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PubMed1998

Expression of matrix proteins in uterine cervical neoplasia using immunohistochemistry.

OBJECTIVE: Neoplastic cells of various tumors are capable of modifying extracellular matrix, and can reduce basement membrane components and express matrix proteins and mRNA. Findings in cervical cancer cells have been consistent concerning their ability to reduce basement membrane, but there is a lack of consensus concerning the expression of matrix proteins in the neoplastic cells. We have investigated the expression of matrix proteins in the subepithelial basement membrane, in blood vessels and in the epithelial cells using immunohistochemistry. STUDY DESIGN: A total of 49 cases, including normal cervix, Cervical Intraepithelial Neoplastia (CIN) grades, I, II and III, and invasive squamous cell carcinoma, were stained for fibronectin (FN), laminin (LN) and collagen IV (C IV) and analyzed by immunohistochemistry. Subepithelial and peritumoral basement membrane staining for C IV was scored as 0, 1, 2 or 3 (0, absent; 1, weak and discontinuous; 2, weak or discontinuous; 3, strong and diffuse). Vascular basement membrane staining by all three markers was interpreted as positive or negative. Staining of normal epithelium, CIN lesions and invasive carcinoma cells was evaluated with all three markers. RESULTS: Subepithelial basement membrane staining was graded as score = 3 in all normal cervices, in contrast to 9/10, 2/10, 1/10 and 0/9 cases of CIN I, CIN, II, CIN III and invasive carcinoma, respectively. Remaining cases showed variable degrees of basement membrane loss. In 6/10 CIN III cases and 8/9 carcinomas, staining was absent (score = 0). Blood vessels stained positive for FN, LN and C IV in all cases studied. Epithelial cells were LN-positive in only one case of CIN II and FN-positive in only two cases of CIN III. Conversely, 3/9 carcinomas were LN-positive, 6/9 were FN-positive and 2/9 were C IV-positive, including two cases positive for all three markers. Staining pattern was cytoplasmic, mainly in the periphery to tumor islands. CONCLUSIONS: Invasive squamous cell carcinomas of the cervix are capable of expressing matrix proteins that are usually absent in normal squamous cervical cells or preinvasive lesions. Secretion or degradation of these proteins could facilitate tumor invasion of stroma and vessels. In addition, basement membrane dissolution becomes pronounced in CIN II-III lesions, being complete in most invasive carcinomas, probably reflecting the ability of pre-invasive neoplastic cells to degrade basement membrane components with metalloproteases.

Basement Membrane↗
PubMed1999

Prognostic significance of p53 protein accumulation in stage pT1 transitional cell carcinoma of the bladder.

OBJECTIVE: Mutations in the tumour suppressor gene p53 results in the production of a mutant type, dysfunctional p53 protein which can readily be detected in the cell nucleus by immunohistochemical staining. This study aims to investigate the association of nuclear p53 protein accumulation with the clinical outcome of stage pT1 transitional cell carcinoma of the bladder which is renowned for high rates of recurrence and progression. METHODS: TUR samples of the tumours from fifty-two patients with primary stage T1 bladder cancer were analyzed immunohistochemically using the standard avidin-biotin peroxidase method for nuclear p53 accumulation. Status of p53 immunostaining was correlated with tumour recurrence, disease progression and three-year survival of each patient. RESULTS: The rate of tumour recurrence in pT1 bladder cancer was 36% in patients with tumours stained negatively for p53 protein and 78% in patients with tumours stained positively for p53 protein. Disease progression was seen in 15% of p53 (-) patients and in 56% of p53 (+) patients. CONCLUSIONS: In stage pT1 bladder tumours p53 nuclear accumulation indicates higher rates of tumour recurrence and disease progression. Accordingly, in patients who have pT1 bladder tumours with nuclear p53 accumulation, institution of more aggressive therapy should be considered and early radical therapeutic modalities should be offered to these patients.

Adult↗
PubMedDate not supplied

p53 and Ki-67 expression as prognostic factors in cystosarcoma phyllodes.

We have reviewed the histopathological, clinical outcome and immunohistochemical status in 21 women with cystosarcoma phyllodes (CSP) tumors of the breast. We assessed 12 tumors as histopathologically benign and 9 tumors as malignant. The median patient ages in benign and malignant CSP tumors were 39.6 and 45.4 years of age, respectively. The stromal cellularity, stromal cellular atypism, high mitotic activity, atypic mitoses, stromal overgrowth, infiltrative tumor contour, and heterologous stromal elements were significant features of the malignant CSP tumors. Benign CSP tumors were predominantly of fibroadenomatous architecture with cellular stroma (mild or moderate) and some distortion and elongation of glandular elements. Five malignant CSP tumors were stained positively with p53, and 6 malignant CSP tumors were stained immunohistochemically with Ki-67. All benign CSP tumors were negatively stained for p53 and Ki-67. The patients with benign CSP tumors were treated with local excision ( n=11) and with subcutaneous mastectomy ( n=1). Malignant CSP tumors were treated with wide local excision ( n=1), partial mastectomy ( n=1), simple mastectomy ( n=2), and modified radical mastectomy ( n=5). Two patients with a high mitotic rate and high values of p53 and Ki-67 received additional radiotherapy and chemotherapy. One case had liver metastasis. This tumor had high mitotic figures, stromal overgrowth, severe stromal cellularity, and 20% Ki-67 and mild p53 positivity. We suggest that p53 and Ki-67 can play an important role in predicting prognosis and yielding additional therapy besides conventional prognostic factors in the treatment of the CSP patients.

Adolescent↗
PubMed2002

Prognostic significance of calcium-binding protein S100A4 in colorectal cancer.

BACKGROUND & AIMS: Prognostication in colon cancer almost exclusively still rests on the tumor stage. Furthermore, tumor-derived markers to improve discrimination of low- and high-risk subtypes generally are not in use. S100A4 has been reported to be associated with invasion and metastasis; however, no data are available on its prognostic value in colorectal carcinoma. Therefore, we investigated the prognostic significance of immunohistochemical S100A4 expression in colorectal carcinoma compared with clinicopathologic parameters and expression of cell-cycle markers p16, p21, p27, p53, Ki-67, and RB. METHODS: Archival tissue from 709 patients with colorectal cancer were retrieved, applied in tissue array technology, and investigated immunohistochemically. Univariate and multivariate survival analyses were carried out on all investigated parameters. RESULTS: Sixteen percent of cases showed high; 31%, low; and 53%, no S100A4 expression. In Kaplan-Meier analysis, S100A4 positively stained cases showed a significantly decreased survival time compared with negatively stained cases (P < 0.0001). In multivariate regression analysis, S100A4 expression emerged as a highly significant independent parameter (P < 0.001) with the highest relative-risk factor among other covariates. Nodal status (pN) lost its prognostic value if S100A4 was added to the model. High S100A4 expression was associated with tumor stage pT3/4, secondary metastasis, women, p16, and RB expression. CONCLUSIONS: S100A4 expression represents a highly significant prognostic marker in colorectal carcinoma, which is able to identify a subset of patients at high risk. In this respect, it is superior to established prognostic markers such as nodal status, pT stage, and p53 expression.

Colorectal Neoplasms↗
PubMed1986

Functional study of a monoclonal antibody to IgE Fc receptor (Fc epsilon R2) of eosinophils, platelets, and macrophages.

An IgM mAb (BB10) was produced by immunization of mice with human eosinophils purified according to their abnormal low density ("hypodense" cells), and previously shown to exhibit increased IgE-dependent antiparasite cytotoxicity. This BB10 antibody, selected for positive fluorescence staining of hypodense blood or lung eosinophils and low or negative staining of normodense eosinophils or neutrophils, could strongly inhibit IgE-dependent cytotoxicity of human eosinophils and platelets. The specificity for the IgE Fc receptor was suggested by the high levels of inhibition of IgE rosettes formed by eosinophils after incubation with the purified IgM fraction of BB10, whereas other receptors (Fc gamma R, CR1) were not affected. On the other hand, BB10, able to inhibit rat eosinophil Fc epsilon R, did not react with the IgE Fc receptor on mast cells or basophils. A technique using radioiodinated BB10 allowed us to quantify the specific binding of BB10 to human eosinophils and platelets. Competition experiments revealed a crossinhibition between the binding of BB10 and IgE, suggesting the specificity of BB10 for the IgE binding site of eosinophil, platelet, and monocyte Fc epsilon R. Three proteins having extrapolated Mr of 32,000, 43,000-45,000, and 97,000 were found in the platelet extract eluted from a BB10 or from an IgE immunosorbent column. These findings confirm the similarities between IgE Fc receptors on human eosinophils, platelets, and macrophages, already observed with polyclonal antibodies directed against the B lymphocyte Fc epsilon receptor. They suggest, moreover, that the mAb BB10 can represent a good reagent for further investigations on the structure and the functions of this IgE Fc receptor (Fc epsilon R2).

Animals↗
PubMed1999

Role of p53 gene mutations in human esophageal carcinogenesis: results from immunohistochemical and mutation analyses of carcinomas and nearby non-cancerous lesions.

In order to characterize p53 alterations in esophageal cancer and to study their roles in carcinogenesis, we performed gene mutation and immunohistochemical analysis on 43 surgically resected human esophageal specimens, which contain squamous cell carcinoma (SCC) and adjacent non-cancerous lesions, from a high-incidence area of Linzhou in Henan, China. A newly developed immunohisto-selective sequencing (IHSS) method was used to enrich the p53 immunostain-positive cells for mutation analysis. p53 gene mutations were detected in 30 out of 43 (70%) SCC cases. Among 29 SCC cases that were stained positive for p53 protein, 25 (86%) were found to contain p53 mutations. In five cases of SCC with homogeneous p53 staining, the same mutation was observed in samples taken from four different positions of each tumor. In a well differentiated cancer nest, p53 mutation was detected in only the peripheral p53-positive cells. In tumor areas with heterogeneous p53 staining, either the area stained positive for p53 had an additional mutation to the negatively stained area or both areas lacked any detectable p53 mutation. In the p53-positive non-cancerous lesions adjacent to cancer, p53 mutations were detected in seven out of 16 (47%) samples with basal cell hyperplasia (BCH), eight out of 12 (67%) samples with dysplasia (DYS), and six out of seven (86%) samples with carcinoma in situ (CIS). All mutations found in lesions with DYS and CIS were the same as those in the nearby SCC. In seven cases of BCH containing mutations, only three had the same mutations as the nearby SCC. The results suggest that p53 mutation is an early event in esophageal carcinogenesis occurring in most of the DYS and CIS lesions, and cells with such mutations will progress to carcinoma, whereas the role of p53 mutations in BCH is less clear.

Adult↗
PubMed2000

Stratified mucin-producing intraepithelial lesions of the cervix: adenosquamous or columnar cell neoplasia?

BACKGROUND: Squamous (CIN) and glandular (ACIS) intraepithelial lesions often coexist in the same cervical specimen. However, a less common and little studied variant consists of a stratified epithelium resembling CIN in which conspicuous mucin production is present (Stratified Mucin-producing Intraepithelial LEsions (SMILE). This report describes the phenotypic characteristics of the SMILE, its associated lesions, and its immunophenotype. METHODS: Eighteen SMILEs were identified by the presence of conspicuous cytoplasmic clearing or vacuoles in lesions otherwise resembling CIN. The morphologic spectrum of SMILEs was detailed; including associated intraepithelial and invasive cervical neoplasms. In addition, selected cases were stained for mucicarmine, markers of squamous cell/reserve cell differentiation (keratin-14 and p63), and proliferative activity (Mib-1). RESULTS: Stratified neoplastic epithelial cells with a high Mib-1 index and a rounded or lobular contour at the epithelialstromal interface characterized SMILEs. In contrast to CIN, in which mucin droplets are confined to surface cells, mucin was present throughout the epithelium, varying from indistinct cytoplasmic clearing to discrete vacuoles. SMILEs were distinguished from benign metaplasia by nuclear hyperchromasia and a high Mib-1 index. All but three coexisted with either a squamous (CIN) or glandular (ACIS) precursor lesion. Nine of nine coexisting invasive carcinomas contained glandular, adenosquamous differentiation, or both. SMILEs stained negative for keratin-14 and variably for p63. When present, staining with p63 was confined to basal areas of SMILEs and was absent in areas of columnar differentiation. CONCLUSIONS: SMILEs are unusual cervical intraepithelial lesions best classified as variants of endocervical columnar cell neoplasia based on immunophenotype. The distribution and immunophenotype of SMILEs are consistent with a neoplasm arising in reserve cells in the transformation zone. The coexistence of a wide spectrum of intraepithelial and invasive cell phenotypes suggests that SMILEs are a marker for phenotypic instability, emphasizing the importance of identifying SMILEs and ensuring a complete examination of specimens containing this unusual precursor lesion.

Adenocarcinoma↗
PubMed1994

p53 gene mutations in human skin cancers and precancerous lesions: comparison with immunohistochemical analysis.

Mutations of exons 3 through 9 of the p53 gene in skin lesions were screened in 23 cases of squamous cell carcinoma (SCC), 25 cases of basal cell carcinoma (BCC), two cases of Bowen's disease, 10 cases of solar keratosis, and five cases of keratoacanthoma by polymerase chain reaction--single strand conformation polymorphism analysis. Mutations of the p53 gene were detected in seven of 23 SCCs (30%), three of 25 BCCs (12%), and none in all cases of Bowen's disease, solar keratosis, or keratoacanthoma. Of 23 cases of SCC, mutations were detected in four of 15 SCCs (27%) that originated in the sunlight-exposed skin region, in two of three SCCs (67%) that originated in the scar tissue, and in one of three SCCs (33%) that originated in radiation dermatitis. Mutations of C-->T transition predominated in SCC and BCC that originated in the sunlight-exposed skin region. Mutations of C-->A or CC-->AT observed in tumors that originated in the predisposed conditions, presumably unrelated to UV light, are different from those found in UV light-related SCC or BCC. Twelve cases of SCC were comparatively analyzed with the immunohistochemical staining with anti-p53 antibody. Two of four cases with positive staining had missense mutations, and three of eight cases with negative staining had nonsense mutations. Based on these findings, immunohistochemical results do not necessarily mean the presence or absence of p53 gene mutations in skin tumors, and sequence analysis is essential for determining whether the gene is mutated.

Aged↗
PubMed2005

Epithelioid sarcoma associated with lung adenocarcinoma.

Epithelioid sarcoma is an uncommon soft tissue malignancy which is often misdiagnosed as necrobiotic granuloma or chronic inflammation. Many patients have local recurrence and distant metastasis because of its infiltrating growth. We report a 49-year-old Japanese man who had an ulcer with surrounding erythema on the left forearm after he sustained a bruise on this spot. His mother and father had died of rectal and bladder carcinoma, respectively, and he had also had a seminoma previously. Therefore, there was familial accumulation of malignancies. A skin biopsy revealed polygonal, plump, or spindle-shaped epithelioid cells and lymphocytes infiltrating through the dermis. Immunohistochemical studies showed positive staining for cytokeratins, epithelial membrane antigen, CD34 and vimentin and negative staining for desmin, CD68, HHF-35, 1A4 and p53. These clinical and histological features were diagnostic of epithelioid sarcoma. CT scans detected nodules in the right lung. A lung biopsy revealed that he had well-differentiated adenocarcinoma which expressed p53. Mutations in the TP53 gene were not searched for. We selected conservative treatment because the patient did not want surgical wide resection or amputation. Therefore, radiation, thermotherapy, application of 0.5% doxorubicin hydrochloride ointment and right lower lobectomy with lymph node dissection were performed. The size of the ulcer and the tumor invasion along the fasciae of muscles were decreased, however, metastasis of the epithelioid sarcoma was detected in the lymph node of the left axilla four years after the diagnosis.

Adenocarcinoma↗
PubMed1994

Abnormalities in p53 and DNA content in transitional cell carcinoma of the bladder.

OBJECTIVE: To determine if transitional cell tumours of the bladder which contain mutations in the p53 gene have alterations in their DNA content. MATERIALS AND METHODS: In 33 transitional cell tumours of the bladder, DNA content was determined by flow cytometry and compared with expression of mutant p53 as assessed by immuno-histochemistry. RESULTS: Abnormal DNA content was associated with increased staining for p53 (P < 0.05), high tumour stage (P < 0.001) and increased histological grade (P < 0.01). Although positive staining for p53 was frequently associated with abnormal DNA content, a significant number of non-diploid tumours stained negatively for mutant p53. CONCLUSION: These data demonstrate that increased staining for p53 is associated with abnormalities in DNA content suggesting that mutation of the p53 gene is associated with an increased rate of chromosomal abnormalities and an increased rate of cell proliferation.

Carcinoma, Transitional Cell↗
PubMed1995

An immunohistochemical study of three equine pulmonary granular cell tumors.

Granular cell tumor (GCT) is a morphologic designation for tumors of varied histogenesis. Most GCTs in human beings are derived from Schwann cells, and rat meningeal GCTs are believed to originate in the neural crest. Three equine pulmonary GCTs from aged horses were studied immunohistochemically with primary antibodies directed against vimentin, cytokeratins (AE1/AE3), S-100, Leu 7, desmin, and neuron-specific enolase (NSE) using a steptavidin-biotin procedure. All three tumors stained similarly with strong and diffuse staining of neoplastic cells for vimentin and S-100 and negative staining with all other antibodies. On the basis of the immunohistochemical results and the previously described histologic and ultrastructural characteristics, equine pulmonary GCT is designated as neural crest and possibly Schwann cell derived, similar to GCT in rats and human beings.

Animals↗
PubMed2005

Multifocal micronodular pneumocyte hyperplasia in a man with tuberous sclerosis.

We report a peculiar case of multifocal micronodular pneumocyte hyperplasia (MMPH) occurring in a 43-year-old man with tuberous sclerosis. Computed tomography of the chest demonstrated multiple micronodules, measuring up to 5 mm in size, present bilaterally in the lung fields, with no cystic change. Histologically, a proliferation of type II pneumocytes without the typical nulclear atypia lined the thickened alveolar septa in an adenomatoid pattern. Proliferation of immature smooth muscle cells suggestive of LAM was not observed. The characteristic findings of the positive immunohistochemical stains for cytokeratin and surfactant apoprotein A and B, and negative stains for HMB-45, alpha-1 smooth muscle actin, desmin, p53 and carcinoembryonic antigen confirmed the presence of alveolar lining cells in each MMPH lesion. Since the MMPH was observed in a male and did not appear to possess malignant potential, the MMPH appears to be a hamartomatous proliferation occurring in a male with tuberous sclerosis that is separate from lymphangiomyomatosis (LAM) which is related to estrogen and progesterone receptors.

Adult↗
PubMed1999

Characteristics of primary osteoblast culture derived from rat fetal calvaria.

Primary osteoblast cultures, which reflect more phenotypic properties of normal osteoblasts than osteoblastic cell lines, can be used as an experimental tool for investigating the osteoblastic functions in vitro. Primary osteoblast cultures were obtained from the parietal bones of calvaria of fetal rats in this study. Differential characteristics of osteoblasts in our culture system were examined and fibroblast cultures were also tested for comparison. We tested the alkaline phosphatase (ALP) and von Kossa stains on osteoblast and fibroblast cultures to examine the expression of ALP and the subsequent matrix mineralization occurred at 2 and 3 weeks after cell confluence respectively. The results showed that osteoblast cultures revealed obvious positive stains of ALP and von Kossa, while fibroblast cultures revealed negative stains, suggesting the osteoblast culture system used in this study reflects the typical phenotypes of primary osteoblasts but not fibroblasts. We tested the ALP activities following various doses of PGE2 or ketorolac treatments in primary osteoblast and fibroblast cultures. The results showed that PGE2 and ketorolac stimulated intracellular ALP activities of osteoblasts in dose dependent fashions, while very low ALP activities were detected in either the control or agents treated cultures of fibroblast. These results suggest that PGE2 may be involved in osteoblastic differentiation and the stimulatory effect of ketorolac on osteoblastic ALP activity may not be PGE2 mediated. The responses of osteoblasts to both agents can be as the characteristics of primary osteoblast derived from rat calvaria.

Alkaline Phosphatase↗
PubMed2002

Clinical pathological analysis and immunohistochemical study of ten solitary fibrous tumors.

OBJECTIVE: To study the clinical and pathological characteristics of solitary fibrous tumor (SFT). METHODS: Clinical pathological analysis and immunohistochemical studies were performed on ten patients with SFT. RESULTS: The SFTs located variously and showed different histological features. All cases showed positive staining for CD(34), VM (vimentin) and Bcl-2, but negative staining for Desmin, S-100, CK (cytokeratin) and EMA (epithelial membrane antigen). CONCLUSIONS: SFT is described as a "patternless" growth pattern. According to clinical pathological features and immunohistochemistry, it is different from other soft tissue tumors. Long-term clinical follow-up is necessary for this kind of tumor.

Adult↗
PubMed2004

Angiotropic large cell lymphoma.

A 67 year old man developed "status epilepticus" and died with acute respiratory failure. An autopsy and concomitant histological examination, revealed intravascular infiltrate of lymphoid cells throughout the body. Immunohistochemical studies showed intense positive staining for leukocyte common antigen (LCA), L26 and CD20 and negative staining for Factor VIII- related antigen, and CD5, demonstrated that the neoplastic cells were of B-cell lineage.

Aged↗
PubMed2004

[Preparation, identification, and analysis on tissue chips of polyclonal anti-peptide antibody to chemokine-like factor 1].

OBJECTIVE: To prepare the polyclonal anti-peptide antibody against chemokine-like factor1 (CKLF1) and apply it to the expression and functional studies of CKLF1. METHODS: CKLF1 was analyzed with bioinformatics methods. The 16 amino acids sequence peptide was selected from CKLF1 C terminal end. Antibody was raised by immunizing rabbits with the peptide conjugated to keyhole limpet hemocyanin (KLH). RESULTS: A high titer polycolonal antibody was obtained from the rabbit against the peptide. ELISA analysis proved that the titer of rabbit serum against anti-peptide of CKLF1 was up to 10(-4). Western blot analysis revealed that it could react not only with recombinant CKLF1 expressed in a cell-Free Protein Biosynthesis System and Drosophila S2 cells, but also recognize the endogenous CKLFs in the tissue array. Positive staining was detected in the normal bronchial cartilage, gastric mucosa, and gastric smooth muscle tissues. Normal rectum and well-differentiated rectal carcinoma showed strong positive staining, but the poor-differentiated rectal carcinoma samples revealed negative staining. CONCLUSION: The anti-peptide antibody can specifically recognize CKLFs and may be a useful reagent for the detection of CKLF1.

Animals↗
PubMed1984

Biogenesis and cytochemistry of unspecialized peroxisomes in root cortical cells of Yucca torreyi L.

Microbodies containing bipyramidal crystalline nucleoid inclusions occur within every cortical cell in roots of Yucca torreyi. Reaction product deposition attributable to catalase, glycolate oxidase, and urate oxidase activities are cytochemically localized to Yucca root microbodies and classifies them as unspecialized peroxisomes on the basis of their enzyme complement and tissue origin. Crystalline nucleoids do not stain for glycolate or urate oxidase activities, appearing as negatively-stained inclusions, but are apparently reactive for catalase activity. Development of unspecialized peroxisomes in Yucca roots is consistent with all evidence for glyoxysome and leaf-type peroxisome biogenesis from ER. Dilated ends of ER cisternae accumulate cytochemically detectable glycolate oxidase activity. After considerable dilation, paracrystalline precursors to nucleoids form within the bulge, and the inclusion enlarges to comprise the majority of peroxisomal volume. Peroxisomes that are not attached to ER are observed with high voltage electron microscopy and in serial thin sections, implying that eventually the budding peroxisomes are vesiculated. The functions of these unspecialized peroxisomes are suggested based upon cytochemical detection of their partial enzyme complement and their spatial and developmental timing relationships within developing Yucca root cortical parenchyma cells.

Alcohol Oxidoreductases↗
PubMed1996

Metastatic pancreatic neuroendocrine carcinoma causing Cushing's syndrome. ACTH secretion by metastases 3 years after resection of nonfunctioning primary cancer.

CONCLUSION: Following resection of a nonfunctioning neuroendocrine carcinoma of the pancreas, subsequent metastases, in the absence of a primary cancer (resected), developed the capacity to secrete ACTH and create the Cushing syndrome. BACKGROUND: Although neuroendocrine carcinomas of the pancreas may produce one or more hormones and may switch secretion to a different hormone, no report is identified of a metastasis, in the absence of the primary tumor, developing de novo the capacity to secrete ACTH. METHODS: A nonfunctioning islet cell carcinoma was resected and immunochemically stained for multiple hormones. Three years later hepatic metastases were partially resected and stained as before. RESULTS: The primary cancer stained negative for ACTH and cortisol, positive for serotonin, and focally positive for gastrin. Three years later, after the development of a florid Cushing syndrome, the metastasis stained strongly for ACTH and negative for serotonin.

Adrenocorticotropic Hormone↗