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Biomedical subjects

R Bicknell

Publications and source records attributed to R Bicknell.

At least 37 records · Page 2Linked to original sources
PubMed2001

Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is essential for the angiogenesis required for the formation of the corpus luteum; however, its role in ongoing luteal angiogenesis and in the maintenance of the established vascular network is unknown. The aim of this study was to determine whether VEGF inhibition could intervene in ongoing luteal angiogenesis using immunoneutralisation of VEGF starting in the mid-luteal phase. In addition, the effects on endothelial cell survival and the recruitment of periendothelial support cells were examined. Treatment with a monoclonal antibody to VEGF, or mouse gamma globulin for control animals, commenced on day 7 after ovulation and continued for 3 days. Bromodeoxyuridine (BrdU), used to label proliferating cells to obtain a proliferation index, was administered one hour before collecting ovaries from control and treated animals. Ovarian sections were stained using antibodies to BrdU, the endothelial cell marker, CD31, the pericyte marker, alpha-smooth muscle actin, and 3' end DNA fragments as a marker for apoptosis. VEGF immunoneutralisation significantly suppressed endothelial cell proliferation and the area occupied by endothelial cells while increasing pericyte coverage and the incidence of endothelial cell apoptosis. Luteal function was markedly compromised by anti-VEGF treatment as judged by a 50% reduction in plasma progesterone concentration. It is concluded that ongoing angiogenesis in the mid-luteal phase is primarily driven by VEGF, and that a proportion of endothelial cells of the mid-luteal phase vasculature are dependent on VEGF support.

Actins↗
PubMed2001

Relation of vascular endothelial growth factor production to expression and regulation of hypoxia-inducible factor-1 alpha and hypoxia-inducible factor-2 alpha in human bladder tumors and cell lines.

Hypoxia is an important regulator of vascular endothelial growth factor (VEGF) expression, and VEGF is associated with poor prognosis in bladder cancer. To investigate further the mechanisms of VEGF regulation, we examined VEGF expression by mRNA and protein analysis in four human bladder cancer cell lines, showing a progression from well to poorly differentiated phenotypes under varying conditions of confluence and hypoxia (0.1% O(2)) and with chemical mimics of hypoxia. Hypoxia significantly increased VEGF protein expression in all cell lines, although this effect was dependent on the degree of confluence. The superficial bladder cancer cell line RT4 lost hypoxia inducibility at confluence, whereas inducibility was maintained in the invasive cell lines 253J and EJ28. This pattern of VEGF expression in the invasive cell lines correlated with the expression of the transcription factor hypoxia inducible factor-1 alpha (HIF-1 alpha) and with hypoxia-inducible factor-2 alpha (HIF-2 alpha) and in RT4 correlated with a marked reduction in HIF-1 alpha inducibility at confluence. Using the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY 294002, we show that this VEGF hypoxia-inducible pathway regulated by HIF-1 alpha is distinct from a PI 3-kinase-dependent pathway, which regulates basal amounts of VEGF, but does not affect inducibility. Both HIF-1 alpha and HIF-2 alpha protein and mRNA were up-regulated in primary human bladder tumors (n = 12) compared with normal bladder specimens (n = 4), with significant intertumor variation. These results suggest that components of the hypoxia response pathway, including HIF-1 alpha and HIF-2 alpha, are important cofactors in the regulation of VEGF in bladder cancer and are therapeutic targets in this disease.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors.

Thymidine phosphorylase (TP) (E.C. 2.4.2.4), also known as platelet-derived endothelial cell growth factor, is a potent angiogenic factor. The expression of TP correlates with poor prognosis in a range of tumor types. 2-Deoxy-D-ribose-1-phosphate, a product of thymidine catabolism by TP, is a strongly reducing sugar that generates oxygen radical species during the early stages of protein glycation. We show that thymidine induces oxidative stress in TP-overexpressing carcinoma cells, promoting secretion of the stress-induced angiogenic factors vascular endothelial growth factor and interleukin-8, and inducing matrix metalloproteinase-1. Our findings outline a putative mechanism for TP-induced angiogenesis and identify novel targets for intervention.

Carcinoma↗
PubMed2000

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

Adult↗
PubMed2000

Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis.

In atherosclerosis, leukocyte migration into the plaque is thought to occur across the endothelium of the arterial lumen. However, intraplaque microvessels have been noted. While the significance of, and stimuli for these are uncertain, it seems possible that they may represent a second portal of entry for leukocytes into the plaque. This study performed a basic characterization of intraplaque microvessels and tested the hypothesis that the novel angiogenic factor thymidine phosphorylase (TP) is expressed in atherosclerosis. Immunocytochemistry was performed on aortic and coronary plaques and morphometry on coronary plaques. In plaques from both sites, macrophages, foam cells, and giant cells were immunoreactive for the angiogenic factors TP and vascular endothelial growth factor. Venule-like intraplaque microvessels expressed endothelial leukocyte adhesion molecules HLA-DR and ICAM-1, in contrast to the endothelium overlying the plaque. In coronary plaques, there was a correlation between severity of stenosis and plaque microvascular density. These results are consistent with a role for plaque macrophage/foam cell TP in stimulating plaque angiogenesis. While attention has focused on dysfunction of the endothelium overlying the plaque, microvascular endothelium may also represent a portal of entry for leukocytes into established plaques.

Aorta↗
PubMed2000

Increasing endothelial cell specific expression by the use of heterologous hypoxic and cytokine-inducible enhancers.

One of the current challenges in gene therapy is to construct a vector that will target specific tissues. Targeting expression to endothelium is of particular interest in the treatment of several pathologies. We have shown previously that defined regions of the E-selectin and KDR promoters confer endothelial cell specific expression following retroviral delivery. However, the levels of expression were low. In an attempt to increase expression but to preserve the tissue specificity we have examined hypoxic and cytokine-inducible enhancer elements in combination with the KDR and E-selectin promoters. Both enhancers should be active in the tumour environment, boosting expression and giving additional specificity of gene expression in the tumour endothelium. The hypoxia response element (HRE) of the murine phosphoglycerate kinase-1 (PGK-1) promoter was used as a hypoxic enhancer and the tandem-binding site for NFKB from the murine vascular cell adhesion molecule-1 (VCAM-1) promoter as a cytokine-inducible enhancer. The HRE conferred hypoxia inducibility to the KDR and E-selectin promoters. Endothelial specificity of expression was retained with the KDR but not the E-selectin promoter. The NFKB-binding site conferred responsiveness to TNF-alpha to the KDR promoter, however the level of induction was less than that achieved with the HRE. Retrovirus combining both enhancer elements transferred inducibility by hypoxia and TNF-alpha, and reached the highest expression levels upon stimulation. These results confirm that heterologous enhancer elements may operate on a single endothelial cell specific promoter. These findings make the use of inducible enhancers a promising strategy for increasing tissue specific gene expression.

Adenoviridae↗
PubMed2000

Elevated serum vascular endothelial growth factor in patients with hormone-escaped prostate cancer.

OBJECTIVE: To investigate the role of serum vascular endothelial growth factor (VEGF) in the assessment of patients with prostate cancer. Patients, subjects and methods Serum from 78 men was assayed for VEGF using a commercially available enzyme-linked immunosorbent assay kit. Forty-eight patients had a histopathological diagnosis of prostate cancer (16 local disease, 32 metastatic), nine had benign prostatic hyperplasia (BPH) and 21 were healthy controls. RESULTS: The mean serum VEGF level was significantly higher in patients with hormone-escaped prostate cancer than in all other groups (P </= 0. 02). There were no significant differences in serum VEGF levels among the other groups. In 18 patients with serial measurements there was no significant difference in serum VEGF level during either response to or escape from hormonal therapy. CONCLUSIONS: The significantly higher serum VEGF level in patients with hormone-escaped prostate cancer suggests a role in the pathogenesis of advanced disease. However, the lack of significant differences among the other groups and the failure to indicate either response to or escape from hormonal therapy suggests that serum VEGF in this setting is of limited use.

Aged↗
PubMed2000

Angiogenesis and lymphangiogenesis in stage 1 germ cell tumours of the testis.

OBJECTIVE: To determine whether angiogenesis can be used as an additional prognostic indicator in patients with stage 1 germ cell tumours of the testis. PATIENTS AND METHODS: Paraffin sections were assessed immunohistochemically from 51 patients with clinical stage 1 germ cell tumours of the testis (28 seminoma, 23 teratoma) treated by orchidectomy and surveillance only. Sections were analysed for microvascular density (MVD), and expression of the angiogenic factors vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP). In addition, in the seminoma cases the presence of mRNA for the lymphangiogenic factor VEGF-C was examined by in situ hybridization, and its corresponding receptor VEGFR-3 by immunohistochemistry. RESULTS: Teratoma specimens had a significantly higher mean (range) MVD (85, 26-163; P < 0.01) than both seminoma (37, 16-91) and four normal specimens (26, 18-30). Teratoma specimens also had significantly higher VEGF expression than both seminoma and normal specimens (P < 0.01). Despite these differences between groups, and indeed individual tumours, there was no significant correlation between MVD and VEGF, or between either MVD or VEGF and relapse-free survival. TP expression was significantly greater in tumours than in normal specimens (P < 0.02) but with very little inter-tumour variation. VEGF-C mRNA and VEGFR-3 protein were detected in a third to a half of cases, with expression mostly around endothelial vessels. CONCLUSIONS: The marked differences between normal testis and tumours implicate angiogenesis in the biology of germ cell tumours of the testis. In addition, the detection of factors involved in lymphangiogenesis in some seminomas, tumours which initially metastasize primarily to lymph nodes, indicate that although not prognostic in this study, further studies are warranted in both these areas in the search for further prognostic indicators and therapeutic targets.

Adult↗
PubMed2000

Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression.

Vascular endothelial growth factor (VEGF) is an important factor mediating tumour angiogenesis. VEGF mRNA is differentially expressed in bladder cancer with high expression in superficial tumours (stage pTa and pT1) contrasting with low expression in muscle invasive tumours (stage > or = pT2). To investigate mechanisms regulating VEGF expression in bladder cancer, VEGF mRNA and protein were measured in normal bladder (n = 12) and primary bladder cancers (n = 57). VEGF protein levels correlated with mRNA expression in normal bladder (r = 0.68, P = 0.02) and bladder cancer (r = 0.46, P = 0.0007). Whilst VEGF mRNA expression was threefold higher in superficial compared to muscle invasive bladder cancers (P = 0.0001) there was no difference in VEGF protein (P = 0.81). Accordingly, the median protein:mRNA ratios increased more than 15-fold with increasing tumour stage (P < 0.0001) suggesting translational regulation. Expression of the eukaryotic initiation factor-4E (elF-4E), a factor implicated in the translational regulation of VEGF, was greater in tumours than normal bladder (P < 0.0001) and correlated with VEGE protein:mRNA ratios (n = 43, r = 0.54, P = 0.0004) pointing to its role in the regulation of VEGF. In superficial tumours (n = 37) high expression of eIF-4E was associated with a poor prognosis and reduced stage progression-free survival (P = 0.04, Cox proportional hazards model). The study demonstrates that eIF-4E may be involved in translational regulation of VEGF in bladder cancer and might have a role as a prognostic factor in bladder cancer.

Carcinoma, Transitional Cell↗
PubMed2000

The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo.

Vascular endothelial growth factor (VEGF) is known to occur as at least six differentially spliced variants, giving rise to mature isoforms containing 121, 145, 165, 183, 189 and 206 amino acids. However, little is yet known concerning the in vivo activities of this differential splicing. Stably transfected MCF-7 breast carcinoma cells were constructed that secreted comparable amounts of the 121, 165 or 189 isoforms. Rabbit corneal angiogenesis assays showed the VEGF121 transfectant to have much greater angiogenic activity than the 165 or 189 expressing MCF-7 cells. While the VEGF121-expressing MCF-7 cells were reproducibly more tumorigenic than the control transfectants, this was not the case with the VEGF165- or VEGF189-expressing cells. More surprising was the observation that VEGF189 located to the nucleus, consistent with the presence of a highly conserved nuclear localization sequence in exon 6a that is expressed in VEGF189 but not 121 or 165. It was concluded that the VEGF121 isoform is both more angiogenic and tumorigenic than are the 165 and 189 isoforms. This is probably due to the ability of the 121 isoform, unlike the 165 and 189 isoforms, to freely diffuse from the cells producing it.

Adenocarcinoma↗
PubMed2000

Adrenomedullin is an autocrine regulator of endothelial growth in human endometrium.

Human endometrium is a mucosa served by a microvascular blood supply that involves benign angiogenesis under the control of ovarian steroids throughout reproductive life. Adrenomedullin is a multifunctional 52-amino acid peptide involved in numerous physiological and pathological processes, including angiogenesis, growth regulation, differentiation, vasodilation and smooth muscle relaxation. We have previously shown that adrenomedullin is present in the human uterus. To investigate further the role of adrenomedullin in human endometrial angiogenesis, a method for the isolation and culture of non-pregnant endometrial endothelium was developed. Enzymatic dispersion and 'Percoll' gradient centrifugation, followed by positive selection using Ulex europaeus agglutinin-coated immunomagnetic beads, yielded pure isolates of endothelium. The cells formed a typical 'cobblestone' monolayer within 5-7 days and expressed the classic endothelial markers, CD31 and von Willebrand factor. The presence of adrenomedullin immunoreactivity in endometrial endothelial cells was shown by immunohistochemistry both in vitro and in vivo. Adrenomedullin promotes growth of endothelial cells as measured by [methyl-(3)H] thymidine uptake. Adrenomedullin also induced cyclic AMP in endometrial endothelial cells. These results demonstrate, for the first time, that adrenomedullin is an autocrine growth factor for human endometrial endothelial cells and is thus involved in endometrial angiogenesis.

Adrenomedullin↗
PubMed2000

In silico cloning of novel endothelial-specific genes.

The endothelium plays a pivotal role in many physiological and pathological processes and is known to be an exceptionally active transcriptional site. To advance our understanding of endothelial cell biology and to elucidate potential pharmaceutical targets, we developed a new database screening approach to permit identification of novel endothelial-specific genes. The UniGene gene index was screened using high stringency BLAST against a pool of endothelial expressed sequence tags (ESTs) and a pool of nonendothelial ESTs constructed from cell-type-specific dbEST libraries. UniGene clusters with matches in the endothelial pool and no matches in the nonendothelial pool were selected. The UniGene/EST approach was then combined with serial analysis of gene expression (SAGE) library subtraction and reverse transcription polymerase chain reaction to further examine interesting clusters. Four novel genes were identified and labeled: endothelial cell-specific molecules (ECSM) 1-3 and magic roundabout (similar to the axon guidance protein roundabout). In summary, we present a powerful novel approach for comparative expression analysis combining two datamining strategies followed by experimental verification.

Adult↗
PubMed2000

Thymidine phosphorylase expression in normal and hyperplastic endometrium.

AIMS: To investigate the expression of thymidine phosphorylase (TP), a known angiogenic factor for endothelial cells, in normally cycling endometrium and various forms of endometrial hyperplasia. METHODS: TP expression was assessed with the P-GF.44C monoclonal antibody, using the alkaline phosphatase anti-alkaline phosphatase method. Ninety two normal and hyperplastic endometria were studied. RESULTS: In normal proliferative endometrium, TP is found exclusively in the basal layer and the inner third of the functionalis; expression is cytoplasmic in glandular epithelium and nuclear in stromal cells. It is invariably patchy. This immunohistochemical picture remains almost unaltered during the early and mid secretory phase of the normal menstrual cycle but, most impressively, TP is expressed uniformly in the epithelium of all endometrial glands towards the end of the cycle. At this stage, expression is mixed nuclear/cytoplasmic and there is very little stromal nuclear staining. In simple endometrial hyperplasia, the staining pattern for TP is identical to normal proliferative endometrium, with a distribution that is usually limited to a few rather weakly proliferating glands and to the adjacent periglandular stroma of the deep endometrium. The distribution is more extensive in complex and atypical endometrial hyperplasias, where a mixed nuclear/cytoplasmic pattern usually prevails over the pure cytoplasmic reaction. CONCLUSIONS: TP is expressed consistently in normal and hyperplastic endometrium, suggesting a role in physiological and pathological angiogenesis. In normal endometrium, TP has a definite pattern of distribution, which is dependent on the phase of the menstrual cycle, whereas in all forms of endometrial hyperplasia the enzyme is randomly distributed and lacks an orderly pattern.

Adult↗
PubMed2000

Suppression of luteal angiogenesis in the primate after neutralization of vascular endothelial growth factor.

Manipulation of angiogenesis may have a profound effect on female reproductive function, but this has not yet been demonstrated by direct experiment in species with ovulatory cycles similar to those in women. To investigate whether angiogenesis could be inhibited in the primate corpus luteum, and the consequences of such inhibition on luteal function, marmosets were treated with an antibody to vascular endothelial growth factor (VEGF). Treatment commenced at the time of ovulation and was continued for 3 days (early luteal group) or 10 days (midluteal group). Bromodeoxyuridine was used to label proliferating cells, being administered 1 h before collecting ovaries from control and treated animals in the early or midluteal phase. Ovarian sections were stained using an antibody to bromodeoxyuridine, and a proliferation index was obtained; endothelial cell quantification was performed using factor VIII as an endothelial cell marker. Intense proliferation in the early luteal phase was suppressed by anti-VEGF treatment. This resulted in blockade of development of the normally extensive capillary bed, as in the animals treated until the mid-luteal phase the numbers of endothelial cells were reduced. The hormone-producing cells remained largely unaltered in the posttreatment corpus luteum, although the presence of lipid accumulation, and small pockets of cells showing basophilia and nuclear condensation were observed. Significantly, luteal function, as judged by secretion of progesterone, was markedly compromised by the treatment, being reduced by 60% in comparison with controls. It is concluded that VEGF-mediated angiogenesis is an essential component of luteal function in primates and therefore has the potential to be regulated.

Animals↗
PubMed2000

Steroids and the endometrium.

Steroids are commonly employed in current clinical practice. The benefits of steroids in hormone replacement therapy, contraception and prevention or treatment of breast cancer are limited by their side effects arising from disorders in endometrial function. These side effects are complex and enclose bleeding problems and endometrial proliferation during hormone replacement therapy and antioestrogen treatment or menstrual disturbances during oral contraception. Numerous reports have identified gene targets influenced by steroids and have implicated these products as contributors to endometrial physiology or pathology. The expression of estrogen and progesterone receptors is regulated by steroids. The new estrogen receptor (ER) subtype ERbeta with different functional characteristics from ERalpha was recently described in endometrium. In addition, there is now increasing evidence that the functionally distinct progesterone receptor (PR) isoforms A and B are differentially expressed in this tissue. The relative proportions of these steroid receptors and their interaction determine the expression of specific genes upon steroidal stimulation. Steroids induce endometrial expression of various growth and angiogenic factors. Dysregulations of this steroid modulated expression is believed to be involved in the pathogenesis of many endometrial diseases. Irregular bleeding induced by steroidal contraception, for example, is thought to involve aberrant endometrial vascular development and expression of angiogenic growth factors. The antioestrogen tamoxifen induces growth factors like vascular endothelial growth factor and adrenomedullin which may be key mediators of endometrial neoplastic effects. This review describes recent advances regarding the mechanism of action of steroids on endometrium. The expression of oestrogen and progesterone receptors as well as steroid hormone dependent growth factors and angiogenic modulators are going to be discussed.

Animals↗
PubMed2000

Application of the enrichment approach to identify putative markers of response to 5-fluorouracil therapy in advanced colorectal carcinomas.

A wide range of tumor response is seen amongst patients with the same stage of colorectal cancer, even with the use of uniform chemotherapy. The significant economic and personal impact of chemotherapy provides the impetus for the identification of markers of response for use in guiding patient treatment. However, practical constraints prevent evaluation of all putative markers in a definitive manner. In this study, the enrichment approach was evaluated by examining the expression of a panel of putative response markers in selected patient populations with advanced colorectal cancer (i.e., those demonstrating the best and the poorest clinical response to a standardized 5-fluorouracil/folinic acid chemotherapy regimen). Patients showing a good response had a significantly increased survival when compared with poor responders (P=0.0013). Markers were then ranked for clinical importance based on differences in expression between the two groups. This allows for the relatively rapid and inexpensive investigation of multiple markers, using defined patient groups. Bcl-2 overexpression in primary colorectal tumor specimens was found to correlate with clinical response of metastatic deposits to chemotherapy (P=0.044), as did the site of the primary tumor (P=0.011). However, no clear association was observed between response status and the other examined factors (p53, PCNA, TP, MMPs 1, 2 or 9, TIMPs 1 or 2, TS, Dukes' stage at initial diagnosis, histological grade, sex or age). This approach has allowed prioritization of markers of clinical response on which larger, statistically definitive studies will be performed.

Adult↗
PubMed2000

Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.

Uterine leiomyomas are the most prevalent benign tumor type in women of reproductive age and are one of the most common indications for hysterectomy. The expression of five angiogenic factors, adrenomedullin (ADM), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived endothelial cell growth factor/thymidine phosphorylase, were examined in 91 uteri collected throughout the menstrual cycle; 52 of which contained leiomyomata, and the remainder were normal controls. The microvascular density and endothelial proliferative indices were then determined for each of the uterine sections. ADM and VEGF were the most widely expressed angiogenic factors in the leiomyomas. Furthermore, the expression of ADM and VEGF in the endometrium and myometrium was up-regulated in leiomyoma-bearing uteri compared with controls. Although acidic fibroblast growth factor and basic fibroblast growth factor were expressed in leiomyomas and endometrium in all of the uterine samples examined, they were only expressed in the myometrium of leiomyomata-bearing uteri. Endothelial proliferation in leiomyomas was statistically greater than that of the myometrium and endometrium, both within and between uteri (P < 0.05). The vascular density in the myometrium but not the endometrium was significantly increased in leiomyoma-containing uteri (P < 0.05). Expression of ADM alone correlated directly with vascular density and endothelial cell proliferation index in leiomyomas and myometrium and may account for the high vascularity found in leiomyomas and the myometrium of leiomyoma-bearing uteri. As such, ADM is identified as a novel target for antiangiogenic therapy of these benign, clinically problematic uterine tumors.

Adrenomedullin↗