Digital finance, innovation transformation, and resilient city growth.

Digital finance is a pivotal catalyst for a contemporary economic system and assumes a significant auxiliary function in the establishment of resilient urban centers. This study empirically examines the enabling influence of digital finance on resilient cities using panel data from 287 prefecture-level cities and above in China between 2011 and 2020. The analysis is based on the mechanisms of innovation and transformation. The importance of digital finance in facilitating the development of resilient cities has been observed, with a specific emphasis on its impact on enhancing the adaptive capacity and growth resilience of urban areas. The utilization of digital finance has the potential to expedite the process of transforming urban industrial structures, invigorating innovation and entrepreneurial activities, and serving as a significant catalyst for the development of resilient cities. The analysis of heterogeneity reveals that various aspects of digital finance have varying degrees of influence on urban resilience. Specifically, the depth of utilization of digital finance exerts the most significant impact, followed by the level of digitalization, while the extent of coverage has the least effect. Furthermore, when considering regional distribution, the promotion effect of digital finance on resilient cities diminishes gradually from the eastern to the central and western regions.

Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival.

PURPOSE: Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro. EXPERIMENTAL DESIGN: We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxol plus carboplatin chemotherapy delayed tumor progression, whereas combined treatment caused tumor regression and a substantially longer growth delay. To test apomab activity in a setting that may more closely mimic lung cancer pathology in patients, we developed a lung orthotopic model. RESULTS: In this model, microcomputed tomography imaging showed that apomab, chemotherapy, or combination treatment significantly inhibited tumor growth compared with vehicle, whereas the combination caused greater inhibition in tumor growth relative to chemotherapy or apomab. Similarly, histologic analysis revealed that apomab, chemotherapy, or the combination significantly reduced tumor size compared with vehicle, whereas the combination induced significantly greater reduction in tumor size than did chemotherapy or apomab. Furthermore, combined treatment improved 105-day survival relative to vehicle (P = 0.0023) as well as to apomab (P = 0.0445) or chemotherapy (P = 0.0415). CONCLUSION: These results show a positive interaction of apomab with chemotherapy, evidenced by significant inhibition of tumor growth as well as improved survival, thus supporting further investigation of this therapeutic approach in lung cancer patients.

MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival.

The hepatocyte growth factor (HGF) and its receptor, c-Met, have been implicated in driving proliferation, invasion, and poor prognosis in pancreatic cancer. Here, we investigated the expression of HGF and c-Met in primary pancreatic cancers and described in vitro and in vivo models in which MetMAb, a monovalent antibody against c-Met, was evaluated. First, expression of HGF and MET mRNA was analyzed in 59 primary pancreatic cancers and 51 normal samples, showing that both factors are highly expressed in pancreatic cancer. We next examined HGF responsiveness in pancreatic cancer lines to select lines that proliferate in response to HGF. Based on these studies, two lines were selected for further in vivo model development: BxPC-3 (c-Met(+), HGF(-)) and KP4 (c-Met(+), HGF(+)) cells. As BxPC-3 cells are responsive to exogenous HGF, s.c. tumor xenografts were grown in a paracrine manner with purified human HGF provided by osmotic pumps, wherein MetMAb treatment significantly inhibited tumor growth. KP4 cells are autocrine for HGF and c-Met, and MetMAb strongly inhibited s.c. tumor growth. To better model pancreatic cancer and to enable long-term survival studies, an orthotopic model of KP4 was established. MetMAb significantly inhibited orthotopic KP4 tumor growth in 4-week studies monitored by ultrasound and also improved survival in 90-day studies. MetMAb significantly reduced c-Met phosphorylation in orthotopic KP4 tumors with a concomitant decrease in Ki-67 staining. These data suggest that the HGF/c-Met axis plays an important role in the progression of pancreatic cancer and that targeting c-Met therein may have therapeutic value.

Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent.

Association with albumin as a means to improve biodistribution and tumor deposition of a Fab was investigated using AB.Fab4D5, a bifunctional molecule derived from trastuzumab (HERCEPTIN) capable of binding albumin and tumor antigen HER2 (erbB2) simultaneously. AB.Fab4D5 was compared with trastuzumab and a trastuzumab-derived Fab (Fab4D5) for the ability to target tumors overexpressing HER2 in mouse mammary tumor virus/HER2 allograft models. Biodistribution was monitored using intravital microscopy, histology, and integrated single-photon emission computed tomography/computed tomography analysis. Fab4D5 tumor deposition was characterized by rapid but transient appearance in tumor at 2 h with little retention, followed by rapid accumulation in kidney by 6 h. Trastuzumab was slow to accumulate in tumors and slow to clear from normal tissues, although significant tumor deposition was achieved by 24 h. In contrast, AB.Fab4D5 was observed at 2 h in tumor and its presence was sustained beyond 24 h similar to trastuzumab. Intravital microscopy revealed that at peak tumor accumulation, tumor cell staining by AB.Fab4D5 was more uniform than for Fab4D5 or trastuzumab. Similar tumor deposition was achieved for both AB.Fab4D5 and trastuzumab at 48 h (35.9 +/- 1.8% and 38.2 +/- 3.1% injected dose/g); however, AB.Fab4D5 targeted tumors more rapidly and quickly cleared from blood, leading to a lower overall normal tissue exposure. Importantly, unlike Fab4D5, AB.Fab4D5 did not accumulate in kidney, suggesting that association with albumin leads to an altered route of clearance and metabolism. Rapid targeting, excellent tumor deposition and retention, coupled with high tumor to blood ratios may make AB.Fab an exceptional molecule for imaging and cancer therapy.

Vasorelaxation induced by vascular endothelial growth factor in the human internal mammary artery and radial artery.

OBJECTIVES: Due to potential therapeutic value of vascular endothelial growth factor (VEGF) in coronary artery disease, the effect and mechanism of VEGF in human arteries used as coronary bypass grafts become important but not fully understood. VEGF-mediated endothelial regulation in vasorelaxation was studied in internal mammary artery (IMA) and radial artery (RA), compared with that of the classical agent-acetylcholine (ACh). The role of nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF) was investigated. METHODS: VEGF- and ACh-induced responses were measured in RA and IMA with or without endothelium and in the absence or presence of inhibitors of nitric oxide synthase or prostacyclin. In addition, the VEGF-induced PGI2 was measured by enzyme immunoassay. RESULTS: VEGF induced similar relaxation in RA (59.2+/-9.3%) and IMA (56.1+/-6.4%) that was significantly inhibited by N(omega)-nitro-L-arginine (L-NNA) plus oxyhemoglobin (HbO) (IMA: 24.9+/-4.3%, P=0.03 vs. RA: 25.0+/-8.6%, P=0.01) or by indomethacin (INDO) (IMA: 21.8+/-2.5%, P=0.000 vs. RA: 30.0+/-6.6%, P=0.04) with more inhibition in IMA than RA (P<0.05). In addition, the VEGF-induced PGI2 was significantly higher in IMA than RA (11.5+/-2.1 vs. 4.9+/-1.1 pg/ml/mg, P=0.002). INDO+L-NNA+HbO reduced the VEGF-induced relaxation to 20.8+/-4.6% in RA vs. 4.8+/-1.6% in IMA (P=0.01). In contrast, the maximal relaxation induced by ACh in RA (55.9+/-6.0%) and IMA (48.5+/-5.3%) was largely inhibited by L-NNA in IMA and RA (14.7+/-3.0%, P=0.000 vs. 15.2+/-3.2%, P=0.004) but little affected by INDO. CONCLUSIONS: VEGF induces similar relaxation in IMA and RA with significantly more PGI2-mediated relaxation and higher stimulated PGI2 level in IMA but more EDHF-mediated relaxation in RA. In comparison, ACh-induced relaxation mainly depends on NO. Thus, our study reveals a significant difference in the mechanism of the endothelium-dependent relaxation induced by VEGF and ACh.

Inhibitory effects of interferon-gamma on myocardial hypertrophy.

Prostaglandin F(2alpha) (PGF(2alpha)) plays an important role in pathologic cardiac growth. After testing several immune cytokines, we found that interferon-gamma (IFN-gamma) inhibited responsiveness of adult myocytes to PGF(2alpha). The present study was designed to test the hypothesis that IFN-gamma inhibits cardiac hypertrophy induced by PGF(2alpha). Incubation of cultured adult rat cardiac myocytes with PGF(2alpha) caused cell spreading, which was inhibited by IFN-gamma. The inhibitory effect was not affected by nitric oxide (NO) synthase inhibitors. In addition, administration of fluprostenol, a more selective agonist at the PGF(2alpha) receptor, induced cardiac hypertrophy in rats. Chronic treatment with IFN-gamma inhibited this myocardial growth, and the inhibitory effect of IFN-gamma was not accompanied by an increase in myocardial NO synthase gene expression. Further, abdominal aortic constriction resulted in a substantial increase in heart, ventricular and left ventricular weights to BW ratio that was significantly attenuated by treatment with IFN-gamma. The results demonstrate that IFN-gamma inhibits the in vitro and in vivo effects of PGF(2alpha) on cardiac hypertrophy, and that the mechanism of action is likely independent of NO production. IFN-gamma also attenuated cardiac hypertrophy induced by pressure overload, suggesting that PGF(2alpha) plays a role in the pathogeneses of this severe type of cardiac hypertrophy.

Vascular endothelial growth factor-induced nitric oxide- and PGI2-dependent relaxation in human internal mammary arteries: a comparative study with KDR and Flt-1 selective mutants.

The role of the vascular endothelial growth factors (VEGF) receptors (KDR and Flt-1) and their characteristics in VEGF-induced vasodilation in human vessels is unclear. This study investigated the in vitro vasorelaxant effects of KDR-selective (KDR-SM) and Flt-1-selective mutants (Flt-1-SM) in the human internal mammary artery (IMA). IMA segments (n = 183) taken from 48 patients were studied in organ baths. The cumulative concentration (-12 to -8 log10M)-relaxation curves were established for VEGF, KDR-SM, Flt-1-SM, and placenta growth factor (PlGF) in the absence or presence of indomethacin (INDO, 7 microM), N-nitro-L-arginine (L-NNA, 300 microM), L-NNA + oxyhemoglobin (HbO, 20 microM), or INDO + L-NNA + HbO. The VEGF-induced relaxation was abolished in endothelium-denuded IMA. In the endothelium-intact vessel rings, VEGF (63.2 +/- 3.9%) induced significantly more (P < 0.001) relaxation than Flt-1-SM (28.5 +/- 4.3%, 95% CI 18.1-51.3%), and PlGF (26.0 +/- 4.7%, 95% CI 17.6-56.8%). The maximal relaxation induced by KDR-SM (53.0 +/- 4.0%) was only slightly less than that by VEGF (P = 0.075) but significantly more than that by Flt-1-SM (P = 0.001, 95% CI 7.8-41.1%). Pretreatment of INDO or L-NNA + HbO significantly (P < 0.001) inhibited the relaxation by VEGF (21.2 +/- 3.9% or 23.3 +/- 4.3%) and KDR-SM (9.8 +/- 8.2% or 10.1 +/- 17.8%). INDO + L-NNA + HbO completely inhibited the relaxation by VEGF, KDR-SM, or Flt-1-SM. KDR may be the dominant receptor in mediating the VEGF-mediated relaxation, which is regulated by both PGI2 and nitric oxide but probably not by endothelium-derived hyperpolarizing factor, in the human IMA. This study gives insight into the characteristics of the VEGF-mediated vasodilation and provides a scientific basis for potential clinical application of VEGF/KDR-SM in ischemic heart disease.

The therapeutic potential of hepatocyte growth factor for myocardial infarction and heart failure.

Hepatocyte growth factor (HGF) is a cytokine whose multipotent actions are mediated by c-Met receptor. This review focuses on effects of HGF on myocardial infarction (MI) and heart failure. Circulating concentrations of HGF and myocardial concentrations of HGF and c-Met mRNA and protein are substantially increased following acute MI. HGF has been shown to be cardioprotective towards acute cardiac ischemia-reperfusion injury. Gene transfection of HGF into rat hearts attenuates acute ischemia injury. Administration of HGF protein reduces infarct size and increases cardiac performance in a rat model of acute ischemia/reperfusion. In contrast, acute blockade of endogenous HGF increases infarct size and mortality. These acute effects of HGF appear to be related to angiogenic and anti-apoptotic mechanisms. Recent studies demonstrate that post-MI treatment with HGF gene or protein attenuates chronic cardiac remodeling and dysfunction. In rats, HGF gene transfer following large MI results in preserved cardiac function and geometry in association with angiogenesis and reduced apoptosis, and treatment with recombinant HGF also significantly improves cardiac performance measured 8 weeks after MI. In mice, post-MI HGF gene therapy improves cardiac remodeling and dysfunction through hypertrophy of cardiomyocytes, infarct wall thickening, preservation of vessels, and antifibrosis. In addition, gene transfer of HGF improves cardiac remodeling, angiogenesis and regional myocardial function in the chronic ischemic myocardium of dogs. Together, these preclinical data highlight the significant acute and chronic cardioprotective effects of HGF following ischemic heart failure. Clinical trials are needed to investigate the therapeutic potential of HGF for postinfarction heart failure in humans.

Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand cooperates with chemotherapy to inhibit orthotopic lung tumor growth and improve survival.

Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a tumor necrosis factor superfamily member that induces apoptosis through the death receptors DR4 and/or DR5 in various cancer cell types but not in most normal cells. Several lung cancer cell lines express DR4 and DR5 and undergo apoptosis in vitro in response to Apo2L/TRAIL. We investigated the efficacy of recombinant soluble human Apo2L/TRAIL and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small cell lung carcinoma cells. In vitro, Taxol enhanced caspase activation and apoptosis induction by Apo2L/TRAIL. In vivo, Apo2L/TRAIL or Taxol plus carboplatin chemotherapy partially delayed progression of established subcutaneous tumor xenografts, whereas combined treatment caused tumor regression and a substantially longer growth delay. Apo2L/TRAIL, chemotherapy, or the combination of both inhibited growth of preformed orthotopic lung parenchymal tumors versus control by 60%, 57%, or 97%, respectively (all P < 0.01; n = 8-10). Furthermore, combination treatment improved day-90 survival relative to control (7 of 15 versus 1 of 15; P = 0.0003 by Mantel-Cox) as well as to Apo2L/TRAIL (3 of 14; P = 0.031) or chemotherapy (3 of 15; P = 0.035). These studies provide evidence for in vivo activity of Apo2L/TRAIL against lung tumor xenografts and underscore the potential of this ligand for advancing current lung cancer treatment strategies.

Thyrotropin-releasing hormone is induced in the left ventricle of rats with heart failure and can provide inotropic support to the failing heart.

BACKGROUND: We reported previously that left ventricular gene expression for thyrotropin-releasing hormone (TRH) precursor was increased in rats with heart failure 8 weeks after myocardial infarction (MI) and that early ACE inhibition tended to cause further myocardial induction of this gene. METHODS AND RESULTS: Here, we show that after MI, the expression of pro-TRH is induced in the heart coordinately with the protease PC1, an important enzyme in TRH biosynthesis. Pro-TRH gene expression was induced in cardiac interstitial cells after MI, and this effect was restricted to the heart, because no increase in TRH mRNA abundance was observed in the hypothalamus, kidney, or lung. Transcript abundance of pro-TRH can be increased in cultured cardiac fibroblasts by several adrenergic agonists, indicating that the adrenergic axis may play a regulatory role in cardiac TRH production. Acute intravenous administration of TRH to rats with ischemic cardiomyopathy caused a significant increase in heart rate, mean arterial pressure, cardiac output, stroke volume, and cardiac contractility. CONCLUSIONS: Taken together, these results indicate that TRH is specifically induced in the heart after MI and that it can increase cardiac performance in rats with ischemic cardiomyopathy. Thus, in addition to catecholamine and angiotensin II, pro-TRH/TRH may be another important axis that affects hemodynamics and cardiac function in heart failure.

Early treatment with hepatocyte growth factor improves cardiac function in experimental heart failure induced by myocardial infarction.

Plasma levels of hepatocyte growth factor (HGF) are increased within hours of cardiac ischemia/reperfusion in rats, and HGF has been shown to be cardioprotective toward acute ischemic injury. Myocardial levels of HGF mRNA and protein are increased for several days after myocardial infarction (MI), however, indicating a possible additional protective effect of HGF toward the progression of MI to heart failure. The purpose of this study was to determine whether HGF administration during the time course of endogenous cardiac HGF induction would lead to long-term improvement in cardiac function in rats with MI. MI was induced by 2-h occlusion of the left coronary artery, followed by reperfusion. HGF was given by intravenous infusion at 0.45 mg/kg/day for 6 days beginning on the day after surgery. Cardiac function and hemodynamic parameters were measured by using indwelling catheters and perivascular flow probes in conscious animals 8 weeks post-MI. Myocardial infarcts were approximately 30% of the left ventricle, and there was no difference in infarct size between the vehicle-treated and HGF-treated groups. Compared with untreated sham-operated rats, vehicle-treated MI animals had significantly lower cardiac index and stroke volume index and higher systemic vascular resistance, indicating heart failure developed. Treatment with HGF caused a significant increase in cardiac index and stroke volume index and a reduction in systemic vascular resistance in rats with MI, restoring these parameters close to those observed in sham-operated control animals. These results provide direct evidence that HGF may be of benefit to cardiovascular function in ischemic cardiomyopathy.

Effects of early treatment with growth hormone on infarct size, survival, and cardiac gene expression after acute myocardial infarction.

OBJECTIVE: This study examined the effects of growth hormone (GH) on infarct size, survival, and cardiac gene expression in rats with acute myocardial infarction. DESIGN: Animals randomly received sc injection of either saline vehicle (n = 98) or GH (2mg/kg/day, n = 105) for 14 days commencing the day of left coronary artery ligation. Infarct size was determined by morphometric analysis at the time of death or at 52 weeks post-surgery. Gene expression was analyzed by real-time RT-PCR after 2-week treatment. RESULTS: GH decreased infarct size by 18% (P < 0.01) and increased survival by 36% at 52 weeks. GH also significantly reduced cardiac expression of atrial natriuretic factor, beta-myosin heavy chain, alpha-smooth muscle actin, collagen I, collagen III, fibronectin, and pro-inflammatory cytokines. CONCLUSIONS: Treatment with GH for 2 weeks beginning on the day of myocardial infarction produced beneficial effects that were associated with reductions in cardiac gene expression symptomatic of pathological remodeling.

KDR (VEGF receptor 2) is the major mediator for the hypotensive effect of VEGF.

Vascular endothelial growth factor (VEGF) exerts vasodilation-induced hypotension as a major side effect for treatment of ischemic diseases. VEGF has 2 receptor tyrosine kinases, KDR and Flt-1. Little is known about which receptor mediates VEGF-induced hypotension. To elucidate the role of each receptor in mediating hypotension, KDR-selective and Flt-1-selective mutants were used for in vitro and in vivo studies. The KDR-selective mutant induced vascular endothelial cell proliferation comparable to VEGF, whereas the Flt-1- selective mutant had no effect on proliferation. Intravenous injection of KDR-selective mutant, Flt-selective mutant, or VEGF caused a dose-related decrease in mean arterial pressure in conscious rats. The hypotensive response to KDR-selective mutant was significantly less than that to VEGF (P<0.01) but was greater than that to Flt-selective mutant (P<0.01). Similarly, VEGF and KDR-selective mutant induced more potent vasorelaxation than Flt-selective mutant or placenta growth factor that binds Flt-1 only (P<0.01), and the vasorelaxation to KDR-selective mutant was not significantly different at low concentrations but less than that to VEGF at high concentrations. The results indicate that the vasodilation and hypotensive effect of VEGF may involve both receptors, but KDR is the predominant receptor mediating this effect. Because KDR-selective mutant induced proliferation and angiogenesis similar to VEGF but was associated with 36% attenuation in hypotension, the data suggest that the KDR-selective mutant may represent an alternative treatment for ischemic diseases.

Exaggerated hypotensive effect of vascular endothelial growth factor in spontaneously hypertensive rats.

Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics, and release of NO and prostaglandin I2 (PGI2) in vivo and on vasorelaxation of mesentery artery rings in vitro in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2 hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY (P<0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (P<0.01). Circulating NO and PGI2 levels after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater hypotension (P<0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia in response to VEGF, which was independent of NO and PGI2. The exaggerated hypotensive response to VEGF in SHR may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more caution should be taken when VEGF is administered in patients with hypertension.

Vascular endothelial growth factor-mediated, endothelium-dependent relaxation in human internal mammary artery.

BACKGROUND: Vascular endothelial growth factor (VEGF) has been shown to have potential to treat ischemic diseases. Moreover, its vasorelaxing or vasodilatory effect might be favorable for relieving graft spasm. In this study, we examined the vasorelaxing effects of recombinant VEGF in isolated human internal mammary artery (IMA) and compared the responses to acetylcholine and nitroglycerin. METHODS: Isometric tension of IMA ring segments was measured with an organ bath technique. With an optimal resting tension determined from its individual length-tension curve, precontraction was induced by 10(-8) M U46619 and cumulative concentration-relaxation was measured by application of VEGF (10(-12) to 10(-15) M), acetylcholine (10(-10) to 10(-5) M), and then nitroglycerin (10(-4.5) M). RESULTS: Vascular endothelial growth factor induced concentration-dependent relaxation (EC50: -9.89+/-0.05 log M; Emax: 63.2%+/-7.3%) in IMA with intact endothelium. The relaxant responses to VEGF were significantly attenuated by pretreatment with Nomega-nitro-L-arginine (L-NNA) alone and indomethacin + L-NNA, and totally abolished by removal of the endothelium or pretreatment with indomethacin + L-NNA + oxyhemoglobin. Internal mammary arteries became more sensitive to VEGF in the presence of indomethacin alone. However, acetylcholine-induced relaxation was not abolished by treatment with indomethacin + L-NNA + oxyhemoglobin (Emax: 16.9%+/-2.7%). The endothelium-independent relaxations induced by nitroglycerin were also significantly inhibited by administration of oxyhemoglobin. CONCLUSIONS: The results demonstrate that VEGF-induced endothelium-dependent relaxation in the human IMA is mainly due to nitric oxide release. Although the vasorelaxing effect is not the primary advantage of this drug when it is used for angiogenesis, such effect may be advantageous in patients who also need a coronary artery bypass operation.