Background Benign metastasizing leiomyoma (BML) is a rare disease with an unknown etiopathogenesis that mostly affects middle-aged women with uterine leiomyoma. Many metastatic nodules outside the uterus characterize the condition. The metastases are smooth muscle lesions without malignancy. Morphologically and immunohistochemically, they resemble uterine leiomyomas, indicating a shared clonal origin. The lungs are the most prevalent site for incidental metastasis detection. BML has a relatively slow progression and good prognosis, and historically, there has been a lack of established guidelines for its treatment. Case presentation Herein, we report a case of BML in a patient with multiple metastases. Through extensive histological and immunohistochemical analyses, this complex case enabled not only the definitive diagnosis of BML, but also shed light on its complex etiopathogenesis. Conclusion This study presents novel histology evidence suggesting a potential causal relationship between metaplasia and the development of BML.

Background and Aims Porto-sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease. Approach and Results We performed genome sequencing of four patients and two healthy individuals of a large multigenerational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCH and double SH3 domains 1 (FCHSD1), an uncharacterized gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1 suggests that the C-to-T substitution at position 547, corresponding to FCHSD1(R183W), may increase both messenger RNA (mRNA) and protein stability and its interaction with MTOR-associated protein, LST8 homolog, a key protein of the mechanistic target of rapamycin (mTOR pathway). These predictions were substantiated by biochemical analyses, which showed that FCHSD1(R183W) induced high FCHSD1 mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1 variant was introduced into mice through CRISPR/Cas9 genome editing. Nine out of the 15 mice carrying the human FCHSD1(R183W) variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein. Conclusions Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.

The development of prophylactic and therapeutic agents for coronavirus disease 2019 (COVID-19) is a current global health priority. Here, we investigated the presence of cross-neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dromedary camels that were Middle East respiratory syndrome coronavirus (MERS-CoV) seropositive but MERS-CoV free. The tested 229 dromedaries had anti–MERS-CoV camel antibodies with variable cross-reactivity patterns against SARS-CoV-2 proteins, including the S trimer and M, N, and E proteins. Using SARS-CoV-2 competitive immunofluorescence immunoassays and pseudovirus neutralization assays, we found medium-to-high titers of cross-neutralizing antibodies against SARS-CoV-2 in these animals. Through linear B cell epitope mapping using phage immunoprecipitation sequencing and a SARS-CoV-2 peptide/proteome microarray, we identified a large repertoire of Betacoronavirus cross-reactive antibody specificities in these dromedaries and demonstrated that the SARS-CoV-2–specific VHH antibody repertoire is qualitatively diverse. This analysis revealed not only several SARS-CoV-2 epitopes that are highly immunogenic in humans, including a neutralizing epitope, but also epitopes exclusively targeted by camel antibodies. The identified SARS-CoV-2 cross-neutralizing camel antibodies are not proposed as a potential treatment for COVID-19. Rather, their presence in nonimmunized camels supports the development of SARS-CoV-2 hyperimmune camels, which could be a prominent source of therapeutic agents for the prevention and treatment of COVID-19.

Background In the past decade, cervical cancer has gone from being the second to the fourth most common cancer in women worldwide, but remains the second most common in developing countries. This cancer is most commonly caused by high-risk types of human papillomavirus (HPV), mainly type 16 (HPV16), which are sexually transmitted. This study aimed to investigate the usefulness of a cyclic synthetic peptide designed from the major L1 capsid protein of HPV16 for detecting anti-HPV16 antibodies. Methods We designed and synthetized a peptide that corresponds to the full sequence of the surface-exposed FG loop. We tested the antigenicity of the linear and the cyclic peptides against HPV16 L1 monoclonal antibodies. We used ELISA to detect anti-peptide antibodies in sera and cervical secretions of 179 Tunisian women, and we applied polymerase chain reaction and direct sequencing methods to detect and genotype HPV DNA. Results Both the linear and the cyclic peptides were recognized by the same neutralizing monoclonal antibodies, but the cyclic peptide was more reactive with human sera. The prevalence of the anti-peptide antibodies in sera was higher in women with low-grade squamous intraepithelial lesions (LGSIL) than in women with high-grade squamous intraepithelial lesions (HGSIL) (44% and 15%, respectively) . This contrasts with HPV16 DNA prevalence. Compared to women from the general population, systemic IgG prevalence was significantly higher among sex workers (25%; P=0.002) and women with LGSIL (44%; P=0.001). In addition, systemic IgA and cervical IgG prevalence was higher among sex workers only (p=0.002 and P=0.001 respectively). We did not observe anti-peptide IgG antibodies in women with a current HPV16 infection. Conclusion Anti-peptide IgG in sera or in cervical secretions could be markers of an effective natural immunization against HPV16. This may open novel perspectives for monitoring vaccinated women and for the design of synthetic peptide-based vaccines.

Little is known about the epidemiological characteristics of papillomavirus (HPV) infection among North African countries. Herein, we conducted a molecular epidemiological study to investigate prevalence of HPV type and HPV-16 variants among cervical-screened unvaccinated Tunisian women.

Up to now, there are no protein tumor markers with a specificity and sensitivity sufficient to have a utility in prognosis and early diagnosis of cancer. Recent advances in proteomics approaches have led to the identification of novel tumor markers of cancer that may have a utility in screening strategies and treatment. The purpose of the current review is to describe the major advances in cancer proteomics, especially those related to the study of serum biomarkers, immune-related responses (autoantibodies) and alterations in cellular proteins. (C) 2011 Elsevier Masson SAS. All rights reserved.

Background and Aims. A prominent clinical feature of nasopharyngeal carcinoma (NPC) is its ability to easily invade local tissues and metastasize. In this field, latent membrane protein-1 (LMP-1), which is the principal Epstein-Barr virus-encoded oncoprotein, induces a set of factors that mediates angiogenesis and invasion. Matrix metalloproteinase-1 (MMP-1) and Ets-1 transcription factor are two other major factors that play crucial roles in tumor progression and may thus contribute to invasiveness of NPC cells. The aim of this study was to investigate the prognostic relevance of LMP-1 and its relationship with MMP-1 and Ets-1 expression in NPC biopsies.Methods. The expressions of LMP-1, MMP-1 and Ets-1 were immunohistochemically examined in 39 undifferentiated NPC specimens from Tunisian patients and the correlation between these proteins and clinicopathological parameters of the disease was statistically determined.Results. A significant association of LMP-1 expression with high T categories, as well as with the young age onset of NPC, has been found (p = 0.003). The expression of MMP-1 correlated with lymph node metastasis (p = 0.035), whereas a significant association between Ets-1 and high T categories, as well as distant metastasis, has been retrieved (p = 0.008; p = 0.047, respectively). In addition, the expression of LMP-1 showed a significant correlation with the expression of MMP-1 (p = 0.02).Conclusions. The results of the current study suggest that LMP-1 may contribute to invasion and metastasis of undifferentiated NPCs through the induction of MMP-1. (C) 2009 IMSS. Published by Elsevier Inc.

Background. Radiation-induced sarcomas are well-known potential late sequelae of radiation therapy. They are of rare occurrence in jaw bones and are even rarer in the maxilla. Case report. We report a case of radiation-induced osteosarcoma involving the maxilla in a patient treated with radiotherapy for nasopharyngeal carcinoma 14 years ago. Despite neoadjuvant chemotherapy, surgical treatment could not be performed, and the patient received palliative chemotherapy. Conclusions. Radiation-induced osteosarcomas are aggressive and often elude early detection and timely intervention, rapidly leading to early demise of afflicted patients. Long-term patient follow-up and a high index of suspicion are crucial for timely intervention.

Improvement of breast-cancer detection through the identification of potential cancer biomarkers is considered as a promising strategy for effective assessment of the disease. The current study has used nonequilibrium pH gradient electrophoresis with subsequent analysis by mass spectrometry to identify protein alterations in invasive ductal carcinomas of the breast from Tunisian women. We have identified multiple protein alterations in tumor tissues that were picked, processed, and unambiguously assigned identities by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF). The proteins identified span a wide range of functions and are believed to have potential clinical applications as cancer biomarkers. They include glycolytic enzymes, molecular chaperones, cytoskeletal-related proteins, antioxydant enzymes, and immunologic related proteins. Among these proteins, enolase 1, phosphoglycerate kinase 1, deoxyhemoglobin, Mn-superoxyde dismutase, α-B-crystallin, HSP27, Raf kinase inhibitor protein, heterogeneous nuclear ribonucleoprotein A2/B1, cofilin 1, and peptidylprolyl isomerase A were overexpressed in tumors compared with normal tissues. In contrast, the IGHG1 protein, the complement C3 component C3c, which are two newly identified protein markers, were downregulated in IDCA tissues.

Granulocytic sarcoma or chloroma is a neoplasia consisting of myeloid precursors in an extramedullary site. Its appearance in chronic myeloid leukaemia is unusual. We report a case of ovary tumor associated with chronic myeloid leukaemia in chronic phase.

Background: Little emphasis has been placed today on the elucidation of protein alterations in male breast carcinogenesis.Methods: Protein extracts were subjected to both isoelectric focusing (IEF) and non-equilibrium pH gradient electrophoretic (NEPHGE) analyses. Differentially expressed proteins in tumor tissues were identified by matrix assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry and database search.Results: Some of the alterations involve variations in the expression of cytokeratins 8, 18 and 19. More interestingly, tropomyosinl, a protein known to play a role in suppression of the malignant phenotype, was found to be under-expressed in cancer tissues, implicating a possible pivotal role for this protein in male breast carcinogenesis. Co-upregulation of molecular chaperones (heat shock protein HSP27 and protein disulfide isomerase), stress related proteins (peroxiredoxin 1 and peptidylprolyl isomerase A) and glycolytic enzymes (enolase 1) occurred also in male breast tumors. Some of the remaining alterations include proteins involved in invasion and metastasis, such as galectin 1 and cathepsin D.Conclusions: The present study represents a first proteomic investigation of protein alterations in infiltrating ductal carcinomas (IDCA) of the male breast. A number of protein alterations in tumor tissues have been characterised thus, providing new insights into the molecular mechanisms underlying this disease. (c) 2007 Elsevier B.V All rights reserved.

In the present study, total proteins from a tissue of an infiltrating ductal carcinoma of the breast (IDCA) were compared by the two-dimensional electrophoresis (2D-PAGE) to proteins from an adjacent non-neoplastic breast tissue. Analysis of multiple gels for each sample identified nine proteins present in the tumor sample that were less present in the matched normal adjacent breast tissue and four proteins present at higher levels in the normal tissue. The altered proteins were identified by matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry and search in protein databases. Protein disulfide isomerase, BiP protein, calreticulin, cathepsin D, inorganic pyrophosphatase, vimentin, apolipoprotein A1 precursor, tropomyosin 4 and beta5-tubulin were identified as being significantly over-expressed in the IDCA with regard to the normal tissue. The expression of fibrinogen E-fragment (known as anti-angiogenic factor) as well as of fibrin E, Pro2619 and actinG1 was found to be inhibited in the tumor sample. The identified proteins might play an important role during malignant transformation, breast cancer progression, and angiogenesis as well as in cellular signaling. This study demonstrates quantitative and qualitative changes in protein abundance between IDCA and normal tissue. The identification of these differentially expressed proteins could lead to a better understanding of the molecular events linked to breast cancer progression.

Background: It is well established that certain types of human papillomavirus (HPV) are the sexually transmitted agents etiologically linked to cervical cancer. Sexual habits have been shown to be a major determining factor for HPV infection. A large study was carried out to investigate the prevalence and risk factors associated with cervical infection with HPV in Tunisian women.Materials and Methods: PCR and restriction enzyme digestion were used to characterize HPV cervical infection in 106 Tunisian married women and 51 Legal prostitutes. Epidemiological data were collected and correlated with HPV molecular genotyping.Results: There was a higher relative frequency of HPV-DNA in prostitutes (39%) than in married women (14%) (p = 0.001). Molecular analyses of HPV types showed the most prevalent type in prostitutes to be HPV-16, a high-risk oncogenic type. In married women, the most prevalent type was HPV-6 which is associated with a low risk for cervical cancer. HPV-DNA detection was markedly increased in young adult women and in those having recent sexual experience.Conclusion: Cervical HPV infection in Tunisia is less frequent than in other African countries, but far from uncommon. The decrease of HPV prevalence in older women, regardless of their sexual behavior, may result from an efficient immune response acquired with age.

Glutathione S-transferase Theta1 and Mu1 (GSTT1 and GSTM1) are involved in the metabolism and detoxification of a wide range of potential environmental carcinogens. Conversely, they contribute to tumour cell survival by detoxification of numerous products induced by cancer therapy. The authors designed a large study to investigate the susceptibility and prognostic implications of the GSTT1 and GSTM1 gene deletions in breast carcinoma. The authors used the polymerase chain reaction to characterise the variation of the GSTT1 and GSTM1 genes in 309 unrelated Tunisian patients with breast carcinoma and 242 healthy control subjects. Associations of the clinic-pathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) were assessed using univariate and multivariate analyses. A significant association was found between gene deletion of GSTT1 and the risk of early onset of breast carcinoma (OR=1.60, P =0.02). The lack of GSTT1 gene deletion was significantly associated with poor clinical response to chemotherapy (OR=2.29, P =0.03). This association was significantly higher in patients with axillary's lymph node-negative breast carcinoma (OR=12.60, P =0.005). The null-GSTT1 genotype showed a significant association with increased DFS in this selected population of patients. This association was even higher in patients carrying both null-GSTT1 and -GSTM1 genotypes. The gene deletion of GSTs may predict not only the early onset of breast carcinoma but also the clinical response to chemotherapy and the recurrence-free survival for patients with lymph node-negative breast carcinoma.

BACKGROUND:Tumor necrosis factor-alpha (TNF-alpha) and stress proteins (heat shock proteins) are determining factors in the immune response to tumor cells. The authors designated a large study to investigate the susceptibility and prognostic implications of the genetic variation in TNF-alpha and hsp70-2 in breast carcinoma.METHODS:The authors used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the TNF-alpha promoter region and that of the hsp70-2 gene in 243 unrelated Tunisian patients with breast carcinoma and 174 healthy control subjects. Associations of the clinicopathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival and the disease free survival (DFS) were assessed using univariate and multivariate analyses.RESULTS:A highly significant association was found between TNF2 homozygous genotype and breast carcinoma (relative risk [RR], 4.44; P = 0.006). A high relative risk of breast carcinoma was found to be associated with one hsp70-2 homozygous genotype (P2/P2; RR, 7.12; P = 0.0001). The TNF2 homozygous genotype showed a significant association with reduced DFS and/or overall survival by univariate test. Conversely, P2-hsp70-2 homozygous genotype associated with increased overall survival but not with DFS. Multivariate analysis retained significance for TNF2 homozygous genotype as an independent prognostic indicator for both DFS (RR, 2.75; P = 0.01) and overall survival (RR, 4.08; P = 0.01).CONCLUSIONS:Genetic variation in TNF-alpha and hsp70-2 may represent not only markers for the increased risk of breast carcinoma but also may predict the clinical outcome.

Tumor necrosis factor‐α (TNF‐α) and stress proteins (heat shock proteins) are determining factors in the immune response to tumor cells. The authors designated a large study to investigate the susceptibility and prognostic implications of the genetic variation in TNF‐α and hsp70‐2 in breast carcinoma.