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The widespread use of pesticides, particularly in combinations, has resulted in enhanced hazardous health effects. However, little is known about their molecular mechanism of interactions. The aim of this study was to assess the neurotoxicity effect of pesticides in mixtures by adopting a 3D in vitro developed neurospheroid model, followed by treatment by increased concentrations of pesticides for 24 h and analysis by a shotgun proteomic-based approach with high-resolution tandem mass spectrometry. Three proteins, namely, glyceraldehyde-3-phosphate-dehydrogenase (GAPDH), α-enolase, and phosphoglycerate-kinase-1, were selected as key targets in the metabolic process. Only high doses of pesticides mitigated cell-density proliferation with the occurrence of apoptotic cells, which unlikely makes any neurological alterations in environmental regulatory exposures. The proteomic analysis showed that majority of altered proteins were implicated in cell metabolism. De novo peptide sequencing revealed ion losses and adduct formation, namely, a trityl-post-translational modification in the active site of 201-GAPDH protein. The study also highlights the plausible role of pyrethroids to be implicated in the deleterious effects of pesticides in a mixture. To the best of our knowledge, our finding is the first in toxicoproteomics to deeply elucidate pesticides' molecular interactions and their ability to adduct proteins as a pivotal role in the neurotoxicity mechanism.

Many inherited conditions cause hepatocellular cholestasis in infancy, including progressive familial intrahepatic cholestasis (PFIC), a heterogeneous group of diseases with highly overlapping symptoms. In our study, six unrelated Tunisian infants with PFIC suspicion were the subject of a panel-target sequencing followed by an exhaustive bioinformatic and modeling investigations. Results revealed five disease-causative variants including known ones: (the p.Asp482Gly and p.Tyr354 * in the ABCB11 gene and the p.Arg446 * in the ABCC2 gene), a novel p.Ala98Cys variant in the ATP-binding cassette subfamily G member 5 (ABCG5) gene and a first homozygous description of the p.Gln312His in the ABCB11 gene. The p.Gln312His disrupts the interaction pattern of the bile salt export pump as well as the flexibility of the second intracellular loop domain harboring this residue. As for the p.Ala98Cys, it modulates both the interactions within the first nucleotide-binding domain of the bile transporter and its accessibility. Two additional potentially modifier variants in cholestasis-associated genes were retained based on their pathogenicity (p.Gly758Val in the ABCC2 gene) and functionality (p.Asp19His in the ABCG8 gene). Molecular findings allowed a PFIC2 diagnosis in five patients and an unexpected diagnosis of sisterolemia in one case. The absence of genotype/phenotype correlation suggests the implication of environmental and epigenetic factors as well as modifier variants involved directly or indirectly in the bile composition, which could explain the cholestasis phenotypic variability., (© 2023 University College London (UCL) and John Wiley & Sons Ltd.)

Introduction: Castleman's disease (CD), known as angiofollicular lymph node hyperplasia, is an uncommon condition. The two most common histological subtypes are hyaline vascular and plasma cell. We performed a retrospective analysis to define the clinic-pathological features and survival of CD, which is quite rare focusing on the particularities of our series with a review of the recent literature., Methods: This is a retrospective study conducted in the department of internal medicine of Hedi Chaker hospital in Sfax, Tunisia over 25 years. The disease was histologically confirmed in all patients. For each file, we collected a set of data by filling in a pre-designed form., Results: 18 patients were included. There were 8 men and 10 women with a mean age of 42.8 years. CD was monocentric in 5 cases (28%) and multicentric in 13 cases (72%). Clinically, peripheral adenopathy was present in 77.7% of patients and deep adenopathy in 72.2%. Systemic signs were found in 13 patients, including general condition (4.4%), fever (16.6%), serositis (27.7%), and skin involvement (33.3%). A biological inflammatory syndrome accompanied the clinical picture in 66% of patients. Abnormalities in the blood count were found in 12 cases (66%), with anemia in 11 cases, thrombocytosis in 3 cases, and hypereosinophilia in 3 cases. Cutaneous Kaposi's sarcoma was associated with Castleman's disease in 2 cases, Hodgkin's lymphoma, angioimmunoblastic T-cell lymphoma, and lymph node T-cell lymphoma were found in 1 case respectively. 3 of the patients had associated connective tissue diseases such as Sjögren's syndrome in 2 cases and rheumatoid arthritis in 1 case. HHV8 serology was positive in 1 case with a multicentric plasma cell form. Histologically, the plasma cell form represented 50% of cases, hyaline-vascular (39% of cases), and mixed (11% of cases). Therapeutically, high-dose corticosteroid therapy was initiated in 13 cases. As a second-line treatment, MOPP chemotherapy was used in 1 case due to transformation into Hodgkin's lymphoma, and biotherapy (rituximab) was used in 2 cases in the multicentric form. Surgical removal of superficial adenopathy was performed in 2 patients with monocentric CD., Conclusion: : Castleman's disease (CD) is a non-malignant lymphoproliferation of localized or multicentric form with a wide and heterogeneous clinical spectrum. Diagnosis can be difficult due to the lack of clinical and radiological specificity. Management depends on the clinical form involving surgical and/or medical management., (© 2024 Imen Chabchoub et al., published by Sciendo.)

Pesticides are increasingly used in combinations in crop protection, resulting in enhanced toxicities for various organisms. Although protein adductomics is challenging, it remains a powerful bioanalytical tool to check environmental exposure and characterize xenobiotic adducts as putative toxicity biomarkers with high accuracy, facilitated by recent advances in proteomic methodologies and a mass spectrometry high-throughput technique. The present study aims to predict the potential neurotoxicity effect of imidacloprid and λ-cyhalothrin insecticides on human neural cells. Our protocol consisted first of 3D in vitro developing neurospheroids derived from human brain tumors and then treatment by pesticide mixture. Furthermore, we adopted a bottom-up proteomic-based approach using nanoflow ultraperformance liquid chromatography coupled with a high-resolution mass spectrometer for protein-adduct analysis with prediction of altered sites. Two proteins were selected, namely, calcium-calmodulin-dependent protein kinase-II (CaMK2) and annexin-A1 (ANXA1), as key targets endowed with primordial roles. De novo sequencing revealed several adduct formations in the active site of 82-ANXA1 and 228-CaMK2 as a result of neurotoxicity, predicted by the added mass shifts for the structure of electrophilic precursors. To the best of our knowledge, our study is the first to adopt a proteomic-based approach to investigate in depth pesticide molecular interactions and their potential to adduct proteins which play a crucial role in the neurotoxicity mechanism.

High-grade gliomas represent the most common group of infiltrative primary brain tumors in adults associated with high invasiveness, agressivity, and resistance to therapy, which highlights the need to develop potent drugs with novel mechanisms of action. The aim of this study is to reveal changes in proteome profiles under stressful conditions to identify prognostic biomarkers and altered apoptogenic pathways involved in the anticancer action of human isocitrate dehydrogenase (IDH) mutant high-grade gliomas. Our protocol consists first of a 3D in vitro developing neurospheroid model and then treatment by a pesticide mixture at relevant concentrations. Furthermore, we adopted an untargeted proteomic-based approach with high-resolution mass spectrometry for a comparative analysis of the differentially expressed proteins between treated and nontreated spheroids. Our analysis revealed that the majority of altered proteins were key members in glioma pathogenesis, implicated in the cellular metabolism, biological regulation, binding, and catalytic and structural activity and linked to many cascading regulatory pathways. Our finding revealed that grade-IV astrocytomas promote the downstream of the mitogen-activated-protein-kinases/extracellular-signal-regulated kinase (MAPK1/ERK2) pathway involving massive calcium influx. The gonadotrophin-releasing-hormone signaling enhances MAKP activity and may serve as a negative feedback compensating regulator. Thus, our study can pave the way for effective new therapeutic and diagnostic strategies to improve the overall survival.

Pesticides are widely used, resulting in continuing human exposure with potential health impacts. Some exposures related to agricultural works have been associated with neurological disorders. Since the 2000s, the hypothesis of the role of pesticides in the occurrence of central nervous system (CNS) tumors has been better documented in the literature. However, the etiology of childhood brain cancers still remains largely unknown. The major objective of this work was to assess the potential role of pesticide exposure as a risk factor for CNS tumors based on questionnaires and statistical analysis of information collected from patients hospitalized in the Neurosurgery Department of the Habib Bourguiba Hospital Medium in Sfax, Tunisia, during the period from January 1, 2022, to May 31, 2023. It also aimed to develop a simple and rapid analytical method by the gas chromatography-mass spectrometry technique for the research traces of pesticide metabolites in some collected human brain tumor tissues in order to more emphasize our hypothesis for such a correlation between pesticide exposure and brain tumor development. Patients with a history of high-risk exposure were selected to conduct further analysis. Chemometric methods were adapted to discern intrinsic variation between pathological and control groups and ascertain effective separation with the identification of differentially expressed metabolites accountable for such variations. Three samples revealed traces of pesticide metabolites that were mostly detected at an early age. The histopathological diagnosis was medulloblastoma for a 10-year-old child and high-grade gliomas for 27- and 35-year-old adults. The bivariate analyses (odds ratio >1 and P value <5%) confirmed the great probability of developing cancer by an exposure case. The Cox proportional hazards model revealed the risk of carcinogenicity beyond the age of 50 as a long-term effect of pesticide toxicity. Our study supports the correlation between pesticide exposure and the risk of development of human brain tumors, suggesting that preconception pesticide exposure, and possibly exposure during pregnancy, is associated with an increased childhood brain tumor risk. This hypothesis was enhanced in identifying traces of metabolites from the carbamate insecticide class known for their neurotoxicity and others from pyridazinone, organochlorines (OCs), triazole fungicide, and N-nitroso compounds known for their carcinogenicity. The 2D-OXYBLOT analysis confirmed the neurotoxicity effect of insecticides to induce oxidative damage in CNS cells. Aldicarb was implicated in brain carcinogenicity confirmed by the identification of oxime metabolites in a stress degradation study. Revealing "aziridine" metabolites from the OC class may better emphasize the theory of detecting traces of pesticide metabolites at an early age. Overall, our findings lead to the recommendation of limiting the residential use of pesticides and the support of public health policies serving this objective that we need to be vigilant in the postmarketing surveillance of human health impacts., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Background: The tumor phenotype may change between primary and metastatic breast cancer. We compared the expression of estrogen receptor (ER), progesterone receptor (PR), and HER2 in a series of primary breast carcinomas (PBC) with their metastatic relapses and analyzed the impact of any changes on survival., Materials and Methods: It was a single-center retrospective study, collecting consecutive cases of metastatic breast carcinoma diagnosed in the pathology and medical oncology departments at Habib Bourguiba University Hospital in Sfax, Tunisia. An immunohistochemical study was used to assess ER, PR, and HER2 expression. Overall survival (OS) and post-metastasis survival (PMS) were evaluated using multivariable Cox regression analysis., Results: Our study included 68 patients. ER and PR status changed in 29.4 % and 39.7 % of cases, respectively. Conversions were mainly from positive to negative status (22 % and 23.5 % for ER and PR, respectively). Differences in HER2 status were observed in 19.6 % of cases, with loss of overexpression in 6 patients (10.7 %). Adjuvant trastuzumab therapy and PBC molecular subtype (HR-, HER2+) were associated with HER2 status discordance (p = 0.02 and 0.03, respectively). On multivariable analysis, HR-negative conversion tumors were significantly associated with a worse OS (p = 0.042) and PMS (p < 0.001), compared to HR-concordant positive tumors., Conclusion: This study establishes that HR and HER2 status discordance between primary and metastatic breast carcinoma has a prognostic impact on patient outcome. Analyzing these receptors' status in all newly diagnosed cases of metastatic breast carcinoma is strongly recommended and would provide information for changing treatment strategies., Competing Interests: Conflict of interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Background: Breast cancer is the first female cancer worldwide. Its prognosis depends mainly on pathological stage and histological grade. These classical prognostic factors are essential but may be insufficient to predict the outcome of the disease. Research focuses on identifying new prognostic factors such as CD10, which is a cell surface metalloproteinase., Objective: This study aims to evaluate CD10 expression on stromal and tumor cells in invasive breast carcinomas and its correlations with other clinicopathological factors and survival., Methods: A series of 100 cases of breast carcinoma of no special type diagnosed from 2009 to 2011, was investigated in this study. CD10 expression was detected by immunohistochemistry. Stromal CD10 expression (=10% stromal positivity was considered positive) and tumor cells expression (=1% stained carcinomatous cells) were noted. Statistical correlations were analyzed with different known prognostic parameters; survival analysis were performed using SPSS 22.0., Results: Stromal CD10 expression was seen in 60% of the cases. It showed positive correlation with high tumor grade (p=0,012) and distant metastasis (p=0,02). CD10 expression on tumor cells was observed in 10% of the cases. It was associated with high tumor grade (p=0,009), hormone receptor negativity (estrogen receptor: p<0,0001), progesterone receptor: p=0,005), triplenegative phenotype (p=0,001), and Ki67 overexpression (p=0,046). Stromal CD10 expression was significantly associated to a shorter overall survival (p=0,029) and disease-free survival (p=0,05) in univariate analysis., Conclusion: Given these results, it can be concluded that CD10 expression predict an aggressive behavior of breast cancer. This marker can be introduced as a determinant prognostic factor.

Metastasis to the nasopharynx is a rare clinical entity. Breast carcinoma is one of the primary tumors that can be responsible for a nasopharyngeal metastasis, which is an extremely rare occurrence. We report the case of a 50-year-old woman with a history of a confirmed breast carcinoma under chemotherapy who presented to our department with a unilateral hearing loss and tinnitus. Nasal endoscopy revealed a small bulging mass at the posterior wall of the nasopharynx. The biopsy of the lesion showed an infiltration of the nasopharyngeal mucosa by a mammary adenocarcinoma that was positive for estrogen and progesterone receptors and negative for human epidermal growth factor receptor 2. Computed tomography scan revealed a thickening of the nasopharyngeal mucosa, a pleural and pericardial effusion and diffused secondary bone lesions. The patient received chemotherapy. Control revealed a partial regression of the nasopharyngeal mass. The patient is still under chemotherapy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hepatic injuries have been reported in patients with Coronavirus disease 2019 infection, particularly in those with moderate to severe illness. To date, pathological changes caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in liver tissue are unclear. Moreover, the mechanisms involved in liver injury in Coronavirus disease 2019 infection are not yet established. In this paper, we summarize the spectrum of pathologic findings of liver injury in patients infected by SARS-CoV-2 and we discuss the clinicopathological correlation and the mechanisms of liver damage in Coronavirus disease 2019 infection., Competing Interests: The authors declare no competing interest., (Copyright: Mouna Zghal et al.)

Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. In the present study, we reported a case of a 63-year-old woman, who presented a biliary pain beginning at the age of 30, recurrent after cholecystectomy, along with "comet-tail shadows" revealed by ultrasonography thus, fulfilling the diagnosis of LPAC. This disease evolved into a cholangiocarcinoma. To understand the molecular basis of this phenotype, we performed the ABCB4 gene sequencing, followed by in silico analysis and Q-RT-PCR assay. The results displayed a homozygous missense sequence variation (c.140G > A, p.Arg47Gln), predicted as pathogenic according to MutPred. Accordingly, this gave rise to a decreased hepatic ABCB4 mRNA level and structural alterations of the mutated protein. Eventually, we reported, here, the first description of an ABCB4 missense mutation (p.Arg47Gln) at homozygous state in a Tunisian LPAC syndrome. An elucidation of its functional consequences was performed. Besides, this case suggests that the delayed diagnosis of LPAC syndrome and the lack of UDCA treatment may contribute in the development of complications, such as cholangiocarcinoma., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The histopathological examination of cholecystectomy specimens has not been standardized with a debate concerning the routine and the selective approach. The aim of this study was to assess the information obtained from routine histopathological examination of cholecystectomy specimens., Methods: All histopathological reports of cholecystectomy specimens between January 2003 and December 2016 were analyzed, including a clinical diagnosis of benign gallstone disease or cholecystitis., Results: A total of 20,584 reports were examined. The mean age of patients was 54.2 years. Patients aged more than 60 years represent 37.6% of the study population. Of all patients, 15,973 (77.6%) were females. Incidental gallbladder cancers (GBC) were present in 155 cholecystectomies specimens (0.8%). 67.1% of GBC are at T2 and T3 stage. Granulomatous cholecystitis was diagnosed in only 19 cases (0.1%). GBC were more prevalent in older patients (P < 10 -6 ) and cholesterolosis was more prevalent in young patients (P < 10 -6 ). There was no gender predilection for GBC (P = 0.739)., Conclusions: The rate of incidental gallbladder carcinoma in our study is low, yet, we found a higher proportion of T2 and T3 carcinomas stage. Granulomatous cholecystitis may need further investigations and treatments. When a selective approch of histopathological examination of cholecystectomy specimens is used, it is important to take into account that clinical parameters are significantly associated with gallbladder cancer., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Microcystic urothelial carcinoma is a rare variant of invasive transitional cell carcinoma recognized by the WHO classification. It is characterized by its deceptively benign appearance. The clinical course of this uncommon variety of carcinoma is not well known and their histological and immunohistological features are not well defined. We report a case of a 37-year-old man with a microcystic transitional cell carcinoma of the urinary bladder. He was diagnosed 4 years ago with cystitis glandularis lesions and nephrogenic adenoma. Through this observation we will try to define the clinical and pathological features of this uncommon tumor which must be differentiated from a number of proliferative lesions of the urothelium. The poor prognosis and aggressiveness of this tumor seems to be related to a higher stage and grade at diagnosis., (© Copyright Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

The present study investigates the toxic effects of acrylamide (ACR) administered to rats at two doses on (i) oxidative stress and disruption of pro-oxidant/antioxidant balance in hepatic cells and (ii) its correlation with metallothioneins (MTs) genes expression, DNA damage and histomorphological changes. Treated rats with 20 and 40 mg/kg body weight of ACR led to an increase in malondialdehyde, hydrogen peroxide, advanced oxidation protein products, protein carbonyl levels as well as an alteration in the antioxidant status. Total MT content in the liver and MT I and MT II genes induction were increased. Plasma transaminases activities, albumin, total protein and glucose levels were also increased, while alkaline phosphatase activity was decreased. Moreover, total cholesterol (TC), triglyceride, low-density lipoprotein cholesterol (LDL-C) levels, TC/high-density lipoprotein cholesterol (HDL-C) and LDL-C/HDL-C ratios were increased, while HDL-C decreased in a dose-dependent manner. A random DNA degradation was observed only in the liver of ACR-treated rats with the highest dose. These changes were confirmed by histopathological observations.

Tubulo-papillary apocrine adenoma (TAA) is a very rare sweat gland tumor. TAA in association with syringocystadenoma papilliferum (SCP) is exceptional. A 2-year-old Tunisian child developed a mixed tumor on the scalp: TAA in association with SCP. Histologically, the tumor consisted of dilated duct-like areas with some apocrine gland-like areas. The superficial part of the tumor was connected to the epidermis and showed the characteristics of SCP. The characteristics and differences in histopathologic and immunohistochemical findings in this mixed tumor are described., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Background: Breast cancer is the most frequent malignant neoplasm affecting Tunisian women. It represents 25 to 35% of all female cancers. There is no published study about the features of Her-2 overexpressing breast carcinomas in North African women., Objective: The aim of this study is to assess the prognostic significance of pathological features in a cohort of a Her-2 overexpressing breast carcinoma originating from the region of south Tunisia., Methods: This study investigated a series of 100 patients followed from January 2006 to December 2011 for a Her-2 positive invasive breast carcinoma. Pathological features included in this study were: histological type, histological grade, tumor size, vascular invasion, perineural invasion, mitotic index, lymph nodes stage, positive lymph node capsular effraction, inflammatory infiltrates, nipple involvement and hormone receptors status., Results: Multivariate analysis showed that pT stage, pN stage, capsular effraction, vascular invasion, perineural invasion and Nipple involvement were independent prognostic factors for overall survival and disease free survival in patients free from distant metastasis at diagnosis. For patients with synchronous metastasis, there is no independent pathologic prognostic factor for survival., Conclusions: Our study demonstrates that pathological features are important prognostic factors for non metastatic Her-2 overexpressing breast carcinomas. This supports the idea that HER2-positive disease is a heterogeneous entity. We believe that these findings reinforce the need to identify molecular predictors of benefit and resistance to anti-Her-2 based therapies.