Massive Infiltration Research Articles

The cathepsin-S/protease-activated receptor-(PAR)-2 axis drives chronic allograft vasculopathy and is a molecular target for therapeutic intervention

BackgroundCathepsin S (CatS) and proteinase-activated receptor (PAR)-2 are involved in the remodelling of vascular walls and neointima formation as well as in alloantigen presentation and T-cell priming. Therefore, we hypothesized that CatS/PAR-2 inhibition/deficiency would attenuate chronic allograft vasculopathy. MethodsHeterotopic aortic murine transplantation was performed from C57BL/6J donors to C57BL/6J recipients (syngeneic control group), Balb/c to C57BL/6J without treatment (allogenic control group), Balb/c to C57BL/6J with twice daily oral CatS inhibitor (allogenic treatment group) and Balb/c to Par2−/− C57BL/6J (allogenic knockout group). The recipients were sacrificed on day 28 and the grafts were harvested for histological analysis and RT-qPCR. ResultsAfter 28 days, mice of the allogenic control group exhibited significant neointima formation and massive CD8 T-cell infiltration into the neointima while the syngeneic control group showed negligible allograft vasculopathy. The mRNA expression level of CatS in allografts was 5-fold of those in syngeneic grafts. Neointima formation and therefore intima/media-ratio were significantly decreased in the treatment and knockout group in comparison to the allogenic control group. Mice in treatment group also displayed significantly fewer CD8 T cells in the neointima compared with allogeneic controls. Additionally, treatment with the CatS inhibitor and PAR2-deficiency decreased mRNA-levels of interleukins and cytokines. ConclusionIn conclusion, our data indicate that inhibiting CatS and PAR-2 deficiency led to a marked reduction of neointima formation and associated inflammation in a murine heterotopic model for allograft vasculopathy.

Клинико-лабораторные, инструментальные, морфологические особенности гангренозного и флегмонозного аппендицита у пациентов с COVID-19-инфекцией

Objective. To present clinical, laboratory, instrumental and morphological features of phlegmonous and gangrenous appendicitis in patients with COVID-19 infection. Patients and methods. During the period from March 2020 to August 2022, 23 patients were observed with positive results of testing of nasopharyngeal sample for SARS-CoV-2 RNA and performed appendectomy. The age group of children is 8–17 years old (the average age is 14.1 years), there were 13 boys, 10 girls. The premorbid state is not burdened. The rationale for appendectomy was: acute abdominal pain, local soreness on the right side of the abdomen, their preservation until the surgical removal of the appendix and their disappearance after surgery. During ultrasound of the abdominal cavity, all patients had ECHO signs of inflammatory transformation of the vermiform process. The disease was accompanied by repeated vomiting on the background of subfebrile (13 children) or normal temperature (10 children). Respiratory syndrome is poor, 4 children had abdominal pain, 9 children had hyperemia of the pharynx, chest CT did not reveal inflammatory changes. Repeated virological examination showed the positive result in 3 of 9 examined; EIA for IgM and IgG detection was positive in 7 (out of 7 examined) with diagnostic titers in 3 patients. During histological examination, the length of the removed appendixes is ~8.1 cm (4–12.5 cm), partial or complete desquamation of the epithelium, massive infiltration by lymphocytes or neutrophils, circulatory disorders, in some cases (gangrenous appendicitis) – the phenomena of thrombosis of small vessels, mesenteriolitis, periappendicitis. Typical E. Coli was found in 4 out of 23 abdominal fluid samples. Conclusion. The complex of clinical, laboratory, instrumental and morphological data confirmed the diagnosis of appendicitis and the course of COVID-19, indicating the need for surgical intervention and the appointment of antiviral therapy, noting the need to continue the study. Key words: phlegmonous, gangrenous appendicitis, children, laparoscopic removal, ultrasound of abdomen, morphological examination of the appendix

MiR-218-5p-Modified Bone Marrow Mesenchymal Stem Cells Mediate the Healing Effect of EphrinB2-EphB4 Signals on Alveolar Bone Defect

Abnormally expressed miR-218-5p involves in alveolar bone defect. We intend to investigate whether miR-218-5p-modified bone marrow mesenchymal stem cells (BMSCs) mediates the healing effects of EphrinB2-EphB4 signals on the alveolar bone defect. Fifty germ-free rats (6-month-old) were utilized in this study. The grouping was set up as follows: blank group, model group, miR-218-5p group, EphrinB2-EphB4 antagonist group, and positive control group (10 rats in each group). HE staining was employed to quantify bone resorption lacunae number. And the following indicators were monitored: miR-218-5p expression, differentiation status of osteoblasts, concentrations of TNF-α/IL-10/ IL-8, and EphrinB2 and EphB4 expression. As shown in HE staining, massive infiltration of inflammatory cells was denoted at the alveolar bone defective sites in rats from model group. However, infiltration of inflammatory cells in lesions was moderate in rats from EphrinB2-EphB4 antagonist group and positive control group, which was accompanied by formation of small bone islands. Furthermore, lesser infiltration of inflammatory cells was denoted at the alveolar bone defective sites in rats from the miR-218-5p group, which also exhibited a larger number of newly formed bone trabeculae growing toward the center of lesions. On the 3rd day of culture, absorption lacunae were rare in the model group, while remaining undetectable in other groups. On the 7th day of culture, bone resorption lacunae number in samples from model group was significantly higher in comparison with that in other groups. Meanwhile, it was reduced significantly in miR-218-5p group. However, it was increased in EphrinB2-EphB4 antagonist group and positive control group (P <0.05). An elevation of the intracellular miR-218-5p level was denoted in the modified BMSCs in comparison with those unmodified BMSCs (P < 0.05). In comparison with blank group, other groups exhibited significantly elevated ALP levels, among which model group showed highest level. However, decline of ALP levels was denoted in positive control group, EphrinB2-EphB4 antagonist group and miR-218-5p group, with lowest ALP level in miR-218-5p group (P <0.05). Except blank group, rats in other groups exhibited a significant elevation of TNF-α, IL-10 and IL-8 in the serum, among which those in the model group displayed the most remarkable increase of these cytokines. Rats in miR-218-5p group, EphrinB2-EphB4 antagonist group and positive control group exhibited significantly reduced levels of IL-8, IL-10 and TNF-α in the serum, with miR-218-5p group showing lowest levels (P < 0.05). In comparison with the blank group, other groups showed significantly enhanced protein expression of EphrinB2 and EphB4, among which the model group displayed the most remarkable enrichment of these proteins. In comparison with the model group, samples from the miR-218-5p group, EphrinB2-EphB4 antagonist group and positive control group exhibited significantly weakened expression of EphrinB2 and EphB4, among which the miR-218-5p group displayed the most remarkable decrease of these proteins (P <0.05). miR-218-5p-modified BMSCs can modulate the EphrinB2-EphB4 signal transduction pathway to produce two-way transmission, which included their inhibition of the osteoclast generation and their enhancement of the osteoclast differentiation. In this way, they aided in alleviating inflammatory response in alveolar bone defective lesions, thereby accelerating the healing process of alveolar bone defect. The function of miR-218-5p-modified BMSCs is mainly achieved in the healing process of the alveolar bone defect.

Putting PLX5622 into perspective: microglia in central nervous system viral infection.

Putting PLX5622 into perspective: microglia in central nervous system viral infection.

Total glycosides of Rhodiola rosea L. attenuate LPS-induced acute lung injury by inhibiting TLR4/NF-κB pathway

Acute lung injury (ALI) is a common respiratory disease in clinics, which is characterized by alveolar-capillary membrane loss, plasma protein leakage, pulmonary edema, massive neutrophil infiltration, and the release of proinflammatory cytokines and mediators. Rhodiola rosea L. an adaptogenic plant rich in phenylethanoloids, phenylpropanoids, monoterpenes, has anti-inflammatory and antioxidant effects. We hope to verify the relieving effect of total glycosides of Rhodiola rosea L. (RTG) on ALI in mice and clarify its mechanism through this study. In this study, we identified the effect and mechanism of RTG on ALI through LPS-induced ALI mice. After RTG treatment, the pathological structure of lung tissue in ALI mice induced by LPS was significantly improved, and the infiltration of inflammatory cells was reduced. In addition, RTG reduced the production of IL-6, IL-1β, and TNF-α in the serum of ALI mice and reduced the content or activity of MPO, T-SOD, GSH, and MDA in lung tissue. RNAseq analysis showed that RTG ameliorated LPS-induced ALI through anti-inflammatory, reduced immune response, and anti-apoptotic activities. The western blotting analysis confirmed that RTG could down-regulate the expression levels of TLR4, MyD88, NF-κB p65, and p-IκBα/IκBα. These results suggest that RTG can attenuate LPS-induced ALI through antioxidants and inhibition of the TLR4/NF-κB pathway.

Detailed Pathophysiological Investigation of Canine Pyometra and the Curative Role of Ovariohysterectomy

Background: Pyometra or cystic endometrial hyperplasia complex in dogs is a hormonally mediated bacterial disease wherein middle-aged bitches are most affected. The current study was carried out in pyometra-affected bitches to determine the alterations in hormonal, histopathological and haemato-biochemical profiles after 14 days of ovariohysterectomy. Methods: Blood samples were collected both from control (n=15) and affected bitches (n=15) showing signs of open cervix pyometra preoperatively and postoperatively on the day of surgery, on the 7th and 14th day after ovariohysterectomy. Blood samples were subjected to the estimation of endocrinological and hematobiochemical parameters. The ovary, oviduct and uterus were collected for gross and histological observations. Result: The pre-operative serum progesterone (ng/ml) recorded in bitches affected with pyometra were 9-fold higher than controls (9.77±2.64 vs 0.61±0.66) (P less than 0.01). There was a non-significant difference in the pre-operative (414.63±62.88) and post-operative (390.6±54.20) estrogen concentration and the results indicated a presence of an extragonadal source of estrogen. The enormous endometrial lumen of these cysts contained eosinophilic hazy granular material and tissue debris along with massive infiltration of inflammatory cells, predominantly neutrophils. The findings of the study revealed that progesterone is the major contributory factor and extragonadal sources of estrogen may be present along with hyperplastic changes in the uterine and glandular epithelium in pyometra-affected bitches.

Secondary iron overload induces chronic pancreatitis and ferroptosis of acinar cells in mice.

Disruption of iron homeostasis is associated with multiple diseases. It has been found that patients with genetic iron overload develop massive iron deposition in the pancreas. However, few studies have focused on the effect of secondary iron overload on the pancreas. The objective of the present study was to investigate the pathogenic consequences of secondary iron overload in mice. An iron overload mouse model was constructed by intraperitoneal injection of 120mg/kg body weight of iron dextran every other week for 12weeks. Iron deposition, immunocyte infiltration, fibrosis, oxidative stress and ferroptosis were assessed using Prussian blue staining, immunohistochemical analysis, Masson staining, Sirius red staining, RT‑qPCR analysis and western blot analysis. It was found that iron‑overloaded mice showed pancreatic iron overload, together with elevated gene expression of the iron storage factor ferritin H, and decreased expression of the iron transportation mediator divalent metal transporter 1, ferroportin 1 and transferrin receptor. Iron‑overloaded mice developed mild pancreatitis with increased serum amylase and lipase activities, as well as elevated gene expression levels of pro‑inflammatory cytokines, including interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase. Acinar atrophy, massive immunocyte infiltration and pancreatic fibrosis were noted in the iron‑overloaded mice. As an underlying mechanism, iron‑overloaded mice showed increased pancreatic oxidative stress, with an elevated malondialdehyde level, and decreased SOD and glutathione peroxidase activity. Furthermore, iron overload led to ferroptosis with promoted expression of cytochrome c oxidase subunit II, and decreased transcripts of glutathione peroxidase 4 and solute carrier family 7 member 11. These results provided evidence that multiple intraperitoneal injections of iron dextran in mice lead to iron overload‑induced chronic pancreatitis, which suggested that secondary iron overload is a risk factor for pancreatitis and highlights the importance of iron in maintaining the normal functions of the pancreas.

Effects of herbal cake-partitioned moxibustion on the expression of thyroid autophagy-related factors LC3B and Beclin-1 in rats with autoimmune thyroiditis

ObjectiveTo observe the anti-inflammatory effect, as well as the effect on the expression of microtubule-associated protein light chain 3B (LC3B) and Beclin-1 of herbal cake-partitioned moxibustion in rats with experimental autoimmune thyroiditis (EAT).MethodsFemale Sprague-Dawley rats were randomly divided into a normal group and a modeling group. The EAT rat model was prepared by a combination of antigen immunization plus iodine agent induction. After the model was prepared, rats in the modeling group were randomly and equally divided into a model group and a herbal cake-partitioned moxibustion group. In the herbal cake-partitioned moxibustion group, moxibustion was alternately applied to two groups of points [Dazhui (GV14)-Mingmen (GV4) and Tiantu (CV22)-Guanyuan (CV4)], and the treatment continued for 30 d. Rats in the normal and model groups were only fixed identically without intervention. Histopathological manifestations of thyroid glands were observed by hematoxylin-eosin staining; the concentrations of thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay; real-time fluorescence quantitative polymerase chain reaction and immunohistochemistry were used to detect the mRNA and protein expression of autophagy-related factors LC3B and Beclin-1 in thyroid tissue.ResultsThere were massive follicular destruction, lymphocytic infiltration, and interstitial fibrous tissue hyperplasia of the thyroid glands in the model group. Some follicles of the thyroid glands were destroyed with few lymphocyte infiltrations and fibrous tissue hyperplasia in the moxibustion group. Compared with the normal group, the concentrations of serum TPOAb, TGAb, IL-1β, IL-6, and TNF-α were increased in the model rats (P<0.05); the mRNA and protein expression levels of LC3B and Beclin-1 in thyroid tissue were reduced in the model group (P<0.05). Compared with the model group, the concentrations of serum TPOAb, TGAb, IL-1β, IL-6, and TNF-α were reduced in the herbal cake-partitioned moxibustion group (P<0.05); the mRNA and protein expression levels of LC3B and Beclin-1 in thyroid tissue were increased in the herbal cake-partitioned moxibustion group (P<0.05). The mRNA and protein expression of LC3B and Beclin-1 in thyroid tissue was negatively correlated with the serum levels of TPOAb and TGAb.ConclusionHerbal cake-partitioned moxibustion reduces the inflammatory response in the thyroid glands of EAT rats and lowers the levels of serum TPOAb and TGAb. This may be related to the regulation of mRNA and protein expression of the autophagy-associated factors LC3B and Beclin-1 in rat thyroid tissue.

Interaction of immune cells and lymphatic vessels in corneal transplantation

AbstractImmune‐mediated graft rejections remain the most common cause for graft failure after organ and tissue transplantation. There is a great unmet medical need for pharmacologic strategies to promote graft survival without unduly compromising the health of the recipient.Corneal allograft rejection is histologically characterized by massive infiltration of CD4+ T‐cells, macrophages and the invasion of blood and lymphatic vessels.We could show that lymphatic vessels determine the high‐risk status of a corneal graft recipient. The healthy cornea is devoid of blood and lymphatic vessels. In contrast, in the high risk situation graft rejection is highly correlated with the degree of corneal vascularisation and presence of numerous pro‐inflammatory immune cells.CD11c+ CD11b+ myeloid dendritic cells (DCs) are present throughout the anterior stroma – even in the healthy cornea. Inflammatory stimuli determine the maturation stage of DCs and their immunogenic properties. It is known that an increasing number of MHC class II‐bearing, antigen specific DCs in cervical draining lymph nodes arise only a few hours after transplantation. This implies that DCs at different maturation stages might be the main initiators of this devastating tissue destruction.The origin of donor antigen presenting cells can be either from the donor tissue or the host. Thereby allo‐antigens from the grafted tissues travel via lymphatic vessels towards the draining lymph nodes of the recipient. Here they are recognized by host T cells either by the direct pathway, which involves the recognition of intact donor MHC molecules on donor‐derived APCs, or by the indirect pathway, which involves the recognition of donor major or minor MHC‐derived peptides, processed and presented by recipient APCs to host T cells. Nowadays it is widely accepted that resident MHC class II APC populations are present in the cornea. These cells are capable of expressing MHC class II antigen and accessory molecules (CD40, CD80) after transplantation. We and others could demonstrate that the immune reaction is triggered by the above described “direct allo‐sensitisation” where APCs travel from the donor tissue via corneal pathological lymphatic vessels into the local draining lymph nodes of the recipient and present the foreign antigen.Recent studies could show that lymphatic vessels not just display an exit route for leukocytes but are in close interaction with these cells and regulate the entry and trafficking of antigen presenting cells into and via lymphatic vessels.This presentation will summarize the current knowledge about the interaction of immune cells and lymphatic vessels in corneal transplantation.

IL-31–generating network in atopic dermatitis comprising macrophages, basophils, thymic stromal lymphopoietin, and periostin

IL-31 is a type 2 cytokine involved in the itch sensation in atopic dermatitis (AD). The cellular origins of IL-31 are generally considered to be TH2 cells. Macrophages have also been implicated as cellular sources of IL-31. We sought to determine the expression of IL-31 by macrophages and to elucidate the productive mechanisms and contributions to itch in AD skin lesions. Expression of IL-31 by macrophages, expressions of thymic stromal lymphopoietin (TSLP) and periostin, and presence of infiltrating basophils in human AD lesions were examined through immunofluorescent staining, and correlations were assessed. Furthermore, mechanisms of inducing IL-31-expressing macrophages were analyzed in an MC903-induced murine model for AD invivo and in mouse peritoneal macrophages exvivo. A significant population of IL-31+ cells in human AD lesions was that of CD68+ cells expressing CD163, an M2 macrophage marker. The number of IL-31+/CD68+ cells correlated with epidermal TSLP, dermal periostin, and the number of dermal-infiltrating basophils. In the MC903-induced murine AD model, significant scratching behaviors with enhanced expressions of TSLP and periostin were observed, accompanied by massive infiltration of basophils and IL-31+/MOMA-2+/Arg-1+ cells. Blockade of IL-31 signaling with anti-IL-31RA antibody or direct depletion of macrophages by clodronate resulted in attenuation of scratching behaviors. To effectively reduce lesional IL-31+ macrophages and itch, basophil depletion was essential in combination with TSLP- and periostin-signal blocking. Murine peritoneal macrophages produced IL-31 when stimulated with TSLP, periostin, and basophils. A network comprising IL-31-expressing macrophages, TSLP, periostin, and basophils plays a significant role in AD itch.

Tolerability and safety of a new elimination diet for pediatric eosinophilic gastritis and duodenitis

BackgroundNon-esophageal eosinophilic gastrointestinal disorders (non-EoE EGIDs) are chronic inflammatory disorders with massive infiltration of eosinophils into the gastrointestinal tract. Food elimination diets are potentially effective treatments. But the existing dietary therapies have various weak points. We developed a new regimen to compensate for the shortcomings of the elemental diet and 6-food elimination diet. The new regimen consists of an amino-acid-based formula, potatoes, vegetables, fruits and restricted seasonings. We named it the “Rainbow Elimination Diet (ED).” The aims of this study were to evaluate the tolerability and safety of this diet. MethodsA retrospective medical record examination was conducted at the National Center for Child Health and Development covering the period from January 2010 through December 2018. The medical records of patients (age 2–17 y) with histologically diagnosed non-EoE EGIDs were reviewed. The tolerability, nutritional intake, symptoms, and blood test findings were evaluated. ResultsNineteen patients were offered several kinds of food-elimination diets. Seven patients (eosinophilic gastritis: 5; gastroenteritis: 1; duodenitis: 1) were treated with Rainbow ED. Six patients were compliant with this diet. The median duration of the diet induction phase was 15 days (range 14–30). All 5 patients who had had symptoms just before the induction phase became symptom-free. The body weight decreased in 5 patients (median −0.6 kg), probably because the serum protein increased, resulting in reduced edema. All 5 patients with hypoproteinemia had elevated serum albumin (median 2.9–3.5 g/dL). The ingested nutritional elements were calculated, and most of them were sufficient, except for fat and selenium. ConclusionsThe Rainbow ED was well-tolerated and safe for pediatric non-EoE EGIDs.

594 Hippo pathway drives excessive fibrosis in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by a massive immune cell infiltrate, tissue destruction and extensive fibrosis. We aimed to elucidate the role of fibroblasts in the pathophysiology of HS. Single-cell RNA-sequencing was performed on chronic lesional skin samples of 8 HS patients and skin samples of 8 controls. Ex vivo experiments were performed on primary dermal fibroblasts from chronic HS lesions (n=3). Fibroblast subclustering revealed 6 subsets (SFRP2+, COL11A+, SFRP4+, LSP1+, RAMP1+, and CXCL13+).

CTIM-21. NRG-BN010: A SAFETY RUN-IN AND PHASE II STUDY EVALUATING THE COMBINATION OF TOCILIZUMAB, ATEZOLIZUMAB, AND FRACTIONATED STEREOTACTIC RADIOTHERAPY IN RECURRENT GLIOBLASTOMA – TRIAL IN PROGRESS

Abstract BACKGROUND The glioblastoma (GBM) tumor microenvironment (TME) is characterized by a paucity of effector T cells and massive infiltration of immunosuppressive tumor-associated macrophages (TAMs). Inhibition of the interleukin-6 receptor (IL6R) has been demonstrated in preclinical models to repolarize TAMs toward an immunostimulatory phenotype, rendering GBM more susceptible to PD-1/PD-L1 inhibition. Additional preclinical data suggest that fractionated stereotactic radiotherapy (FSRT) can stimulate the release and presentation of tumor-specific antigens, acting as an in-situ vaccine and potentially converting a “cold” TME to a T cell-inflamed state. We designed a safety run-in and phase II study to evaluate the efficacy, safety, and impact on the TME of the combination of IL6R inhibition (tocilizumab), PD-L1 inhibition (atezolizumab), and FSRT in patients with recurrent GBM (rGBM). METHODS NRG-BN010 (NCT04729959) is open to enrollment for adults with rGBM following prior radiotherapy and has 3 components: a safety run-in to determine the recommended phase II dose (RP2D) of the treatment regimen, a phase II single-arm nonsurgical cohort to assess efficacy of the treatment regimen at the RP2D, and a window-of-opportunity surgical cohort. Once the safety run-in (n=12, 3 + 3 design) has determined the RP2D, the phase II and surgical cohorts will open. Phase II patients (n=25, Simon 2-stage design, primary endpoint objective radiographic response) receive an initial pre-FSRT cycle of tocilizumab (plus atezolizumab if included in the RP2D). Within 3-7 days later, the patient receives FSRT (8 Gy x 3 fx), followed by resumption of systemic therapy. Surgical cohort patients (n=16, 1:1 randomization) receive a neoadjuvant cycle of atezolizumab with (n=8) vs. without (n=8) tocilizumab, then FSRT 3-7 days later, then surgical resection 7-14 days after FSRT. Post-operatively, all patients resume systemic therapy at the RP2D. Fresh tumor tissues will be subjected to deep immune profiling to understand the impact of tocilizumab on TAMs in the GBM TME.

Alpha-1 Antitrypsin Inhibits Tumorigenesis and Progression of Colitis-Associated Colon Cancer through Suppression of Inflammatory Neutrophil-Activated Serine Proteases and IGFBP-3 Proteolysis.

Colitis-associated colon cancer (CAC) accompanies the massive infiltration of neutrophils during tumorigenesis and progression of CAC. Depletion of neutrophils in circulation results in significant inhibition of tumor incidence in CAC. However, the underlying mechanisms are largely unclear. In this study, we provide evidence for the crucial involvement of inflammatory neutrophil-activated serine proteases (NSPs) on the dysregulation of the anti-inflammatory and antitumor IGFBP-3/IGFBP-3R signaling axis in CAC using a chronic AOM/DSS mouse model. We also provide preclinical evidence for α1-antitrypsin (AAT) as a preventive and as a therapeutic for CAC. AAT administration not only prevented colitis-associated tumorigenesis but also inhibited established CAC. AOM/DSS treatment results in the significant activation of NSPs, leading to CAC through increased pro-inflammatory cytokines and decreased anti-inflammatory and antitumor IGFBP-3. Collectively, these data suggest that the NSPs proteolyze IGFBP-3, whereas AAT inhibits chronic colonic inflammation-induced NSP activity and subsequently suppresses IGFBP-3 proteolysis. Therefore, the anti-inflammatory and antitumor functions of the IGFBP-3/IGFBP-3R axis are restored. AAT mimicking small peptides also showed their inhibitory effects on NSP-induced IGFBP-3 proteolysis. These results suggest that targeting the NSP-IGFBP-3/IGFBP-3R axis using NSP inhibitors such as AAT and the AAT mimics and IGFBP-3R agonists could lead to novel approaches for the prevention and treatment of CAC.

Squamous cell carcinoma as a primary pleural tumor – case report

The differential diagnosis of primary pleural tumors is a very difficult challenge. The clinical symptoms are insufficient to make a clear and definitive diagnosis. This report presents the case of a 63-year-old male patient who was admitted to Department of Pulmonology due to evidence of increasing respiratory failure due to COVID-19 infection. The X-ray showed massive infiltrate on the left pleural cavity. A bronchofiberoscopy was performed with material removal for histopathological examination. No tumor cells were found in the first pathomorphology report. A videothoracoscopy was performed, in which excerpts from the wall and pleura of the lungs were taken. Pathomorphologic findings excluded mesotheliomas and adenocarcinomas, and after additional reactions a low-differentiated squamous cell carcinoma with adenomatoid differentiation features. The final diagnosis was squamous cell carcinoma. This case highlights that the diagnosis of tumors of the pleura requires cooperation between pathomorphologists and clinicians. Further studies are needed to associate COVID-19 infection with the occurrence of rare pleural tumours.

Pneumonia-related infiltration of the pericardium mimics pericardial effusion, with an echocardiographic finding, surgical result, and outcome

The pericardial sac in a healthy person holds 15–50 mL (mL) of serous fluid. Pericardial effusion (PE) is caused by an abnormal buildup of pericardial fluid in the space around the heart. We present here a 2-year-old healthy child who presented with shortness of breath, fever, and poor feeding for 2 days. Based on echocardiography and following the patient's condition detoriation, the patient was taken to the operation theater. Massive infiltration like substances were seen in the pericardial space instead of suspected pericardial effusion and the sample was sent to the pathology center. The child was extubated on day three postoperatively while serial lab tests, echocardiography, and chest x-ray follow-up demonstrated significant improvement. Follow up 1 week and 3 months later, the child's chest x-ray, inflammatory markers lab test, and echocardiography were normal.

Therapeutic Targeting of NF-κB in Acute Lung Injury: A Double-Edged Sword.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a devastating disease that can be caused by a variety of conditions including pneumonia, sepsis, trauma, and most recently, COVID-19. Although our understanding of the mechanisms of ALI/ARDS pathogenesis and resolution has considerably increased in recent years, the mortality rate remains unacceptably high (~40%), primarily due to the lack of effective therapies for ALI/ARDS. Dysregulated inflammation, as characterized by massive infiltration of polymorphonuclear leukocytes (PMNs) into the airspace and the associated damage of the capillary-alveolar barrier leading to pulmonary edema and hypoxemia, is a major hallmark of ALI/ARDS. Endothelial cells (ECs), the inner lining of blood vessels, are important cellular orchestrators of PMN infiltration in the lung. Nuclear factor-kappa B (NF-κB) plays an essential role in rendering the endothelium permissive for PMN adhesion and transmigration to reach the inflammatory site. Thus, targeting NF-κB in the endothelium provides an attractive approach to mitigate PMN-mediated vascular injury, not only in ALI/ARDS, but in other inflammatory diseases as well in which EC dysfunction is a major pathogenic mechanism. This review discusses the role and regulation of NF-κB in the context of EC inflammation and evaluates the potential and problems of targeting it as a therapy for ALI/ARDS.

Lymphoepithelioma-like hepatocellular carcinoma, case report of a rare indolent subtype of hepatic cancer

Background: Lymphoepithelioma - Like Carcinomas (LELC) of the liver are tumors of poorly differentiated epithelial cells with prominent lymphoid cell infiltration of the stroma. Unlike common primary liver cancers, LELC is a rare subtype of primary liver cancer with notably better prognosis. Unfortunately, available data and understanding of this unique cancer type is limited. Case report: A 72-year-old Hispanic female with compensated cirrhosis due to treatment-naïve hepatitis C and Primary Biliary Cirrhosis (PBC) presented with chronic abdominal pain. Computed Tomography scan (CT) of her abdomen at that time showed nodular liver with a mass measuring 4.6 x 3.7 cm in the right hepatic lobe with heterogeneous enhancement on arterial phase associated with mild venous washout, concerning for Hepatocellular Carcinoma (HCC). She was lost to follow up but re-presented 4 years later with an interval increase in the liver mass to 6.4 x 4.8 cm. Staging work up was unremarkable and patient underwent resection of the mass. Histopathologic examination showed moderately differentiated HCC with massive lymphocytic infiltration within the tumor with lymphocyte outnumbering tumor cells and diagnosed as lymphoepithelial-like carcinoma-HCC. The patient remained asymptomatic with no tumor recurrence at 16 months post resection. Conclusion: This report of an indolent course of untreated EBV positive LELC-hepatocellular carcinoma provides valuable insight about this rare tumor type

UTERINE GRANULOCYTIC SARCOMA AS AN EXTRAMEDULLARY RELAPSE OF ACUTE MYELOID LEUKAEMIA IN AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION RECIPIENT

Myeloid Sarcoma (MS) is a common condition characterized by proliferation of immature myeloid cells in extramedullary sites. It most often develops in patients with Acute Myelogenous Leukaemia (AML), myeloproliferative neoplasms or myelodysplastic syndromes. MS in AML may precede the disease, appear during the onset or as a relapse, especially in patients after bone marrow transplantation (BMT). Although MS can present in various parts of the body, the most common sites are lymph nodes, central nervous system, bones and soft tissues. MS of the gynaecologic tract is rare, especially in the cervix and uterus. We report an unusual case of EM relapse in the uterus without evidence of a bone marrow (BM) recurrence, two years after an allogeneic BMT. A nulliparous female 32 years old patient was currently attending the hematologic service at a quaternary Brazilian Naval Hospital since 2018, due to AML. She had no specific molecular mutation in the diagnosis. The patient was submitted to an unrelated BMT after her second complete remission in 2020 and had a relapse nine months after, with loss of variable number of tandem repeats (VNTR) from the donor and minimum residual disease (MRD) positive. Donor's Lymphocytes were infused twice and chemotherapy with a hypomethylating agent and BCL-2 inhibitor Venetoclax was established. The patient achieved her third complete remission and was in follow-up until she presented herself with complains of neuropathic and acute abdominal pain. Clinical examination revealed several soft tissue tumorations resembling MS. During the investigation, an abdominal pelvic magnetic resonance imaging (MRI) peculiarly demonstrated a large uterine mass with compression of the right ureter and pyelocalyceal dilation. Gynaecological clinical exam showed a large violaceus mass about four cm with anterior and right vaginal wall infiltration. The first diagnostic hypothesis was primary cervical cancer stage IV. The biopsy revealed a massive infiltration of immature myeloid cells with the expression of anti-ERG and myeloperoxidase antibodies, confirming MS. The immunophenotypical analysis of the bone marrow aspirates showed the patient still had a complete remission with MRD negative and a VNTR with full donor chimerism. The patient started systemic chemoterapy with a hypomethylating agent and BCL-2 inhibitor Venetoclax. Decision making on the treatment of cervical MS is challenging due to the absence of gynaecological classification guidelines. In patients in this age group with no offspring, the choice of therapy should consider the fertility issue, covering from hysterectomy to radiation, with or without a second BMT. Finally, MS should be a differential diagnosis in a patient with a uterine mass and a previous medical history of AML and BMT.

Protective effect of propolis on liver and kidney injury caused by methotrexate in chicks

The current study aimed to explain propolis's protective effect on the liver and kidney damage caused by methotrexate (MTX). A total of 80 chickens at one day old were used and divided into three groups; the first group was the control group, the second group received the propolis, the second group was treated with MTX, and the fourth group received both propolis and treated with MTX. After 15 days of experimental, all chickens were euthanized, and blood samples and liver and kidney tissue were collected. The result showed that the treated group with MTX showed an increase in serum levels of AST, ALT, AP, urea, creatinine, and uric acid in comparison with both the control and propolis group, while in the group treated with both Propolis and MTX showed serum level of AST, ALT, AP, urea, creatinine, and uric acid similar to that recorded in both in the control group and MTX group. The liver sections treated with methotrexate showed hyperplasia of fibrocytes in the portal area with infiltration of mononuclear inflammatory cells represented by macrophages, and coagulative necrosis in affected hepatocytes, clear vacuoles in the hepatocytes, massive infiltration of macrophages. Sections of the liver treated with methotrexate and propolis explain a marked decrease in fatty degeneration, with few infiltrations of mononuclear inflammatory cells around portal areas. The liver section from the propolis-treated group and the control group showed typical hepatic tissue architecture. The kidney sections treated with methotrexate showed coagulative necrosis in the endothelial cells, glomeruli appearing irregular in shape, and hemorrhaging in the extracellular matrix. The sections of the kidney treated with methotrexate and propolis explain a marked rise in the renal tubules with the typical feature of a healthy one. The section of the kidney from the propolis treated group and control group showed typical architecture of renal tissue. In conclusion, propolis greatly protects against MTX's toxic effect on chicks' liver and kidneys.