Biomedical subjects

B Jansen

Publications and source records attributed to B Jansen.

At least 37 records · Page 2Linked to original sources

PubMed2000

[Prevention of infection with Streptococcus pneumoniae].

Streptococcus pneumoniae is the most common etiologic agent in outpatients pneumonia. Pneumococcal infections are often associated with high mortality risk in immunocompromised patients. An increasing resistance of Streptococcus pneumoniae to antibiotics is observed worldwide. This led to the official recommendation by the STIKO to use the vaccination in special risk groups. The commercially available 23-valent polysaccharide vaccine produces a reliable immune response against pneumococcal infection in children aged over 2 years and adults. The recommendation should be more realized in practice.

Adolescent↗

PubMed2000

Chemosensitisation of malignant melanoma by BCL2 antisense therapy.

BACKGROUND: Chemoresistance of malignant melanoma has been linked to expression of the proto-oncogene BCL2. Antisense oligonucleotides (ASO) targeted against BCL2 mRNA decreased BCL2 protein concentrations, increased tumour-cell apoptosis, and led to tumour responses in a mouse xenotransplantation model when combined with systemic dacarbazine. This phase I-II clinical study investigated the combination of BCL2 ASO (augmerosen, Genasense, G3139) and dacarbazine in patients with advanced malignant melanoma expressing BCL2. METHODS: In a within-patient dose-escalation protocol, 14 patients with advanced malignant melanoma were given augmerosen intravenously or subcutaneously in daily doses of 0.6-6.5 mg/kg plus standard dacarbazine treatment (total doses up to 1000 mg/m2 per cycle). Toxicity was scored by common toxicity criteria. Plasma augmerosen concentrations were assayed by high-performance liquid chromatography. In serial tumour biopsy samples, BCL2 protein concentrations were measured by western blotting and tumour-cell apoptosis was assessed. FINDINGS: The combination regimen was well tolerated, with no dose-limiting toxicity. Haematological abnormalities were mild to moderate. Lymphopenia was common, but no febrile neutropenia occurred. Higher doses of augmerosen were associated with transient fever. Four patients had liver-function abnormalities that resolved within 1 week. Steady-state plasma concentrations of augmerosen were attained within 24 h, and increased with administered dose. By day 5, daily doses of 1.7 mg/kg and higher led to a median 40% decrease in BCL2 protein in melanoma samples compared with baseline, concomitantly with increased tumour-cell apoptosis, which was greatly increased after dacarbazine treatment. Six patients have shown antitumour responses (one complete, two partial, three minor). The estimated median survival of all patients now exceeds 12 months. INTERPRETATION: Systemic administration of augmerosen downregulated the target BCL2 protein in metastatic cancer. Such downregulation of BCL2, combined with standard anticancer therapy, offers a new approach to the treatment of patients with resistant neoplasms.

Adult↗

PubMed2000

The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells.

The congenital fibrosarcoma t(12;15)(p13;q25) rearrangement splices the ETV6 (TEL) gene on chromosome 12p13 in frame with the NTRK3 (TRKC) neurotrophin-3 receptor gene on chromosome 15q25. Resultant ETV6-NTRK3 fusion transcripts encode the helix - loop - helix (HLH) dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. We show here that ETV6-NTRK3 homodimerizes and is capable of forming heterodimers with wild-type ETV6. Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues. To determine if the fusion protein has transforming activity, NIH3T3 cells were infected with recombinant retroviral vectors carrying the full-length ETV6-NTRK3 cDNA. These cells exhibited a transformed phenotype, grew macroscopic colonies in soft agar, and formed tumors in severe combined immunodeficient (SCID) mice. We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation. To test this hypothesis, we expressed a series of ETV6-NTRK3 mutants in NIH3T3 cells and assessed their transformation activities. Deletion of the ETV6 HLH domain abolished dimer formation with either ETV6 or ETV6-NTRK3, and cells expressing this mutant protein were morphologically non-transformed and failed to grow in soft agar. An ATP-binding mutant failed to autophosphorylate and completely lacked transformation activity. Mutants of the three NTRK3 PTK activation-loop tyrosines had variable PTK activity but had limited to absent transformation activity. Of a series of signaling molecules well known to bind to wild-type NTRK3, only phospholipase-Cgamma (PLCgamma) associated with ETV6-NTRK3. However, a PTK active mutant unable to bind PLCgamma did not show defects in transformation activity. Our studies confirm that ETV6-NTRK3 is a transforming protein that requires both an intact dimerization domain and a functional PTK domain for transformation activity. Oncogene (2000) 19, 906 - 915.

3T3 Cells↗

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

Effects of betulinic acid alone and in combination with irradiation in human melanoma cells.

Recently, betulinic acid was identified as a highly selective inhibitor of human melanoma growth and was reported to induce apoptosis in these cells. We have investigated the growth-inhibitory properties of this compound alone and in combination with ionizing radiation in a panel of established human melanoma cell lines as well as in normal human melanocytes. Betulinic acid strongly and consistently suppressed the growth and colony-forming ability of all human melanoma cell lines investigated. In combination with ionizing radiation the effect of betulinic acid on growth inhibition was additive in colony-forming assays. Betulinic acid also induced apoptosis in human melanoma cells as demonstrated by Annexin V binding and by the emergence of cells with apoptotic morphology. The growth-inhibitory action of betulinic acid was more pronounced in human melanoma cell lines than in normal human melanocytes. Notably, despite the induction of apoptosis, analysis of the expression of Bcl-2 family members in betulinic-acid-treated cells revealed that expression of the anti-apoptotic protein Mcl-1 was induced. Furthermore, the antiproliferative action of betulinic acid seemed to be independent of the p53 status. The properties of betulinic acid make it an interesting candidate, not only as a single agent but also in combination with radiotherapy. We conclude that the strictly additive mode of growth inhibition in combination with irradiation suggests that the two treatment modalities may function by inducing different cell death pathways or by affecting different target cell populations.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Erythropoietin receptor expression in human melanoma cells.

Erythropoietin is well known for its role in the control of erythropoiesis, where it acts by binding to its cognate receptor (EpoR) on the surface of erythroid progenitor cells. Here we present the novel finding that the EpoR is also expressed in cells of the melanocytic lineage. It is expressed in transformed cell lines established from normal melanocytes and also in established human melanoma cell lines derived from melanoma metastases, but not in normal primary human melanocytes. The analysis of individual subclones isolated from spontaneously transformed melanocytes revealed that approximately 50% of all the clones examined expressed the EpoR. Further analysis of the individual growth characteristics of EpoR-positive and EpoR-negative clones indicated that, under standard cell culture conditions, expression of the receptor did not affect cell growth. Expression of this receptor is consequently most likely driven by an event that is associated with, but not absolutely required for, the transformed phenotype. While the definite function of this receptor in melanoma cells is still unknown and additional studies are required, our findings support the hypothesis that the EpoR may serve as a progression marker for human melanoma. This observation might be useful in the early diagnosis of melanoma.

Cell Division↗

PubMed2000

Use of scanning electron microscopy to investigate the prophylactic efficacy of rifampin-impregnated CSF shunt catheters.

Infection continues to be one of the major complications of cerebrospinal fluid (CSF) shunting procedures, and is caused mainly by skin-derived bacteria. Production of an extracellular biofilm plays an important role in the pathogenesis of shunt-associated infections by protecting bacteria from immune mechanisms and antibiotics. So far, removal of the original shunt and implantation of a new shunting device has been the only successful treatment for most patients. As an alternative strategy to prevent CSF infections, a rifampin-impregnated silicone catheter was designed to provide high initial and long-lasting (>60 days) release of bactericidal drug. To investigate the pathophysiological mechanism of its function, this new device was investigated both in vitro and in a rodent model of CSF infection by scanning electron microscopy (SEM) and bacterial culture. Staphylococcus epidermidis (10(8) cfu/ml) and S. aureus (10(4) cfu/ml) served as test strains. SEM demonstrated that, in contrast to the unloaded catheters, initial bacterial adherence on the catheter surface could be reduced to a few single cells, which did not show visible signs of proliferation. Bacterial cultures obtained simultaneously were all sterile, showing that adherent bacteria were killed immediately by the rifampin released from the catheter. Although rifampin incorporation into silicone polymers was not able to prevent initial bacterial adhesion completely, subsequent colonisation could be prevented.

Animals↗

PubMed2000

Comparative evaluation of three different genotyping methods for investigation of nosocomial outbreaks of Legionnaires' disease in hospitals.

The increased incidence of nosocomial Legionnaires' disease in two hospitals prompted investigation of possible environmental sources. In the search for an effective DNA-typing technique for use in hospital epidemiology, the performance and convenience of three methods-SfiI macrorestriction analysis (MRA), amplified fragment length polymorphism (AFLP), and arbitrarily primed PCR (AP-PCR)-were compared. Twenty-nine outbreak-associated and eight nonassociated strains of Legionella pneumophila with 13 MRA types and subtypes were investigated. These strains comprised isolates from bronchoalveolar lavages, from environmental, patient-related sources, and type strains. All three typing methods detected one predominant genotype associated with the outbreaks in both hospitals. All of them correctly assigned epidemiologically associated, environmental isolates to their respective patient specimens. AP-PCR was the least discriminating and least reproducible technique. In contrast, AFLP was demonstrated as being the method with the best interassay reproducibility (90%) and concordance (94%) in comparison to the genotyping standard of MRA and the epidemiological data. Analysis of AFLP fragments revealed 12 different types and subtypes. Because of its simplicity and reproducibility, AFLP proved to be the most effective technique in outbreak investigation.

Bacterial Typing Techniques↗

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

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

Deletions of the region 17p11-13 in advanced melanoma revealed by cytogenetic analysis and fluorescence in situ hybridization.

The significance of the p53 tumour-suppressor gene in the oncogenesis of a variety of malignant tumours has been demonstrated over recent years. However, the role of p53 in human malignant melanoma is still unclear. Therefore, we investigated melanoma metastases from 11 patients cytogenetically and with fluorescence in situ hybridization (FISH) after short-term culture, employing a p53 region-specific probe for 17p13.1 and a probe detecting the centromere of chromosome 17. Furthermore, paraffin-embedded tissue samples from nine of these patients were investigated immunohistochemically for expression of the p53 protein. Deletions of the short arm of chromosome 17 were seen in six melanomas in cytogenetic analysis. With FISH, three malignant melanomas had clones with only one p53-allele and an additional four malignant melanomas showed a reduced number of signals at the p53 tumour-suppressor gene locus compared with signals for the centromeric region of chromosome 17. This was confirmed by immunohistochemistry. Our results suggest that the 17p11-13 region is frequently deleted in malignant melanomas and that p53 or other genes located on this band might contribute to the malignant potential of advanced melanoma.

Chromosome Deletion↗

PubMed1999

Inducible nitric oxide synthase (iNOS) expression may predict distant metastasis in human melanoma.

Expression of inducible nitric oxide synthase (iNOS) and its cellular localization was investigated in subcutaneous or lymph node metastases of human melanoma. Immunohistochemistry revealed that iNOS expression was limited to melanoma cells. In samples of patients without distant metastases, the number of iNOS+ tumour cells/total tumour cells was 55% +/- 17% (n = 12) compared with 9% +/- 8% when distant metastases of lung, liver or brain occurred within an observation period of 3 years (n = 10) (P < 0.001). Western blotting confirmed the expression of iNOS protein in select cases. Notably, iNOS is expressed in regional melanoma metastases and its expression is inversely related to the tumour's metastatic potential. Thus, iNOS expression may have predictive value for the development of distant metastases of human melanoma.

Adult↗

PubMed1999

Influence of increased c-Myc expression on the growth characteristics of human melanoma.

Overexpression of the proto-oncogene c-myc has been associated with neoplastic transformation in a variety of tumors. For human melanoma high c-myc expression has been found in the vertical growth phase and higher positivity reported in metastases than primary tumors. The principle aim of this study was to determine, whether c-Myc expression influences the metastatic behavior of human melanoma in the absence of lymphocyte-mediated immune phenomena. The growth characteristics and tumor biology of two c-myc transfectants of the human melanoma cell line IGR39D, expressing c-Myc 1.7 and three times over baseline and the respective vector control were analyzed both in vitro and in a severe combined immunodeficient mouse model in vivo. Both c-myc transfectants showed increased growth rates, anchorage independent growth and directed cell movement in culture. Subcutaneously implanted IGR39D melanomas highly overexpressing c-Myc spontaneously formed macroscopic metastases (lymph nodes and lung) in severe combined immunodeficient mice in all cases (n = 7 per group), whereas less prominent c-Myc overexpression caused the development of only lung micrometastases. During the time period leading to terminal disease in animals injected with c-myc transfected human melanoma cells, melanoma development was not seen in vector controls. These findings suggest that constitutive high c-Myc expression in human melanoma results in a more aggressive growth behavior both in vitro and in vivo and favors metastasis in severe combined immunodeficient mice by factors unrelated to immune phenomena such as class I human leukocyte antigen downregulation known to be associated with c-Myc expression.

Animals↗

PubMed1999

Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice.

Activation of the N-ras gene by point mutation occurs in about 15% of all human melanomas. In recently established severe combined immunodeficiency (SCID) mouse xenotransplantation models for human melanoma, we demonstrated that mutated N-ras not only contributes to tumour growth by enhancing cellular proliferation, but also by blocking apoptosis. Mutated N-ras overexpression protected human melanomas from naturally occurring apoptosis and, in a more pronounced way, from chemotherapy-induced apoptosis in vitro and in vivo. Given the potential clinical importance of these findings we sought to determine the underlying mechanism. We found that mutated N-ras specifically upregulates the expression of the anti-apoptosis gene bcl-2 in two human melanoma cell lines in vitro and in SCID mice. Neither the expression of the anti-apoptotic protein Bcl-xL nor that of the pro-apoptotic proteins Bax and Bak were altered in cells expressing mutated N-Ras. The increase in Bcl-2 expression mediated by mutated ras therefore qualifies as a rational explanation for the enhanced chemoresistance of human melanoma expressing mutated N-Ras.

Animals↗

PubMed1998

Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c.

Following exposure of cells to stimuli that trigger programmed cell death (apoptosis), cytochrome c is rapidly released from mitochondria into the cytoplasm where it activates proteolytic molecules known as caspases that specifically cleave the amino-acid sequence DEVD and are crucial for the execution of apoptosis. The protein Bcl-2 interferes with this activation of caspases by preventing the release of cytochrome c. Here we study these molecular interactions during apoptosis induced by the protein Bax, a pro-apoptotic homologue of Bcl-2. We show that in cells transiently transfected with bax, Bax localizes to mitochondria and induces the release of cytochrome c, activation of caspase-3, membrane blebbing, nuclear fragmentation, and cell death. Caspase inhibitors do not affect Bax-induced cytochrome c release but block caspase-3 activation and nuclear fragmentation. Unexpectedly, Bcl-2 also fails to prevent Bax-induced cytochrome c release, although it co-localizes with Bax to mitochondria. Cells overexpressing both Bcl-2 and Bax show no signs of caspase activation and survive with significant amounts of cytochrome c in the cytoplasm. These findings indicate that Bcl-2 can interfere with Bax killing downstream of and independently of cytochrome c release.

Animals↗

PubMed1998

Role of an acidic compartment in tumor-necrosis-factor-alpha-induced production of ceramide, activation of caspase-3 and apoptosis.

Tumor necrosis factor-alpha (TNF-alpha) apoptosis by recruiting a complex of cytosolic proteins at its plasma membrane receptor. Among them is caspase-8, an interleukin-1beta-converting enzyme (ICE)-like protease that initiates an amplified protease cascade to activate the cell-death machinery. The latter comprises at least caspase-3 and caspase-7, which execute cell death by cleaving numerous protein substrates, including poly(ADP-ribose) polymerase. In addition, TNF-alpha stimulates the production of ceramide, which also activates the death machinery. Whether the signaling pathways elicited by caspase-8 and ceramide proceed independently or intersect at a specific subcellular site is unknown. Using the lysosomotropic agent NH4Cl and the vesicularization inhibitor brefeldin A, we show here the convergence of TNF-alpha-induced death signaling on an acidic, subcellular compartment reminiscent of lysosomes. This compartment generates at least two signaling pathways that account for the caspase-3 activation and apoptosis induced by TNF-alpha, one involving ceramide and caspase-unrelated adapter molecules and another involving yet unknown lysosomal mediators. The apoptosis inhibitor Bcl-2 specifically acts on the ceramide-activated pathway to block caspase-3 activation and apoptosis. The latter result explains why Bcl-2 only partially blocks TNF-alpha-induced apoptosis.

Ammonium Chloride↗