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Biomedical subjects

X Sun

Publications and source records attributed to X Sun.

At least 55 records · Page 3Linked to original sources

Rational design and assembly of M(2)M'(3)L(6) supramolecular clusters with C(3h) symmetry by exploiting incommensurate symmetry numbers.

A rational approach to heterometallic cluster formation is described that uses incommensurate symmetry requirements at two different metals to control the stoichiometry of the assembly. Critical to this strategy is the proper design and synthesis of hybrid ligands with coordination sites selective toward each metal. The phosphino-catechol ligand 4-(diphenylphosphino)benzene-1,2-diol (H(2)L) possesses both hard catecholate and soft phosphine donor sites and serves such a role, using soft (C(2)-symmetric) and hard (C(3)-symmetric) metal centers. The ML(3) catecholate complexes (M = Fe(III), Ga(III), Ti(IV), Sn(IV)) have been prepared and characterized as C(3)-symmetry precursors for the stepwise assembly (aufbau) of heterometallic clusters. While the single-crystal X-ray structure of the Cs(2)[TiL(3)] salt shows a C(1) mer-configuration in the solid -state, room-temperature solution NMR data of this and related complexes are consistent with either exclusive formation of the C(3)-fac-isomer with all PPh(2) donor sites syn to each other or facile fac/mer isomerization. Coordination of these [ML(3)](2)(-) (M = Ti(IV), Sn(IV)) metallaligands via their soft P donor sites to C(2)-symmetric PdBr(2) units gives exclusively pentametallic [M(2)Pd(3)Br(6)L(6)](4)(-) (M = Ti, Sn) clusters. These clusters have been fully characterized by spectral and X-ray structural data as C(3h) mesocates with Cs(+) or protonated 1,4-diazabicyclo[2.2.2]octane (DABCO.H(+)) cations incorporated into deep molecular clefts. Exclusive formation of this type of supramolecular species is sensitive to the nature of the counterions. Alkali cations such as K(+), Rb(+), and Cs(+) give high-yield formation of the respective clusters while NEt(3)H(+) and NMe(4)(+) yield none of the desired products. Extension of the aufbau assembly to produce related [M(2)Pd(3)Cl(6)L(6)](4)(-), [M(2)Pd(3)I(6)L(6)](4)(-), and [M(2)Cr(3)(CO)(12)L(6)](4)(-) (M = Ti, Sn) clusters has also been realized. In addition to this aufbau approach, self-assembly of several of these [M(2)Pd(3)Br(6)L(6)](4)(-) clusters from all eleven components (two M(IV), three PdBr(2), six H(2)L) was also accomplished under appropriate reaction conditions.

Journal Article↗

A novel multicomponent synthesis of polysubstituted 5-aminooxazole and its new scaffold-generating reaction to pyrrolo[3,4-b]pyridine.

A novel three-component synthesis of 5-amino oxazole (1) is reported. Its subsequent reaction with alpha,beta-unsaturated acyl chloride leads to polysubstituted pyrrolopyridine (2). A triple domino process, acylation/IMDA/retro-Michael cycloreversion, was involved in the latter process. The methodology allows the quick preparation, from simple and readily available inputs, of highly functionalized title compounds not easily accessed by other methods.

Journal Article↗

Synergistic transcriptional activation of human Acyl-coenzyme A: cholesterol acyltransterase-1 gene by interferon-gamma and all-trans-retinoic acid THP-1 cells.

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation. Human ACAT-1 gene contains two promoters (P1 and P7), each located in a different chromosome (1 and 7) (Li, B. L., Li, X. L., Duan, Z. J., Lee, O., Lin, S., Ma, Z. M., Chang, C. C., Yang, X. Y., Park, J. P., Mohandas, T. K., Noll, W., Chan, L., and Chang, T. Y. (1999) J. Biol Chem. 274, 11060-11071). Interferon-gamma (IFN-gamma), a cytokine that exerts many pro-atherosclerotic effects in vivo, causes up-regulation of ACAT-1 mRNA in human blood monocyte-derived macrophages and macrophage-like cells but not in other cell types. To examine the molecular nature of this observation, we identified within the ACAT-1 P1 promoter a 159-base pair core region. This region contains 4 Sp1 elements and an IFN-gamma activated sequence (GAS) that overlaps with the second Sp1 element. In the monocytic cell line THP-1 cell, the combination of IFN-gamma and all-trans-retinoic acid (a known differentiation agent) enhances the ACAT-1 P1 promoter but not the P7 promoter. Additional experiments showed that all-trans-retinoic acid causes large induction of the transcription factor STAT1, while IFN-gamma causes activation of STAT1 such that it binds to the GAS/Sp1 site in the ACAT-1 P1 promoter. Our work provides a molecular mechanism to account for the effect of IFN-gamma in causing transcriptional activation of ACAT-1 in macrophage-like cells.

Base Sequence↗

Fh-Souassi: a founder frameshift mutation in exon 10 of the LDL-receptor gene, associated with a mild phenotype in Tunisian families.

Familial hypercholesterolemia (FH) has a higher prevalence in central Tunisia together with a milder clinical expression than in western countries. The molecular basis of FH in Tunisia remains unknown. Our aim was to identify FH-causing mutations in three unrelated families (21 subjects) from the area of Souassi (central Tunisia). In probands with a presentation of homozygous FH, the promoter and 18 exons of the low density lipoprotein (LDL)-receptor gene were sequenced in both orientations. A novel complex frameshift mutation was identified in exon 10, nucleotides 1477-1479 (TCT) at Serine 472 were replaced by an insertion of seven nucleotides (AGAGACA), producing a premature termination codon 43 amino acids downstream. Binding of 125I-labelled LDL at 4 degrees C to cultured fibroblasts from two probands showed <2% normal LDL-receptor activity. AvaII digestion of PCR amplified genomic DNA identified this unique mutation in all families; homozygotes n=11, heterozygotes n=10. All mutation carriers shared the same haplotype (7 RFLPs), suggesting that they had a common ancestor. Despite high plasma LDL levels (m=16.0+/-3.0 mmol/l) and extravascular cholesterol deposits, most homozygotes were diagnosed after puberty and had a delayed onset of cardiovascular complications. Moreover, most heterozygotes were free of clinical signs and had plasma LDL cholesterol in the normal range (4.7+/-1.3 mmol/l) without taking any lipid-lowering medication. This mild clinical phenotype which contrasted with the severity of the mutation, could not be explained by specific apolipoprotein E or lipoprotein lipase alleles.

Adolescent↗

8-Amido-Bearing pseudomycin B (PSB) analogue: novel antifungal agents.

During the course of a structure-activity relationship (SAR) study on novel depsinonapeptide pseudomycin B, we synthesized a total of 12 8-amidopseudomycin analogues via standard two-step sequence from either ZPSB 2 or AllocPSB 3. A number of these amides exhibited good in vitro antifungal activities.

Animals↗

Evolution of hematopoiesis: Three members of the PU.1 transcription factor family in a cartilaginous fish, Raja eglanteria.

T lymphocytes and B lymphocytes are present in jawed vertebrates, including cartilaginous fishes, but not in jawless vertebrates or invertebrates. The origins of these lineages may be understood in terms of evolutionary changes in the structure and regulation of transcription factors that control lymphocyte development, such as PU.1. The identification and characterization of three members of the PU.1 family of transcription factors in a cartilaginous fish, Raja eglanteria, are described here. Two of these genes are orthologs of mammalian PU.1 and Spi-C, respectively, whereas the third gene, Spi-D, is a different family member. In addition, a PU.1-like gene has been identified in a jawless vertebrate, Petromyzon marinus (sea lamprey). Both DNA-binding and transactivation domains are highly conserved between mammalian and skate PU.1, in marked contrast to lamprey Spi, in which similarity is evident only in the DNA-binding domain. Phylogenetic analysis of sequence data suggests that the appearance of Spi-C may predate the divergence of the jawed and jawless vertebrates and that Spi-D arose before the divergence of the cartilaginous fish from the lineage leading to the mammals. The tissue-specific expression patterns of skate PU.1 and Spi-C suggest that these genes share regulatory as well as structural properties with their mammalian orthologs.

Amino Acid Sequence↗

Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau.

Formation of neurofibrillary tangles (NFTs) is the most common feature in several neurodegenerative diseases, including Alzheimer's disease (AD). Here we report the formation of filamentous tau aggregations having a beta-sheet structure in transgenic mice expressing mutant human tau. These mice contain a tau gene with a mutation of the frontotemporal dementia parkinsonism (FTDP-17) type, in which valine is substituted with methionine residue 337. The aggregation of tau in these transgenic mice satisfies all histological criteria used to identify NFTs common to human neurodegenerative diseases. These mice, therefore, provide a preclinical model for the testing of therapeutic drugs for the treatment of neurodegenerative disorders that exhibit NFTs.

Animals↗

Expression of P53 during lens epithelial cell apoptosis induced by ultraviolet.

The apoptosis of lens epithelial cells (LECs) induced by ultraviolet and the expression of P53 were investigated. Wistar rats received 100 mW/m2 ultraviolet irradiation (UVR) (lambda = 280 nm-315 nm) for 15 min. One, 6, 24 h after irradiation the lens capsules were dissected. The percentages of apoptotic cells were evaluated by the TdT-dUTP terminal nick-end labeling (TUNEL) technique and the expression of P53 was detected by using immunohistochemical assay. The results showed that the percentages of TUNEL-positive nuclei at 24 h after irradiation was significantly higher than in the control group and those 1 h, 6 h after irradiation. The percentages of P53-positive cells at 6 h, 24 h after irradiation were significantly higher than in the control group and those 1 h after irradiation. It was concluded that UVR could induce the apoptosis of lens epithelial cell. The expression of P53 might be responsible for the apoptosis of lens epithelial cells.

Animals↗

An electrophysiological study of neural pathways for corticofugally inhibited neurons in the central nucleus of the inferior colliculus of the big brown bat, Eptesicus fuscus.

This electrophysiological study tests the hypothesis that one possible neural pathway for corticofugally inhibited neurons in the central nucleus of the inferior colliculus (ICc) of the big brown bat, Eptesicus fuscus, is mediated through excitatory projections from the auditory cortex (AC) to the external nucleus of the IC (ICx), which then sends inhibitory inputs to the ICc. This study shows that all neurons in the ICx are broadly tuned to stimulus frequency. Electrical stimulation in the AC typically increases the number of impulses, expands the auditory spatial response areas, and broadens the frequency tuning curves (FTCs) of neurons in the ICx. This corticofugal facilitation is mediated at least in part through NMDA receptors, since application of DL-2-amino-5-phosphonovaleric acid (APV), an antagonist for NMDA, decreases these response properties of neurons in the ICx. Electrical stimulation in the ICx typically decreases the number of impulses, reduces the auditory spatial response areas, and narrows the FTCs of neurons in the ICc. This inhibition is mediated at least in part through GABAA receptors, since application of bicuculline, an antagonist for GABA, increases these response properties of neurons in the ICc. These data suggest that corticofugal facilitation of the ICx and the inhibition of the ICx to the ICc may be one of the polysynaptic pathways for corticofugal inhibition of neurons in the ICc. Possible functions of this polysynaptic pathway in acoustic orientation and signal processing are discussed.

Animals↗

Viability of liver grafts from fasted donor rats: relationship to sinusoidal endothelial cell apoptosis.

Previous studies have shown that livers from fasted donors appear to tolerate long-term preservation better than livers from fed donors, but the mechanism is not clear. Some studies have shown that the apoptosis of sinusoidal endothelial cells (SEC) appeared to be a pivotal mechanism of ischemia/reperfusion injury in liver transplantation. The purpose of the present investigation was to evaluate the relation of SEC apoptosis to liver viability in rats after liver transplantation, comparing findings for fasted and fed donors. Wistar rats were used as donors and recipients. The fed group had access to solid feed and water ad libitum. The fasted group was allowed access only to water for 4 days prior to liver harvest. All rat livers were preserved with University of Wisconsin (UW) solution at 2 degrees C for 24 h. After preservation, the livers were orthotopically transplanted, and survival time was measured. Apoptosis was determined by in-situ staining for apoptotic cells, using a TdT-mediated dUTP-digoxigenin nick-end labeling (TUNEL) assay and electron microscope (EM) examination separately. The 14-day survival rates after 24-h preservation were 0% (0/11) for recipients of livers from fed donors and 91% (10/11) for recipients of livers from fasted donors. There was no significant difference in the numbers of TUNEL-positive SEC after 24-h preservation between the two groups. However, at 6 h after transplantation, the number of TUNEL-positive SEC was significantly higher in the fed group than in the fasted group. These results suggest that donor fasting decreases SEC apoptosis after reperfusion alone, and that this may be related to the protection of the liver graft from reperfusion injury.

Analysis of Variance↗

Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway.

Hepatic apoptosis has been shown to occur in both experimental and clinical alcoholic liver disease, but the signaling pathway remains unknown. This study was undertaken to examine specifically the involvement of the upstream signals, Fas and cytochrome c, in alcohol-induced caspase-3 activation and apoptosis in the liver. Male FVB mice were administrated intragastrically a single dose of alcohol at 6 g/kg, which has been shown to represent binge drinking in humans. Hepatic apoptosis was detected by a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Active form of caspase-3 was identified by immunoperoxidase staining and confirmed by immunogold labeling and was found to be in the cytosol and nucleus. Enzymic assay further confirmed caspase-3 activation and nucleus localization. Systemic administration of caspase-3 inhibitor, Ac-DEVD-FMK, inhibited caspase-3 activity and abrogated apoptosis. Elevation of cytosolic cytochrome c was found by immunoperoxidase staining, immunogold labeling, and Western blot. Increased Fas ligand expression was detected by immunoperoxidase staining. Intravenous administration of a neutralizing Fas ligand monoclonal antibody resulted in suppression of caspase-3 activation and attenuation of apoptosis, but did not inhibit mitochondrial cytochrome c release. The results thus demonstrate that Fas/Fas ligand system-mediated caspase-3 activation plays a central role in the ethanol-induced hepatic apoptosis.

Animals↗

Regulation of Ca(2+) signals in a parotid cell line Par-C5.

The Ca(2+) signaling system in an established immortalized rat parotid acinar cell line, Par-C5, was examined using the Ca(2+)-sensitive fluorescent indicator fura-2 and by measuring inositol 1,4,5-trisphosphate (IP(3)) formation. Agonist-induced increase in intracellular Ca(2+) ([Ca(2+)](i)) by mobilization of intracellular stores and influx across the cell membrane was stimulated by acetylcholine (ACh) and ATP, whereas noradrenaline-(NA)-induced a small [Ca(2+)](i) increase mediated primarily by release from intracellular Ca(2+) stores. [Ca(2+)](i) increase by ACh and ATP was mediated through the phosphoinositide signal pathway since both agonists significantly increased 1,4,5-IP(3) formation and Ca(2+) mobilization was abolished by the phospholipase C inhibitor U73122. In Ca(2+)-free medium, ACh or ATP discharged the IP(3)-sensitive Ca(2+) store and essentially abolished subsequent [Ca(2+)](i) response to thapsigargin (TG). Exposure to ionomycin and monensin after TG induced a further mobilization of Ca(2+), suggesting IP(3)-insensitive stores are present. Furthermore, depletion of IP(3)-sensitive Ca(2+) stores by TG, ACh and ATP enhanced plasmalemmal Ca(2+)-entry pathways. Exposure to tumor necrosis factor-alpha (TNF-alpha), a cytokine associated with lymphocyte invasion of salivary epithelial cells in autoimmune disorders, significantly reduced ACh-stimulated Ca(2+) mobilization. TNF-alpha inhibitory effect on Ca(2+) mobilization was not directly due to an interaction on muscarinic receptors since ACh-induced 1,4,5-IP(3) formation was not altered. These results in the Par-C5 cell line indicate 1) [Ca(2+)](i) is regulated by muscarinic and P2Y-nucleotide receptors and partly by alpha(1)-adrenergic receptors; 2) IP(3)-sensitive and -insensitive Ca(2+) stores exist; 3) Ca(2+) influx activated by ACh, ATP or TG is mediated by the store-operated Ca(2+) entry pathway; and 4) muscarinic agonist-stimulated Ca(2+) mobilization is altered by the cytokine TNF-alpha.

Adrenergic alpha-Agonists↗

Transgenic rice plants expressing the ferredoxin-like protein (AP1) from sweet pepper show enhanced resistance to Xanthomonas oryzae pv. oryzae.

We used particle bombardment to cotransform mature seed-derived rice callus (Oryza sativa L., ssp. japonica, cv. Eyi 105) with plasmids containing the linked marker genes gusA and hpt, and the ap1 gene encoding an amphipathic protein previously shown to delay the hypersensitive response induced in non-host plants by the pathogen Pseudomonas syringae pv. syringae (Pss). Thirty-two independent lines of transgenic rice plants were regenerated, and 27 of these lines carried all three transgenes as shown by molecular analysis. A bacterial blight inoculation test was carried out on ten lines. In each case, plants carrying the ap1 gene showed enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo) race 6 at various levels. This suggests the ap1 gene could be a useful candidate for genetic engineering strategies in rice to provide bacterial blight resistance.

Journal Article↗

Effects of window and threshold levels on the accuracy of three-dimensional rendering techniques in coronary artery electron-beam CT angiography.

RATIONALE AND OBJECTIVES: The authors performed this study to evaluate the effect of window level and gray-scale threshold on the demonstration of coronary artery lumina at three-dimensional electron-beam computed tomographic (CT) angiography. MATERIALS AND METHODS: Forty-four coronary artery branches in postmortem pigs were evaluated with electron-beam CT angiography, and the findings were compared with those from conventional angiography. Images from electron-beam CT angiography were reconstructed with maximal intensity projection (MIP), multiplanar reformation (MPR), and shaded-surface display (SSD). Four categories of window level and gray-scale threshold were evaluated. RESULTS: Three-dimensional electron-beam CT angiography accurately depicted the luminal diameters of the coronary arteries compared with conventional angiography (r = 0.83-0.90, P < .0001). The length of lumina visualized at electron-beam CT angiography was significantly shorter than that visualized with conventional angiography (P < .001). The use of MPR enabled visualization of longer segments of coronary arteries than did the use of MIP or SSD (P < .05). The higher the window level and gray-scale threshold used, the smaller the coronary luminal diameters measured (P < .05). The most accurate window level and gray-scale threshold (82.6 HU +/- 29.8 and 89.5 HU +/- 29.7, respectively) were found to correspond to the attenuation of the lumina (275.8 HU +/- 58.8). Results of simple linear regression showed a strong correlation between luminal attenuation and window level (r = 0.89, P < .0001) or gray-scale threshold (r = 0.95, P < .0001). CONCLUSION: Electron-beam CT angiography shows promise in the visualization of coronary artery lumina. For accurate display of lumina, a proper window level and gray-scale threshold for three-dimensional rendering techniques should be determined and used on the basis of the attenuation of the target vessel.

Animals↗

Digital mammography: wavelet transform and Kalman-filtering neural network in mass segmentation and detection.

RATIONALE AND OBJECTIVES: The authors developed a new adaptive module to improve their computer-assisted diagnostic (CAD) method for mass segmentation and classification. The goal was an adaptive module that used a novel four-channel wavelet transform with neural network rather than a two-channel wavelet transform with manual subimage selection. The four-channel wavelet transform is used for image decomposition and reconstruction, and a novel Kalman-filtering neural network is used for adaptive subimage selection. MATERIALS AND METHODS: The adaptive CAD module was compared with the nonadaptive module by comparing receiver operating characteristic curves for the whole CAD system. An image database containing 800 regions of interest enclosing all mass types and normal tissues was used for the relative comparison of system performance, with electronic ground truth established in advance. RESULTS: The receiver operating characteristic curves yield Az values of 0.93 and 0.86 with and without the adaptive module respectively, suggesting that overall CAD performance is improved with the adaptive module. CONCLUSION: The results of this study confirm the importance of using a new class of adaptive CAD methods that allow a more generalized application for larger image databases or images generated from different sensors or by means of direct x-ray detection, as required for clinical trials.

Humans↗

Purification and characterization of a putative vitellogenin from the ovary of amphioxus (Branchiostoma belcheri tsingtaunese).

An oocyte-yolk protein was purified by double-step chromatography from amphioxus ovaries. The purified protein appeared to exist as a homodimer of approximately 320 kDa in native polyacrylamide gel electrophoresis (PAGE), and was reduced to a single monomer of approximately 160 kDa in sodium dodecyl sulfate-PAGE (SDS-PAGE). The protein was characterized as a phospholipoglycoprotein by native PAGE and staining of gels for phosphorus with methyl green, for lipids with oil red O and Sudan black B, and for carbohydrates using periodic acid/Schiff reagent. In addition, the amino acid composition of the oocyte-yolk protein was generally similar to that of vitellogenins (Vgs) isolated from different phyla of animals including both vertebrates and invertebrates. The purified phospholipoglycoprotein is thus considered as putative amphioxus Vg.

Animals↗

Phase II study of vinorelbine in patients with androgen-independent prostate cancer.

PURPOSE: To evaluate the efficacy and toxicity of vinorelbine in a phase II study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Forty-seven men with progressive metastatic prostate cancer refractory to first-line or second-line hormonal therapy were treated with vinorelbine, a semisynthetic vinca-alkaloid. Vinorelbine was given, on an outpatient schedule, at 25 mg/m2 weekly for at least eight weeks or until progression or excessive toxicity. RESULTS: Forty-seven patients were included in the study, 33 being evaluable for tumour response, 36 for response to PSA, 21 for clinical benefit and 45 for toxicity. Median actual weekly dose was 19 mg/m2 (range 12.0-26.2 mg/m2). Six of thirty-six patients (17%) demonstrated a biologic response with a 50% or more decline in serum PSA on two consecutive measurements taken at least two weeks apart. The median duration of biologic response was 2.7 months. Two of three patients with measurable disease obtained an objective response but remained unconfirmed. No change disease was reported in 23 patients (49%). On entry into the study, 30 patients had symptomatic bone pain and required narcotic or non-narcotic analgesics. Clinical benefit from vinorelbine was achieved in 15 patients out of 21 (32% of the intent to treat analysis population and 71% of the assessable patients). Due to the low number of questionnaires (QLQ-C30) filled in, it was insufficient to allow any statistical analysis. The median survival was 10.2 months. Toxicity was mainly haematologic with 51% of patients experiencing grade 3 or 4 granulocytopenia. Three patients developed deep vein thrombosis. Non-haematologic toxicity, mainly nausea and neurotoxicity, was mild. CONCLUSION: The administration of weekly vinorelbine appears to be a safe treatment for those patients with androgen-independent prostate cancer and poor prognosis features who require chemotherapy. These results provide data for future investigation of vinorelbine in combination regimens.

Adenocarcinoma↗

Effects of radiation on Ca2+ signaling in salivary epithelial cell lines transfected with Bcl-2 and Bcl-XL.

The effects of radiation on the Ca2+ signaling system in HSY cells transfected with the Bcl-2 or Bcl-XL gene were studied. Bcl-2 overexpression did not alter carbachol (CCh)-elicited initial increase in cytosolic free Ca2+ concentrations ([Ca2+]i), but Bcl-XL overexpression dramatically reduced this response. Exposure to 10 Gy gamma-ray did not alter basal [Ca2+]i. By contrast, the CCh-stimulated initial [Ca2+]i increase was reduced at 0.5 and 4 h post-irradiation in all cell types and remained decreased at 24 h in wild-type and control-transfected cells, but recovered in Bcl-2- and Bcl-XL-transfectants. The formation of inositol 1,4,5-trisphosphate (IP3) in response to CCh at 4-h post-irradiation was decreased in wild-type and control-transfected cells, but not in Bcl-2 and Bcl-XL transfectants. The capacity of the IP3-sensitive Ca2+ store was significantly reduced by radiation in all cells except Bcl-XL transfectants. Ca2+ influx after stimulation with CCh was suppressed by exposure to radiation in wild-type and control-transfected cells, but not in Bcl-2- and Bcl-XL-transfectants. However, radiation enhanced Ca2+ influx activated by thapsigargin in all cell types. These results suggest that 1) radiation diminishes IP3 formation and Ca2+ release in response to CCh, but potentiates the store-operated Ca2+ influx; and 2) overexpression of Bcl-2 or Bcl-XL partially protects cells from radiation-induced inhibition of Ca2+ signaling.

Adenocarcinoma↗