Guillain-Barré syndrome (GBS) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are the most common autoimmune polyneuropathies. Their aetiology is unclear. The pathomechanism includes damage mainly to the myelin sheath and, in the long-term process, secondary axonal loss. Both inflammatory polyneuropathies involve different combinations of motor, sensory and autonomic fibres in the peripheral nerves. The differential diagnosis should be based on clinical and neurophysiological features, and laboratory tests. Numerous studies aim to demonstrate the most common errors in the diagnosis of Guillain-Barré syndrome and acute-onset CIDP. Misdiagnosis can result in the wrong treatment. We still do not have reliable markers to help diagnose the disease or to monitor the effectiveness of the therapy.

This review presents a perspective on the pathobiology of acute myocardial infarction, a major manifestation of ischemic heart disease, and related mechanisms of ischemic and toxic cardiomyocyte injury, based on advances and insights that have accrued over the last seventy years, including my sixty years of involvement in the field as a physician-scientist-pathologist. This analysis is based on integration of my research within the broader context of research in the field. A particular focus has been on direct measurements in cardiomyocytes of electrolyte content by electron probe X-ray microanalysis (EPXMA) and Ca fluxes by fura-2 microspectrofluorometry. These studies established that increased intracellular Ca develops at a transitional stage in the progression of cardiomyocyte injury in association with ATP depletion, other electrolyte alterations, altered cell volume regulation, and altered membrane phospholipid composition. Subsequent increase in total calcium with mitochondrial calcium accumulation can occur. These alterations are characteristic of oncosis, which is an initial pre-lethal state of cell injury with cell swelling due to cell membrane dysfunction in ATP depleted cells; oncosis rapidly progresses to necrosis/necroptosis with physical disruption of the cell membrane, unless the adverse stimulus is rapidly reversed. The observed sequential changes fit a three-stage model of membrane injury leading to irreversible cell injury. The data establish oncosis as the primary mode of cardiomyocyte injury in evolving myocardial infarcts. Oncosis also has been documented to be the typical form of non-ischemic cell injury due to toxins. Cardiomyocytes with less energy impairment have the capability of undergoing apoptosis and autophagic death as well as oncosis, as is seen in pathological remodeling in chronic heart failure. Work is ongoing to apply the insights from experimental studies to better understand and ameliorate myocardial ischemia and reperfusion injury in patients. The perspective and insights in this review are derived from basic principles of pathology, an integrative discipline focused on mechanisms of disease affecting the cell, the organizing unit of living organisms.

Telomere length is an important biomarker of biological aging and is affected by nutrition and physical activity. This study investigated the effects of diets with different fat contents and increased physical activity on certain pro/anti-inflammatory and oxidative stress markers and aging. The study is performed in a randomized, experimental, and controlled design with 48 rats, 8 weeks old, divided into 6 different groups (Control (C), exercise (E), unsaturated fat diet (USF), saturated fat diet (SF), unsaturated fat diet + exercise (USF + E), and saturated fat diet + exercise (SF + E)). The rats performed aerobic swimming exercise for 50 days and were fed a diet with different fat content. TAS, TOS, and MDA levels were determined by colorimetric analysis while 8-OHdG, IL-10, and TNF-α were determined by ELISA. Additionally, leukocyte telomere length is determined by the PCR method. Weight changes were also recorded. Plasma TOS, OSI, and TNF-α were lowest in the USF group and highest in the SF and SF + E groups. MDA, 8-OHdG and TG levels were highest in the SF group. The lowest IL-10 level was detected in group C. TL level was the highest in the USF group. There was also a moderate, negative, and significant correlation between telomeres and TOS, OSI, and TNF-α. The groups with the highest body weight gain were C, SF, and SF + E. Diets low in saturated fat or high in unsaturated fat, and physical activity were associated with leukocyte telomere length and alteration of oxidative and pro/anti-inflammatory markers.

During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.

Pancreatic ductal adenocarcinoma (PDAC) is reported to be amongst the cancers with the lowest survival rate at 5 years. In the present study we aimed to validate a targeted next-generation sequencing (tNGS) panel to use in clinical routine, investigating genes important for PDAC diagnostic, prognostic and potential theragnostic aspect. In this NGS panel we also designed target regions to inquire about loss of heterozygosity (LOH) of chromosome 18 that has been described to be possibly linked to a worse disease progression. Copy number alteration has also been explored for a subset of genes. The last two methods are not commonly used for routine diagnostic with tNGS panels and we investigated their possible contribution to better characterize PDAC. A series of 140 formalin-fixed paraffin-embedded (FFPE) PDAC samples from 140 patients was characterized using this panel. Ninety-two % of patients showed alterations in at least one of the investigated genes (most frequent KRAS, TP53, SMAD4, CDKN2A and RNF43). Regarding LOH evaluation, we were able to detect chr18 LOH starting at 20% cell tumor percentage. The presence of LOH on chr18 is associated with a worse disease- and metastasis-free survival, in uni- and multivariate analyses. The present study validates the use of a tNGS panel for PDAC characterization, also evaluating chr18 LOH status for prognostic stratification.

Histomorphology is a powerful and cost-efficient tool for evaluating inflammatory and neoplastic conditions. Inflammatory bowel disease (IBD) is a widespread condition with globally rising incidences, and a lot of research is done to better understand the pathogenesis of IBD and to identify potential therapeutic approaches. However, standardized and reproducible scores for the histomorphological evaluation of murine IBD models are lacking. Therefore, we aimed to develop an easy-to-use and reproducible score for standardized assessment of colitis and associated cancer models.

Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.

Functional analyses are the main method to classify mismatch repair (MMR) gene variants of uncertain significance (VUSs). However, the pathogenicity remains unclear for many variants because of conflicting results between clinical, molecular, and functional data. In this study, we evaluated whether whole exome sequencing (WES) could add another layer of evidence to elucidate the pathogenicity of MMR variants with conflicting interpretations. WES was performed on formalin-fixed paraffin-embedded tumor tissue of eight patients with a constitutional MMR VUS (seven families), including eight colorectal and two endometrial carcinomas and one ovarian carcinoma. Cell-free CIMRA assays were performed to assign Odds of Pathogenicity to these VUSs. In four families, seven tumors showed MMR deficiency-associated mutational signatures, supporting the pathogenicity of the VUS. Moreover, somatic (second) MMR hits identified in the WES data were found to explain MMR staining patterns when the MMR staining was discordant with the reported germline MMR gene variant. In conclusion, WES did not significantly reclassify VUS in these cases but clarified some phenotypic aspects such as age of onset and explanations in case of discordant MMR stainings.

Irisin is a myokine that is cleaved from 5-domain type III fibronectin (FNDC5), and is known for its metabolic functions as it stimulates browning of white adipose tissue; similarly, effects on the central nervous system have been described, specifically in neurodevelopmental and neuroprotection processes. The purpose of this review is to describe recent information on the effects of irisin on neuroinflammation to contribute to the knowledge about the mechanisms by which irisin and exercise could generate benefits for some neurological diseases. The review conducted found several studies describing the effect of irisin on pathways such as STAT3, p38, cAMP/PKA/CREB, as well as effects on GFAP protein expression or apoptosis processes in both in vitro and in vivo models; likewise, these pathways are associated with better BDNF expression. Despite increasing information on this topic, it is still necessary to clarify the mechanisms by which irisin has effects on neuroinflammation and this could represent an opportunity to generate more treatments for diseases such as Alzheimer's, Parkinson's or Diabetes Mellitus.

Breast cancer (BC) is classified into four major histological subtypes, namely luminal A, luminal B, HER2, and basal-like, and its treatment is based on these subtypes. The use of immune checkpoint inhibitors against BC depends on the expression of PD-1/PD-L1. Another tumor immune system-the cGAS-STING pathway-is a potential target for cancer immunotherapy. However, the status of the cGAS-STING pathway in BC has not been fully established. Therefore, we investigated the expression status of the cGAS-STING pathway and immune-related proteins in BC. We classified 111 BCs into six groups-29 hormone receptor-positive carcinomas, 12 HER2+ carcinomas (HER2), 8 luminal-HER2 carcinomas, 26 triple-negative breast carcinomas (TNBCs), 21 lobular carcinomas (LC), and 15 carcinomas with apocrine differentiation (CAD)-and investigated the relationship between BC and tumor immunity via the cGAS-STING pathway using histopathological and immunohistochemical methods. Expression of cGAS was high in CADs (100%) and low in TNBCs (35%); STING-positive lymphocytes were high in TNBC (85%, P = 0.0054). Expression of pSTAT3 was significantly high in patients with TNBC (≥10%, 88%). The proportion of PD-L1-positive tumor cells was higher in TNBCs (54%) than in other BCs (30%). SRGN expression was significantly higher in the TNBC group than in the other BC groups (58%). Tumor immune responses may differ among tumor subtypes. The cGAS-STING pathway may be functional in TNBC and CAD but not in LC. Therefore, targeting the cGAS-STING pathway might be useful in BC, particularly TNBC and CAD.

Necrotizing enterocolitis (NEC) is a serious condition in premature infants, in which a portion of the intestine undergoes inflammation and necrosis. The preterm pig develops NEC spontaneously, making it a suitable model for exploring novel NEC treatments. We aimed to revise the intestinal scoring system to more accurately describe the diversity of NEC lesions in the preterm piglet model. We included 333 preterm piglets from four experiments, each delivered via cesarean section. The piglets were fed either a gently processed (GP) or harshly processed (HP) milk formula for 96 h before euthanasia. At necropsy, the gastrointestinal tract was assessed with 1) an established 6-grade score and 2) a descriptive approach focusing on the distribution and severity of hyperemia, hemorrhage, pneumatosis intestinalis (intramural gas), and necrosis. Subsequently, the descriptive registrations were converted into a weighted and cumulative point (WCP) score. Compared to the 6-grade score, the WCP score enabled a greater segregation of severity levels, especially among organs with more prominent NEC lesions. IL-1β in small intestinal lesions and both IL-8 and IL-1β in colon lesions correlated positively with the WCP scale. A histopathological grade system (0-8) was established and revealed mucosal pathology in lesion biopsies, which were not recognized macroscopically. Finally, the WCP score showed a higher NEC-promoting effect of the HP formula compared to the GP formula. The descriptive registrations and extended score range of this revised intestinal scoring system enhance the accuracy of describing NEC lesions in preterm pigs. This approach may increase the efficiency of preclinical NEC experiments.

Seizures are neurological disorders triggered by an imbalance in the activity of excitatory and inhibitory neurotransmitters in the brain. When triggered chronically, this imbalance can lead to epilepsy. Critically, many of the affected individuals are refractory to treatment. Given this, anti-inflammatory drugs, in particular glucocorticoids, have been considered as a potential antiepileptogenic therapy. Glucocorticoids are currently used in the treatment of refractory patients, although there have been contradictory results in terms of their use in association with antiepileptic drugs, which reinforces the need for a more thorough investigation of their effects. In this context, the present study evaluated the effects of dexamethasone (DEX, 0.6 mg/kg) on the electroencephalographic (EEG) and histopathological parameters of male Wistar rats submitted to acute seizure induced by pentylenetetrazol (PTZ). The EEG monitoring revealed that DEX reduced the total brainwave power, in comparison with PTZ, in 12 h after the convulsive episode, exerting this effect in up to 36 h (p < 0.05 for all comparisons). An increase in the accommodation of the oscillations of the delta, alpha, and gamma frequencies was also observed from the first 12 h onwards, with the accommodation of the theta frequency occurring after 36 h, and that of the beta frequency 24 h after the seizure. The histopathological analyses showed that the CA3 region and hilum of the hippocampus suffered cell loss after the PTZ-induced seizure (control vs. PTZ, p < 0.05), although DEX was not able to protect these regions against cell death (PTZ vs. DEX + PTZ, p > 0.05). While DEX did not reverse the cell damage caused by PTZ, the data indicate that DEX has beneficial properties in the EEG analysis, which makes it a promising candidate for the attenuation of the epileptiform wave patterns that can precipitate refractory seizures.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

Older people experience a greater incidence of lower bowel disorders, including constipation. Causes can include factors associated with growing older, such as use of medications or disease, but compounded by degenerative changes within the bowel wall. It has been suggested that the latter is exacerbated by loss of an effective mucosal barrier to luminal contents. In human colon, little is known about the impact of ageing on key components of this barrier, namely the goblet cells and mucin content.

Phytocannabinoids and terpenes from Cannabis sativa have demonstrated limited anti-inflammatory and analgesic effects in several inflammatory conditions. In the current study, we test the hypothesis that phytocannabinoids exert immunomodulatory effects in vitro by decreasing inflammatory cytokine expression and activation.

For many people living at high altitudes for long or short periods of time, hypoxia is a challenge affecting many aspects of the body, including the immune system. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population that plays an important role in several pathological conditions. However, to the best of our knowledge, there are no data regarding the behavior of MDSCs under hypoxic conditions. Therefore, the aim of this study is to investigate the monocytic type (M)- and polymorphonuclear type (PMN)-MDSC ratios in different hypoxic conditions to reveal the relationship between MDSCs and high-altitude hypoxia, as well as to determine whether MDSCs are involved in the regulation of the immune balance under hypoxic conditions as immunosuppressive factors. For the first time, we showed that MDSC abundance varies under different lengths of hypoxic exposure. We found that acute normobaric hypoxia led to an initial increase in the number of M-MDSCs, which decreased within 30 d. Both M- and PMN-MDSC ratios initially decreased under hypobaric hypoxia conditions within 30 d, but after 6 months in the real high altitude environment, M-MDSC ratio increased significantly. In summary, our data suggest that different hypoxic conditions influence MDSCs in mice, thereby contributing to a better understanding of the process of hypoxia adaptation and the occurrence and development of high-altitude disease.

Immune evasion is one of the mechanisms by which cancer cells acquire immunity during cancer development and progression. One of these is the increased expression of cluster of differentiation 47 (CD47), a transmembrane glycoprotein that protects cells from phagocytic elimination. The interaction between CD47 and signal regulatory protein alpha (SIRPα) on macrophages alleviates the phagocytic signal. The present group previously reported high CD47 expression in cholangiocarcinoma (CCA), a major health problem in Thailand and East Asia, and that blocking CD47 using anti-CD47 antibodies promoted the removal of CCA. However, the mechanism through which CD47 inhibition attenuates CCA growth remains unclear. This study explored the clinical significance of targeting CD47 in CCA. Expression levels of CD47 and the macrophage marker CD68 were determined in CCA tissues by immunohistochemistry and correlated with clinical parameters. The role of CD47 in CCA cells was established using CD47-deficient KKU-213A CCA clones in vitro and in vivo. The results showed that CD47 was highly expressed in CCA tissues and significantly correlated with lymph node metastasis (P = 0.038). Moderate-to-dense CD68-positive infiltrating cells in CCA tissues were significantly associated with shorter survival of patients (P = 0.019) and were an independent prognostic factor of CCA patients as determined by the Cox proportional hazard model (hazard ratio, 2.040; 95 % confidence interval, 1.109-3.752; P = 0.022). Three CD47-deficient KKU-213A clones (#19, #23, and #28) were generated. The elimination of CD47 did not affect cell proliferation but increased monocyte-derived macrophage-mediated phagocytosis in vitro. Decreased tumor weights and volumes were observed in mice injected with CD47-deficient CCA clones. This revealed a significant role for CD47 in CCA, with a focus on protecting cancer cells from macrophage phagocytosis.

Rheumatoid arthritis (RA) is one of the most common chronic, inflammatory, autoimmune diseases affecting mainly the joints. Piperine (PIP), an alkaloid found in black pepper, has anti-inflammatory properties and its use in drug delivery systems such as nanoparticles might be a treatment for RA. This study aims to evaluate the possible anti-inflammatory and anti-arthritic effects of PIP and its use in albumin nanoparticles as a possible approach for the treatment of Adjuvant-induced arthritis (AIA) rats.

A subset of head and neck squamous cell carcinomas present solely as metastatic disease in the neck and are of unknown primary origin (SCCUP). Most primary tumors will ultimately be identified, usually in the oropharynx. In a minority of cases, the primary site remains elusive. Here, we examine the role of ancillary testing, including mutational signature analysis (MSA), to help identify likely primary sites in such cases. Twenty-two cases of SCCUP in the neck, collected over a 10-year period, were classified by morphology and viral status; including human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) and RT-qPCR, as well as Epstein-Barr virus (EBV) testing by EBER-ISH. CD5 and c-KIT (CD117) IHC was done to evaluate for possible thymic origin in all virus-negative cases. Whole exome sequencing, followed by MSA, was used to identify UV signature mutations indicative of cutaneous origin. HPV was identified in 12 of 22 tumors (54.5%), favoring an oropharyngeal origin, and closely associated with nonkeratinizing tumor morphology (Fisher's exact test; p = 0.0002). One tumor with indeterminant morphology had discordant HPV and p16 status (p16+/HPV-). All tumors were EBV-negative. Diffuse expression of CD5 and c-KIT was identified in 1 of 10 virus-negative SCCUPs (10%), suggesting a possible ectopic thymic origin rather than a metastasis. A UV mutational signature, indicating cutaneous origin, was identified in 1 of 10 (10%) virus-negative SCCUPs. A cutaneous auricular primary emerged 3 months after treatment in this patient. Primary tumors became clinically apparent in 2 others (1 hypopharynx, 1 hypopharynx/larynx). Thus, after follow-up, 6 tumors remained unclassifiable as to the possible site of origin (27%). Most SCCUPs of the neck in our series were HPV-associated and thus likely of oropharyngeal origin. UV signature mutation analysis and additional IHC for CD5 and c-KIT for possible thymic origin may aid in further classifying virus-negative unknown primaries. Close clinical inspection of hypopharyngeal mucosa may also be helpful, as a subset of primary tumors later emerged at this site.