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Biomedical subjects

M Birrer

Publications and source records attributed to M Birrer.

At least 19 recordsLinked to original sources
PubMed2005

Dose optimization of contrast-enhanced carotid MR angiography.

The purpose of this work was to compare the diagnostic performance of a single-contrast or a double-contrast dose of carotid contrast-enhanced MR angiography (MRA). One-hundred nineteen patients (mean age 65+/-14.4 years) underwent carotid contrast-enhanced MRA with a standardized protocol (repetition time/echo 3.73 ms/1.38 ms, flip-angle 25 degrees, acquisition-time 19 s, voxel size 1.2 x 1.2 x 0.9 mm3) on a 1.5-T scanner (Sonata, Siemens-Medical-Systems) using a neck phased-array coil. Contrast agent was administered intravenously at a rate of 3.0 ml/s, either as a single dose (n=57; 0.1 mmol/kg body weight) or as a double dose (n=62; 0.2 mmol/kg body weight) of meglumine gadoterate (0.5 M/l), followed by 30 ml saline. Qualitative image analysis was performed on maximum intensity projections using a five-point scale. Signal intensities were measured at three different vascular levels on both sides to assess the contrast-to-noise ratios (CNRs). Image quality was rated as good or excellent in all cases. A double dose did not influence the efficacy of carotid enhancement (CNR single dose 69.12+/-19.8; CNR double dose 70.01+/-20.7; p = 0.81) compared with a single dose. In both dose groups the mean CNRs were inversely related to bodyweight, despite adjusted contrast volumes (p=0.0005). Double-dose contrast-enhanced carotid MRA is not superior to single-dose MRA, as overall diagnostic performance and quantitative contrast enhancement are equal. Being more cost-efficient, a single-dose administration of contrast agent is recommended for MRA of the carotid arteries.

Adult↗
PubMed2002

Treatment of renal artery fibromuscular dysplasia with balloon angioplasty: a prospective follow-up study.

OBJECTIVES: to assess restenosis rates and blood pressure response after percutaneous transluminal renal angioplasty (PTRA) in patients treated for fibromuscular dysplastic renal artery stenosis. METHODS: a prospective 12-month follow-up study of 27 patients with 31 treated renal artery stenosis. Follow-up assessment included colour-coded duplex sonography (CCD) of renal arteries, monitoring of blood pressure, antihypertensive medication, and creatinine measurements before discharge and at 3, 6, and 12 months. Primary end point was defined as a haemodynamically significant restenosis >60% assessed by CCD. RESULTS: there was a cumulative 23% restenosis rate at 12 months. Arterial hypertension was cured or improved in 93% of patients immediately after the intervention and remained cured/improved in 74% of patients at 12 months of follow-up. Renal failure present in five patients before PTRA stabilised or improved in all patients. CONCLUSION: although restenosis rate after PTRA in fibromuscular dysplasia is as high as in non-ostial atherosclerotic lesions, there remains a considerable higher therapeutic effect. Profound pressure response and recurrent arterial hypertension with restenosis support the high probability of a renovascular origin of arterial hypertension in this young and otherwise healthy population compared to patients with atherosclerotic renal artery lesions.

Adult↗
PubMed2001

[Macroangiopathy in diabetes mellitus].

In patients with diabetic angiopathy until today, no histological nor histochemical evidence has been found to define a specific type of diabetic arteriopathy. Consequently, diabetic arteriosclerosis is considered as a more serious form of atherosclerosis characterized by its premature onset. Hyperglycemia is assumed to be the crucial pathophysiological cause of the development of macro- and microangiopathy in diabetes mellitus. Apparently, hyperglycemia has a direct toxic influence on the arterial wall by increased accumulation of irreversible glycosylation end products, and secondly, it provokes endothelial dysfunction. The frequently occurring ulcerations of the diabetic foot are primarily caused by neuropathy; however, peripheral vascular disease (PVD) is often associated. The risk of suffering from PVD in diabetic patients is approximately four-fold. Usually, the distal segments of the lower leg arteries are concerned, where reconstructive intervention is complicated or even impossible. Diabetes is considered as an independent risk factor for cardio- and cerebrovascular diseases with almost twice as high rates for recurrent myocardial infarction, and a 3.7 fold higher relative risk for stroke in diabetic, compared to non-diabetic patients. This review looks at the correlations between hyperglycemia and arteriosclerosis, but also the treatment options in diabetic patients. Until now, there is no evidence for an association between an optimal control of blood glucose levels and a decrease in the risk of coronary heart disease, stroke, or PVD. In contrast, an attenuation of microvascular lesions is achieved by stringent control of blood glucose levels. Thus, although the development of macroangiopathy may not be significantly influenced, the conduction of a stringent control regimen of plasmatic glucose levels is advisable.

Arterial Occlusive Diseases↗
PubMed2000

Alterations in the gene expression profile of MCF-7 breast tumor cells in response to c-Jun.

MCF7 breast tumor cells overexpressing human c-Jun exhibit a transformed phenotype characterized not only by increased tumorigenicity but also by enhanced motility and invasion. The cellular phenotypic response to c-Jun overexpression is likely due, at least in part, to altered patterns of gene expression. In order to begin to understand the complexities by which elevated production of c-Jun alters the state of the cell, we have profiled the expression of 588 different genes by comparative hybridization. By using this approach, we have identified a total of 21 upregulated or downregulated gene targets responsive to c-Jun overexpression. Interestingly, 8 of these genes have been previously found associated with c-Jun or AP-1 activity and therefore provide internal validation for this approach to target gene discovery. The remaining 13 genes represent potential new c-Jun regulated target genes. Genomic sequence information was available for 15 of the 21 genes identified in this screen. Analysis of these genomic sequences revealed the presence of AP-1 or AP-1-like sequences in 12 of the 15 genes examined. Consistent with a direct mechanism of target regulation by c-Jun, gel shift analysis of selected AP-1-containing promoter regions revealed elevated and specific binding by proteins present in nuclear extracts of c-Jun expressing MCF7 cells.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2000

Expression of human papilloma virus E7 protein causes apoptosis and inhibits DNA synthesis in primary hepatocytes via increased expression of p21(Cip-1/WAF1/MDA6).

The impact of human papilloma virus (HPV16) E7 proteins and retinoblastoma (RB) antisense oligonucleotides upon mitogen-activated protein kinase (MAPK)-mediated inhibition of DNA synthesis via p21(Cip-1/WAF1/MDA6) (p21) was determined in primary hepatocytes. Prolonged activation of the MAPK pathway in p21(+/+) or p21(-/-) hepatocytes caused a large decrease and increase, respectively, in DNA synthesis. Either transfection with RB antisense oligonucleotides, expression of wild type E7, or RB binding mutant E7 (C24S) proteins increased p21 levels and reduced DNA synthesis in p21(+/+) hepatocytes. RB antisense oligonucleotides and E7 proteins increased apoptosis in p21(+/+), but not p21(-/-), hepatocytes. Expression of wild type E7 increased DNA synthesis above control levels in p21(-/-) cells, which was additive with prolonged MAPK activation. In contrast, expression of mutant E7 did not alter DNA synthesis above control levels in p21(-/-) cells and was supra-additive with prolonged MAPK activation. Antisense ablation of RB in p21(-/-) hepatocytes had a weak stimulatory effect upon DNA synthesis itself but enhanced the capacity of mutant E7 protein to stimulate DNA synthesis to the same level observed using wild type E7. The ability of prolonged MAPK activation to stimulate DNA synthesis in the presence of mutant E7 and antisense RB was additive. Collectively, the present data demonstrate that loss of RB function together with loss of p21 function plays an important role in the E7- and MAPK-dependent modulation of apoptosis and DNA synthesis in primary hepatocytes.

Animals↗
PubMed2000

Percutaneous catheter thrombus aspiration for acute or subacute arterial occlusion of the legs: how much thrombolysis is needed?

OBJECTIVE: To evaluate the role of a combined percutaneous endovascular approach including thrombus aspiration, catheter thrombolysis, and percutaneous transluminal angioplasty (PTA) to treat acute and subacute occlusions of native leg arteries. MATERIALS AND METHODS: Retrospective evaluation of the effectiveness and safety of this catheter therapy in 89 consecutive patients (93 legs) in a single centre. RESULTS: Treatment was initially successful in 90% of legs. Mortality at 30 days was 8%, and at 12 months 19%. Amputation-free survival at 12 months was 78%. Aspiration alone was sufficient in 31% of cases, urokinase (mean dose 112 500+/-55 900 IU) was used in 22%, PTA was added in 69%. There was no major bleeding except for one false aneurysm treated by ultrasound-guided compression. Secondary interventions within 12 months were required in 30% of cases (14 endovascular, 16 open surgical procedures). CONCLUSIONS: Catheter thrombus aspiration in combination with thrombolysis and/or PTA is highly effective. Only in a minority of patients are thrombolytics in modest doses necessary, and serious bleeding complications are rare. We recommend this procedure as first-line treatment for acute or subacute infrainguinal arterial occlusions.

Acute Disease↗
PubMed2000

Stent placement in ostial and nonostial atherosclerotic renal arterial stenoses: a prospective follow-up study.

PURPOSE: To compare the results of balloon percutaneous transluminal renal angioplasty (PTRA) and stent placement in atherosclerotic ostial, proximal, and isolated truncal stenoses. MATERIALS AND METHODS: Between January 1994 and April 1998 the authors prospectively followed up 163 consecutive patients with 200 atherosclerotic renal arterial lesions after primary PTRA or primary stent placement. Duplex ultrasonography was performed 1 day and 3, 6, and 12 months later. RESULTS: The primary 12-month PTRA patency rates were 34% (21 of 33 atherosclerotic lesions) for ostial stenoses, 65% (20 of 60) for proximal stenoses, and 83% (five of 30) for truncal stenoses (chi(2) value, 15.63; P <.001). The corresponding stent patency rates were 80% (four of 21), 72% (nine of 34), and 66% (five of nine), respectively (chi(2) value, 4.11; not significant). Significant stent-related reduction in risk of restenosis was limited to the ostial stenoses (P =.002). CONCLUSION: Renal arterial stent placement considerably improves patency in ostial stenoses, but compared with the technically successful PTRA, it does not significantly improve primary patency in proximal and isolated truncal renal arterial stenoses.

Adult↗
PubMed2000

Inhibition of the mitogen activated protein kinase pathway potentiates radiation-induced cell killing via cell cycle arrest at the G2/M transition and independently of increased signaling by the JNK/c-Jun pathway.

The ability of low dose ionizing radiation (2 Gy) to modulate the activities of the mitogen activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK1) cascades in human monocytic leukemia (U937/pREP4) cells and in cells over-expressing dominant negative c-Jun (TAM67) (U937/TAM67) was investigated. Radiation exposure caused prolonged ( approximately 1 h) MAPK activations in U937 cells. In contrast, low dose irradiation weakly modulated JNK1 activity in these cells. Inhibition of the MAPK pathway by use of the specific MEK1/2 inhibitor (10 microM PD98059) in both U937/pREP4 and U937/TAM67 cells prior to radiation exposure permitted strong prolonged radiation-induced activations of JNK1. Expression of TAM67 decreased the ability of radiation to cause apoptosis compared to control transfected cells. However, combined MEK1/2 inhibition and radiation exposure in both cell types caused a large decrease in suspension culture growth and a large increase in apoptosis, when compared to either treatment alone. Reduced proliferation after combined irradiation and PD98059 treatment in both cell types correlated with prolonged cell cycle arrest in G2/M phase. Prolonged growth arrest was abolished when MEK1/2 inhibitor was removed 6 h following irradiation, which was associated with a reduction in apoptosis. The ability of MEK1/2 inhibition to cause prolonged G2/M growth arrest was reduced in U937 cells stably transfected with a p21Cip-1/WAF1 antisense construct (U937/p21AS). This data correlated with an enhancement of radiation-induced apoptosis and a reduced ability of MEK1/2 inhibition to potentiate apoptosis. Collectively our data demonstrate that inhibition of MEK1/2 function increases the radiation sensitivity of U937 cells, independently of c-Jun function, and decreases the ability of these cells to recover from the radiation-induced G2/M cell cycle checkpoint arrest. In addition, our data also demonstrate that the ability of MEK1/2 inhibition to potentiate radiation-induced cell death in U937 cells in part requires an ability of cells to express low levels of p21Cip-1/WAF1.

Apoptosis↗
PubMed2000

Activator protein-1 mediates induced but not basal epidermal growth factor receptor gene expression.

BACKGROUND: The epidermal growth factor receptor (EGFR) is expressed at different levels in many cell types and found overexpressed in many cancers. EGFR expression is increased or decreased in response to extracellular stimuli. We examined the effect of increased c-Jun expression on EGFR promoter activity. MATERIALS AND METHODS: We used DNAse I foot-printing analysis to determine the binding of activator protein 1 (AP-1) to the promoter region. We also used cotransfection experiments and western blotting analysis to determine the effect of AP-1 family members on EGFR expression. RESULTS: AP-1 was able to bind to at least seven sites in the EGFR promoter region. Cotransfection of MCF-7 cells with a c-Jun expression vector and the EGFR promoter reporter resulted in a 7-fold increase in promoter activity. JunB, but not c-fos, also enhanced the EGFR promoter activity. An A-Fos-dominant negative shown to inhibit Jun-dependent transactivation was able to prevent c-Jun induction of the promoter activity, but only slightly decreased the basal activity of the promoter. Furthermore, the A-Fos dominant negative was able to inhibit phorbol ester induction of the EGFR promoter. Examination of EGFR expression of MCF-7 stable cell lines that overexpress c-Jun revealed an increase in EGFR expression. Additionally, a cisplatin-resistant cell line, A2780/CP70, which has an increase in AP-1 activity compared with the parental cell line, A2780, was found to have an increase in EGFR level. CONCLUSIONS: These results indicate that AP-1 can act to increase the expression of EGFR and may play a role in upregulation of EGFR in cancer cells.

3T3 Cells↗
PubMed1998

Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells.

The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1 Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21(Cip-1/WAF1) via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the specific MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased approximately sixfold 60 min after irradiation. In the presence of MAP kinase blockade by PD98059 the ability of a single 1 Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24-48 h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4-8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizing radiation. Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death in vitro.

Amino Acid Sequence↗
PubMed1998

The Ras/Rac1/Cdc42/SEK/JNK/c-Jun cascade is a key pathway by which agonists stimulate DNA synthesis in primary cultures of rat hepatocytes.

The ability of signaling via the JNK (c-Jun NH2-terminal kinase)/stress-activated protein kinase cascade to stimulate or inhibit DNA synthesis in primary cultures of adult rat hepatocytes was examined. Treatment of hepatocytes with media containing hyperosmotic glucose (75 mM final), tumor necrosis factor alpha (TNFalpha, 1 ng/ml final), and hepatocyte growth factor (HGF, 1 ng/ml final) caused activation of JNK1. Glucose, TNFalpha, or HGF treatments increased phosphorylation of c-Jun at serine 63 in the transactivation domain and stimulated hepatocyte DNA synthesis. Infection of hepatocytes with poly-L-lysine-coated adenoviruses coupled to constructs to express either dominant negatives Ras N17, Rac1 (N17), Cdc42 (N17), SEK1-, or JNK1- blunted the abilities of glucose, TNFalpha, or HGF to increase JNK1 activity, to increase phosphorylation of c-Jun at serine 63, and to stimulate DNA synthesis. Furthermore, infection of hepatocytes by a recombinant adenovirus expressing a dominant-negative c-Jun mutant (TAM67) also blunted the abilities of glucose, TNFalpha, and HGF to stimulate DNA synthesis. These data demonstrate that multiple agonists stimulate DNA synthesis in primary cultures of hepatocytes via a Ras/Rac1/Cdc42/SEK/JNK/c-Jun pathway. Glucose and HGF treatments reduced glycogen synthase kinase 3 (GSK3) activity and increased c-Jun DNA binding. Co-infection of hepatocytes with recombinant adenoviruses to express dominant- negative forms of PI3 kinase (p110alpha/p110gamma) increased basal GSK3 activity, blocked the abilities of glucose and HGF treatments to inhibit GSK3 activity, and reduced basal c-Jun DNA binding. However, expression of dominant-negative PI3 kinase (p110alpha/p110gamma) neither significantly blunted the abilities of glucose and HGF treatments to increase c-Jun DNA binding, nor inhibited the ability of these agonists to stimulate DNA synthesis. These data suggest that signaling by the JNK/stress-activated protein kinase cascade, rather than by the PI3 kinase cascade, plays the pivotal role in the ability of agonists to stimulate DNA synthesis in primary cultures of rat hepatocytes.

Animals↗
PubMed1998

Tumor necrosis factor alpha gene regulation: enhancement of C/EBPbeta-induced activation by c-Jun.

Tumor necrosis factor alpha (TNF alpha) is a key regulatory cytokine whose expression is controlled by a complex set of stimuli in a variety of cell types. Previously, we found that the monocyte/macrophage-enriched nuclear transcription factor C/EBPbeta played an important role in the regulation of the TNF alpha gene in myelomonocytic cells. Abundant evidence suggests that other transcription factors participate as well. Here we have analyzed interactions between C/EBPbeta and c-Jun, a component of the ubiquitously expressed AP-1 complex. In phorbol myristate acetate (PMA)-treated Jurkat T cells, which did not possess endogenous C/EBPbeta, expression of c-Jun by itself had relatively little effect on TNF alpha promoter activity. However, the combination of C/EBPbeta and c-Jun was synergistic, resulting in greater than 130-fold activation. This effect required both the leucine zipper and DNA binding domains, but not the transactivation domain, of c-Jun, plus the AP-1 binding site centered 102/103 bp upstream of the transcription start site in the TNF alpha promoter. To determine if C/EBPbeta and c-Jun might cooperate to regulate the cellular TNF alpha gene in myelomonocytic cells, U937 cells that possess endogenous C/EBPbeta and were stably transfected with either wild-type c-Jun or the transactivation domain deletion mutant (TAM-67) were examined. U937 cells expressing ectopic wild-type c-Jun or TAM-67 secreted over threefold more TNF alpha than the control line in response to PMA plus lipopolysaccharide. Transient transfection of the U937 cells expressing TAM-67 suggested that TAM-67 binding to the -106/-99-bp AP-1 binding site cooperated with endogenous C/EBPbeta in the activation of the -120 TNF alpha promoter-reporter. DNA binding assays using oligonucleotides derived from the TNF alpha promoter suggested that C/EBPbeta and c-Jun interact in vitro and that the interaction may be DNA dependent. Our data demonstrate that the TNF alpha gene is regulated by the interaction of the ubiquitous AP-1 complex protein c-Jun and the monocyte/macrophage-enriched transcription factor C/EBPbeta and that this interaction contributes to the expression of the cellular TNF alpha gene in myelomonocytic cells. This interaction was unique in that it did not require the c-Jun transactivation domain, providing new insight into the cell-type-specific regulation of the TNF alpha gene.

CCAAT-Enhancer-Binding Proteins↗
PubMed1997

PACAP hybrid: a new PACAP receptor antagonist.

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) hybrid, a synthetic antagonist, was investigated on NIH/3T3 cells containing PACAP receptor (R) splice variants (SVs). PACAPhybrid inhibited 125I-PACAP-27 binding to NIH/3T3 cells stably expressing PACAP-R basic, SV-1, SV-2 or SV-3 with an IC50 of 1000 nM. PACAPhybrid antagonized the ability of PACAP-27 to elevate cAMP regardless of the PACAP-R SV used. PACAP was more efficacious at increasing cytosolic Ca2+ in NIH/3T3 cells containing PACAP-R SV-2 than PACAP-R basic, SV-1 or SV-3. PACAPhybrid antagonized the increase in cytosolic Ca2+ caused by PACAP-27 regardless of the PACAP-R SV used. PACAP was more potent at elevating c-fos mRNA using NIH/3T3 cells transfected with PACAP-R SV-2 than PACAP-R basic, SV-1 or SV-3. PACAPhybrid antagonized the increase in c-fos mRNA caused by PACAP-27. These data suggest that PACAPhybrid is a useful PACAP receptor antagonist for PACAP-R SVs.

3T3 Cells↗
PubMed1996

Breast cancer growth is inhibited by vasoactive intestinal peptide (VIP) hybrid, a synthetic VIP receptor antagonist.

Breast cancer vasoactive intestinal peptide (VIP) receptors were characterized. Using in vitro autoradiographic techniques, 125I-labeled VIP bound with high affinity to breast biopsy sections. 125I-labeled VIP bound specifically to give breast cancer cell lines examined using receptor-binding techniques. Specific 125I-labeled VIP binding to MDA-MB-231 cells was inhibited with high affinity by VIP and pituitary adenylate cyclase-activating polypeptide (IC50, = 2 nM) and with moderate affinity by the VIP hybrid (IC50 = 0.5 microM). VIP elevated the cAMP in a dose-dependent manner, and VIP hybrid (10 microM) inhibited the increase in cAMP caused by VIP. Using Northern blot analysis, VIP (10 nM) stimulated c-fos and c-myc mRNA, and the increase caused by VIP was reversed by the VIP hybrid. The VIP hybrid inhibited breast cancer growth in vitro and in vivo using nude mice bearing breast cancer xenografts. These data suggest that the VIP hybrid is a breast cancer VIP receptor antagonist.

Animals↗
PubMed1996

PACAP stimulates c-fos mRNAs in small cell lung cancer cells.

The effects of PACAP on c-fos mRNA using small cell lung cancer (SCLC) cell was investigated. PACAP-27 (100 nM) increased c-fos mRNA 5-fold using NCI-N417 cells. The increase was concentration dependent with 0.1 nM PACAP-27 half maximally increasing c-fos mRNA. Also the increase in c-fos mRNA caused by PACAP was time dependent; being maximal after 1 hour and returning to basal values after 4 hours. PACAP-38 but not PACAP(28-38) increased c-fos mRNA. One uM PACAP(6-38), a PACAP receptor antagonist, inhibited the increase in c-fos mRNA caused by 1 nM PACAP. These data indicate that PACAP stimulates nuclear oncogene expression in SCLC cells.

Carcinoma, Small Cell↗
PubMed1995

Regulation of urokinase-type plasminogen activator expression by the v-mos oncogene.

We undertook a study to determine if the serine-threonine kinase-encoding v-mos oncogene regulated the expression of the urokinase-type plasminogen activator. An expression vector encoding v-mos, but not a kinase-inactive mutant, stimulated urokinase promoter activity in CAT assays employing a squamous cell carcinoma cell line. The induction of urokinase promoter activity by v-mos was mediated, in part, via an increased AP-1 activity since (a) mutation of 2 AP-1 binding sites (at -1967 and -1885), or the co-expression of a transactivation domain-lacking c-jun mutant reduced the induction of the urokinase promoter by v-mos and (b) expression of v-mos increased the activity of a CAT reporter driven by three AP-1 tandem repeats. The stimulation of the urokinase promoter by v-mos was partially countered by co-expression of an ERK1/ERK2-inactivating phosphatase. Western blotting and zymographic analysis indicated that v-mos-transformed NIH3T3 cells (MSV NIH-3T3) secreted more urokinase compared with NIH3T3 cells and this was associated with a higher level of activated ERK1 and ERK2. Expression of a catalytically-inactive MAPKK mutant reduced the activity of a urokinase promoter-driven CAT reporter in the MSV NIH-3T3 cells. In conclusion, the data herein indicate that urokinase expression is regulated by v-mos through a MAPKK-dependent signaling pathway.

3T3 Cells↗