Alleviation of acetaminophen-induced liver failure using silibinin nanoliposomes: An in vivo study.

BACKGROUND: Acetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity. METHODS: We have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model. RESULTS: Data demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment. CONCLUSION: The results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.

Leiomyosarcoma, a rare smooth muscle cancer in the pancreas: An adjuvant radiotherapy treatment approach.

BACKGROUND: Leiomyosarcoma of visceral organs is uncommon, and pancreatic primary occurrence is even rarer. In terms of curative treatment, patients are generally managed with surgery alone, without significant data on the role or efficacy of adjuvant chemotherapy. CASE PRESENTATION: This manuscript presents a case of a 22-year-old female with advanced primary leiomyosarcoma of the pancreas, treated with radical surgery and adjuvant radiation therapy. CONCLUSION: With a low-survival rate, consideration of radiation therapy in some advanced and unresectable cases could be potentially beneficial.

Prognostic Significance of Integrin Subunit Alpha 2 (ITGA2) and Role of Mechanical Cues in Resistance to Gemcitabine in Pancreatic Ductal Adenocarcinoma (PDAC).

INTRODUCTION: PDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine. METHODS: The prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling. RESULTS: High ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT. CONCLUSIONS: ITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC.

Association of a Genetic Variant in the Cyclin-Dependent Kinase Inhibitor 2B with Risk of Pancreatic Cancer.

Background: Pancreatic cancer (PC) is among the most aggressive tumors with a poor prognosis, indicating the need for the identification of a novel prognostic biomarker for risk stratifications. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of different malignancies. Methods: In the present study, we explore the possible relationship between genetic variant, rs10811661, and gene expression of CDKN2B in 75 pancreatic cancer patients, and 188 healthy individuals. DNAs were extracted and genotyping and gene expression were performed by TaqMan real-time PCR and RT-PCR, respectively. Logistic regression was used to assess the association between risk and genotypes, while the significant prognostic variables in the univariate analysis were included in multivariate analyses. Results: The patients with PDAC had a higher frequency of a TT genotype for rs10811661 than the control group. Also, PDAC patients with dominant genetic model, (TT + TC), was associated with increased risk of developing PDAC (OR= 14.71, 95% CI [1.96-110.35], p= 0.009). Moreover, patients with CC genotype had a higher expression of CDKN2B, in comparison with TT genotype. Conclusion: Our findings demonstrated that CDKN2A/B was associated with the risk of developing PDAC, supporting further investigations in the larger and multicenter setting to validate the potential value of this gene as an emerging marker for PDAC.

A study on musculoskeletal complaints and working postures in pathology specialists in Iran.

BACKGROUND: Musculoskeletal disorders (MSDs) are one of the most common causes of occupational injuries and disabilities among health care workers. This study investigates the relationship between musculoskeletal complaints and pathologist postures in laboratories. METHOD: In this cross-sectional study, 40 pathologists were evaluated. MSDs in different body segments of the participants were evaluated by Nordic questionnaire. For postural analysis, 20 min film was recorded while using a microscope by subjects. Posture analysis was done by the Rapid Upper Limb Assessment (RULA) method and their repetitive movements were scored. The data was analyzed by SPSS Version 11.5. RESULTS: The mean age and duration of employment of subjects was 36.57 ± 7.54 years and 6.50 ± 6.30 years, respectively. Most MSDs were found in neck (65%), wrist (57.5%), upper back (50%) and lower back (47.5%). The mean RULA grand score was higher in participants with upper back and shoulder pain. A statistically significant relationship was found between the mean RULA grand, the upper back pain (P = 0.02) and the wrist pain (P = 0.003), as well as between the mean RULA B, the neck pain (P = 0.02) and the lower back pain (P = 0.05). The results showed a significant relationship between mean weekly working hours and tight (P < 0.001), wrist (p = 0.01) and ankle (P = 0.008). CONCLUSION: This study revealed high prevalence of MSDs among the pathologists. Therefore, performing ergonomic corrective actions is essential in order to improve their physical conditions at work.

Bone metastasis from noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); a case report.

BACKGROUND: The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a non-malignant thyroid lesion with indolent behavior that does not require post-operative radio-iodine treatment. We are reporting a case of NIFTP with bone metastasis that is the second case reported so far. CASE PRESENTATION: We describe a 38-year-old woman who presented with an indeterminate thyroid nodule and underwent total thyroidectomy with the finding of NIFTP on careful pathologic examination. However, her initial follow-up evaluation revealed a serum thyroglobulin level of > 300 ng/ml and a diagnostic whole body 131I scan demonstrated a focus of increased uptake in the left hemipelvis, confirmed on CT scan to be a lytic lesion in the left iliac bone. She was treated with 7.4GBq (200 mCi) of 131I and her follow-up 1 year later revealed an undetectable serum thyroglobulin and a negative whole body 131I scan with no visible uptake in the iliac bone indicating an excellent response. CONCLUSION: This case presentation reminds us to be alert to the rare occurrence of distant metastasis in NIFTP and the need for a case by case analysis and continuing post-operative follow-up for detection of residual or recurrent disease.

Nkx3-1 and Fech genes might be switch genes involved in pituitary non-functioning adenoma invasiveness.

Non-functioning pituitary adenomas (NFPAs) are typical pituitary macroadenomas in adults associated with increased mortality and morbidity. Although pituitary adenomas are commonly considered slow-growing benign brain tumors, numerous of them possess an invasive nature. Such tumors destroy sella turcica and invade the adjacent tissues such as the cavernous sinus and sphenoid sinus. In these cases, the most critical obstacle for complete surgical removal is the high risk of damaging adjacent vital structures. Therefore, the development of novel therapeutic strategies for either early diagnosis through biomarkers or medical therapies to reduce the recurrence rate of NFPAs is imperative. Identification of gene interactions has paved the way for decoding complex molecular mechanisms, including disease-related pathways, and identifying the most momentous genes involved in a specific disease. Currently, our knowledge of the invasion of the pituitary adenoma at the molecular level is not sufficient. The current study aimed to identify critical biomarkers and biological pathways associated with invasiveness in the NFPAs using a three-way interaction model for the first time. In the current study, the Liquid association method was applied to capture the statistically significant triplets involved in NFPAs invasiveness. Subsequently, Random Forest analysis was applied to select the most important switch genes. Finally, gene set enrichment (GSE) and gene regulatory network (GRN) analyses were applied to trace the biological relevance of the statistically significant triplets. The results of this study suggest that "mRNA processing" and "spindle organization" biological processes are important in NFAPs invasiveness. Specifically, our results suggest Nkx3-1 and Fech as two switch genes in NFAPs invasiveness that may be potential biomarkers or target genes in this pathology.

Characteristics of gastric precancerous conditions and Helicobacter pylori infection among dyspeptic patients in north-eastern Iran: is endoscopic biopsy and histopathological assessment necessary?

BACKGROUND: Early detection and appropriate treatment of precancerous, mucosal changes could significantly decrease the prevalence of life-threatening gastric cancer. Biopsy of the normal-appearing mucosa to detect Helicobacter pylori and these conditions is not routinely obtained. This study assesses the prevalence and characteristics of H. pylori infection and precancerous conditions in a group of patients suffering from chronic dyspepsia who were subjected to gastric endoscopy and biopsy mapping. METHODS: This cross-sectional study included dyspeptic patients, not previously treated for H. pylori, undergoing esophagogastroduodenoscopy (EGD) with their gastric endoscopic biopsies obtained for examination for evidence of H. pylori infection and precancerous conditions. Demographic and clinical data on the gender, smoking, opium addiction, alcohol consumption, medication with aspirin, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) and family history of cancer were collected by interviewing the patients and evaluating their health records. The cohort examined consisted of 585 patients with a mean (SD) age of 48.0 (14.46) years, 397 (67.9%) of whom were women. RESULTS: H. pylori infection was identified in 469 patients (80.2%) with the highest prevalence (84.2%) in those aged 40-60 years. Opium addiction correlated with a higher a H. pylori infection rate, while alcohol consumption was associated with a lower rate by Odds Ratio 1.98 (95% CI 1.11-3.52) and 0.49 (95% CI 0.26-0.92), respectively. The prevalence of intestinal metaplasia, gastric atrophy and gastric dysplasia was 15.2, 12.6 and 7.9%, respectively. Increased age, positive H. pylori infection, endoscopic abnormal findings and opium addiction showed a statistically significant association with all precancerous conditions, while NSAID consumption was negatively associated with precancerous conditions. For 121 patients (20.7% of all), the EGD examination revealed normal gastric mucosa, however, for more than half (68/121, 56.2%) of these patients, the histological evaluation showed H. pylori infection, and also signs of atrophic mucosa, intestinal metaplasia and dysplasia in 1.7, 4.1 and 1.7%, respectively. CONCLUSION: EGD with gastric biopsy mapping should be performed even in the presence of normal-appearing mucosa, especially in dyspeptic patients older than 40 years with opium addiction in north-eastern Iran. Owing to the high prevalence of precancerous conditions and H. pylori infection among patients with dyspepsia in parts of Iran, large-scale national screening in this country should be beneficial.

Prevalence of Mismatch Repair-Deficient Colorectal Adenoma/Polyp in Early-Onset, Advanced Cases: a Cross-Sectional Study Based on Iranian Hereditary Colorectal Cancer Registry.

BACKGROUND: Lynch syndrome (LS) increases the risk of many types of cancer, mainly colorectal cancer (CRC). The purpose of this study was to assess the prevalence of mismatch repair (MMR) deficiency in patients under the age of 50 with advanced adenomatous polyps, aiming at an early diagnosis of LS. METHODS: This retrospective, cross-sectional study included eligible patients with advanced adenomas diagnosed ≤ 50 years of age registered between April 2014 and February 2017 at three pathology centers in Mashhad. Pathological records were reviewed, and colon tissue specimens were analyzed by immunohistochemistry (IHC) staining to identify proteins which serve as markers for LS as they are related to loss of MMR gene (MLH1, MSH2, MSH6, and PMS2) expression. RESULTS: Of 862 consecutive patients, a total of 50 adenomas (54% males, 46% females of mean age 41.24 ± 6.5) met the eligibility criteria. Of the adenomas examined, 20 (40%) had a tubulovillous component, 34 (68%) had high-grade dysplasia, and 30 (60%) had were larger than 10 mm protrusions. None of the patients had loss of MMR protein expression. CONCLUSION: No individual with MMR genetic disorder was identified by IHC screening of early-onset advanced colorectal adenomas. This strategy is therefore not an effective strategy for detecting MMR mutation carriers.

Routine Multiple Duodenal Biopsy during Endoscopy of Dyspeptic Patients Seems Unnecessary for Screening of Celiac Disease.

INTRODUCTION: Celiac disease (CD) is a chronic and common cause of dyspepsia with a rising prevalence worldwide. This study is aimed at investigating the prevalence of CD in dyspeptic patients based on serology and biopsy, determining the associated factors, and assessing the necessity of regular duodenal biopsies from normal mucosa in diagnosis of CD among dyspeptic patients. METHODS: This cross-sectional study was performed on 530 adult dyspeptic patients who underwent gastroduodenoscopy in Imam Reza hospital, Mashhad, during 2016-2018. Demographic characteristics, clinical data, and laboratory analyses were extracted from hospital records. CD was diagnosed based on intestinal biopsy and serum antitissue transglutaminase (anti-TTG) levels. Mucosal lesions were classified according to the modified Marsh classification. Data were analyzed in SPSS with P < 0.05 being considered significant. RESULTS: Overall, 163 males (30.8%) and 367 females (69.2%) with an average age of 46.38 ± 15.54 years were studied. High anti-TTG levels were seen in 36 (6.8%) patients, and duodenal pathologies were seen in 23 (4.5%) patients. Fifteen (2.8%) were diagnosed with CD based on both serology and biopsy. Bloating was the most common type of dyspepsia in CD patients (7, 46.7%), followed by epigastric pain (6, 40%), and postprandial fullness (2, 13.3%). Two CD patients (13.3%) reported a positive family history for CD. Logistic regression model showed that iron deficiency anemia (IDA), anti-TTG level, and Helicobacter pylori infection were predictors of histological changes of CD, whereas IDA was the only independent predictor of CD in dyspeptic patients (OR = 17.65, 95%CI = 1.53-202.52, and P = 0.021). CONCLUSION: CD is prevalent in dyspeptic patients, but routine biopsy from normal-appearing duodenal mucosa is not recommended for all patients. Serological studies, complete history, and careful endoscopic evaluation may provide better cost-effective clinical solutions to improve the diagnostic yield of celiac disease in dyspeptic patients.

P53 expression in various types of hydropic placentas (through ploidy analysis as a complementary tool in diagnosis of samples).

BACKGROUND: Placentas characterized by hydropic swelling of chorionic villi occur in a spectrum of pathological conditions including hydropic abortion (HA), partial hydatidiform mole (PHM) and complete hydatidiform mole (CHM). The purpose of this study was to investigate whether the expression of p53 tumour suppressor protein could differentiate these various types of hydropic placentas. METHODS: p53 immunohistochemical staining was performed in 19 molar (8 PHM and 11 CHM) and 10 non-molar (HA) formalin-fixed, paraffin-embedded tissue samples. Ploidy analysis using flow cytometry was performed as a complementary tool in diagnosis of samples. RESULTS: DNA histograms obtained from all samples had confirmed diploidy in HAs and CHMs and triploidy in PHMs. p53 immunoreactivity was assessed in villous cytotrophoblasts, syncytiotrophoblasts and stromal cells. The p53 positive reaction was predominantly observed in the nuclei of cytotrophoblastic cells and rarely in stromal cells, no reaction was seen in syncytiotrophoblasts. The mean percentage of p53 positive cells were 6.10±3.75 for HA, 25.87±13.4 for PHM and 39.83±18.76 for CHM. There was a significant difference in P53 immunoreactivity of cytotrophoblastic cells between CHM and HA (P<0.001), and between PHM and HA (P=0.004). There was no significant difference in immunohistochemical reactivity between CHM and PHM (P=0.068). CONCLUSION: This study confirms that p53 immunostaining may be helpful in distinguishing complete and partial hydatidiform mole from hydropic abortion, but not complete hydatidiform mole from partial hydatidiform mole.

Prevalence and clinicopathological characteristics of mismatch repair-deficient colorectal carcinoma in early onset cases as compared with late-onset cases: a retrospective cross-sectional study in Northeastern Iran.

OBJECTIVES: Lynch syndrome (LS), a genetically inherited autosomal disorder, increases the incidence of colorectal carcinoma (CRC). We aimed to perform a universal strategy to assess the prevalence and clinicopathological characteristics of early onset CRCs at high risk of LS versus late-onset ones in the Iranian population. SETTING: A local population-based study from Northeastern Iran. PARTICIPANTS: 321 consecutive CRCs and pathology specimen screened between 2013 and 2016. PRIMARY AND SECONDARY OUTCOME MEASURES: Retrospectively, information regarding the clinical criteria was obtained by interviewing the patients with CRC or, their families. Pathologists tested tumours with immunohistochemistry (IHC) staining of four mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Tumours with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs. Prevalence of early onset CRCs at high risk of LS and familial CRC type X were assessed as primary and secondary outcome measures, respectively. RESULTS: Of 321 CRCs (13/123 (10.57%), early onset vs 21/198 (10.6%) late-onset) were detected to be MMR-deficient (dMMR). Nine early onset cases and 14 late-onset ones with a loss of MLH1 underwent testing for the BRAF mutation, none of the early onset and four (2.02%) late-onset were recognised as sporadic. The difference in the outcome of IHC-analysis between early and late-onset CRCs at high risk of LS was not statistically significant (p=0.34). Majority of the suspected LS tumours from early onset patients had arisen in distal part (8/11 (72.72%) vs 8/14 (57.14%)), all of which were occurred in the rectum or sigmoid. CONCLUSION: Clinically, these findings suggest that in case of limitation for BRAF testing, the practitioner in Iran may consider managing early onset dMMR cases like LS until access to BRAF testing becomes available to them, before germline testing to accurately diagnose LS.

Bilateral Conjunctival Infiltration as an Extramedullary Relapse of AML.

Acute myelogenous leukemia (AML) accounts for 1.2% of all cancer deaths. Relapse is the major cause of treatment failure in acute myeloid leukemia (AML) patients. AML rarely presents as ocular manifestation in relapse or at presentation. The M4 subtype of AML is most commonly presented with extramedullary involvement. In this report, we presented a young female with AML who was diagnosed and treated for AML about 40 months ago. She did not transplant because she did not have a full-match donor. About 4 months ago, she visited with a red eye and conjunctival infiltration. She was referred to an ophthalmologist for a biopsy, and the pathology report showed the relapse of AML which was treated with systemic chemotherapy. Red eyes with subconjunctival nodules in patients with a history of previous AML should raise the suspicion for recurrent disease that warrants urgent biopsy and systemic treatment. Eye involvement with leukemia is usually responsive to systemic chemotherapy.

Five chambered heart: case of a huge left atrial appendage aneurysm.

Aneurysmal enlargement of the left atrial appendage is an extremely rare pathology and can predispose to adverse events, including cardiac arrest, respiratory distress, arrhythmia, heart failure, systemic thromboembolism, or rupture. It is usually diagnosed incidentally or after the occurrence of atrial tachyarrhythmias or thrombotic events in the second to fourth decades of life. We describe a rare case of a symptomatic giant congenital left atrial appendage aneurysm (LAAA) in a 26-year-old man presenting with neurologic event, in whom surgical resection of the aneurysm was successfully performed. This is the largest LAAA reported in the literature so far.

Correction to: Laminin-derived Ile-Lys-Val-ala-Val: a promising bioactive peptide in neural tissue engineering in traumatic brain injury.

There is only one problem with Table 3. The references mentioned in this table were wrong in the final proof.

Laminin-derived Ile-Lys-Val-ala-Val: a promising bioactive peptide in neural tissue engineering in traumatic brain injury.

The adult brain has a very limited regeneration capacity and there is no effective treatment currently available for brain injury. Neuroprotective drugs aim to reduce the intensity of cell degeneration but do not trigger tissue regeneration. Cell replacement therapy is a novel strategy to overcome brain injury-induced disability. To enhance cell viability and neuronal differentiation, developing bioactive scaffolds combined with stem cells for transplantation is a crucial approach in brain tissue engineering. Cell interactions with the extracellular matrix (ECM) play a vital role in neuronal cell survival, neurite outgrowth, attachment, migration, differentiation, and proliferation. Thus, appropriate cell-ECM interactions are essential when designing and modifying scaffolds for application in neural tissue engineering. To improve cell-ECM interactions, scaffolds can be modified with bioactive peptides. Here, we discuss the characteristic features of laminin-derived Ile-Lys-Val-Ala-Val (IKVAV) sequence as a bio-functional motif in scaffolds and the behavior of stem cells in scaffolds conjugated with the IKVAV peptide. The incorporation of this bioactive peptide in nanofiber scaffolds markedly improves stem cell behavior and may be a potential method for cell replacement therapy in traumatic brain injury.

Nonocclusive mesenteric ischemia after renal transplantation: A case report and literature review.

Nonocclusive mesenteric ischemia (NOMI) is a very rare occurrence after renal transplantation. This disorder is difficult to diagnose and can even be fatal. We describe a 51- year-old man with end-stage renal disease who developed intestinal ischemia and infarction due to NOMI three days after deceased donor kidney transplantation, which was managed success- fully and his renal graft function was saved. To the best of our knowledge, this is one of the few cases of NOMI occurring after renal transplantation reported in the literature.

Bacille Calmette-Guérin Osteomyelitis.

BACKGROUND: Tuberculosis is an essential problem for healthcare systems especially in developing countries. All newborns are given Bacillus Calmette-Guérin (BCG) vaccine in Iran which is prepared from live bovine tuberculosis bacillus, and is given to protect against tuberculosis. Osteomyelitis secondary to BCG vaccination is rare and usually involves epiphysis of long tubular bones. METHODS: 4 patients, 3 males and a female entered this study and were between 11 to 24 months old. The involved bones were first metatarsi, talus, humerus and tibia bone. The main radiologic finding was lytic lesion with cortical destruction and periosteal reaction. RESULTS: 3 patients underwent core needle biopsy and the one with the proximal tibia involvement, underwent open surgery. Pathology report suggested granulomatous osteomyelitis and typical caseous necrosis compatible with tuberculosis. Surgical treatment for these patients was curettage and debridement of the bone lesion and involved tissues around. The patients got standard anti TB pharmacotherapy, were completely cured and no short term complication was seen in a one year follow up. CONCLUSION: BCG osteomyelitis and cold abscess, should be kept in mind when assessing a child presenting chronic symptoms like pain, limping or local swelling of extremities. The long interval time between BCG vaccination and outbreak of the culture-negative abscess is a major point which emphasizes on pathologic evaluation. Image guided tissue biopsy and PCR studies confirm diagnosis. Early use of a surgical curettage and debridement along with chemotherapy soon afterwards, enabled these children to enjoy a satisfactory clinical outcome.