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PubMed2004

Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades.

Hepatitis D virus (HDV) is a satellite of hepatitis B virus (HBV) for transmission and propagation and infects nearly 20 million people worldwide. The HDV genome is a compact circular single-stranded RNA genome with extensive intramolecular complementarity. Despite its different epidemiological and pathological patterns, the variability and geographical distribution of HDV are limited to three genotypes and two subtypes that have been characterized to date. Phylogenetic reconstructions based on the delta antigen gene and full-length genome sequence data show an extensive and probably ancient radiation of African lineages, suggesting that the genetic variability of HDV is much more complex than was previously thought, with evidence of additional clades. These results relate the geographic distribution of HDV more closely to the genetic variability of its helper HBV.

Adolescent↗

PubMed1989

Clinically occult ductal carcinoma in situ detected with mammography: analysis of 100 cases with radiologic-pathologic correlation.

One hundred consecutive cases of clinically occult ductal carcinoma in situ (DCIS) detected with mammography were retrospectively analyzed to determine the spectrum of mammographic appearances and to study pathologic correlations. Seventy-two percent of the lesions appeared as microcalcifications, 10% as soft-tissue abnormalities, and 12% as a combination of the two. Six percent of lesions were found incidentally in the biopsy specimen. On the basis of mammographic measurements, 22% of the lesions were 5 mm or smaller, and 75% were 20 mm or smaller. Thirty-five percent of the microcalcification clusters were categorized as predominantly casts (linear), 52% as granular, and 13% as granular with several casts. Related pathologic features included the location of the tumor within the ductal system, pattern of growth (histologic subtype), amount and distribution of calcium formation, and presence or absence of reactive changes. Women aged 49 years or less with DCIS were more likely to have microcalcifications and less likely to have a soft-tissue mass than women aged 50 years or more (P = .04). The authors conclude that there is a wide spectrum of mammographic appearances of clinically occult DCIS.

Adult↗

PubMed2005

Lack of expression of the EP2 but not EP3 receptor for prostaglandin E2 results in suppression of skin tumor development.

The EP2 receptor for prostaglandin E2 (PGE2) is a membrane receptor that mediates at least part of the action of PGE2. It has been shown that EP2 plays a critical role in tumorigenesis in mouse mammary gland and colon. However, the possibility that the EP2 receptor is involved in the development of skin tumors was unknown. The purpose of this study was to investigate the role of the EP2 receptor in mouse skin carcinogenesis. Unlike EP3 knockout mice, the EP2 knockout mice produced significantly fewer tumors and reduced tumor incidence compared with wild type (WT) mice in a 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage carcinogenesis protocol. EP2 knockout mice had significantly reduced cellular proliferation of mouse skin keratinocytes in vivo and in vitro compared with that in WT mice. In addition, the epidermis of EP2 knockout mice 48 hours after topical TPA treatment was significantly thinner compared with that of WT mice. The inflammatory response to TPA was reduced in EP2 knockout mice, based on a reduced number of macrophages in the dermis and a reduced level of interleukin-1alpha mRNA expression, compared with WT mice. EP2 knockout mice also had significantly reduced epidermal cyclic AMP levels after PGE2 treatment compared with WT mice. Tumors from WT mice produced more blood vessels and fewer apoptotic cells than those of EP2 knockout mice as determined by immunohistochemical staining. Our data suggest that the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in skin tumor development.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Morphological pattern of testicular tumors.

OBJECTIVE: To find out the mode of presentation, age distribution and the prevalence of various histological subtypes of testicular tumors. METHOD: All consecutive cases of testicular tumors diagnosed in the department of pathology, the Aga Khan University Hospital, Karachi, during the period of eight years (1991-98) were included in this study. Relevant clinical details such as age, clinical presentation and side of involvement of the testis were also recorded, where available. RESULTS: During the span of eight years (1991-98), 170 cases of testicular tumors were diagnosed at the Aga Khan University Hospital, Karachi. Most of the tumors were diagnosed in the third and fourth decade of life. Scrotal mass or swelling was the predominant mode of presentation. There was a slight predominance of right-sided testicular tumors. Germ cell tumors constituted 83.5% of all malignant testicular neoplasms. Amongst these seminoma was the most common (36.5%) tumor followed by mixed germ cell tumors (28.82%). Yolk-sac tumor was the commonest testicular neoplasm in children while lymphoma was the predominant neoplasm in the elderly population. CONCLUSION: The overall relative frequency of testicular malignancy in this series correlated with that reported in the international literature.

Adolescent↗

PubMed2000

Central nervous system lymphomas: a histologic and immunophenotypic analysis.

OBJECTIVE: To observe the spectrum of non-Hodgkin's lymphomas involving the central nervous system including morphological subtypes and immunophenotypic status. SETTING: Retrospective analysis of eleven years (1986 to 1996) data from surgical pathology files of Department of Pathology. RESULTS: Forty-three cases of non-Hodgkin's lymphomas were diagnosed during the period of eleven years (from 1986 to 1996), all of which were diffuse types. A total of 1177 Central Nervous CNS biopsies were examined, out of which 937 cases were diagnosed as CNS neoplasms, the remaining were non-neoplastic in nature. Among 937 CNS neoplasms, 43 cases (4.6%) were reported as non-Hodgkin's lymphomas. As most of the cases were outside referrals, the primary or secondary nature of the lymphomatous process could not be assessed. Seventeen cases were intracranial, while 26 cases were spinal in location. Majority of the intracranial lymphomas were biopsied from the cerebrum (12 cases). Male to female ratio was 1:2. The median age for intracranial lymphomas was 50 years and for spinal lymphomas 29 years. There were 16 cases (37%) of diffuse large cell lymphomas; 7 cases (16%) of diffuse mixed small and large cell lymphomas; 3 cases (7%) of diffuse large cell immunoblastic lymphomas; 2 cases (4.6%) of lymphoblastic lymphomas and diffuse small non-cleaved cell lymphomas and one case of small lymphocytic lymphoma and diffuse small cleaved cell lymphoma. One case of T cell rich B cell lymphoma was also diagnosed in the thoracic spine as primary extranodal lymphoma. Eight cases were unclassifiable and in 2 cases the features were suggestive of lymphoma. Immunophenotypic analysis was performed in 20 cases, however, in 2 cases the results were inconclusive. Fifteen cases (83%) showed immunoreactivity for B cell markers and 3 cases showed T cell phenotype out of which one case was lymphoblastic lymphoma. CONCLUSION: CNS lymphomas were uncommon tumors and comprised 4.6% of the total CNS neoplasms in our study. Moreover, these CNS lymphomas accounted for 2.2% of the total non-Hodgkin's lymphomas, including both nodal and extranodal. There was a higher incidence of location of these lymphomas within the spinal cord than brain. Most of the lymphomas were of intermediate or high grade (75%) according to the working formulation. Immunophenotypical status revealed B-cell phenotype in 84% of the lymphomas, in which it was tested (JPMA 50:141, 2000).

Central Nervous System Neoplasms↗

PubMed2000

[The role of galanin in the endocrine system].

Galanin, a 29-30 amino-acid neuropeptide is distributed in the central and peripheral nervous systems, the pituitary gland, the gastrointestinal tract and also in the pancreas. The endogenous and exogenous effects of galanin are mediated by three receptor subtypes, which are termed: GALR1, GALR2, and GALR3. Galanin has a significant role in physiological and pathological processes in adults as well as in children. It has an ability to contract smooth muscles in GI (facilitation and inhibition), stimulates reflexes in the CNS, decreases pancreatic amylase secretion, changes transport of electrolytes Na+ and CL-. It takes part in etiopathogenesis of depression, Alzheimer's disease and diarrhoea, exerts tonic inhibition of nociceptive input to the central nervous system and regulates a function of hypothalamic-pituitary system. Galanin decreases insulin and somatostatin secretion, increases glucagon secretion, takes part in prolactin release, stimulates growth hormone-releasing hormone, hypothalamic gonadotropin releasing hormone and corticotropin releasing hormone. It causes increase of somatotropin secretion, luteinizing hormone and foliculotropin release and adrenocorticotropin secretion. The hypothalamic galanin takes part in etiopathogenesis of obesity not only in human reproductive period, but also in adolescence, increasing the appetite and changing fat metabolism. This variety of actions emphasizes the potential importance of this peptide in the regulation of cells function and the need to understand the mechanism by which they act.

English Abstract↗

PubMed2003

[Adult primary myelodysplastic syndromes. Report of 36 cases].

Between 1989 and 1999, 36 cases with primary myelodysplastic syndromes were diagnosed. They were 15 male and 21 females, the median age was 62 years (range: 22 to 90 years). Eighty one per cent of patients were presented symptoms of anemia. Lymphadenopathy, splenomegaly and skin manifestations were noted in 25% of cases. Hemogram showed anemia, leucopenia and thrombocytopenia respectively in 97%, 44% and 55% of cases. Refractory anemia with excess blasts (AREB) is the most frequent FAB subtypes of MDS (17 cases). Cytogenetic study concerned 24 patients. In 13 cases the karyotype was pathological with deletion 5 q in 64% of cases. Seventeen patients have received a chemotherapy. Survival rate to 36 months is 11%. At the time, the only curative treatment is the bone marrow transplantation, which is proposed to young patients with HLA identical donor.

Adult↗

PubMed2004

[Morphologic and clinical study of 131 cases of plasma cell myeloma].

OBJECTIVE: To study the characteristics histologic and cytologic features and clinical usefulness of plasma cell myeloma (PCM) subtyping according to WHO PCM classification. METHODS: Bone marrow biopsy plastic-embedded sections were stained with H-G-E and Gomori's stains, and bone marrow aspirate smears were stained with Wright's stain. The clinicopathologic findings were then analyzed. RESULTS: Of the 131 cases with PCM, three types of growth patterns were noted: interstitial (21 cases, 16.0%), nodular (46 cases, 35.1%) and packed (64 cases, 48.9%). Besides, there were three cytologic subtypes: mature plasma cell type (43 cases, 32.8%), immature (81 cases, 61.8%) and pleomorphic (7 cases, 5.3%) types. The age of patients with mature plasma cell type was significantly higher than that of immature type (P = 0.005); and the number of tumour cells in bone marrow smears was significantly higher than that of immature type (P = 0.003). The numbers of WBC and platelets in peripheral blood were also significantly higher than that of pleomorphic type (P = 0.024, P = 0.002, respectively). On the other hand, the number of platelets in peripheral blood of immature type was significantly higher than that of pleomorphic type (P = 0.019). Marrow fibrosis was more frequently observed in immature type than in mature plasma cell type (P = 0.000). The incidence of marrow fibrosis and osteolytic lesions was higher in high risk group than in low risk group (P = 0.000, P = 0.023 respectively). Twenty-one cases (56.8%) of the 37 cases treated with MP or MP and M2 chemotherapeutic regimens showed good response. However, there was no significant difference in treatment response and survival between different subtypes. CONCLUSIONS: Each subtype of PCM carries different clinicopathologic features in some aspects. The classification carries important value in pathologic diagnosis and probably in predicting prognosis.

Adult↗

PubMed1990

Staphylococcus aureus phage types in barrier-maintained colonies of SPF mice and rats.

From 1985 to 1987 within the framework of our health monitoring programme, the occurrence of S. aureus in our rodent colonies and their caretakers have been surveyed. To obtain further information on S. aureus subtypes, isolates were subjected to phage typing using the international set of bacteriophages. Strains derived from pathological processes but also randomly chosen isolates from healthy animal carriers and the personnel underwent lysotyping. With respect to the animals every hygienic unit harbours its characteristic S. aureus lysotype(s). Among these, usually one pattern dominates in pathological processes and healthy carriers, although the spectrum of phage types distributed among the caretakers shows a much greater variation and some of the attendants are suspected to be not only transient carriers. A comparison with an earlier investigation done in our institute about a decade ago (Lenz et al. 1978) shows the prevalence of completely different phage types.

Animals↗

PubMed1990

[Vector cardiography features of right ventricular activation delays: nosologic classification and clinical correlation].

Electrovectorcardiographic features of 150 patients showing right ventricular activation delays (RVAD) has been analyzed. This analysis of RAVD, especially for type I, which is the group with the widest morphologic variability, has permitted a more detailed classification: a type I with 5 subtypes, a type II with 1 subtype, a type III and an intermediate type between type II and III. Fifty-five per cent of the patients were included in type I and its variant and most were classified, often without cardiac disease, as belonging to the classic type I. Thirty per cent of RVAD were of type II; 12% of type III and the remaining were in the intermediate group between type II and III. The various morphologies, moreover, were correlated with the clinical picture: the classic type I was never seen in subjects with cardiac disease, while the others types and subtypes were present either in subjects with cardiac disease or in elderly subjects, also without relevant pathologies (senile heart, especially, the type IA") or in otherwise healthy subjects. In a medical-social context, checking for RVAD, in the absence of cardiac disease, might usefully avoid further investigation. It is underlined the usefulness of this correlation for clinical prognostic judgement.

Adolescent↗

PubMed1988

Bone marrow in hairy cell leukemia.

HCL is a well-recognized entity among the lymphoproliferative disorders. With better appreciation of the wide variability in its clinical and hematologic manifestations, some authors have proposed several subtypes of HCL such as leukopenic and nonleukopenic subtypes and subtypes with and without massive splenomegaly. As opposed to such a clinical and hematologic variability, the pathology of HCL in the spleen and bone marrow is consistent and highly characteristic. Since the spleen becomes available for pathologic examination only after therapeutic splenectomy, the bone marrow pathology often plays the most important role in the differential diagnosis of HCL. It is characterized by focal or diffuse mononuclear cell infiltration with a wide spacing between individual nuclei in most patients and by a severely hypocellular marrow with individual hairy cells infiltrating between the marrow fat cells in the remaining minority of patients. The bone marrow biopsy also serves as one of the criteria in selecting the therapeutic modality as well as monitoring the therapeutic effect. Further, new insights into the pathogenesis of HCL are emerging from recent studies of the bone marrow microenvironment.

Adult↗

PubMed1993

Choreas, hereditary and other ataxias, tics, myoclonus, and other movement disorders.

Developments in the field of Huntington's disease have focused on the potential benefits of predictive testing. Markers have been described for autosomal dominant cerebellar ataxia and for certain subtypes of Friedrich's ataxia. Argentophilic neuronal and glial inclusions appear to be the first specific pathologic hallmark of multiple system atrophy. "Pure" hereditary spastic paraplegia is not a multisystem disorder of the central nervous system, but a monomorphic and stereotyped disease. Advances in Tourette's syndrome are limited because the presumed gene eludes identification. A new type of myoclonus, propiospinal myoclonus, has been described. Clinical and electrophysiologic criteria for defining primary orthostatic tremor have been proposed. Understanding of the neurophysiologic substrate of essential tremor and myoclonus is improving. New neurologic disorders presenting clinically with prominent movement disorder continue to be described.

Ataxia↗

PubMed2002

The significance of tumor persistence after incomplete excision of basal cell carcinoma.

BACKGROUND: Physicians inevitably receive a pathology report after excision of a basal cell carcinoma that indicates that it is incompletely excised. The physician and patient are then left with the dilemma of whether immediate re-excision or close clinical follow-up is indicated. OBJECTIVE: Our purpose was to identify characteristics of incompletely excised basal cell carcinomas that are at low risk for recurrence. METHODS: We retrospectively reviewed the charts and pathology slides of all incompletely excised basal cell carcinomas from 1991 to 1994 in a university hospital tumor registry. RESULTS: Incompletely excised basal cell carcinomas of superficial or nodular subtype, less than 1 cm in diameter, located anywhere except the nose or ears, with less than 4% marginal involvement on the initial inadequate excision had no evidence of tumor persistence. CONCLUSION: When physicians receive a pathology report indicating the incomplete excision of a basal cell carcinoma, they face the dilemma of further management. The majority of patients should undergo immediate re-excision or Mohs micrographic surgery because tumor persistence was found in 28% of cases. Occasionally, for a small group of select patients, close clinical follow-up may be indicated if the risk of recurrence is very low.

Basal Cell Carcinoma↗

PubMed2004

Distinct beta-adrenergic receptor subtype signaling in the heart and their pathophysiological relevance.

In the heart, stimulation of beta-adrenergic receptors (betaAR) serves as the most powerful means to increase cardiac contractility and relaxation in response to stress or a "fight-or-flight" situation. However, sustained beta-adrenergic stimulation promotes pathological cardiac remodeling such as myocyte hypertrophy, apoptosis and necrosis, thus contributing to the pathogenesis of chronic heart failure. Over the past decade, compelling evidence has demonstrated that coexisting cardiac betaAR subtypes, mainly beta(1)AR and beta (2)AR, activate markedly different signaling cascades. As a result, acute beta(1)AR stimulation activates the G(s) -adenylyl cyclase-cAMP-PKA signaling that can broadcast throughout the cell, whereas beta(2)AR-evoked cAMP signaling is spatially and functionally compartmentalized, due to concurrent G(i) activation. Chronic stimulation of beta(1)AR and beta(2)AR elicits opposing effects on the fate of cardiomyocytes: beta(1)AR induces hypertrophy and apoptosis; but beta(2)AR promotes cell survival. The cardiac protective effect of beta(2)AR is mediated by a signaling pathway sequentially involving G(i), G(betagamma), PI3K and Akt. Unexpectedly, beta(1)AR-induced myocyte hypertrophy and apoptosis are independent of the classic cAMP/PKA pathway, but require activation of Ca(2+)/calmodulin-dependent kinase II (CaMK II). The outcomes of cardiac-specific transgenic overexpression of either beta AR subtype in mice have reinforced the fundamentally different functional roles of these betaAR subtypes in governing cardiac remodeling and performance. These new insights regarding betaAR subtype stimulation not only provide clues as to cellular and molecular mechanisms underlying the beneficial effects of beta AR blockers in patients with chronic heart failure, but also delineate rationale for combining selective beta(1)AR blockade with moderate beta(2)AR activation as a potential novel therapy for the treatment of chronic heart failure.

Adenylyl Cyclases↗

PubMed2004

Sigma receptor ligands: applications in inflammation and oncology.

Sigma (sigma) receptors were initially proposed as a subtype of opiate receptors, and bind several psychoactive compounds. They are classified into sigma 1 (sigma1) and sigma 2 (sigma2) subtypes. The characterization of these subunits, and the discovery of new specific sigma receptor ligands, demonstrated that sigma receptors belong to a specific entity distinct from opiate receptors. Radioligand-binding data have recently demonstrated that the sigma1 subtype is related to a sterol isomerase, which is involved in the cholesterol biosynthesis pathway, and also to another protein of unknown function, SRBP2 (SR-31747 binding-protein 2), which shares a high homology with this enzyme. This complex group of proteins also binds molecules devoid of central effect, which demonstrate potent anti-inflammatory properties, and so are potentially useful in pathologies where pro-inflammatory cytokines are involved, particularly rheumatoid arthritis, Crohn's disease or psoriasis. In addition, the two sigma receptor subtypes and their two related proteins are also expressed on tumor cells, where they could be of prognostic relevance, and their ligands could potentially be used in the detection and targeting of tumors.

Adamantane↗

PubMed1997

Differences in age and body site distribution of the histological subtypes of basal cell carcinoma. A possible indicator of differing causes.

OBJECTIVE: To assess if there are any significant differences in the sex, anatomical site, and age distribution of patients with different histological subtypes of basal cell carcinoma (BCC). DESIGN: Histopathology reports were analyzed with respect to the subtype of BCC, site of a tumor, and age and sex of a patient. SETTING: Histopathology reports were reviewed from 1 private laboratory that derived its cases from general practitioners, surgeons, and dermatologists. PATIENTS: Patients with BCC (N = 3885) for whom case data were received by the pathology laboratory from January 2, 1991, to June 12, 1991, were included in the study. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Superficial BCCs differed from other subtypes of BCC by occurring more commonly on the trunk and in younger patients. RESULTS: The mean age (56.8 years) of the patients with superficial BCCs was significantly lower than that of the patients with other subtypes of BCC who were examined (P < .001); the mean ages of the patients with these other subtypes were as follows: nodulosuperficial BCC, 62.9 years; nodular BCC, 63.9 years; nodulomorpheic BCC, 66.1 years; and morpheic BCC, 66.0 years. The majority of superficial BCCs occurred on the trunk and limbs (73.3%), while the majority of all other subtypes occurred on the head and neck. CONCLUSIONS: Superficial BCC differs from the other subtypes of BCC in terms of patient age and tumor site, and these findings may reflect differences in the etiology.

Adolescent↗

PubMed2004

Development and validation of fluorescent receptor assays based on the human recombinant estrogen receptor subtypes alpha and beta.

This article describes the development and validation of two fluorescent receptor assays for the hRec-estrogen receptor subtypes alpha and beta. As a labelled ligand an autofluorescent phyto-estrogen (coumestrol) has been used. The estrogen receptor (ER) belongs to the nuclear receptor family, a class of soluble DNA binding proteins, mainly present in the cytoplasm of the cell, that act as ligand-activated enhancer factors. It consists of two different forms, expressed as ER-alpha (66 kDa) and ER-beta (59 kDa). The ER-alpha is mainly located in the uterus and the ER-beta can be found in vascular tissue. Detection and identification of compounds having estrogenic effects is of importance in drug discovery programmes within the pharmaceutical industry for their search for ER-subtype selective (ant)agonists which may prove to be of therapeutic value in treating a variety of estrogen-linked pathologies (breast cancer, osteoporosis, cardiovascular disease, type II diabetes and Alzheimer disease). Furthermore, interactions of (xeno-)estrogens with the endogenous hormonal system of the exposed organism can affect embryos, gonads, and reproductive behaviour. The latter can eventually lead to reduced reproduction and deterioration of a population. For that reason, monitoring of (xeno-)estrogens in food products and in the environment, attracts considerable attention by health councils throughout the world. The following characteristics were obtained for the human recombinant (hRec) estrogen receptor-beta assay, which is suitable for ER subtype selective drug-discovery purposes (IC50 values for 17-beta-estradiol and genistein were 5.1 nM and 25 nM, respectively): goodness of fit (R2) was always > 0.98 (x = 0.9933, n = 10). LLOQ of the assay is typically > or = 500 picomolar, whereas the ULOQ of the assay is < or = 20.0 nanomolar. For the hRec-estrogen receptor-alpha assay, which is suitable for monitoring of (xeno-)estrogens (IC50 values for 17-beta-estradiol and genistein were 0.68 nM and 65 nM, respectively) the following characteristics were obtained: goodness of fit (R2) was always > 0.96 (x = 0.9838, n = 10). LLOQ of the assay is typically > or = 200 picomolar, whereas the ULOQ of the assay is < or = 5.0 nanomolar.

Estrogen Receptor alpha↗

PubMedDate not supplied

From the archives of the AFIP: imaging of musculoskeletal liposarcoma with radiologic-pathologic correlation.

Liposarcoma is the second most common type of soft-tissue sarcoma, accounting for 10%-35% of these lesions. The World Health Organization has categorized soft-tissue liposarcomas into five distinct histologic subtypes: well differentiated, dedifferentiated, myxoid, pleomorphic, and mixed type. Well-differentiated liposarcomas frequently demonstrate a diagnostic appearance on computed tomographic (CT) or magnetic resonance (MR) images, with a largely lipomatous mass (>75% of the lesion) and nonlipomatous components in thick septa or focal nodules. The CT or MR imaging finding of a nodular dominant focus (>1 cm in size) of nonlipomatous tissue in a well-differentiated liposarcoma suggests dedifferentiated liposarcoma, and biopsy should be directed at the nonadipose component. The high water content of myxoid liposarcoma seen at pathologic analysis and constituting the majority of the lesion is reflected at sonography, CT, and MR imaging. However, the detection of a small amount of adipose tissue in the septa or as small nodular foci superimposed on the background of myxoid tissue allows prospective diagnosis in 78%-95% of myxoid liposarcomas. Pleomorphic liposarcomas are high-grade sarcomatous lesions and typically appear as heterogeneous soft-tissue masses, although small amounts of fat are seen on MR images in 62%-75% of cases, findings that suggest the diagnosis. Mixed-type liposarcomas have features representing a combination of the other subtypes. Primary liposarcoma of bone is exceedingly rare and usually demonstrates aggressive nonspecific features, although fat may be seen. Understanding and recognition of the spectrum of appearances of the various types of musculoskeletal liposarcoma, which reflect their underlying pathologic characteristics, improves radiologic assessment and is vital for optimal patient management.

Adolescent↗