Chasing Graphene-Based Anticancer Drugs: Where are We Now on the Biomedical Graphene Roadmap?

Graphene and graphene-based materials have attracted growing interest for potential applications in medicine because of their good biocompatibility, cargo capability and possible surface functionalizations. In parallel, prototypic graphene-based devices have been developed to diagnose, imaging and track tumor growth in cancer patients. There is a growing number of reports on the use of graphene and its functionalized derivatives in the design of innovative drugs delivery systems, photothermal and photodynamic cancer therapy, and as a platform to combine multiple therapies. The aim of this review is to introduce the latest scientific achievements in the field of innovative composite graphene materials as potentially applied in cancer therapy. The "Technology and Innovation Roadmap" published in the Graphene Flagship indicates, that the first anti-cancer drugs using graphene and graphene-derived materials will have appeared on the market by 2030. However, it is necessary to broaden understanding of graphene-based material interactions with cellular metabolism and signaling at the functional level, as well as toxicity. The main aspects of further research should elucidate how treatment methods (e.g., photothermal therapy, photodynamic therapy, combination therapy) and the physicochemical properties of graphene materials influence their ability to modulate autophagy and kill cancer cells. Interestingly, recent scientific reports also prove that graphene nanocomposites modulate cancer cell death by inducing precise autophagy dysfunctions caused by lysosome damage. It turns out as well that developing photothermal oncological treatments, it should be taken into account that near-infrared-II radiation (1000-1500 nm) is a better option than NIR-I (750-1000 nm) because it can penetrate deeper into tissues due to less scattering at longer wavelengths radiation.

Recommendations of the Polish Association of Neuropathologists on performing post-mortem examination of the brain and spinal cord.

Neuropathological central nervous system (CNS) post-mortem examination is a highly specialistic element of the autopsy procedure with methodological specificity. Herein we propose updated recommendations for CNS autopsy for pathologists and neuropathologists. The protocol includes the compendium of neuroanatomy with current nomenclature, consecutive steps of gross examination, as well as appropriate sampling algorithms in different clinical and pathological settings. The significance of pathoclinical cooperation in differential diagnosis is exposed. We believe it is essential to create and promote the guidelines to improve the quality of CNS post-mortem examination at the national level.

Neuropeptide Y and its receptors in prostate cancer: associations with cancer invasiveness and perineural spread.

PURPOSE: Neuropeptide Y (NPY) is a pleiotropic peptide, which is involved in many biological mechanisms important in regulation of cell growth and survival. The aim of this study was a comprehensive analysis of the NPY system in prostate pathology. METHODS: The study was based on immunohistochemical analysis of NPY and its receptors, Y1R, Y2R and Y5R, in tissue samples from benign prostate (BP), primary prostate cancer (PCa) and PCa bone metastases. Tissue microarray (TMA) technique was employed, with analysis of multiple cores from each specimen. Intensity of the immunoreactivity and expression index (EI), as well as distribution of the immunostaining in neoplastic cells and stromal elements were evaluated. Perineural invasion (PNI) and extraprostatic extension (EPE) were areas of special interests. Moreover, a transwell migration assay on the LNCaP PCa cell line was used to assess the chemotactic properties of NPY. RESULTS: Morphological analysis revealed homogeneous membrane and cytoplasmic pattern of NPY staining in cancer cells and its membrane localization with apical accentuation in BP glands. All elements of the NPY system were upregulated in pre-invasive prostate intraepithelial neoplasia, PCa and metastases. EI and staining intensity of NPY receptors were significantly higher in PCa then in BP with correlation between Y2R and Y5R. The strength of expression of the NPY system was further increased in the PNI and EPE areas. In bone metastases, Y1R and Y5R presented high expression scores. CONCLUSION: The results of our study suggest that the NPY system is involved in PCa, starting from early stages of its development to disseminated states of the disease, and participates in the invasion of PCa into the auto and paracrine matter.

"Neuropatologia Polska". The journal and its topics in the first decade of existence (1963-1972).

In this article authors would like to present the history of the "Neuropatologia Polska" journal (since 1994: "Folia Neuropathologica") in its first decade of existence. It outlines the circumstances surrounding the creation of the journal and shows how it evolved in the first years. The vast material analysed from the consecutive issues of the journal in the years from 1963 to 1972 was subjected to statistical and content analysis. From its first year, the journal has included works of a very high substantive level and a wide range of topics. The authors presented the results of contemporary research in many areas. The "Neuropatologia Polska" journal (later "Folia Neuropathologica") set paths for the development of neuropathology in clinical and experimental aspects. What is very important, it created a platform for international cooperation in many fields, included researchers and scientists from Western countries and foreign academic centres in difficult times. This article was created on the 60th anniversary of creation of "Neuropatologia Polska".

Hypoxic hepatitis as a complication of newly diagnosed type 1 diabetes in a teenager.

Hypoxic hepatitis is a rare complication of type 1 diabetes with unknown prevalence in Pediatrics. We present a case report of an 11-year-old boy admitted to the ER in the spring of 2020 (the beginning of the COVID19 pandemic in Poland) due to nausea, abdominal pain, and weight loss. A diagnosis of type 1 diabetes accompanied by severe ketoacidosis (pH 6.9, blood glucose 632mg/dl, ketone bodies in urine - 150mg/dl) was made. The hyperglycemia, ketoacidosis, and water-electrolyte disturbances were treated in the Pediatric Intensive Care Unit. On day 4, the boy developed fulminant septic shock with high aminotransferases (AST 9026 U/l, ALT 3559 U/l). CT scan revealed hepatic enlargement and steatosis. Acute viral hepatitis was suspected. The levels of anti-CMV IgM and IgG antibodies were slightly elevated. At autopsy, the liver was enlarged, with petechial bleedings on the surface. The liver parenchyma was congested, with signs of steatosis. Microscopically, there was extensive centrilobular necrosis, acute passive sinusoidal congestion, and steatosis of hepatocytes. There were no signs of CMV infection. Based on the entire clinicopathological picture, the patient was diagnosed with hypoxic hepatitis, complicated by septic shock and multiple organ failure.

Voices from the past: results of the ESP history of pathology working group survey on pathology museums.

While keeping their original purpose of training medical students, pathology museums hold great biological value, offering unique specimens for scientific research through modern radiological, pathological and biomolecular techniques. Moreover, the artefacts, models and drawings displayed in these museums are a precious cultural and artistic heritage. Preservation of the anatomical samples and maintenance of the facilities are neither easy nor inexpensive and call for patronage. The development of a European Pathology Museum Network would undoubtedly facilitate study, access and divulgation of antique pathology collections. Data from a survey conducted by the European Society of Pathology (ESP) History of Pathology Working Group have allowed creation of a comprehensive, multifaceted portrait of European university museums, reflecting their history, diversity, geography, institutional status, stakeholders, projects, professionals, audiences, policies and best practices.

Central nervous system autopsy - a neuropathological procedure based on multidisciplinary pathoclinical cooperation.

INTRODUCTION: Neuropathological brain and spinal cord post mortem examination is a distinct procedure that still plays an important role in modern medicine. In front of increasing amounts of clinical and genetic data, together with important developments in the field of neuroimaging, the Polish Association of Neuropathologists have updated their recommendations regarding central nervous system (CNS) examination. These guidelines are aimed at neuropathologists, pathologists and clinicians. AIM OF THE STUDY: Presentation of the outlined recommendations as their goal is to improve the quality, informativity, and cost effectiveness of CNS post mortem examinations. A comprehensive study of the literature was conducted to provide a clinical background of neuropathological autopsy. There are numerous open questions in neuroscience, and new strategies are required to foster research in CNS diseases. These include the challenge of organizing brain banks tasked with managing and protecting detailed multidisciplinary information about their resources. Complex neuropathological analyses of post mortem series are also important to assess the effectiveness of diagnostics and therapy, identify environmental impact on the development of neurological disorders, and improve public health policy. The recommendations outline the need for collaboration between multiple specialists to establish the proper diagnosis and to broaden knowledge of neurological disorders.

Code of practice for medical autopsies: a minimum standard position paper for pathology departments performing medical (hospital) autopsies in adults.

The medical autopsy (also called hospital or clinical autopsy) is a highly specialised medical procedure, which requires professional expertise and suitably equipped facilities. To ensure high standards of performance, the Working Group of Autopsy Pathology of the European Society of Pathology (ESP) suggests a code of practice as a minimum standard for centres performing medical autopsies. The proposed standards exclusively address autopsies in adults, and not forensic autopsies, perinatal/or paediatric examinations. Minimum standards for organisation, standard of premises, and staffing conditions, as well as minimum requirements for level of expertise of the postmortem performing specialists, documentation, and turnaround times of the medical procedure, are presented. Medical autopsies should be performed by specialists in pathology, or by trainees under the supervision of such specialists. To maintain the required level of expertise, autopsies should be performed regularly and in a number that ensures the maintenance of good practice of all participating physicians. A minimum number of autopsies per dedicated pathologist in a centre should be at least 50, or as an average, at least one autopsy per working week. Forensic autopsies, but not paediatric/perinatal autopsies may be included in this number. Turnaround time for final reports should not exceed 3 weeks (14 working days) for autopsies without fixation of brain/spinal cord or other time-consuming additional examinations, and 6 weeks (30 working days) for those with fixation of brain/spinal cord or additional examinations.

Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors.

BACKGROUND: Cancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear. METHODS: The present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients' age, tumor stage, grade, angioinvasion, and ERG status were examined. RESULTS: The study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression. CONCLUSIONS: The analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.

COVID-19 - neuropathological point of view, pathobiology, and dilemmas after the first year of the pandemic struggle.

This article constitutes a summary of the knowledge on the involvement of the nervous system in COVID-19, concerning its general pathobiology, clinical presentation and neuropathological features as well as the future directions of investigation. Variable definitions, selection bias, mainly retrospective analyses of hospitalized patients and different methodologies are implemented in the research of this new disease. Central nervous system (CNS) pathology presents most frequently features of non-specific neuroinflammation with microglial activation and lymphoid infiltrations, ischemic/hypoxic encephalopathy, acute cerebrovascular disease, and microthrombi. Some brain specimens remain unaffected or show only non-specific changes of the critical status. Interpretations of the neuropathological findings are not always balanced in a clinical context and discrepant in consequence. Designing of longitudinal neuropathological studies, more frequent autopsies, and building of COVID-19 brain banks, together with neuroimaging analyses is essential. Genetic predispositions or immunological factors corresponding to the disease profile as well as cerebrospinal fluid (CSF) or serum biomarkers of COVID-19, the impact of different virus variants and influence of the therapy need to be identified. The mechanisms causing neuroCOVID and cognitive impairment - whether they are infectious, toxic, vascular or metabolic - create other aspects under research. There are also many existential questions about post-COVID and delayed sequelae of the infection. The fight with pandemic is a challenge for the global society, with neuropathologists and neuroscientists as important allies in struggle for understanding and conquering COVID-19.

"Old School" Islet Purification Based on the Unit Gravity Sedimentation as a Rescue Technique for Intraportal Islet Transplantation-A Case Report.

Here, we present a case that required a supplemental "old school" islet purification for a safe intraportal infusion. Following pancreas procurement from a brain-dead 26-year-old male donor (body mass index: 21.9), 24.6 ml of islet tissue was isolated after continuous density gradient centrifugation. The islet yield was 504,000 islet equivalent (IEQ), distributed among the following three fractions: 64,161 IEQ in 0.6 ml of pellet, 182,058 IEQ in 10 ml, and 258,010 IEQ in 14 ml with 95%, 20%, and 10% purity, respectively. After a 23-h culture, we applied supplemental islet purification, based on the separation of tissue subfractions during unit gravity sedimentation, a technique developed over 60 years ago ("old school"). This method enabled the reduction of the total pellet volume to 11.6 ml, while retaining 374,940 IEQ with a viability of over 90%. The final islet product was prepared in three infusion bags, containing 130,926 IEQ in 2.6 ml of pellet, 108,079 IEQ in 4 ml of pellet, and 135,935 IEQ in 5 ml of pellet with 65%, 40%, and 30% purity, respectively, and with the addition of unfractionated heparin (70 units/kg body weight). Upon the islet infusion from all three bags, portal pressure increased from 7 to 16 mmHg. Antithrombotic prophylaxis with heparin was continued for 48 h after the infusion, with target activated partial thromboplastin time 50-60 s, followed by fractionated heparin subcutaneous injections for 2 weeks. ß-Cell graft function assessed on day 75 post-transplantation was good, according to Igls criteria, with complete elimination of severe hypoglycemic episodes and 50% reduction in insulin requirements. Time spent within the target glucose range (70-180 mg/dl) improved from 42% to 98% and HbA1c declined from 8.7% to 6.7%. Supplemental "old school" islet purification allowed for the safe and successful utilization of a robust and high-quality islet preparation, which otherwise would have been discarded.

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer.

The tumor microenvironment (TME) plays an essential role in the development and progression of neoplasms. TME consists of the extracellular matrix and numerous specialized cells interacting with cancer cells by paracrine and autocrine mechanisms. Tumor axonogenesis and neoneurogenesis constitute a developing area of investigation. Prostate cancer (PC) is one of the most common malignancies in men worldwide. During the past years, more and more studies have shown that mechanisms leading to the development of PC are not confined only to the epithelial cancer cell, but also involve the tumor stroma. Different nerve types and neurotransmitters present within the TME are thought to be important factors in PC biology. Moreover, perineural invasion, which is a common way of PC spreading, in parallel creates the neural niche for malignant cells. Cancer neurobiology seems to have become a new discipline to explore the contribution of neoplastic cell interactions with the nervous system and the neural TME component, also to search for potential therapeutic targets in malignant tumors such as PC.

Limb body wall complex - the history of the entity and presentation of our series of cases.

We present an analysis of two first historically documented limb body wall complex (LBWC) cases and our own contemporary perinatal autopsy series of this rare complex. So far it was supposed that the first case of this complex was reported in 1685 by Paul Portal. Studying the Joachim Oelhaf's autopsy report from 1613 with attached engraving showing the neonate with multiple birth defects led our research team to a conclusion that it was genuinely the first description of LBWC in the medical literature so far. We compared the Oelhaf's case from 1613 and the Portal's autopsy report from 1685 with our series of LBWC cases dissected in the Medical University of Gdansk between 1999 and 2011. Reviewing 1100 autopsy reports performed we encountered 9 cases of this unique complex. The analysis was supported by the literature review.

Anatomopathological research in nineteenth-century Gdansk - an outline of the problem.

Between 1793 and 1914, there were many internationally recognised physicians active in Gdansk. Their scientific activities included, among other things, anatomopathological research, constituting a determinant of progress in medical sciences during this period. One of the most important people was Martin Heinrich Rathke (1793-1860). He is recognised as one of the founders of modern embryology. In Gdansk Rathke's successor was Wilhelm Baum (1799-1883). Baum introduced compulsory post-mortem examinations in the city hospital even after the outbreak, and he was mentor to Theodor Billroth (1829-1894). The successor of Baum as the head of the city hospital was Emil Friedrich Götz (1806-1858). He took up an important topic, which was the consent of the family of the deceased to perform an autopsy. Furthermore, it described the gradual broadening of the scope of anatomopathological activities, consistent with the postulates of the first and second Viennese school, performed in Gdansk in the nineteenth century. However, a detailed analysis of the relationship between the discoveries of nineteenth-century medicine, especially in the field of pathological anatomy, and research carried out in Gdansk, remains in the sphere of research to be done.

Endometrial glial polyp and peritoneal gliomatosis: Neuropathological lesions in gynecological biopsy.

The wide scope of neuropathology is also connected to different systemic pathology findings. Neuroectodermal-type female genital tract lesions are not frequent. This article presents a short review of such entities in gynecological pathology and reports on two rare cases. The first described lesion is an endometrial glial polyp in a young woman. The second is a mature cystic teratoma accompanied by a peritoneal gliomatosis in an adolescent girl. Both presented entities posed diagnostic difficulties from the clinical and pathological perspective. They demanded careful sampling, immunophenotyping, as well as neuropathological consultation.

An insight into the history of anatomopathological museums. Part 2.

The second part of the comprehensive work concerning pathology museums and collections presents their history since the 19th century. The evolution and specialisation of museums, depending on the attitude of their creators and geographic localization, have been analysed. The changing aspects of obtaining the exhibits and how they were preserved, presented, and stored are also a part of this work. The methods of human organ fixation reached excellence in the 19th century, but the rarity of some pathologies urged the scientists to recreate them artificially in models for didactic purposes. In the 19th and 20th centuries one could observe the flourishing development with a plateau and then decline from the second part of the 20th century to the reorientation of the museums that took place in Europe and North America. The history of anatomopathological museums is connected with ethical problems related to acquisition of exhibits in previous centuries and especially during World War II. The changing purpose of the collections, as well as their unclear future and the impact on the visitors, are evident. For the last 50 years, many museums have been closing completely, but some collections have been digitalised and are still in permanent use. The uniqueness of old specimens with certain diseases, often long gone and not observed anymore, makes them important in many aspects nowadays. Pathology museums are themselves relics of the past, being at the same time tangible proof of ways of development in medicine, but also a way of preservation of human knowledge in a special type of relation with the human body.

HOTAIR in relation to epithelial-mesenchymal transition and cancer stem cells in molecular subtypes of endometrial cancer.

BACKGROUND: Endometrial cancer (EC) is a hormone-related disease, showing highly diverse features of ER/PR/HER2 status-based molecular subtypes. Long noncoding RNA (lncRNA) HOX antisense intergenic RNA (HOTAIR) has recently emerged as a key molecule in many cancers, triggering epithelial-mesenchymal transition (EMT)-mediated cancer stem cell (CSC) formation, but little is known about its significance in EC. Thus, we aimed to investigate the clinical significance of HOTAIR itself in different molecular subtypes of EC and possible links between HOTAIR, EMT and CSC-related markers. METHODS: The study group included 156 consecutive, stage I-IV EC patients treated between 2000 and 2010. ER, PR and HER2 protein expression were examined by immunohistochemistry (IHC) on tissue microarrays. RT-qPCR was used to analyze the expression levels of HOTAIR, EMT-related genes - SNAIL and SLUG - and the CSCs marker CD133. RESULTS: Molecular subtypes, defined as ER/PR+HER2+, ER/PR+HER2-, ER-PR-HER2+ and ER-PR-HER2-, occurred in 40.2%, 52.3%, 4.7% and 1.9% of cases, respectively. The expression of HOTAIR did not differ between the subtypes, but high HOTAIR expression correlated with shorter overall survival (p = 0.04) in the entire group. The expression levels of HOTAIR, SNAIL, SLUG and CD133 were similar in defined EC molecular subtypes. CONCLUSIONS: Our data do not confirm the role of HOTAIR in EMT-mediated CSC formation in EC. Neither does the diversity of EC molecular subtypes influence these processes. But HOTAIR expression could serve as an independent prognostic factor in EC. The clinical importance of the above discoveries requires further studies.