact among inpatients with decompensated cirrhosis concerning long-term mortality. SUBJECTS/METHODS: Malnutrition, visceral obesity, and visceral adiposity were defined by the Global Leadership Initiative on Malnutrition (GLIM), visceral fat area (VFA), and visceral to subcutaneous adipose tissue area ratio (VSR) on computed tomography, respectively. Accordingly, the patients were categorized into different groups given their nutritional status and visceral obesity/adiposity. Multivariate Cox regression was performed to identify independent risk factors associated with 1-year all-cause mortality. Kaplan-Meier curves with log-rank tests were compared among distinct groups. RESULTS: Totally, 295 patients were recruited. GLIM, VFA, and VSR identified 131 (44.4%), 158 (53.6%), and 59 (20%) patients with malnutrition, visceral obesity and visceral adiposity, respectively. Malnutrition coexisted with visceral obesity in 55 (MO group) relative to visceral adiposity in 40 patients (MA group). Multivariate Cox analysis showed that MA (hazard ratio: 2.48; 95% confidence interval: 1.06, 5.79; P = 0.036) was independently associated with dire outcome rather than MO. Moreover, patients with cirrhosis in the MA group had the worst survival status when compared with other groups (log-rank test: P < 0.001). CONCLUSIONS: The current study indicated that coexisting GLIM-defined malnutrition and VSR-defined visceral adiposity were in relation to worse long-term mortality among inpatients. It is imperative to delicately manage nutritional status and provide personalized treatment in this vulnerable subgroup for achieving better prognosis.

Association Between Quality of Life Defined by EuroQol Group 5 Dimension and Composite Inferior Outcome Among Inpatients with Cirrhosis.

Purpose: The utility of the EuroQol Group 5 Dimension (EQ-5D) measuring health-related quality of life (HRQoL) has been verified; however, knowledge gaps remain concerning predictive performance in cirrhosis. We aimed to identify the optimal threshold for risk stratification and the pronounced domain in the EQ-5D linked to inferior outcomes. Patients and Methods: The X-tile project was used to obtain a threshold, considering the composite outcome of 1-year all-cause mortality or readmission. A restricted cubic spline (RCS) was performed to test the non-linear relationship between the EQ-5D utility value and the primary outcome. Six multivariate Cox regression models incorporating EQ-5D utility value and each of the five domains were constructed. Setting/Participants: Totally, 420 patients with cirrhosis were recruited. Results: The median utility value of the study population was 0.77 and 59.8% reported impairment in minimal one EQ-5D domain. RCS indicated a linear relationship between the utility value and composite inferior outcome. X-tile pinpointed a utility value of 0.59 stratifying populations into high- and low-risk groups based on the outcome. Inpatients with cirrhosis and deteriorated HRQoL (utility value ≤0.59) were at higher risk of death or readmission (adjusted HR: 2.18, P < 0.001). Furthermore, mobility and usual activities were the most pronounced domains associated with composite inferior outcome. Conclusion: A utility value ≤0.59 can identify cirrhotic inpatients exhibiting compromised HRQoL and mortality/readmission risk. It is tempting to reverse the decreased HRQoL by applying longitudinal measurements and keeping surveillance on utility value, while interventions appear to mainly focus on improving mobility and usual activities.

Machine learning screening of high-performance single-atom electrocatalysts for two-electron oxygen reduction reaction.

Electrocatalysis has emerged as one of the most promising alternatives to conventional anthraquinone for preparing hydrogen peroxide (H2O2) with high energy consumption and pollution because of its simplicity, convenience, and environmental friendliness. However, the oxygen reduction reaction (ORR) generating H2O2viathe2e- path is acompetitive path for 4e-ORR to generate H2O. Therefore, it is crucial to identify an electrocatalyst with high selectivity and activity of 2e-ORR. Here, we established five machine learning (ML) models based on the adsorption free energy of O* (△G (O*)) of 149 single-atom catalysts (SACs) collected and the limiting potential (UL) of 31 SACs calculated using density functional theory (DFT) from the literature. We then obtained descriptors that could accurately describe SACs. Furthermore, 690 unknown SACs' 2e-ORR catalytic performance was well predicted. Four 2e-ORR materials with high selectivity and activity were screened: Zn@Pc-N3C1, Au@Pd-N4, Au@Pd-N1C3, and Au@Py-N3C1. We verified the UL of these SACs through DFT calculation, which was higher than the standard value, proving the ML model's validity. The ML-based method to predict the material properties with highly selective and active electrocatalysts provides an efficient, rapid, and low-cost method for discovering and designing more valuable SACs catalysts.

A pH- and enzymatic-responsive nanopesticide to control pea aphids and reduce toxicity for earthworms.

Thiacloprid is a new chlorinated nicotinoid insecticide against stinging-oral pests, such as aphids. It is less toxic to bees but more toxic to earthworms. In this study, a pH- and amylase-responsive MOF (ZIF-8) was constructed for site-specific delivery of thiacloprid to control pea aphids and more safety for earthworms. Thiacloprid from α-cyclodextrin@Thiacloprid@ZIF-8 (α-CD@T@ZIF-8) could be released quickly in pea aphids, which was ascribed to disintegration of ZIF-8 at low pH values in pea aphid intestines and degradation of α-CD under the action of α-amylase. The release results showed a significant pH dependence of α-CD@T@ZIF-8, with an approximately 65 % release amount at pH = 7 and a 95 % release amount at pH = 5 for 7 d. The results of the pot experiment and biosafety showed that for α-CD@T@ZIF-8, 88 % pea aphids could be killed compared with 32 % aphids for commercially available formulation on the 7th day after application. Meanwhile the LC50 of thiacloprid OD was 0.034 µg/cm2 and the LC50 of α-CD@T@ZIF-8 was 0.564 µg/cm2 on earthworms, and it was more safety for pea and lower acute toxicity and enrichment for the earthworms. α-CD@T@ZIF-8 could be used for intelligently controlled release of other insecticides against aphids.

HOXD11 upregulates JAM-A and exerts oncogenic properties via NF-κB signaling pathway in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is a tumor with high incidence and poor prognosis in developing countries. Junctional adhesion molecule A (JAM-A, also known as F11R) affects numerous biological processes, which is a vital regulator of the development of malignant tumors. However, its exact role and underlying mechanism in ESCC remain obscure. Our present study demonstrated that JAM-A was upregulated in ESCC tissues and cell lines by RNA sequencing and immunohistochemistry (IHC). JAM-A knockdown significantly suppressed the proliferation of the ESCC cells, induced cell cycle arrest at the G1 and promoted apoptosis, and suppressed the ability of invasion and migration in vivo and in vitro. Mechanistically, JAM-A may activate the NF-κB signaling pathway to regulate malignant behavior of ESCC. Further research showed that Homeobox D11 (HOXD11) could directly regulate JAM-A transcription by binding to specific sequences of JAM-A promoter region, thereby activating NF-κB signaling pathway to regulate malignant behavior of ESCC. Functional experiments indicated that HOXD11 could exert an oncogenic role in ESCC. Collectively, our findings support the hypothesis that the HOXD11/JAM-A/NF-κB signal axis plays a role in regulating malignant behavior in ESCC patients, highlighting its potential therapeutic value for ESCC.

Left atrial appendage filling defects restricted to the early phase of cardiac computed tomography is significantly associated with ischemic stroke.

PURPOSE: To investigate the relationship between filling defects in the left atrial appendage restricted to the early phase of cardiac computed tomography (CCT), and ischemic stroke in patients with atrial fibrillation (AF). MATERIALS AND METHODS: A total of 152 patients with non-valvular AF were retrospectively enrolled and divided into two groups according to the stroke history, as confirmed by brain computed tomography (CT) or magnetic resonance imaging (MRI), as the non-stroke group (n = 89) and stroke group (n = 63), respectively. The numbers of patients with filling defects in the early phase of CCT images without thrombi were recorded. Morphological parameters of the LAA were measured for all participants. All patients with early-phase filling defects (n = 44) were assigned to two groups according to ischemic stroke history: the filling defects with stroke group (n = 28) and the filling defects without stroke group (n = 16). The clinical characteristics and LAA morphological parameters were compared. RESULTS: Univariate analysis showed that compared with the non-stroke group，LAA volume index and age were higher in the stroke group, and the ratio of early phase filling defect in LAA, hypertension and diabetes were also higher, in the meanwhile the LVEF and BMI were lower (P < 0.05).After adjusting confounding factors by the multivariate logistic regression analysis, filling defect was significantly related with stroke [odds ratio (OR): 4.339, 95% confidence interval (CI): 1.951-9.653, P = 0.000]. LAA morphological parameters were not significantly different between the filling defects with stroke group and the group without stroke. CONCLUSION: AF patients with LAA non-thrombotic filling defects in the early-phase of CCT had an increased risk of ischemic stroke compared to those without filling defects. This finding may help to optimize stroke risk stratification in patients with AF.

Diagnostic pitfalls: a case of prostate cancer and rectal cancer accompanied by prostate cancer invasion of the rectum.

INTRODUCTION: Case of double primary cancer of the prostate and rectum is rare, prostate cancer involving the postoperative intestinal anastomotic mucosal tissue is even rarer. CASE PRESENTATION: We report a case of rectal cancer discovered 1 year after a diagnosis of prostate cancer and a tumour in the postoperative anastomotic intestinal mucosal tissue involving prostatic adenocarcinoma at 1 year after the diagnosis of rectal cancer. Due to the poor differentiation of both prostate and rectal cancers, there are some pitfalls in the diagnosis of intestinal mucosal lesions at an anastomosis. The lack of an accurate diagnosis of a tumour in anastomosis intestinal mucosal tissue will affect treatment and patient survival. CONCLUSIONS: The pathologists should have a detailed understanding of the patient's medical history and carefully observe the histopathological morphology and, if necessary, immunohistochemistry or other techniques should be used to assist in the pathological diagnosis and avoid both misdiagnosis and missed diagnosis.

Preparation and performance characteristics of spider venom peptide nanocapsules.

BACKGROUND: ω-hexatoxin-Hvn1b is an insecticidal toxin produced by the Tasmanian funnel-web spider (Hadronyche venenata), that can be exploited for development of novel bioinsecticides. Due to its larger size and low membrane permeability, this toxin usually has a slower mode of action compared to conventional small molecule insecticides. Nanoscale materials have unique optical, electrical, mechanical and biological properties, and show great application prospects for pesticide delivery. RESULTS: The physical and chemical properties of nanocapsules were characterized using transmission electron microscopy, laser particle size analysis, Fourier transform infrared spectroscopy, contact angle testing and with a fluorescence spectrophotometer. The results indicated that the nanocapsules were spherical, with an average particle size of 197.70 nm, the encapsulation efficiency rate was 75.82% and the Zeta potential was -32.90 mV. Penetration experiments showed that the nanocapsules could promote protein passage through the intestinal tract of Spodoptera litura and reach the body fluid. Then we expressed ω-hexatoxin-Hvn1b by prokaryotic expression. Bioassay results showed that the oral toxicity of ω-hexatoxin-Hvn1b nanocapsules to S. litura was higher than that of the ω-hexatoxin-Hvn1b. CONCLUSION: In this paper, we reported a construction method of spider venom peptide nanocapsules based on polylactic-co-glycolic acid by multiple emulsion for delivery of protein to improve the insecticidal effect and oral activity of ω-hexatoxin-Hv1a. © 2022 Society of Chemical Industry.

A Meta-Analysis on the Effect and Safety of LCZ696 in the Treatment of Hypertension.

OBJECTIVES: To systematically evaluate the differences in effect and safety of LCZ696 and angiotensin receptor blockers (ARBs) in the treatment of hypertension. METHODS: We searched PubMed, Cochrane, Web of Science, and Ovid, collected randomized controlled trials (RCTs) about the effect and safety of LCZ696 and ARBs in hypertensive patients, extracted relevant data and evaluated the quality of the included literature according to the RCT quality evaluation standard recommended by Cochrane Reviewer's Handbook, using RevMan 5.3, and performed meta-analysis. RESULTS: Eight RCTs studies were included, with a total of 4313 patients. Compared with ARBs, LCZ696 can better reduce systolic blood pressure (msSBP) (WMD -4.29 mmHg; 95% CI: -5.37 to -3.21; P < 0.001), diastolic blood pressure (msDBP) (WMD -1.87 mmHg; 95% CI:-2.38 to -1.36; P < 0.01), ambulatory systolic blood pressure (maSBP) (WMD -3.37 mmHg; 95% CI:-4.26 to -2.47; P < 0.01), and ambulatory diastolic blood pressure (maDBP) (WMD -1.47 mmHg; 95% CI: -1.97 to -0.97; P < 0.01). In terms of safety, LCZ696 is basically the same as ARBs, but LCZ696 is more likely to cause cough than ARBs (OR = 2.38; 95% CI: 1.27 to 4.47; P < 0.01). CONCLUSION: LCZ696 can significantly reduce the blood pressure level of patients with hypertension, but it is necessary to pay attention to whether the patient will experience coughing after taking the drug.