F-box protein FBXO16 functions as a tumor suppressor by attenuating nuclear ß-catenin function.

Aberrant activation of ß-catenin has been implicated in a variety of human diseases, including cancer. In spite of significant progress, the regulation of active Wnt/ß-catenin-signaling pathways is still poorly understood. In this study, we show that F-box protein 16 (FBXO16) is a putative tumor suppressor. It is a component of the SCF (SKP1-Cullin1-F-box protein) complex, which targets the nuclear ß-catenin protein to facilitate proteasomal degradation through the 26S proteasome. FBXO16 interacts physically with the C-terminal domain of ß-catenin and promotes its lysine 48-linked polyubiquitination. In addition, it inhibits epithelial-to-mesenchymal transition (EMT) by attenuating the level of ß-catenin. Therefore, depletion of FBXO16 leads to increased levels of ß-catenin, which then promotes cell invasion, tumor growth, and EMT of cancer cells. Furthermore, FBXO16 and ß-catenin share an inverse correlation of cellular expression in clinical breast cancer patient samples. In summary, we propose that FBXO16 functions as a putative tumor suppressor by forming an SCFFBXO16 complex that targets nuclear ß-catenin in a unique manner for ubiquitination and subsequent proteasomal degradation to prevent malignancy. This work suggests a novel therapeutic strategy against human cancers related to aberrant ß-catenin activation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Reciprocal regulation of pro-inflammatory Annexin A2 and anti-inflammatory Annexin A1 in the pathogenesis of rheumatoid arthritis.

Annexin A2 has been implicated in several immune modulated diseases including Rheumatoid arthritis (RA) pannus formation. The most relied treatment option for RA pathogenesis is glucocorticoids. Glucocorticoids regulate the synthesis, phosphorylation and cellular deposition of Annexin A1. This annexin mediates the anti-inflammatory actions of glucocorticoids. These two first characterized members of annexin superfamily proteins acts reciprocally, one as an anti-inflammatory and the other proinflammatory in nature. The possibility of these molecules as soluble biomarkers and as an upstream regulator of major cytokine devastation at RA microenvironment has not been previously explored. Current study elucidates the reciprocal regulation of these two annexins in RA pathogenesis. These Annexin A2/A1 and downstream cytokines in RA serum were analysed by ELISA. Western blot, Immunocytochemistry, immunoprecipitation and Immunohistochemistry were adapted to analyse these molecules in tissue and synovial fibroblasts and also in different experimental conditions. Significant increase in the level of Annexin A2 was noticed in naïve RA patients compared to controls (14.582 ± 1.766 ng/ml vs. 7.37 ± 1.450 ng/ml; p ≤ 0.001). In remission cases significant low levels was detected. On the contrary, significant decrease in the level of Annexin A1 was noticed in naïve RA patients compared to healthy controls (12.322 ± 2.91 vs. 16.998 ± 4.298 ng/ml; p ≤ 0.001), wherein remission cases serum Annexin A1 was significantly high. The knockdown of proinflammatory Annexin A2 by siRNA/antibody treatment could mimic the glucocorticoid treatment as which induced cellular Annexin A1 and membrane translocation resulting in the terminal action. Current data elucidating the regulatory interplay between Annexin A2 and Annexin A1 in RA pathogenesis.

Cell surface interaction of annexin A2 and galectin-3 modulates epidermal growth factor receptor signaling in Her-2 negative breast cancer cells.

Overexpression and activation of tyrosine kinase receptors like EGFR and Src regulate the progression and metastasis of Her-2 negative breast cancer. Recently we have reported the role of cell membrane interaction of phospholipid-binding protein annexin A2 (AnxA2) and EGFR in regulating cellular signaling in the activation of angiogenesis, matrix degradation, invasion, and cancer metastasis. Beta-galactoside-specific animal lectin galectin-3 is an apoptosis inhibitor, and cell surface-associated extracellular galectin-3 also has a role in cell migration, cancer progression, and metastasis. Similar expression pattern and membrane co-localization of these two proteins made us to hypothesize in the current study that galectin-3 and AnxA2 interaction is critical for Her-2 negative breast cancer progression. By various experimental analyses, we confirm that glycosylated AnxA2 at the membrane surface interacts with galectin-3. N-linked glycosylation inhibitor tunicamycin treatment convincingly blocked AnxA2 membrane translocation and its association with galectin-3. To analyze whether this interaction has any functional relevance, we tried to dissociate this interaction with purified plant lectin from chickpea (Cicer arietinum agglutinin). This highly specific 30 kDa plant lectin could dissociate AnxA2 from endogenous lectin galectin-3 interaction at the cell surface. This dissociation could down-regulate Bcl-2 family proteins, cell proliferation, and migration simultaneously triggering cell apoptosis. Targeting this interaction of membrane surface glycoprotein and its animal lectin in Her-2 negative breast cancer may be of therapeutic value.

Intravascular Papillary Endothelial Hyperplasia as an unusual diagnosis for peri-orbital tumour - A case report.

Intravascular papillary endothelial hyperplasia (IPEH) is a rare cause of orbital mass which can affect healthy individuals of any age/sex/race/region. It usually requires a histopathological examination, characterized by the appearance of papillary proliferation of vascular endothelial cells within the lumen of the blood vessel, for the final diagnosis. One should be aware that this is a highly vascular lesion which can cause excessive intraoperative bleeding and incomplete removal can lead to recurrences. IPEH of the orbit/eyelid has been reported in few parts of the world as isolated case reports but none from India so far.

Cdc20 directs proteasome-mediated degradation of the tumor suppressor SMAR1 in higher grades of cancer through the anaphase promoting complex.

The Tumor suppressor SMAR1 (scaffold matrix attachment region binding protein 1) has a crucial role in maintaining genomic stability, cell cycle progression and apoptosis.Our previous finding showed that it is highly suppressed in higher grade of cancer. However, the underlying mechanism of this suppression was not well understood. In this study, we show that SMAR1 expression levels are controlled at the proteasomal level by five RING finger E3 ubiquitin ligases including, Cdc20, a substrate receptor of ubiquitin ligase APC/C complex. We found that Cdc20 binds and promotes proteasomal degradation of SMAR1 in a D-box motif dependent manner. Further, our results demonstrated that Cdc20 promotes proteasomal degradation of SMAR1 through K48-linked specific polyubiquitylation, and that short hairpin RNA mediated inactivation of Cdc20 leads to significant stabilization of SMAR1. These findings suggest that Cdc20 is responsible for maintaining the cellular levels of SMAR1. However, since Cdc20 fails to target SMAR1 upon exposure to genotoxic stresses, SMAR1 helps to maintain genomic stability under these conditions through its DNA damage repair activity. Interestingly, Cdc20-mediated degradation of SMAR1 promotes cell migration and invasion.The reciprocal relationship of the duo is evident in breast cancer cell lines as well as in patient samples, suggesting that Cdc20 functions as an important negative regulator of SMAR1 in higher grades of cancer. Our study reveals for the first time, the molecular mechanism associated with lower levels of expression of the important tumor suppressor SMAR1 in higher grades of breast cancer.

Annexin A2 and its downstream IL-6 and HB-EGF as secretory biomarkers in the differential diagnosis of Her-2 negative breast cancer.

Background AnnexinA2 (AnxA2) membrane deposition has a critical role in HB-EGF shedding as well as IL-6 secretion in breast cancer cells. This autocrine cycle has a major role in cancer cell proliferation, migration and metastasis. The objective of the study is to demonstrate annexinA2-mediated autocrine regulation via HB-EGF and IL-6 in Her-2 negative breast cancer progression. Methods Secretory annexinA2, HB-EGF and IL-6 were analysed in the peripheral blood sample of Her-2 negative ( n = 20) and positive breast cancer patients ( n = 16). Simultaneously, tissue expression was analysed by immunohistochemistry. The membrane deposition of these secretory ligands and their autocrine regulation was demonstrated using triple-negative breast cancer cell line model. Results Annexina2 and HB-EGF expression are inversely correlated with Her-2, whereas IL-6 expression is seen in both Her-2 negative and positive breast cancer cells. RNA interference studies and upregulation of annexinA2 proved that annexinA2 is the upstream of this autocrine pathway. Abundant soluble serum annexinA2 is secreted in Her-2 negative breast cancer (359.28 ± 63.73 ng/mL) compared with normal (286.10 ± 70.04 ng/mL, P < 0.01) and Her-2 positive cases (217.75 ± 60.59 ng/mL, P < 0.0001). In Her-2 negative cases, the HB-EGF concentrations (179.16 ± 118.81 pg/mL) were highly significant compared with normal (14.92 ± 17.33 pg/mL, P < 0.001). IL-6 concentrations were increased significantly in both the breast cancer phenotypes as compared with normal ( P < 0.001). Conclusion The specific expression pattern of annexinA2 and HB-EGF in triple-negative breast cancer tissues, increased secretion compared with normal cells, and their major role in the regulation of EGFR downstream signalling makes these molecules as a potential tissue and serum biomarker and an excellent therapeutic target in Her-2 negative breast cancer.

Gilbert's syndrome in healthy blood donors what next??

SETTINGS: This study was done in a tertiary care hospital having bed strength of more than 700 beds at SDM Medical College of Medical Sciences and Hospital, Dharwad, located in Northern Karnataka. AIM: The study was done to ascertain prevalence of Gilbert's syndrome in healthy blood donors and review the literature about feasibility of utilizing blood components from Gilbert's syndrome donors. MATERIALS AND METHODS: The study was done for 18 months and 7030 whole blood units were collected and all the units were subjected to mandatory transfusion-transmitted screening and all the plasma bags which were icteric on visual inspection were subjected to hematological and biochemical investigations to rule out other causes of hyperbilirubinemia. RESULTS: Seven thousand and thirty units were collected and 445 (6.3%) were discarded due to various reasons. Of them, 50 units (0.71%) had Gilbert's syndrome. All had unconjugated hyperbilirubinemia and other hematological and liver function tests were within normal range. Statistical analysis was done to find mean, median, and standard deviation from mean and standard error of mean with lower and upper confidence limits. CONCLUSION: Majority of blood donors whose plasma is icteric are suffering from Gilbert's syndrome (GS). This disease does not cause any harm to donor or patient but raises a lot of concern as many severe disorders also manifest in similar way. The available literature shows that all blood components can be used from donors suffering from GS. There should be introspection. Proper guidelines are to be framed about the use and discarding of blood components in donors with GS.

Non Functional Unilateral Adrenal Myelolipoma, A Case Report.

Adrenal myelolipoma is characterized by presence within the adrenal gland of mature adipose tissue and active bone marrow elements. Owing to their non functional nature most cases are incidental, either at autopsy or through computer tomography scan. Occasionally the lesions attain a large size to become clinically apparent. We present a case of a 58-year-old female with mass per abdomen. Preoperative computer tomography scan of abdomen, hormonal and urine analysis showed features of non functional adrenal myelolipoma. Gross specimen consists of unilateral ovoid mass, external surface having capsule with adherent fat and areas of congestion. Microscopic examination showed well encapsulated tumour tissue composed of mature adipose tissue with major blood forming elements like myeloid, erythroid and megakaryocytic series. The diagnosis was confirmed by histopathological examination of right sided adrenalectomy specimen.

Dyschromatosis universalis hereditaria with involvement of palms.

Dyschromatosis universalis hereditaria is a rare genodermatosis characterized by hyper- and hypopigmented macules in a reticulate pattern. Here, we present a case of DUH with involvement of the palms.

A clinico-histopathological study of lupus vulgaris: A 3 year experience at a tertiary care centre.

BACKGROUND: Lupus vulgaris is the most common form of cutaneous tuberculosis in adults. Lupus vulgaris is caused by hematogenous, lymphatic, or contiguous spread from elsewhere in the body. histologically it is charecterised by typical tubercles with or without caseation, surrounded by epitheloid histiocytes and multinucleate giant cells in the superficial epidermis with prominent peripheral lymphocytes. MATERIALS AND METHOD: All cases of clinically and histopathologicaly diagnosed lupus vulgaris over the previous five years were included in the study. RESULTS: Fourteen cases of lupus vulgaris cases reported during the study period with eaqual incidence among males and females. DISCUSSION: Plaque type of lupus vulgaris was the most common type. Histopathologically tubercular granulomas were seen in all cases as compared to other studies. CONCLUSION: Different patterns of lupus vulgaris are reported.

Multiple cutaneous malignancies in a patient of xeroderma pigmentosum.

Xeroderma pigmentosum is a genodermatosis characterized by photosensitivity and the development of cutaneous and internal malignancies at an early age. The basic defect underlying the clinical manifestations is a nucleotide excision repair defect, leading to defective repair of DNA damaged by ultraviolet radiation. These patients exhibit enhanced sensitivity to ionizing radiation. Patients with xeroderma pigmentosum who are younger than 20 years of age have a greater than 1000-fold increased risk of developing skin cancer. Early detection of these malignancies is necessary because they are fast growing, metastasize early and lead to death. Although, early detection and treatment of cutaneous malignancies will reduce the morbidity and mortality, genetic counseling remains the most important measure for preventing xeroderma pigmentosum. We report a case of xeroderma pigmentosum in an 18-year-old male presenting with multiple cutaneous malignancies: squamous cell carcinoma, malignant melanoma and pigmented basal cell carcinoma.

Ossifying luteinized thecoma of the ovary with endometrial adenocarcinoma.

Luteinized thecomas are one of the sex cord stromal tumors of the ovary rarely undergoing ossification. We report a case of a 66-year-old post-menopausal female with the chief complaint of uterine bleeding of 7 months duration. Endometrial curettage performed showed features of endometrial adenocarcinoma. Follow-up total abdominal hysterectomy revealed bilateral luteinized thecomas of the ovary, one of which had undergone massive ossification converting the ovary into a bone. True bone formation in ovarian tumors is rare. This case is the second in the literature of osseous metaplasia in an ovarian luteinized thecoma, with the association of endometrial adenocarcinoma suggesting its functional status.

Large mammary hamartoma with focal invasive ductal carcinoma.

Mammary hamartomas are uncommon benign lesions rarely associated with malignancy. We report a case of a 25-year-old female patient presenting with a lump in the left breast. Fine needle aspiration cytology showed features of invasive ductal carcinoma along with normal benign glands that were mistaken for normal breast tissue. However, the mastectomy specimen revealed the malignant mass within a larger hamartomatous mass. Mammary hamartomas are benign lesions but, on exceedingly rare occasions, they may be involved by incidental, coexisting carcinoma, as illustrated in this case report.

Subtotal colectomy for intestinal Behcet's disease: a histopathological surprise.

A 40-year-old male who was diagnosed to be having ileocaecal tuberculosis by colonoscopy elsewhere was put on antitubercular treatment. Despite therapy over three months patient had recurrent bouts of lower abdominal pain and was admitted repeatedly with features of subacute intestinal obstruction. CT- abdomen revealed concentric large bowel thickening at multiple sites with features of stenosing lesions. Patient underwent an exploratory laparotomy and subtotal colectomy was done for the diseased large bowel. Post operative histopathological examination revealed it to be Behcet's disease. We report a rare case of intestinal Behcet's disease requiring subtotal colectomy.