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K Wolff

Publications and source records attributed to K Wolff.

At least 55 records · Page 3Linked to original sources
PubMed2000

Bcl-2 antisense oligonucleotides (G3139) inhibit Merkel cell carcinoma growth in SCID mice.

Merkel cell carcinoma was first described in 1972 by Toker and is an aggressive neuroendocrine skin tumor with a high metastatic potential. Merkel cell carcinoma is thought to derive from the neuroendocrine (Merkel) cells of the skin, although in contrast to fetal and especially adult Merkel cells, Merkel cell carcinomas express high levels of the Bcl-2 oncoprotein. Bcl-2 is capable of blocking programmed cell death and has been shown to play an important role in normal cell turnover, tumor biology, and chemoresistance. High Bcl-2 expression leading to prolonged survival of cells may therefore be of importance in the biological and clinical characteristics of Merkel cell carcinoma. In a SCID mouse xenotransplantation model for human Merkel cell carcinoma, we investigated the influence of the bcl-2 antisense oligonucleotide G3139 (Genta) on tumor growth in comparison with control oligonucleotides or cisplatin. Bcl-2 antisense treatment, targeting the first six codons of the bcl-2 mRNA, resulted in either a dramatic reduction of tumor growth or complete remission, whereas reverse sequence and two-base mismatch control oligonucleotides or cisplatin had no significant antitumor effects compared with saline-treated controls. Apoptosis was enhanced 2.4-fold in the bcl-2 antisense treated tumors compared with the saline-treated group, and no other treatment showed a comparable increase in apoptosis. Our findings suggest that bcl-2 antisense treatment may be a novel approach to improve treatment outcome of human Merkel cell carcinoma.

Animals↗
PubMed2000

Follow-up of melanocytic skin lesions with digital epiluminescence microscopy: patterns of modifications observed in early melanoma, atypical nevi, and common nevi.

BACKGROUND: Digital epiluminescence microscopy (DELM) has been reported to be a useful technique for the follow-up of melanocytic nevi. One of the promises of this technique is to identify modifications over time that indicate impending or incipient malignancy and to facilitate surveillance of melanocytic skin lesions, particularly in patients with multiple clinically atypical nevi. OBJECTIVE: Our purpose was to report on patterns of modifications over time observed in benign melanocytic skin lesions and melanoma. METHODS: A total of 1862 sequentially recorded DELM images of melanocytic lesions from 202 patients (mean age, 36.1 years; 54.0% female patients) with multiple clinically atypical nevi were included in the analysis. The median follow-up interval was 12. 6 months. Melanocytic lesions with substantial modifications over time (enlargement, changes in shape, regression, color changes or appearance of ELM structures known to be associated with melanoma) were excised and referred to histopathologic examination. RESULTS: A total of 75 melanocytic skin lesions (4.0%) from 52 patients (mean age, 33.3 years; 63.5% female patients) showed substantial modifications over time and were excised and referred to histopathologic examination. Eight changing lesions were histologically diagnosed as early melanomas. These lesions frequently showed focal enlargement associated with a change in shape as well as appearance of ELM structures that are known to be associated with melanoma. In contrast, the majority of benign changing lesions (common and atypical nevi) showed symmetric enlargement without substantial structural ELM changes. Six of the 8 patients in whom melanoma developed were unaware of the fact that the lesion had changed over time. CONCLUSION: We demonstrate that follow-up of melanocytic lesions with DELM helps to identify patterns of morphologic modifications typical for early melanoma. DELM may therefore serve as a useful tool to improve the surveillance of patients with multiple atypical nevi.

Adult↗
PubMed2000

Computer-aided epiluminescence microscopy of pigmented skin lesions: the value of clinical data for the classification process.

Early melanoma is often difficult to differentiate from benign pigmented skin lesions (PSLs). Digital epiluminescence microscopy (DELM) and automated image analysis could represent possible aids for inexperienced clinicians. We designed an automated computerized image analysis system that has the potential for use as an additional tool for the differentiation of melanoma from dysplastic naevi and common naevi. The PC-based pilot system was attached to a common DELM system as the image source. Digital images of PSLs were automatically segmented and a panel of 107 morphological parameters were measured. Additionally, seven clinical parameters were evaluated and used as an additional source of information. Neural networks were then trained to distinguish melanoma from benign PSLs. One class of networks was trained solely based on the morphometric features, whereas the second class of networks was trained on the combination of morphometric and clinical features. The automatic segmentation algorithm was correct in 96% of cases. Using three-way receiver operating characteristic (ROC) analysis, for networks trained solely on morphometric features the volume under surface (VUS) was 0.617 (SD 0.036). The performance was significantly better for networks trained on the combination of both morphometric and clinical features (VUS = 0.682, SD 0.035). In a dichotomous model, distinguishing benign lesion (common naevi + dysplastic naevi) from melanoma, the area under the curve (AUC) from two-way ROC analysis was 0.942 (SD 0.018) for networks trained solely on morphometric features and 0.968 (SD 0.012) for those trained on the combination of clinical and morphometric data (P= NS). Automated feature extraction from PSLs and the training of neural networks as classifiers has thus shown satisfactory performance in a large scale experiment. The addition of clinical data significantly increases the diagnostic performance for distinguishing three classes of lesions (i.e. common naevi, dysplastic naevi and melanoma). Such integrated systems hold promise as a decision aid for the diagnosis of PSLs.

Algorithms↗
PubMed2000

Influenza virus NS1 protein counteracts PKR-mediated inhibition of replication.

The availability of an influenza virus NS1 gene knockout virus (delNS1 virus) allowed us to establish the significance of the biological relationship between the influenza virus NS1 protein and double-stranded-RNA-activated protein kinase (PKR) in the life cycle and pathogenicity of influenza virus. Our results show that the lack of functional PKR permits the delNS1 virus to replicate in otherwise nonpermissive hosts, suggesting that the major function of the influenza virus NS1 protein is to counteract or prevent the PKR-mediated antiviral response.

Animals↗
PubMed2000

Excessive use of cesarean section for the second twin?

BACKGROUND: In Sweden, the frequency of cesarean section of the second twin after vaginal birth of the first twin has increased in recent years. METHODS: To investigate the indications for second twin cesarean sections, all twin deliveries at Huddinge University Hospital from 1995 to 1997 were reviewed retrospectively. The rates of cesarean section for the second twin were compared with figures from the whole country, based on the Swedish medical birth register. RESULTS: Thirty-one percent of all twin deliveries had a spontaneous onset and spontaneous vaginal delivery. The total twin cesarean section rate, including cesarean section for the second twin, was 45% at Huddinge University Hospital in 1995-1997 and 44% in Sweden in 1995. Cesarean section for the second twin after vaginal delivery of the first twin occurred in 11%. On review, 2/3 of the cesarean sections for the second twin were considered potentially avoidable. CONCLUSION: In normal twin pregnancies with vertex/nonvertex presentation, the favorable fetal outcome and also the maternal risks associated with cesarean section support vaginal delivery as the recommended delivery route. Extraction or version of a second nonvertex twin should be attempted before cesarean section for this twin is performed.

Adult↗
PubMed2000

Autoantibody reactivity in a case of Schnitzler's syndrome: evidence for a Th1-like response and detection of IgG2 anti-FcepsilonRIalpha antibodies.

Schnitzler's syndrome is a rare disease characterized by chronic urticaria, monoclonal IgM, and clinical and laboratory signs of inflammation. In a subset of patients, the urticarial lesions cause pruritus. However, the pathophysiology of the disease and the biochemical basis of urticaria are not known. We describe a female patient with Schnitzler's syndrome suffering from chronic urticaria associated with pruritus. The patient's serum was found to contain IgG antibodies recognizing cellular components of the microvasculature. In particular, IgG3 antibodies directed against proteins (14-100 kD) expressed in cultured dermal microvascular endothelial cells and mast cells, were found by immunoblotting. Moreover, IgG2 antibodies specific for the alpha-chain of the FcepsilonRI were detectable. However, the autoantibodies did not mediate histamine release in mast cells or basophils. In patients with IgM paraproteinemia who did not have Schnitzler's syndrome, antibodies against endothelial/mast cells or FcepsilonRI were not detectable. In summary, we describe subclass-specific IgG reactivity against microvascular endothelial cells and mast cells indicating Th1 autoimmunity in a patient with Schnitzler's syndrome. Whether such autoantibodies are recurrently produced in patients with Schnitzler's syndrome and play a role in the pathophysiology of the disease remains to be determined.

Adult↗
PubMed2000

Clozapine pharmacokinetics and pharmacodynamics studied with Cyp1A2-null mice.

The aim of this study was to use the CYP1A2-null mouse to investigate the in-vivo contribution of CYP1A2 to clozapine pharmacokinetics and pharmacodynamics. An intraperitoneal injection of 10 mg/kg clozapine was administered to four male CYP1A2 -/- mice and four male wild-type mice. Clozapine, desmethylclozapine, and clozapine N-oxide concentrations in sequential tail blood samples were measured by HPLC with UV detection. Behavioural parameters were recorded at each time point. The area under the curve (AUC) of clozapine was 2.6 times greater, the clearance of clozapine was 2.6 times slower, and the half-life was 1.2 times longer in the CYP1A2 -/- mice (p = 0.0143) as compared to the wild-type mice. Sixty-one percent of the clozapine clearance in wild-type mice was calculated to be mediated by CYP1A2. The AUC of desmethylclozapine was 1.6 times lower in the CYP1A2 -/- mice compared to the wild-type mice (p = 0.0286), while there was a trend for the AUC of clozapine N-oxide to be greater in the CYP1A2 -/- mice (p = 0.0571). The CYP1A2 -/- mice were significantly more drowsy and showed more motor impairment (p = 0.0145) and myoclonus than the wild-type mice. Our results indicate that, in vivo, CYP1A2 is the major determinant of clozapine clearance, contributes significantly to the demethylation of clozapine, and has a negligible contribution to the N-oxidation. Our data also indicate that CYP1A2 poor metabolizers might be more susceptible than extensive metabolizers to dose-related adverse effects of clozapine, such as sedation, myoclonus and seizures.

Animals↗
PubMed2000

Prediction of maternal and fetal complications in preeclampsia.

INTRODUCTION: Preeclampsia is associated with an increased risk for maternal and fetal morbidity. The aim of this study was to identify factors predicting for maternal or fetal complications. MATERIAL AND METHODS: One hundred and eleven patients with preeclampsia were included. Endpoint variables were maternal and fetal complications. Any of the diagnosis eclampsia, hemolysis elevated liver low platelet (HELLP) syndrome, oliguria or placental abruption was considered a maternal complication. Fetal complications were: small for gestational age (SGA) infant, umbilical artery pH<7.10 and admittance of the infant to a neonatal intensive care unit (NICU). Independent variables were maternal age, parity, gestational age, renal function, platelet count, liver enzymes and blood pressure. Logistic regression analysis was used for statistical evaluation. RESULTS: The following independent significant predictors were identified: Maternal complication (n=10) was predicted only by diastolic blood pressure; odds ratio (OR) 1.13 (95% confidence interval 1.01-1.25). SGA (n=21) was associated with maternal prepregnancy weight, OR 0.94 (0.89-0.99) and gestational age at debut of preeclampsia, OR 0.97 (0.94-0.99). NICU admittance (n=31) was only predicted by gestational age at delivery, OR 0.80 (0.67-0.96). No association was found between any of the independent variables and a low umbilical artery pH (n= 10). CONCLUSIONS: In the surveillance of patients with established preeclampsia, the value of serial blood and urine sampling, which is common practice in many obstetrical units, might be questioned.

Abruptio Placentae↗
PubMed2000

A novel Ras antagonist regulates both oncogenic Ras and the tumor suppressor p53 in colon cancer cells.

BACKGROUND: In colon cancer, K-Ras oncogenes, which appear to be linked to chemoresistance and poor prognosis, are activated in more than 50% of cases, whereas the tumor suppressor gene p53 is mutationally altered in about 70% of all cases. The transcription factor p53, which is frequently mutated at codon 273, maintains wild-type configuration and possibly carries out residual functions. Although blocking of activated K-Ras may constitute a rational therapeutic concept for this treatment-resistant malignancy, a strategy influencing both oncogenic Ras and the tumor suppressor p53 may be even more promising. MATERIALS AND METHODS: We evaluated the effects of S-trans, trans-farnesyl-thiosalicylic acid (FTS), a novel Ras antagonist on human SW480 and HT-29 colon cancer cells, which both harbor a p53 His273 mutation but express activated K-Ras and wild-type, but overexpressed, H-Ras, respectively. Besides cell growth and morphology, levels of cellular Ras proteins, regulation of p53 and p21(waf1/cip1) expression were analyzed by immunoblotting. The cell cycle arresting potential of FTS was quantified by flow cytometry. RESULTS: We demonstrate that FTS treatment alters the morphology and blocks the growth of SW480 and HT-29 colon cancer cells by both reducing the total amount of Ras and up-regulating the tumor suppressor p53. Furthermore, FTS caused an upregulation of the cyclin-cyclin-dependent kinase (CDK) inhibitor p21(waf1/cip1) and blocked the cell cycle. p53 antisense oligonucleotides not only reduced the level of p53 proteins but correspondingly also blocked the expression of p21(waf1/cip1) in FTS-treated colon cancer cells. CONCLUSIONS: FTS, a unique compound capable of regulating both oncogenic Ras and the tumor suppressor p53 may prove particularly useful for the therapy of colon cancer and other treatment-resistant malignancies where Ras is altered and p53 is either wild-type or mutated in positions that allow residual p53 functions.

Blotting, Western↗
PubMed1999

Novel Ras antagonist blocks human melanoma growth.

During past decades, knowledge of melanoma biology has increased considerably. Numerous therapeutic modalities based on this knowledge are currently under investigation. Advanced melanoma, nevertheless, remains a prime example of poor treatment response that may, in part, be the consequence of activated N-Ras oncoproteins. Besides oncogenic Ras, wild-type Ras gene products also play a key role in receptor tyrosine kinase growth factor signaling, known to be of importance in oncogenesis and tumor progression of a variety of human neoplasms, including malignant melanoma; therefore, it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a sensible approach to inhibit melanoma growth. To test this concept, the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a recently discovered Ras antagonist that dislodges Ras from its membrane-anchoring sites, was evaluated. The antitumor activity of FTS was assessed both in vitro and in vivo in two independent SCID mouse xenotransplantation models of human melanoma expressing either wild-type Ras (cell line 518A2) or activated Ras (cell line 607B). We show that FTS (5-50 microM) reduces the amounts of activated N-Ras and wild-type Ras isoforms both in human melanoma cells and Rat-1 fibroblasts, interrupts the Ras-dependent extracellular signal-regulated kinase in melanoma cells, inhibits the growth of N-Ras-transformed fibroblasts and human melanoma cells in vitro and reverses their transformed phenotype. FTS also causes a profound and statistically significant inhibition of 518A2 (82%) and 607B (90%) human melanoma growth in SCID mice without evidence of drug-related toxicity. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for human melanoma and possibly other tumors that either carry activated ras genes or rely on Ras signal transduction more heavily than nonmalignant cells.

Animals↗
PubMed1999

Influence of MUC18/MCAM/CD146 expression on human melanoma growth and metastasis in SCID mice.

The cell surface glycoprotein MUC18MCAM/CD146 was originally defined as a marker of melanoma progression and has been suspected to be directly linked to the metastatic process of this malignancy. In order to address this question, 2 MCAM negative human melanoma cell lines, SK-2 and XP44RO(Mel), were transfected with MCAM-encoding cDNA. Surface MCAM expression on SK-2 and XP44RO(Mel) transfectants was similar to that observed in naturally occurring MCAM positive human melanoma cells and transfectants demonstrated MCAM-dependent increase in homotypic adhesion in vitro. The growth behavior of 7 MCAM transfectants and their respective vector controls was evaluated in SCID mice. Tumor size at 4-5 weeks after s.c. implantation was highly variable, but did not correlate with MCAM expression. Despite massive primary tumor formation at the injection site, no spontaneous metastasis was observed with any of the investigated MCAM transfectants. The influence of MCAM expression on lung metastases formation in an experimental metastasis assay was system dependent, converting only XP44RO(Mel) transfectants into metastatic cells, although increased homotypic adhesion, leading to formation of tumor cell clusters, was observed with transfectants of both cell lines in vitro. Our findings indicate that MCAM expression of human melanoma cells has an influence on later stages of the metastatic process only, namely, extravasation and establishment of new foci of growth, but is per se not sufficient for this process.

Animals↗
PubMed1999

Léri-Weill syndrome as part of a contiguous gene syndrome at Xp22.3.

We report on a mother and her 5-year old son, both with a terminal deletion of the short arm of the X chromosome. By molecular genetic analysis the breakpoint was located distal to steroid sulfatase gene. The boy manifested, due to nullisomy of this region, short stature (SHOX), chondrodysplasia punctata (ARSE), and mental retardation (putative mental retardation gene MRX 49). Short stature is present in mother and son, but both also had bilateral Madelung deformity, a key finding in the Léri-Weill syndrome. We discuss the phenotype in relationship to hitherto published cases with chromosomal aberrations and contiguous gene syndromes of Xp22.3.

Abnormalities, Multiple↗
PubMed1999

Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study.

We performed a phase I trial to evaluate the safety and tolerability of repeated skin injections of IL-2-transfected autologous melanoma cells into patients with advanced disease. Cell suspensions, propagated from excised metastases, were IL-2 gene transfected by adenovirus-enhanced transferrinfection and X-irradiated prior to injection. Vaccine production was successful in 54% of the patients. Fifteen patients (37%) received two to eight skin vaccinations of either 3 x 10(6) (intradermal) or 1 x 10(7) (half intradermal, half subcutaneous) transfected melanoma cells per vaccination (secreting 140-17,060 biological response modifier program units of IL-2/10(6) cells/24 hr). Analyses of safety and efficacy were carried out in 15 and 14 patients, respectively. Overall, the vaccine was well tolerated. All patients displayed modest local reactions (erythema, induration, and pruritus) and some experienced flu-like symptoms. Apart from newly appearing (4 of 14) and increasing (5 of 14) anti-adenovirus and newly detectable anti-nuclear antibody titers (1 of 15), recipients developed de novo or exhibited increased melanoma cell-specific delayed-type hypersensitivity (DTH) reactions (8 of 15) and vitiligo (3 of 15) and showed signs of tumor regression (3 of 15). This supports the idea of a vaccine-induced or -amplified anti-cancer immune response. None of the patients exhibited complete or partial regressions, but five of them experienced periods of disease stabilization. Three of these individuals received more than the four planned vaccinations and their mean survival time was 15.7 +/- 3.5 months as compared to 7.8 +/- 4.6 months for the entire patient cohort. These data indicate that IL-2-producing, autologous cancer cells can be safely administered to stage IV melanoma patients and could conceivably be of benefit to patients with less advanced disease.

Adult↗
PubMed1999

A standardized, a computer-assisted in vitro assay for the assessment of neutrophil transmigration across endothelial monolayers.

We describe an automated, observer-independent and highly reproducible assay for the quantification of transmigrated neutrophils across endothelial monolayers. Endothelial cells grown on collagen gels were loaded with a dye emitting red fluorescence. Neutrophils loaded with dye emitting green fluorescence were allowed to adhere to and transmigrate across endothelial monolayers. For quantification of adherent and migrated cells, randomly selected fields were scanned by confocal laser scan microscopy at defined depths within and below the endothelial monolayers. The images obtained were transferred into the public domain NIH image program and numbers and distribution of cells within scanned sectors were automatically calculated. We demonstrate that adherent neutrophils are easily discriminated from transmigrated cells; absolute numbers of migrated cells can be reproducibly calculated by counting cells at a depth of -20 microm, thus permitting evaluation of large-scale experiments: the efficacy of neutrophil transmigration depends on the level of endothelial activation after TNF stimulation and mAbs to cell surface adhesion molecules interfere with migration in a manner similar to that previously shown in in vivo experiments. This assay lends itself to the identification of molecules influencing in cell migration in each phase of EC activation and to the screening of pro- and anti-migratory properties of biological or pharmacological reagents.

Animals↗
PubMed1999

Farnesylthiosalicylic acid inhibits the growth of human Merkel cell carcinoma in SCID mice.

Merkel cell carcinoma (MCC) is a neuroendocrine malignancy showing poor response to a variety of therapeutic strategies. We evaluated the antitumor activity of S-trans, trans-farnesylthiosalicylic acid (FTS), a new inhibitor of Ras signal transduction, in a newly established SCID mouse xenotransplantation model for human MCC (seven animals per group). FTS injected intraperitoneally at 5 mg/kg per day for 2 weeks up-regulated the tumor suppressor p53 and induced tumor cell apoptosis in established MCCs growing subcutaneously in SCID mice. These effects led to a statistically significant inhibition of MCC growth (P<0.002). The mean tumor weights following FTS or control treatment were 0.32+/-0.15 g and 1.08+/-0.29 g, respectively. There was no evidence of FTS related toxicity at the effective dose used. Our findings stress the notion that FTS may qualify as a novel and rational treatment approach for MCC and possibly for other tumors that rely on tyrosine kinase signaling.

Aged↗
PubMed1999

Reevaluation of the ABCD rule for epiluminescence microscopy.

BACKGROUND: Epiluminescence microscopy (ELM) provides for increased accuracy in the clinical diagnosis of pigmented skin lesions (PSL). It is based on pattern analysis of ELM criteria, which requires experience. The recently introduced application of the ABCD score to ELM facilitates this by permitting lesion evaluation on the basis of predefined clinical criteria. OBJECTIVE: The present study was performed to evaluate the diagnostic performance of the ABCD rule for ELM in pigmented skin lesions testing dermatologists with varying skills from novice to expert. METHODS: Two hundred fifty electronic images of randomly selected, histologically proven PSL including 41 early melanomas (16.4%) were presented to the raters, and each image was scored according to the rules of the ABCD score and rated without the guidance of a scoring system on a scale from 1 = definitely benign to 5 = definitely melanoma. RESULTS: Our data show that the application of the ABCD rule significantly enhances diagnostic ability in less experienced dermatologists compared with rating without the guidance of a scoring system. In contrast, the diagnostic accuracy of dermatologists who are moderately to greatly experienced is not improved by use of the ABCD rule. CONCLUSION: Our experiments indicate that the application of the ABCD rule to ELM introduced by Stolz et al represents a useful enhancement for diagnosis of pigmented skin lesions in less experienced users. However, the method does fail to detect melanomas with 100% accuracy. Therefore further effort has to be made to make the diagnosis of melanoma easier and more accurate.

Clinical Competence↗
PubMed1999

Morphologic changes of pigmented skin lesions: a useful extension of the ABCD rule for dermatoscopy.

BACKGROUND: Epiluminescence microscopy (ELM) significantly increases the early diagnosis of pigmented skin lesions (PSL) using established criteria and pattern analysis. The ABCD rule for dermatoscopy (ie, ELM) provides a simplified approach to the interpretation of ELM images on the basis of asymmetry (A), border (B), color (C), and dermatoscopic structure (D). OBJECTIVE: We set out to determine whether the diagnostic accuracy of the ABCD scoring algorithm can be significantly improved by incorporating information about morphologic changes of the lesion observed and provided by the patient. METHODS: We prospectively collected 356 small pigmented skin lesions (< 1 cm) including 73 (20.5%) melanomas. Before excision all patients were asked whether the lesion had changed in size, color, or shape within the last year or whether they experienced any sign of ulceration or spontaneous bleeding. ELM images of the lesions were evaluated according to the ABCD rule for dermatoscopy to yield a semiquantitative score. Accuracy of diagnosis was evaluated in terms of sensitivity, specificity, and area under receiver operating characteristic curves (AUC). RESULTS: The frequency of reported changes was significantly higher for melanomas than benign PSL (65.8% vs 29.7%, P < .001). In a multivariate model morphologic change was a significant independent predictor of malignancy (odds ratio = 3.17, 95% confidence interval [CI]: 1.96 to 5.14, P < .001). The mean final score achieved when using the enhanced ABCD-E criteria including morphologic change (E) was significantly higher for melanomas (5.7, 95% CI: 5.3 to 6.0) than benign PSL (2.9, 95% CI: 2.8 to 3.1, P < .001). Diagnostic accuracy was significantly higher when the lesions were evaluated by the enhanced ABCD-E criteria as compared with the standard ABCD score (AUC(ABCD) = 0.87 vs AUC(ABCD-E) = 0.90; P = .006). CONCLUSION: Information about morphologic changes of PSL as reported by the patient is a useful extension of the ABCD rule for dermatoscopy.

Adult↗