Vascular Endothelial Growth Factor Response Research Articles

Screening of herbal extracts binding with vascular endothelial growth factor by applying HerboChip platform

BackgroundTraditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip.MethodsSelected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated.ResultsOver 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities.ConclusionsThe current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms.

Efficacy of bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed POEMS syndrome patients.

Due to the rarity of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, the best first-line treatment has not been established, although there are several options in guidelines. The preferred treatments vary according to the preference of the physician and anecdote. First, to analyze the efficacy of a new treatment mode in POEMS syndrome that uses the four-cycle treatment as the induction regimen, followed by sequential transplantation as the consolidation regimen for transplantation-eligible patients, or received another two-cycle treatment for transplantation-ineligible patients. Second, to compare the efficacy and safety of regimens with a proteasome inhibitor (bortezomib-cyclophosphamide-dexamethasone, BCD) or without a proteasome inhibitor (cyclophosphamide-dexamethasone ± thalidomide, CD ± T). We conducted a retrospective study using real-world data from Capital Medical University, Xuanwu Hospital. A total of 34 newly diagnosed POEMS syndrome patients met Dispenzieri's diagnostic criteria, and those who completed at least four cycles of treatment from July 2013 to March 2021 were included. The overall vascular endothelial growth factor (VEGF) response rate of this new treatment mode was 100%. The cumulative VEGF complete remission (CRV) rate was 67.9%, and the cumulative complete hematological response (CRH) rate was 55.6%. During the median 49-month follow-up, the 5-year-overall survival (OS) rate was 90.7%, the 3-year-progression-free survival (PFS) rate was 78.4%, and the 5-year-PFS rate was 73.8%. The BCD regimen achieved a 75% CRV rate (median time from diagnosis to CRV = 130 days) and 66.7% CRH rate (median time from diagnosis to CRH = 218 days). In addition, the VEGF response was less than the partial remission (PRV) after four-cycle induction treatment, which, together with a decrease on the Overall Neurological Limitation Scale of less than three points 1 year after consolidation treatment, was an independent poor prognostic factor. Bortezomib was well-tolerated by patients with POEMS syndrome. Compared with CD ± T regimen, BCD as the induction regimen achieved better VEGF response and earlier hematological remission. Autologous stem cell transplantation used as consolidation therapy further improved the neurological and hematological remission rates, resulting in better OS and PFS.

Differential endothelial hydrogen peroxide signaling via Nox isoforms: Critical roles for Rac1 and modulation by statins

Statins have manifold protective effects on the cardiovascular system. In addition to lowering LDL cholesterol levels, statins also have antioxidant effects on cardiovascular tissues involving intracellular redox pathways that are incompletely understood. Inhibition of HMG-CoA reductase by statins not only modulates cholesterol synthesis, but also blocks the synthesis of lipids necessary for the post-translational modification of signaling proteins, including the GTPase Rac1. Here we studied the mechanisms whereby Rac1 and statins modulate the intracellular oxidant hydrogen peroxide (H2O2) via NADPH oxidase (Nox) isoforms. In live-cell imaging experiments using the H2O2 biosensor HyPer7, we observed robust H2O2 generation in human umbilical vein endothelial cells (HUVEC) following activation of cell surface receptors for histamine or vascular endothelial growth factor (VEGF). Both VEGF- and histamine-stimulated H2O2 responses were abrogated by siRNA-mediated knockdown of Rac1. VEGF responses required the Nox isoforms Nox2 and Nox4, while histamine-stimulated H2O2 signals are independent of Nox4 but still required Nox2. Endothelial H2O2 responses to both histamine and VEGF were completely inhibited by simvastatin. In resting endothelial cells, Rac1 is targeted to the cell membrane and cytoplasm, but simvastatin treatment promotes translocation of Rac1 to the cell nucleus. The effects of simvastatin both on receptor-dependent H2O2 production and Rac1 translocation are rescued by treatment of cells with mevalonic acid, which is the enzymatic product of the HMG-CoA reductase that is inhibited by statins. Taken together, these studies establish that receptor-modulated H2O2 responses to histamine and VEGF involve distinct Nox isoforms, both of which are completely dependent on Rac1 prenylation.

Prognostic Role of IL-6 in POEMS Syndrome

Prognostic Role of IL-6 in POEMS Syndrome

Major Reservoir for Heparin-Releasable TFPIα (Tissue Factor Pathway Inhibitor α) Is Extracellular Matrix.

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Efficacy and Safety of Regimens Used for the Treatment of POEMS Syndrome- a Systematic Review

Introduction: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy/edema, myeloma protein, skin changes) is a rare disorder associated with plasma cell neoplasia where an overproduction of proinflammatory cytokines such as vascular endothelial growth factor (VEGF) upregulates vasculogenesis and increases vascular permeability resulting in multiple symptoms of the disease e.g. edema and hemangioma. Although the limited-stage disease can be treated with radiotherapy, treatment for the more advanced disease remains unclear. Here we offer a systematic review of the efficacy and safety of treatment regimens used to treat POEMS syndrome in the adult population. Methods: Databases i.e. PubMed, Embase, Web of Science, and clinicaltrials.gov were searched since inception through May 15th, 2020, following the PRISMA guidelines. Out of 421 studies, 8 articles (5 prospective clinical trials, and 3 retrospective studies) were included. Phase I clinical trials, abstracts, case reports, case series, and review articles were excluded. Results: A total of 171 patients (21-79 years of age) were evaluated in 8 clinical studies. Immunomodulator Based Regimens: In the 5 clinical studies (N=96) where lenalidomide (Len) plus dexamethasone (Dex) were used, the hematological (heme) complete response (CR) ranged from 20% to 46%. Heme CR was defined as the absence of monoclonal immunoglobulins in serum or urine. VEGF CR defined as normalization of serum VEGF levels ranged from 35% to 80%. Neurological response defined as the improvement in the overall neuropathy limitations scale (ONLS) by at least one score ranged from 0% to 95%. These studies reported 2-3 year progression-free survival (PFS) and overall survival (OS) of 59% to 92% and 90% to 100%, respectively. In the study by Suichi et al. (N=5), VEGF CR was reported to be 80%. However, no neurological improvement was seen in these patients. Proteasome Inhibitor Based Regimens: In the study by He et al. (N=20) bortezomib in combination with cyclophosphamide and Dex yielded heme, VEGF, and neurological responses in 76%, 88%, and 95% of the patients, respectively. No grade ≥3 treatment-related adverse effects (TRAE) were seen. Conventional Chemotherapy Based Regimens: In the phase II trial conducted by Misawa et al. (N=25) the reduction in serum VEGF levels, as well as clinical response as measured by improvement in muscle strength, was higher in the thalidomide arm as compared to the placebo arm. Grade ≥3 TRAE reported in the treatment arm were cardiac arrest, heart failure, and dehydration in 1 (8%) patient each. In the study by Li et al. (N=31) melphalan (Mel) in combination with Dex achieved heme, VEGF, and neurological response rates of 81%, 100%, and 100%, respectively. Twenty percent of the patients experienced grade ≥3 TRAE. Conclusion: Immunomodulator and chemotherapy based regimens appear to have a reasonable safety and efficacy profile. Lenalidomide and melphalan based therapies were most effective. Proteasome inhibitors based regimens yielded efficacious results without significant toxicity. More studies with existing and newer combinations with autologous stem cell transplantation are warranted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

VEGF and TNF-α Responses to Acute and Chronic Aerobic Exercise in the Patients with Multiple Sclerosis

Background: Aerobic exercise has been shown to decrease the functional disorders related to multiple sclerosis (MS). Nevertheless, the effect of aerobic exercise training on the cytokines and neuroprotective mediators associated with the disease activity has remained relatively unknown. Objectives: The present research was conducted to evaluate the responses of the vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) to single-bout and six-week aerobic exercise training in the patients with MS. Methods: Totally, 20 subjects ((n = 10) patients with MS and (n = 10) controls) who were matched in terms of gender, weight, body mass, and age were included in the study. Participants received aerobic exercise training at approximately 60% of VO2max in 30-min sessions 3 times a week for six weeks. Serum concentrations of the VEGF and TNF-α were analyzed pre- and post-exercise training (in the first session and after 18 sessions of the study). Results: Serum concentration of the TNF-α decreased significantly after a single bout and 6-week aerobic exercise training (P = 0.002 and P = 0.005) in the intervention group. Serum concentration of the VEGF increased significantly only after exercise in the first and 18th sessions in the intervention group (P = 0.017 and P = 0.022). Conclusions: Our results revealed that exercise may influence the VEGF regulation in patients with MS. Although, further research is needed to determine the effect of exercise on the immune variables in patients with MS.

Levodopa Positively Affects Neovascular Age-Related Macular Degeneration

BackgroundAge-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology. MethodsIn an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months. ResultsLevodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002). ConclusionsOur findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.

Predictive value of changes in plasma vascular endothelial growth factor at eight weeks after lenvatinib administration in patients with unresectable hepatocellular carcinoma.

4594 Background: Lenvatinib (LEN) has been used in patients with unresectable hepatocellular carcinoma (u-HCC) and there is no established predictive biomarker. Previously it was reported that a plasma vascular endothelial growth factor (VEGF) concentration decrease at 8 weeks after starting sorafenib might predict favorable overall survival (OS) in patients with u-HCC (Tsuchiya, et al. Cancer, 2013). We aimed to investigate the value of changes in plasma VEGF at 8 weeks after LEN administration in patients with u-HCC. Methods: Forty-six patients with u-HCC who received LEN between April 2018 and August 2019 at our institution were enrolled. Plasma concentrations of VEGF and serum α-fetoprotein (AFP) levels were measured at baseline, 4 and 8 weeks after administration of LEN. A VEGF decrease was defined as > 5% decrease during 8 weeks after the beginning of LEN therapy. AFP response was defined as > 20% decrease during 8 weeks according to the previous reports. Results: Median overall survival (OS) was not reached and progression-free survival (PFS) was 5.9 months. Median observation period and treatment duration were 10.1 and 6.3 months. The objective response rate and disease control rate by mRECIST criteria were 43.5% and 82.6%. Median PFS in patients who had a VEGF decrease at week 8 (n = 29) was significantly longer than those who did not have a VEGF decrease (n = 17; 7.1 months vs 5.0 months; p = 0.014). AFP response was not associated with PFS. There were no significant differences in baseline VEGF, AFP, ALBI score, and extrahepatic metastasis between the patients with and without a VEGF decrease. A VEGF decrease was significantly associated with radiological objective response (p = 0.001) and 18 of 20 patients who achieved CR (n = 3) or PR (n = 17) had a VEGF response in LEN therapy. Conclusions: A decrease of plasma VEGF level at 8 weeks in patients with u-HCC on LEN was significantly associated with PFS. Changes in plasma VEGF could become a new biomarker for molecular targeted therapies including VEGF inhibitors in patients with unresectable HCC.

The acute and chronic effects of resistance training with blood flow restriction on hormonal responses in untrained young men: A comparison of frequency

The present study aimed to determine the effect of low-intensity training with blood flow restriction (BFR) on the response rate of anabolic hormones. Forty healthy and untrained young men, aged 18 to 25 years old, were randomly divided into five groups: one session of BFR training (BFR1), two sessions of BFR training (BFR2), one session of resistance training without BFR (WBFR1), two sessions of resistance training without BFR (WBFR2), and the control group (without training). BFR groups had three sets of 20 repetitions with 20-30% 1RM, and none-BFR groups had three sets of 10 repetitions with 70-80% 1RM for six weeks. Both BFR1 and WBFR1 groups trained 3day a week (1 session in a day and three sessions a week), BFR2 and WBFR2 groups trained three days a week (but two sessions a day and six sessions in a week) and Control group did not perform any training. The mean changes in growth hormone(GH), testosterone(TS), and vascular endothelial growth factor (VEGF) hormones were determined by ELISA technique before, after a first training session and after six weeks of the training program. To the analysis of data, two way repeated measures ANOVA at a significant level of P<0.05 also were used. The results showed a significant increase in GH levels in each of the four training groups as compared with the pre-test and the control group after a first training session and after six weeks of the training program (P<0.05). There was no significant increase in TS levels in each of the four training groups, as compared with the pre-test and the control group in both acute and chronic TS response (P>0.05). Only the WBFR1 group did not significantly increase in VEGF levels after the first training session (P>0.05). In chronic VEGF response, there were no significant changes observed in all training groups as compared with the control group(P>0.05). Despite the effectiveness of low-intensity BFR training, such as high-intensity resistance training on hormonal responses, two sessions per day training with the same volume does not necessarily result in larger responses in all hormones than one session per day training.

Sources and lesion-induced changes of VEGF expression in brainstem motoneurons.

Motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration compared to other cranial motoneurons, as seen in amyotrophic lateral sclerosis (ALS). The overexpression of vascular endothelial growth factor (VEGF) is involved in motoneuronal protection. As previously shown, motoneurons innervating extraocular muscles present a higher amount of VEGF and its receptor Flk-1 compared to facial or hypoglossal motoneurons. Therefore, we aimed to study the possible sources of VEGF to brainstem motoneurons, such as glial cells and target muscles. We also studied the regulation of VEGF in response to axotomy in ocular, facial, and hypoglossal motor nuclei. Basal VEGF expression in astrocytes and microglial cells of the cranial motor nuclei was low. Although the presence of VEGF in the different target muscles for brainstem motoneurons was similar, the presynaptic element of the ocular neuromuscular junction showed higher amounts of Flk-1, which could result in greater efficiency in the capture of the factor by oculomotor neurons. Seven days after axotomy, a clear glial reaction was observed in all the brainstem nuclei, but the levels of the neurotrophic factor remained low in glial cells. Only the injured motoneurons of the oculomotor system showed an increase in VEGF and Flk-1, but such an increase was not detected in axotomized facial or hypoglossal motoneurons. Taken together, our findings suggest that the ocular motoneurons themselves upregulate VEGF expression in response to lesion. In conclusion, the low VEGF expression observed in glial cells suggests that these cells are not the main source of VEGF for brainstem motoneurons. Therefore, the higher VEGF expression observed in motoneurons innervating extraocular muscles is likely due either to the fact that this factor is more avidly taken up from the target muscles, in basal conditions, or is produced by these motoneurons themselves, and acts in an autocrine manner after axotomy.

Effects of Exercise Intensity on Acute Circulating Molecular Responses Poststroke

Background. Exercise intensity can influence functional recovery after stroke, but the mechanisms remain poorly understood. Objective. In chronic stroke, an intensity-dependent increase in circulating brain-derived neurotrophic factor (BDNF) was previously found during vigorous exercise. Using the same serum samples, this study tested acute effects of exercise intensity on other circulating molecules related to neuroplasticity, including vascular-endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF1), and cortisol, with some updated analyses involving BDNF. Methods. Using a repeated-measures design, 16 participants with chronic stroke performed 3 exercise protocols in random order: treadmill high-intensity interval training (HIT-treadmill), seated-stepper HIT (HIT-stepper), and treadmill moderate-intensity continuous exercise (MCT-treadmill). Serum molecular changes were compared between protocols. Mediation and effect modification analyses were also performed. Results. VEGF significantly increased during HIT-treadmill, IGF1 increased during both HIT protocols and cortisol nonsignificantly decreased during each protocol. VEGF response was significantly greater for HIT-treadmill versus MCT-treadmill when controlling for baseline. Blood lactate positively mediated the effect of HIT on BDNF and cortisol. Peak treadmill speed positively mediated effects on BDNF and VEGF. Participants with comfortable gait speed ≥0.4 m/s had significantly lower VEGF and higher IGF1 responses, with a lower cortisol response during MCT-treadmill. Conclusions. BDNF and VEGF are promising serum molecules to include in future studies testing intensity-dependent mechanisms of exercise on neurologic recovery. Fast training speed and anaerobic intensity appear to be critical ingredients for eliciting these molecular responses. Serum molecular response differences between gait speed subgroups provide a possible biologic basis for previously observed differences in training responsiveness.

Hyperglycemia-induced endothelial dysfunction is alleviated by thioredoxin mimetic peptides through the restoration of VEGFR-2-induced responses and improved cell survival

BackgroundDiabetes mellitus is an important cardiovascular risk factor characterized by elevated plasma glucose levels. High glucose (HG) negatively influences endothelial cell (EC) function, which is characterized by the inability of ECs to respond to vascular endothelial growth factor (VEGF-A) stimulation. We aimed to identify potential strategies to improve EC function in diabetes. Methods and resultsHuman umbilical cord endothelial cells (HUVECs) were subjected to hyperglycemic milieu by exposing cells to HG together with glucose metabolite, methylglyoxal (MG) in vitro. Hyperglycemic cells showed reduced chemotactic responses towards VEGF-A as revealed by Boyden chamber migration assays, indicating the development of “VEGF resistance” phenotype. Furthermore, HG/MG-exposed cells were defective in their general migratory and proliferative responses and were in a pro-apoptotic state. Mechanistically, the exposure to HG/MG resulted in reactive oxygen species (ROS) accumulation which is secondary to the impairment of thioredoxin (Trx) activity in these cells. Pharmacological and genetic targeting of Trx recapitulated VEGF resistance. Functional supplementation of Trx using thioredoxin mimetic peptides (TMP) reversed the HG/MG-induced ROS generation, improved the migration, proliferation, survival and restored VEGF-A-induced chemotaxis and sprouting angiogenesis of hyperglycemic ECs. Importantly, TMP treatment reduced ROS accumulation and improved VEGF-A responses of placental arterial endothelial cells isolated from gestational diabetes mellitus patients. ConclusionsOur findings suggest a putative role for Trx in modulating EC function and its functional impairment in HG conditions contribute to EC dysfunction. Supplementation of TMP could be used as a novel strategy to improve endothelial cell function in diabetes.

Inflammatory, Oxidative Stress, and Angiogenic Growth Factor Responses to Repeated-Sprint Exercise in Hypoxia.

The present study was designed to determine the effects of repeated-sprint exercise in moderate hypoxia on inflammatory, muscle damage, oxidative stress, and angiogenic growth factor responses among athletes. Ten male college track and field sprinters [mean ± standard error (SE): age, 20.9 ± 0.1 years; height, 175.7 ± 1.9 cm; body weight, 67.3 ± 2.0 kg] performed two exercise trials in either hypoxia [HYPO; fraction of inspired oxygen (FiO2), 14.5%] or normoxia (NOR; FiO2, 20.9%). The exercise consisted of three sets of 5 s × 6 s maximal sprints with 30 s rest periods between sprints and 10 min rest periods between sets. After completing the exercise, subjects remained in the chamber for 3 h under the prescribed oxygen concentration (hypoxia or normoxia). The average power output during exercise did not differ significantly between trials (p = 0.17). Blood lactate concentrations after exercise were significantly higher in the HYPO trial than in the NOR trial (p < 0.05). Plasma interleukin-6 concentrations increased significantly after exercise (p < 0.01), but there was no significant difference between the two trials (p = 0.07). Post-exercise plasma interleukin-1 receptor antagonist, serum myoglobin, serum lipid peroxidation, plasma vascular endothelial growth factor (VEGF), and urine 8-hydroxydeoxyguanosine concentrations did not differ significantly between the two trials (p > 0.05). In conclusion, exercise-induced inflammatory, muscle damage, oxidative stress, and VEGF responses following repeated-sprint exercise were not different between hypoxia and normoxia.

PF745 HIGH‐DOSE THERAPY AND AUTOLOGOUS TRANSPLANT FOR POEMS SYNDROME: EFFECTIVE, BUT HOW TO OPTIMISE?

Background:POEMS syndrome is a paraneoplastic phenomenon whose pathogenesis is not fully understood, but an underlying plasmaproliferative process appears to promote cytokine release, including vascular endothelial growth factor (VEGF) which induces capillary leakage and tissue damage. High dose melphalan‐conditioned autologous stem cell transplantation (ASCT) is an effective therapy for patients with adequate performance status who have non‐localised disease, but some patients relapse.Aims:To study the effectiveness of ASCT in POEMS syndrome, factors influencing the natural history and management of relapse.Methods:We reviewed 42 patients who underwent ASCT from 1998 to 2018. Patient characteristics, previous lines of treatment, harvesting regimens, engraftment data, episodes of engraftment syndrome (ES) and transplant‐related morbidity were recorded. Disease status at ASCT was used as the baseline. Response assessment was carried out at 3, 6 and 12 months and a tailored frequency thereafter. Time to maximal VEGF, haematological, radiological, clinical responses and the nature and management of progression events were recorded.Results:Median age at diagnosis/ASCT was 49.5/52 years; median time from diagnosis to ASCT 5.5 months. POEMS features were varied; 100% had neuropathy and raised VEGF, 80% had multifocal bone lesions, 50–70% had fluid overload, skin changes, endocrinopathy, organomegaly and other features at lower incidence; 73.8% had a serum M protein, 80.1% lambda‐restricted; 64% had up to 10% BM involvement.Overall survival (OS) was 92.9% (mean follow up 62.6 months, range 4–226 months). One‐year OS was 95.4% and progression‐free survival (PFS) was 81.6%; 5‐year OS 89.5% and PFS 76.9%. Three patients died without POEMS progression (1 peri‐transplant, I unknown cause, 1 MDS). Three patients (16.7%) had ES. Haem CR or VGPR was achieved by 50%. Average VEGF levels improved from 4,959pg/mL to 489.5pg/mL at 6 months and 330pg/mL at 1 year (p &lt; 0.001). Significant neurological improvement was seen in all but 2 patients (median pre‐ to post‐transplant Overall Neuropathy Limitation Scale score from 6 to 2 (p &lt; 0.01)). Median time to first improvement was 4 months. Nerve conduction studies demonstrated continued improvement even 3 years after ASCT. Six patients (14.3%) have relapsed to date. No patient who achieved haem CR has relapsed, compared to those with &lt;CR (31.6% relapse rate (p = 0.027)). Treatment for relapse was implemented for symptomatic reasons; fatigue and raised VEGF were common to all, other features were varied and unique to each patient. Of the 4 patients treated with lenalidomide and dexamethasone, 2 have stopped (unacceptable toxicity; no clinical benefit despite VEGF response).Summary/Conclusion:This analysis confirms that ASCT is an effective treatment for POEMS and attainment of haem CR after ASCT is associated with a lower relapse rate. No patients who achieved clearance of bone marrow plasma cell clones and paraproteinaemia in our cohort have relapsed, compared to almost a third of those with a persistent clonal burden. How to manage relapse remains contentious; identification of clinically significant relapse remains challenging; a raised VEGF alone does not tell the whole story. Appropriate management of relapse, including optimum treatment agents, depth and duration remains unclear. Clinical trials of novel agents are urgently needed. More informative, readily applicable clinical and laboratory tools are needed to guide therapeutic decision‐making, including biomarkers that have prognostic significance.image

Prognostic factors for response to chemotherapy in advanced tumors of the uterine cervix: the role of neoangiogenesis.

to analyze the expression of Vascular Endothelial Growth Factor (VEGF), its receptor (VEGFR-2), age and histological type of advanced cervical carcinomas with respect to the clinical response to neoadjuvant chemotherapy. we studied 40 patients with cervical carcinoma (IB2 and IVA) diagnosed by biopsies prior to treatment. All patients underwent neoadjuvant chemotherapy and evaluation for clinical response and expression of VEGF. We considered a tumor regression greater than 50% as a good clinical response. eighteen patients (45%) had good response to chemotherapy, and 22 (55%), poor response. VEGF expression was positive in 16 patients and negative in 24. When analyzed separately for response to chemotherapy, only the positive expression of VEGF was associated with good clinical response (p=0.0157). VEGF expression alone was an important marker of good response to neoadjuvant chemotherapy in patients with advanced carcinoma of the cervix.

Acute and chronic exercise in patients with heart failure with reduced ejection fraction: evidence of structural and functional plasticity and intact angiogenic signalling in skeletal muscle.

The vascular endothelial growth factor (VEGF) responses to acute submaximal exercise and training effects in patients with heart failure with reduced ejection fraction (HFrEF) were investigated. Six patients and six healthy matched controls performed knee-extensor exercise (KE) at 50% of maximum work rate before and after (only patients) KE training. Muscle biopsies were taken to assess skeletal muscle structure and the angiogenic response. Before training, during this submaximal KE exercise, patients with HFrEF exhibited higher leg vascular resistance and greater noradrenaline spillover. Skeletal muscle structure and VEGF response were generally not different between groups. Following training, resistance was no longer elevated and noradrenaline spillover was curtailed in the patients. Although, in the trained state, VEGF did not respond to acute exercise, capillarity was augmented. Muscle fibre cross-sectional area and percentage area of type I fibres increased and mitochondrial volume density exceeded that of controls. Structural/functional plasticity and appropriate angiogenic signalling were observed in skeletal muscle of patients with HFrEF. This study examined the response to acute submaximal exercise and the effect of training in patients with heart failure with reduced ejection fraction (HFrEF). The acute angiogenic response to submaximal exercise in HFrEF after small muscle mass training is debated. The direct Fick method, with vascular pressures, was performed across the leg during knee-extensor exercise (KE) at 50% of maximum work rate (WRmax ) in patients (n= 6) and controls (n= 6) and then after KE training in patients. Muscle biopsies facilitated the assessment of skeletal muscle structure and vascular endothelial growth factor (VEGF) mRNA levels. Prior to training, HFrEF exhibited significantly higher leg vascular resistance (LVR) (≈15%) and significantly greater noradrenaline spillover (≈385%). Apart from mitochondrial volume density, which was significantly lower (≈22%) in HFrEF, initial skeletal muscle structure, including capillarity, was not different between groups. Resting VEGF mRNA levels, and the increase with exercise, was not different between patients and controls. Following training, LVR was no longer elevated and noradrenaline spillover was curtailed. Skeletal muscle capillarity increased with training, as assessed by capillary-to-fibre ratio (≈13%) and number of capillaries around a fibre (NCAF ) (≈19%). VEGF mRNA was now not significantly increased by acute exercise. Muscle fibre cross-sectional area and percentage area of type I fibres both increased significantly with training (≈18% and ≈21%, respectively), while the percentage area of type II fibres fell significantly (≈11%), and mitochondrial volume density now exceeded that of controls. These data reveal structural and functional plasticity and appropriate angiogenic signalling in skeletal muscle of HFrEF patients.

Responses of Angiogenic Regulators to Resistance Exercise Under Systemic Hypoxia.

Kon, M, Ikeda, T, Homma, T, and Suzuki, Y. Responses of angiogenic regulators to resistance exercise under systemic hypoxia. J Strength Cond Res 35(2): 436-441, 2021-Resistance exercise and hypoxia powerfully affect the secretions of angiogenic regulators. However, the effects of resistance exercise under acute systemic hypoxia on circulating levels of angiogenic regulators are unknown. Therefore, we investigated the effects of resistance exercise under systemic hypoxia on angiogenic regulator responses. Twelve healthy male subjects completed 2 experimental trials: (a) resistance exercise under normoxia (NRE), and (b) resistance exercise under systemic hypoxia (13% oxygen) (HRE) using a hypoxic generator. The subjects performed 2 consecutive resistance exercises (bench press and bilateral leg press), consisting of 5 sets with 10 repetitions at 70% of 1 repetition maximum with a 1-minute rest between sets. Serum vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-2, MMP-9, and endostatin concentrations were measured before exercise (and before exposure to hypoxia in the HRE trial) and at 0, 15, and 30 minutes after the resistance exercises. In both trials, serum VEGF, MMP-2, MMP-9, and endostatin concentrations significantly increased after the exercises compared with preexercise values (p < 0.05). At 0 minutes after exercise, the percentage change in VEGF concentration was significantly higher in the HRE trial compared with that in the NRE trial (p < 0.05). However, the exercise-induced changes in MMP-2, MMP-9, and endostatin concentrations did not differ between trials. The present results demonstrate that acute systemic hypoxia induces a greater resistance exercise-induced VEGF response, suggesting that hypoxia plays an important role in increasing the VEGF response to a bout of resistance exercise.

RELATIONSHIP OF BRAIN STRUCTURE AND GLUCOSE METABOLISM TO VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)

Vascular endothelial growth factor (VEGF), the primary regulator of angiogenesis, is upregulated to enhance oxygen and glucose delivery to nutrient-deficient tissue. Amyloid disrupts VEGF signaling and may result in VEGF upregulation. This effect may explain why human studies in-vivo have found discrepant relationships between VEGF levels and Alzheimer's Disease (AD) diagnosis. We hypothesize that in individuals with high amyloid (Aβ+), higher CSF VEGF levels will partially compensate for Aβ effects on the brain, and therefore be associated with better aging outcomes: 1) a thicker cortex, 2) greater regional FDG-PET signal, and 3) better cognitive function. We evaluated 310 participants (92 cognitively intact, 149 mild cognitive impairment, 69 AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Separately in Aβ+ (CSF Aβ ≤ 192 pg/ml) and Aβ- participants, we used multiple linear regression (controlling for age, sex, education, APOE4 carrier status, CSF T-tau, and diagnosis) to relate CSF VEGF levels to: 1) MRI-derived cortical thickness in mean bilateral AD-relevant regions-of-interest (ROIs), grouping regions by their shared variances (Figure 1); 2) mean bilateral temporal lobe glucose metabolism (FDG-PET); and 3) established neuropsychological composite measures (executive function including language measures, and memory). False discovery rate (FDR) was applied to correct for multiple comparisons. We evaluated the direct and indirect effect of VEGF on executive function and memory through causal mediation analysis using the package mediation 4.4.6 in R (percentile bootstrap, B=1000). AD-relevant cortical thickness ROIs: A) Posterior cingulate, entorhinal cortex, temporal cortex (superior, middle, and inferior temporal gyri), B) parietal cortex (superior and inferior parietal gyri, precuneus). In Aβ+ participants only, higher CSF VEGF levels were significantly associated with a thicker temporal cortex (FDR-adjusted VEGF partial p=0.009, omnibus p<0.001), higher temporal lobe FDG-PET signal (VEGF partial p=0.007, omnibus p<0.001), and better executive function, driven largely by category naming (VEGF partial p=0.024, omnibus p<0.001). Mean bilateral temporal lobe FDG-PET signal mediated the relationship between CSF VEGF and executive function (estimated mediation effect=0.509; 95% CI [0.0693, 1.30]; p=0.004). Our results indicate that 1) CSF VEGF has regionally specific structural and metabolic associations in Aβ+ older adults, 2) CSF VEGF has an indirect effect on executive function, mediated by temporal lobe glucose metabolism, and 3) upregulation of VEGF in response to Aβ deposition may serve a compensatory neuroprotective role.

Hypoxia inducible factor-1α/vascular endothelial growth factor signaling activation correlates with response to radiotherapy and its inhibition reduces hypoxia-induced angiogenesis in lung cancer.

Like other tumors, lung cancer must induce angiogenesis as it grows. Hypoxia-inducible factor 1α (HIF-1α) is the inducible subunit of the HIF-1 transcription factor that regulates genes involved in the response to hypoxia, some of which contributes to angiogenesis. Vascular endothelial growth factor (VEGF) is one of the genes upregulated by HIF-1 and is the primary cytokine in relation to angiogenesis. In this study we tested whether aberrant activation of hypoxia inducible factor-1α/vascular endothelial growth factor (HIF-1α/VEGF) pathway correlates with response to radiotherapy and examined the response of lung cancer cells to hypoxia in vitro. We determined increased expressions of HIF-1α and VEGF-A in 76 cancerous tissues of responders (complete remission and partial remission). HIF-1α and VEGF-A were shown to be upregulated in lung cancer cells in response to hypoxia. The treatment with anti-HIF-1α siRNA prior to hypoxia exposure was shown to decrease HIF-1α and VEGF-A expressions and reduce hypoxia-induced angiogenesis, suggesting that HIF-1α expression resulted in increased VEGF-A expression and activation of HIF-1α/VEGF pathway was responsible for hypoxia-induced angiogenesis. In conclusion, we identified the relationship between HIF-1α/VEGF pathway and response to radiotherapy and its role in angiogenesis in lung cancer in vitro. HIF-1α/VEGF pathway as a target for antiangiogenic treatment strategies for this tumor requires further investigation.