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We investigated the capacity of human islets to produce monocyte chemoattractant protein-1 (MCP-1). Primary cultures of pancreatic islets expressed and secreted MCP-1, as determined by Northern blot, immunohistochemistry, in situ hybridization, and enzyme-linked immunosorbent assay. The produced MCP-1 was biologically active as it attracted monocytes in chemotaxis assay, and chemotactic activity was almost abrogated by a neutralizing anti-MCP-1 monoclonal antibody. Expression of MCP-1 was increased by primary inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha) and lipopolysaccharide at both the mRNA and protein levels but not by glucose. However, MCP-1 did not modulate insulin secretion. MCP-1 secreted by pancreatic islets plays a relevant role in the clinical outcome of islet transplant in patients with type 1 diabetes. In fact, low MCP-1 secretion resulted as the most relevant factor for long-lasting insulin independence. This finding opens new approaches in the management of human islet transplantation. Finally, the finding that MCP-1 appears constitutively present in normal human islet beta-cells (immunohistochemistry and in situ hybridization), in the absence of an inflammatory infiltrate, suggests that this chemokine could have functions other than monocyte recruitment and opens a new link between the endocrine and immune systems. [ABSTRACT FROM AUTHOR]

In patients with advanced triple-negative breast cancer (TNBC), translational research efforts are needed to improve the clinical efficacy of immunotherapy with checkpoint inhibitors. Here, we report on the immunological characterization of an exceptional, long-lasting, tumor complete response in a patient with metastatic TNBC treated with dual PD-1 and LAG-3 blockade within the phase I/II study CLAG525X2101C (NCT02460224) The pre-treatment tumor biopsy revealed the presence of a CD3+ and CD8+ cell infiltrate, with few PD1+ cells, rare CD4+ cells, and an absence of both NK cells and LAG3 expression. Conversely, tumor cells exhibited positive staining for the three primary LAG-3 ligands (HLA-DR, FGL-1, and galectin-3), while being negative for PD-L1. In peripheral blood, baseline expression of LAG-3 and PD-1 was observed in circulating immune cells. Following treatment initiation, there was a rapid increase in proliferating granzyme-B+ NK and T cells, including CD4+ T cells, alongside a reduction in myeloid-derived suppressor cells. The role of LAG-3 expression on circulating NK cells, as well as the expression of LAG-3 ligands on tumor cells and the early modulation of circulating cytotoxic CD4+ T cells warrant further investigation as exploitable predictive biomarkers for dual PD-1 and LAG-3 blockade. Trial registration: NCT02460224. Registered 02/06/2015. [ABSTRACT FROM AUTHOR]

Background: Tumor microenvironment (TME) is a dynamic setting and changes in TILs and their subpopulations are potential candidates to influence the metastatic process. Aim of this pilot study is to describe the changes occurring between primary breast cancers and their paired metastases in terms of TILs composition. To assess if these changes influence the process of metastasis development, we used a control group of patients.Methods: We retrospectively identified 18 Luminal patients, for whom primary and metastatic tissue were available (cases) and 18 paired-matched patients (controls), not relapsed after at least 9 years of follow-up, and we quantified TILs and their composition (i.e. T CD8+ and CD4+/FOXP3+). The presence of TILs was defined as ≥10%.Results: Our results showed that the microenvironment composition of relapsed patients was poor of TILs (median = 5%, I-III quartiles = 0.6-5%), CD8+ (2.5%, 0-5%) and CD4+/FOXP3 + (0%, 0-0.6%) in the primary tumor. Comparable results were observed in their related metastases (TILs 3.8%, 0.6-5%; CD8+ 0%, 0-1.3%; CD4+/FOXP3+ 0%,0-1.9%). On the contrary, the microenvironment in the control group was richer of TILs (5%, 5-17.5%) in comparison to cases, both in primary tumor (p = 0.035) and related metastases (p = 0.018). Although CD8+ in controls were similar to cases at primary tumor (p = 0.6498), but not at metastasis (p = 0.0223), they expressed only one part on the TILs subpopulations (p = 0.0060), while TILs in the cases at primary tumor were almost completely CD8+ (p = 0.5034).Conclusions: These findings suggest that the lack of activation of immune system in the primary tumor might influence the multifactor process of cancer progression. [ABSTRACT FROM AUTHOR]

In the context of cervical cancer prevention, where human papillomavirus (HPV) infection is pivotal, HPV testing is replacing Pap Smear in primary screening. This transition offers an opportunity for integrating self-sampling to enhance coverage. We evaluated the accuracy of HPV testing using self-collected urine and vaginal samples, comparing them to physician-collected cervical swabs. From a cohort of 245 women with abnormal cytology, we collected self-sampled vaginal, urine, and clinician-administered cervical specimens. Employing Anyplex™II HPV28 assay, outcomes revealed HPV positivity rates of 75.1% (cervical), 78.4% (vaginal), and 77.1% (urine). Significant, hr-HPV detection concordance was observed between self-taken cervical samples and clinical counterparts (k = 0.898 for vaginal; k = 0.715 for urine). This study extends beyond accuracy, highlighting self-collected sample efficacy in detecting high-grade cervical lesions. The insight underscores self-sampling's role in bolstering participation and aligns with WHO's goal to eliminate cervical cancer by 2030. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite important advances in the understanding of the genetics of infant acute myeloid leukemia (AML), it is still unclear why this blood cancer has features that are distinct to adult AML. Infant AML can often have prenatal origins, but the cell of origin has not been conclusively determined. Using transgenic mice, we found that the introduction of the Mll-Af9 inter-chromosomal rearrangement in hematopoietic stem cell (HSC)-independent progenitors results in a transplantable myeloid leukemia. Thus, we hypothesize that the peculiar characteristics of embryonic hematopoiesis might play a key role in determining the disease phenotype and leukemic progression. Infant acute myeloid leukemia (AML) is a heterogeneous disease, genetically distinct from its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially common in affected infants of less than 1 year of age, and are associated with a dismal prognosis. While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively identified. This knowledge could lead to a better understanding of the biology of the disease and support the identification of new therapeutic vulnerabilities. Over the last few years, important progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis, which is instead largely sustained by HSC-independent progenitors. Here, we used conditional Cre-Lox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSC-independent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced leukemic transformation, and can likely act as cells of origin of infant AML. [ABSTRACT FROM AUTHOR]

The majority of patients with Follicular Lymphoma (FL) experience subsequent phases of remission and relapse, making the disease "virtually" incurable. To predict the outcome of FL patients at diagnosis, various clinical-based prognostic scores have been proposed; nonetheless, they continue to fail for a subset of patients. Gene expression profiling has highlighted the pivotal role of the tumor microenvironment (TME) in the FL prognosis; nevertheless, there is still a need to standardize the assessment of immune-infiltrating cells for the prognostic classification of patients with early or late progressing disease. We studied a retrospective cohort of 49 FL lymph node biopsies at the time of the initial diagnosis using pathologist-guided analysis on whole slide images, and we characterized the immune repertoire for both quantity and distribution (intrafollicular, IF and extrafollicular, EF) of cell subsets in relation to clinical outcome. We looked for the natural killer (CD56), T lymphocyte (CD8, CD4, PD1) and macrophage (CD68, CD163, MA4A4A)-associated markers. High CD163/CD8 EF ratios and high CD56/MS4A4A EF ratios, according to Kaplan–Meier estimates were linked with shorter EFS (event-free survival), with the former being the only one associated with POD24. In contrast to IF CD68+ cells, which represent a more homogeneous population, higher in non-progressing patients, EF CD68+ macrophages did not stratify according to survival. We also identify distinctive MS4A4A+CD163-macrophage populations with different prognostic weights. Enlarging the macrophage characterization and combining it with a lymphoid marker in the rituximab era, in our opinion, may enable prognostic stratification for low-/high-grade FL patients beyond POD24. These findings warrant validation across larger FL cohorts. [ABSTRACT FROM AUTHOR]

HPV testing in cervical cancer screening programs offers the possibility of introducing molecular standardized biomarkers for the triage of HPV-positive women. This study aimed to evaluate the role of HPV genotyping and viral load as possible diagnostic biomarkers of high-grade cervical lesions (CIN2+) by performing a preliminary evaluation of a new HPV test. Cervical specimens were obtained from 200 women referred for a colposcopy. Samples were tested using both Anyplex™ II HR-HPV as well as OncoPredict HPV® Screening (SCR) and quantitative typing (QT). Using a cycle threshold cutoff (Ct) of 36.8 for the SCR assay and 1.27 log10 (viral copies/104 cells) for the QT assay, relative clinical sensitivity for CIN2+ and relative clinical specificity for CIN2− as compared to Anyplex™ II HR-HPV were, respectively, 0.92 and 1.00 for SCR and 1.35 and 1.24 for QT. The distribution of high-risk HPV (HR-HPV) genotypes (p = 0.009) as well as the viral copy numbers (CIN2−: 3.7 log10 (viral copies/104 human cells); CIN2+: 4.3 log10 (viral copies/104 human cells); p = 0.047) were found to differ in women with high- and low-grade cervical lesions, suggesting a possible role of HPV genotyping and normalized viral load as potential biomarkers to identify women at increased risk of cervical lesions. [ABSTRACT FROM AUTHOR]

Background: To evaluate fluorescence cystoscopy with hexaminolevulinate (HAL) in the early detection of dysplasia (DYS) and carcinoma in situ (CIS) in select high risk patients. Methods: We selected 30 consecutive bladder cancer patients at high risk for progression. After endoscopic resection, all patients received (a) induction BCG schedule when needed, and (b) white light and fluorescence cystoscopy after 3 months. HAL at doses of 85 mg (GE Healthcare, Buckinghamshire, United Kingdom) dissolved in 50 ml of solvent to obtain an 8 mmol/L solution was instilled intravesically with a 12 Fr catheter into an empty bladder and left for 90 minutes. The solution was freshly prepared immediately before instillation. Cystoscopy was performed within 120 minutes of bladder emptying. Standard and fluorescence cystoscopy was performed using a double light system (Combilight PDD light source 5133, Wolf, Germany) which allowed an inspection under both white and blue light. Results: The overall incidence was 43.3% dysplasia, 23.3% CIS, and 13.3% superficial transitional cell cancer. In 21 patients, HAL cystoscopy was positive with one or more fluorescent flat lesions. Of the positive cases, there were 4 CIS, 10 DYS, 2 association of CIS and DYS, 4 well-differentiated non-infiltrating bladder cancers, and 1 chronic cystitis. In 9 patients with negative HAL results, random biopsies showed 1 CIS and 1 DYS. HAL cystoscopy showed 90.1% sensitivity and 87.5% specificity with 95.2% positive predictive value and 77.8% negative predictive value. Conclusion: Photodynamic diagnosis should be considered a very important tool in the diagnosis of potentially evolving flat lesions on the bladder mucosa such as DYS and CIS. Moreover, detection of dysplasic lesions that are considered precursors of CIS may play an important role in preventing disease progression. In our opinion, HAL cystoscopy should be recommended in the early follow-up of high risk patients. [ABSTRACT FROM AUTHOR]

This report describes a malignant neoplasia of the pineal region in a 65-year-old woman who presented with symptoms of intracranial hypertension and dissemination to CSF with radiologically documented lumbar intradural localizations. The histological examination of the lesion showed fragments of a cystic malignant neoplasia with epithelial elements resembling squamous cell carcinoma. We excluded the possibility of a cerebral metastasis from a squamous cell carcinoma arising in the genital or gastrointestinal tract, lung and skin. We propose this unique report for cyto- histological correlation and, as suggested in the American and Japanese literature, we discuss the hypothesis of the development of a squamous cell carcinoma arising from the malignant degeneration of a cerebral epidermoid cyst and we show by cytological examination of the CSF the exceptional presence of malignant cells and by lumbar MRI their intradural localizations. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present study was too investigate prevalence and persistence of human papilloma virus (HPV) and cytological abnormalities (CAs) in the anal swabs of people living with HIV (PLWH): men who have sex with men (MSM), men who have sex with women (MSW) and women (W). Methods: Between March 2010 and January 2019, an anal swab for cytological and HPV genotyping tests was offered to all PLWH attending our clinic. Logistic regression analysis was conducted to identify predictors of infection. Results: In all, 354 PLWH were screened: 174 MSM, 90 MSW and 61 W. Prevalence of at least one high‐risk (HR) HPV was higher in MSM (91%) and W (85%) than in MSW (77%) (P < 0.05). Cytological abnormalities were found in 21.1% of the entire population. At multivariable regression analysis a lower risk for HPV infection was found for W than for MSM [odds ratio = 0.24 (95% confidence interval: 0.115–0.513)] and for MSW than for MSM [0.37 (0.180–0.773)] and there was a significantly higher risk of CAs in PLWH with HPV 16 and 18 [3.3 (1.04–10.49)]. A total of 175 PLWH (103 MSM, 33 MSW and 26 W) had at least one follow‐up visit (T1) after a median (interquartile range) follow‐up of 3.6 (2.1–5.7) years. The acquisition rate of HR‐HPV was high, with 66.7% of PLWH negative for HR‐HPV at T0 who became positive at T1 (P < 0.001). The prevalence of CAs was stable (20.6%). A significant association between CAs at T1 and persistence of HPV‐16 and/or 18 was found (P < 0.05). Conclusions: HPV 16 and 18 are associated with the presence and development of CAs irrespective of sexual orientation. [ABSTRACT FROM AUTHOR]

The GNA15 gene is ectopically expressed in human pancreatic ductal adenocarcinoma cancer cells. The encoded Gα15 protein can promiscuously redirect GPCR signaling toward pathways with oncogenic potential. We sought to describe the distribution of GNA15 in adenocarcinoma from human pancreatic specimens and to analyze the mechanism driving abnormal expression and the consequences on signaling and clinical follow-up. We detected GNA15 expression in pre-neoplastic pancreatic lesions and throughout progression. The analysis of biological data sets, primary and xenografted human tumor samples, and clinical follow-up shows that elevated expression is associated with poor prognosis for GNA15, but not any other GNA gene. Demethylation of the 5′ GNA15 promoter region was associated with ectopic expression of Gα15 in pancreatic neoplastic cells, but not in adjacent dysplastic or non-transformed tissue. Down-modulation of Gα15 by shRNA or CRISPR/Cas9 affected oncogenic signaling, and reduced adenocarcimoma cell motility and invasiveness. We conclude that de novo expression of wild-type GNA15 characterizes transformed pancreatic cells. The methylation pattern of GNA15 changes in preneoplastic lesions coincident with the release a transcriptional blockade that allows ectopic expression to persist throughout PDAC progression. Elevated GNA15 mRNA correlates with poor prognosis. In addition, ectopic Gα15 signaling provides an unprecedented mechanism in the early steps of pancreas carcinogenesis distinct from classical G protein oncogenic mutations described previously in GNAS and GNAQ/GNA11. [ABSTRACT FROM AUTHOR]

Background: The protein ki67 (pki67) is a marker of tumor aggressiveness, and its expression has been proven to be useful in the prognostic and predictive evaluation of several types of tumors. To numerically quantify the pki67 presence in cancerous tissue areas, pathologists generally analyze histochemical images to count the number of tumor nuclei marked for pki67. This allows estimating the ki67-index, that is the percentage of tumor nuclei positive for pki67 over all the tumor nuclei. Given the high image resolution and dimensions, its estimation by expert clinicians is particularly laborious and time consuming. Though automatic cell counting techniques have been presented so far, the problem is still open. Results: In this paper we present a novel automatic approach for the estimations of the ki67-index. The method starts by exploiting the STRESS algorithm to produce a color enhanced image where all pixels belonging to nuclei are easily identified by thresholding, and then separated into positive (i.e. pixels belonging to nuclei marked for pki67) and negative by a binary classification tree. Next, positive and negative nuclei pixels are processed separately by two multiscale procedures identifying isolated nuclei and separating adjoining nuclei. The multiscale procedures exploit two Bayesian classification trees to recognize positive and negative nuclei-shaped regions. Conclusions: The evaluation of the computed results, both through experts' visual assessments and through the comparison of the computed indexes with those of experts, proved that the prototype is promising, so that experts believe in its potential as a tool to be exploited in the clinical practice as a valid aid for clinicians estimating the ki67-index. The MATLAB source code is open source for research purposes. [ABSTRACT FROM AUTHOR]

Abstract Background Atherosclerosis is a slowly progressing, chronic multifactorial disease characterized by the accumulation of lipids, inflammatory cells, and fibrous tissue that drives to the formation of asymmetric focal thickenings in the tunica intima of large and mid-sized arteries. Despite the high therapeutic potential of ApoA-1 proteins, the purification and delivery into the disordered organisms of these drugs is still limited by low efficiency in these processes. Methods and results We report here a novel production and delivery system of anti-atherogenic APOA-1Milano muteins (APOA-1M) by means of genetically modified rice plants. APOA-1M, delivered as protein extracts from transgenic rice seeds, significantly reduced macrophage activation and foam cell formation in vitro in oxLDL-loaded THP-1 model. The APOA-1M delivery method and therapeutic efficacy was tested in healthy mice and in Apoe −/− mice fed with high cholesterol diet (Western Diet, WD). APOA-1M rice milk significantly reduced atherosclerotic plaque size and lipids composition in aortic sinus and aortic arch of WD-fed Apoe −/− mice as compared to wild type rice milk-treated, WD-fed Apoe −/− mice. APOA-1M rice milk also significantly reduced macrophage number in liver of WD-fed Apoe −/− mice as compared to WT rice milk treated mice. Translational impact The delivery of therapeutic APOA-1M full length proteins via oral administration of rice seeds protein extracts (the ‘rice milk’) to the disordered organism, without any need of purification, might overcome the main APOA1-based therapies' limitations and improve the use of this molecules as therapeutic agents for cardiovascular patients. Highlights • A novel production and delivery system, via oral administration, of anti-atherogenic APOA-1Milano muteins (APOA-1M) • APOA-1M muteins expressed in rice seeds retained anti-atherogenic and anti-inflammatory properties in vitro and in vivo • Orally delivered full length APOA-1M proteins are athero-protective even if the organism is still exposed to high fat diet [ABSTRACT FROM AUTHOR]

Background: In the clinical practice, the objective quantification of histological results is essential not only to define objective and well-established protocols for diagnosis, treatment, and assessment, but also to ameliorate disease comprehension. Software: The software MIAQuant_Learn presented in this work segments, quantifies and analyzes markers in histochemical and immunohistochemical images obtained by different biological procedures and imaging tools. MIAQuant_Learn employs supervised learning techniques to customize the marker segmentation process with respect to any marker color appearance. Our software expresses the location of the segmented markers with respect to regions of interest by mean-distance histograms, which are numerically compared by measuring their intersection. When contiguous tissue sections stained by different markers are available, MIAQuant_Learn aligns them and overlaps the segmented markers in a unique image enabling a visual comparative analysis of the spatial distribution of each marker (markers' relative location). Additionally, it computes novel measures of markers' co-existence in tissue volumes depending on their density. Conclusions: Applications of MIAQuant_Learn in clinical research studies have proven its effectiveness as a fast and efficient tool for the automatic extraction, quantification and analysis of histological sections. It is robust with respect to several deficits caused by image acquisition systems and produces objective and reproducible results. Thanks to its flexibility, MIAQuant_Learn represents an important tool to be exploited in basic research where needs are constantly changing. [ABSTRACT FROM AUTHOR]

• Autopsy is fundamental to evaluate cases related to alleged medical claims. • Biventricular hypertrophy with normal blood pressure may suggest an amyloid cardiomyopathy. • AL (light chains) amyloidosis is the most common type of systemic amyloidosis. • Congo Red staining shows a yellow-green birefringence of amyloid under polarized light. • Immunohistochemistry identifies the amyloid deposits and the amyloid precursors. The authors present a case of fatal amyloid cardiomyopathy, which was diagnosed only upon autopsy. A 57-year-old man was admitted to the hospital for scheduled percutaneous cardiac procedure of transcatheter radiofrequency ablation due to persistent atrial fibrillation and atrial flutter. Ventricular fibrillation was recorded in the monitor 2 h after the surgical procedure. Therefore, he was defibrillated and intubated, but he died for nosocomial pneumonia 26 days after being admitted. A judicial autopsy was ordered by the prosecutor due to an alleged medical malpractice. The autopsy confirmed the cause of death being pneumonia, but also revealed an occult restrictive cardiomyopathy with a thick and firm myocardium. Viscera samples were then collected for microscopic examination. Histopathologic analysis showed diffuse amyloid deposits in the myocardium, especially in the perivascular and subendocardial spaces. Amyloid deposits were also detected in all the other organs, except for the brain. Furthermore, immunohistochemistry for light chains was performed on the heart tissue sample, resulting to be positive. In the case presented herein, autopsy and histopathologic examination were crucial to diagnose an occult systemic amyloidosis (AL-type). In fact, it has been observed that the rarity of systematic amyloidosis and its unusual clinical onset were at first mistakenly perceived as a medical malpractice due to a technical error within the catheter ablation for atrial fibrillation. As a consequence, upon discussing the clinical and medicolegal implications concerning the case, the focus was placed on the undiagnosed systemic amyloidosis and on the causality between surgical procedure and the patient's death. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Most strategies against intimal hyperplasia developed in several preclinical models failed in terms of clinical application, often due to a discrepancy between animal and human disease. The aim of this study was to setup for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis resembling human settings and investigate the pathogenetic role of hypercholesterolemia on protective genes and inflammatory response affecting matrix deposition and cell proliferation. Methods: Pigs were fed with standard (SD, n =7) or high-cholesterol diet (HCD, n =7) for 120 days. A balloon angioplasty injury was induced in carotid arteries. Results: Hypercholesterolemia induced a mild significant increase of total and LDL cholesterolemia. HCD significantly increased the degree of stenosis (48±3% vs. 13±4%, p =0.001), with induction of cell proliferation, matrix deposition, TGF-β1/TGFβRII and MMP2 expression and reduction of collagen. The reduced expression of the protective gene heme oxygenase-1 and inducible-nitric oxide synthase in HCD was associated to a systemic inflammation with a significant increase in circulating leukocytes, serum IFN-γ and TNF-α and a local inflammatory response with an increase of CD3-positive cell infiltrates. There was a significant correlation between CD3 infiltrates and the degree of stenosis. Conclusion: We developed for the first time a porcine vascular injury model with mild hypercholesterolemia able to significantly increase the degree of stenosis and showed the pathogenetic role of hypercholesterolemia on intimal hyperplasia. New therapeutical strategies to prevent restenosis can be tested in this preclinical hypercholesterolemic model resembling human disease. [Copyright &y& Elsevier]

Innate immunity cells play a crucial role in host anticancer defense: cancer patients with high levels of natural killer (NK) cells and eosinophils have a better prognosis. Recombinant interleukin-2 (rIL-2) immunotherapy stimulates innate immunity cells. This study aims to evaluate the toxicity of pre- and postoperative rIL-2 treatment and the effects on innate immunity both in peripheral blood and in cancer tissue of patients with resectable pancreatic adenocarcinoma. Seventeen patients received high dose rIL-2 preoperative subcutaneous administration and two low dose postoperative cycles. We evaluated NK cell and eosinophil count in blood and in pancreatic surgical specimens. Toxicity was moderate. In the early postoperative period, blood NK cells and eosinophils significantly increased compared to basal values ( p < 0.02). Histopathological analysis did not find significant intratumoral infiltration of NK cells nor of eosinophils. Preoperative high dose rIL-2 administration is able to counteract surgery-induced deficiency of NK cells and eosinophils in peripheral blood in the early postoperative period, although it cannot overcome local mechanisms of immune tumor escape in cancer tissue. The amplification of innate immunity, induced by immunotherapy, may improve the control of metastatic cells spreading in the perioperative period. [ABSTRACT FROM AUTHOR]

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins' synthesis and lipoproteins' assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins' levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a study regarding the use of the cytoplasmic protein β-catenin as immunohistochemical (IHC) staining morphologic marker in the diagnosis of papillary thyroid carcinoma (PTC).

Sporadic cases of a particular group of renal cancers associated with a translocation involving Xp11.2, known as the TFE3 transcription factor gene, have been reported in the last 20 years. The group was also classified in 2004 WHO kidney carcinoma classifications. A 79-year-old male patient was investigated at the outpatient department for gross intermittent hematuria. Sonography showed a spherical left kidney with increased total size, without evidence of the corticomedullary differentiation due to parenchymal dyshomogeneity with a neoplasm aspect. CT confirmed the sonographic left kidney findings and showed gross node involvement. Angiography did not show any pathological arterial circulation, but massive thrombotic involvement of the renal vein was evident. Radical nephrectomy with thrombectomy and staging lymphectomy were performed. At pathological examination the kidney parenchyma was completely substituted by white firm tissue. Microscopically the tumor was composed of papillary structures lined by epithelial cells with a clear cytoplasm. Multiple node metastases were found. Immunohistochemical examination showed negativity for epithelial markers (cytokeratin and epithelial membrane antigen) and reactivity for CD10 and TFE3. The genetic and histological aspects of this rare tumor are reported. In addition, we describe clinical, radiological and surgical findings. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods: The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results: miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions: Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. 4ZiY3nqT8xQ_yvPXVejWjw Video Abstract [ABSTRACT FROM AUTHOR]

In 2017, the WHO classification of tumours of the endocrine organs established the criteria for a NIFTP diagnosis. The present paper considers some aspects that are still debated or unresolved: the real incidence and clinical meaning of multifocal/multinodular lesions, the biological behaviour of micro-NIFTP, the sprinkling phenomenon and the corresponding modifications to the FNA reporting systems based on changes to the ROM. Moreover, the paper suggests possible scenarios for the clinical-pathological management of this entity. From the initial 1470 cases, a group of 68 NIFTPs was recruited in a 9 year-long period. The average age at diagnosis was 55 years. The average diameter of the lesion was 1.7 cm (0.1 cm–10 cm). In 41 cases (60.1%), the lesion was inserted in the context of a multinodular background. In 12 cases, the diagnosis was incidental and the pre- operative FNA was performed on a different target. In 10 out of 68 cases, there was a multifocal NIFTP; in 14.7% of patients, PTC-like nuclear features showed sprinkling phenomenon. The cytological revision allocated 21 cases (49%) to the SIAPEC TIR3 indeterminate class and a nuclear score 2 or 3 were identified in 25 smears. Multifocality is part of the spectrum of NIFTPs, that can arise in a multinodular background with variable sizes from microscopic lesions to very large ones. Cytopathological criteria such as an evaluation of the nuclear score may help the pathologists in promoting a NIFTP diagnosis in the preoperative setting. [ABSTRACT FROM AUTHOR]

The article discusses the implications of black pigment in human tissue for pathological diagnosis. It explains the need for a diagnostic pathologists to distinguish endogenous pigment from exogenous and artifactual pigments. The different conditions where black pigments can be found are cited, such as ochronosis, regional lymph nodes and lung lymph nodes. Radiographic images of a surgical specimen taken from a 70-year-old patient, that show black pigment, are also presented.

Objective:The aim of the present study was to comprehensively evaluate systemic and local inflammation as well as progression of vascular inflammation in normal and mechanically injured vessels in a large animal model of mild hypercholesterolemia. Our aim was also to test the effect of high-dose statin treatment on these processes. Methods:Pigs were kept for 120 days on a standard diet (SD, n=7), high-cholesterol diet (HCD, n=7) or high-cholesterol diet with Atorvastatin starting after 50 days (STATIN, n=7). Left carotid artery balloon injury was conducted in all groups after 60 days of diet treatment. Biochemical analysis together with evaluation of blood and tissue markers of vascular injury and inflammation were performed in all groups at the end of experiment. Results:HCD compared to SD induced systemic inflammation demonstrated by increased number of circulating monocytes and lymphocytes. HCD compared to SD induced also local inflammation demonstrated by adipocyte hypertrophy and infiltration of T-lymphocytes in abdominal white adipose tissue, activation of hepatic stellate cells with infiltration of T- and B-lymphocytes and macrophages in the liver and increased macrophage content in lung parenchyma. These changes were accompanied by increased Intima/Media thickness, stenosis, matrix deposition and activated T-cell infiltrates in injured but not in uninjured contralateral carotid artery as we previously reported. The treatment with high-dose statin attenuated all aspects of systemic and local inflammation as well as pathological changes in injured carotid artery. Conclusions:Diet related mild hypercholesterolemia induce systemic and local inflammation in the liver, lung and adipose tissue that coincide with enhanced inflammation of injured vessel but is without deleterious effect on uninjured vessels. High dose statin attenuated systemic and local inflammation and protected injured vessels. However, finding exact role of reduced systemic and remote inflammation in vascular protection requires further studies. [ABSTRACT FROM AUTHOR]

Summary Granuloma is a typical feature of tuberculosis. We evaluated the chemotaxis of selected human leucocyte subsets induced by macrophages incubated with Mycobacterium tuberculosis (MT)-derived products in vitro . The release of monocyte chemotactic protein 1 (MCP-1) and interleukin-8 (IL-8) correlated with the specific induction of strong chemotaxis towards monocytes and polymorphonuclear leucocytes (PMNs). γδ and T helper type 1 (Th1) αβ lymphocytes were chemoattracted, while T-resting, IL-2-activated and Th2 lymphocytes were unaffected. Activation with mycobacterium-derived, phosphate-containing components, modulated the chemokine receptor profile of γδ T lymphocytes as well as their pattern of cyto-chemokine production, disclosing a potential for their active participation in granuloma formation. In particular, CXCR3 and IP-10, which we found to be released by MT-pulsed alveolar macrophages, seem to represent the receptor–counter-receptor pair implicated in the chemotaxis of γδ lymphocytes. Immunohistochemical analysis and in situ hybridization revealed the in vivo presence of IL-8, MCP-1 and IL-10 in lymph node and lung tuberculous granulomas. Our results underscore the role of MT extracts in the induction of macrophage-derived chemokines responsible for the orchestrated recruitment of PMNs, monocytes, and Th1 and γδ T cells, as well as in the regulation of γδ function. [ABSTRACT FROM AUTHOR]