Importance of surface charge of soot nanoparticles in determining inhalation toxicity in mice.

Physicochemical properties of nanoparticles are important in regulating nanoparticle toxicity; however, the contribution of nanoparticle charge remains unclear. The objective of this study was to investigate the pulmonary effects of inhalation of charged soot nanoparticles. We established a stably charged nanoparticle generation system for whole-body exposure in BALB/c mice, which produced positively charged, negatively charged, and neutral soot nanoparticles in a wide range of concentrations. After a 7-day exposure, pulmonary toxicity was assessed, together with proteomics analysis. The charged soot nanoparticles on average carried 1.17-1.35 electric charges, and the sizes for nanoparticles under different charging conditions were all fixed at 69 ~ 72 nm. We observed that charged soot nanoparticles induced cytotoxic LDH and increased lung permeability, with the release of 8-isoprostane and caspase-3 and systemic IL-6 in mice, especially for positively charged soot nanoparticles. Next, we observed that positive-charged soot nanoparticles upregulated Eif2, Eif4, sirtuin, mammalian target of rapamycin (mTOR), peroxisome proliferator-activated receptors (PPAR), and HIPPO-related signaling pathways in the lungs compared with negatively charged soot nanoparticles. HIF1α, sirt1, E-cadherin, and Yap were increased in mice's lungs by positively charged soot nanoparticle exposure. In conclusion, carbonaceous nanoparticles carrying electric ions, especially positive-charged, are particularly toxic when inhaled and should be of concern in terms of pulmonary health protection.

De novo podocytopathy following moderna COVID-19 vaccine: A case report and racial disproportionality in adverse effect reports.

In this study, we report a case of de novo minimal change disease shortly after the second dose of the Moderna COVID-19 vaccine. A previously healthy 51-year-old Asian man presented with lower-limb edema and foamy urine 3 days after receiving the second dose of the vaccine. Laboratory data revealed the following: serum creatinine, 0.65 mg/dl; serum albumin, 1.3 g/dl; urine protein-to-creatinine ratio, 15.3 g. A renal biopsy was performed, and minimal change in the disease was confirmed. The patient achieved complete remission in the tenth week after starting treatment with prednisolone (1 mg/kg/day). Ethnic differences may influence the adverse effects of drugs and vaccines. However, there is very limited data to address the influence of ethnic diversity on disease prevalence, clinical presentation, and treatment outcomes in COVID-19 vaccine-associated glomerulonephritis.

High-Grade B-Cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Rearrangements Is Predominantly BCL6-Rearranged and BCL6-Expressing in Taiwan.

This study investigated the epidemiological and clinical peculiarities of BCL2 and BCL6 rearrangement in patients with high grade B-cell lymphoma (HGBL) from Taiwan, compared with data from Western countries. Two hundred and eighty-two DLBCL cases from Taipei Medical University-affiliated hospitals (n = 179) and Tri-Service General Hospital (n = 103) were enrolled for this study. From the 282, 47 (16.7%) had MYC translocation; 24 of these harbored concurrent BCL2 and/or BCL6 translocation (double-hit, DH or triple-hit, TH). Twelve DH-HGBL cases had simultaneous MYC and BCL6 translocations, 8 harbored MYC and BCL2 rearrangement, while the remaining 4 patients exhibited TH. Together, 66.7% of DH/TH-HGBL patients were BCL6 rearrangement positive. Among these BCL6-rearranged DH/TH-HGBL patients, only 6 (37.5%) overexpressed MYC and BCL6 proteins simultaneously, indicating that MYC-BCL6 co-overexpression may not be plausible surrogate biomarker for screening BCL6-rearranged DH-HGBL. By the end of year 5, all patients with TH-HGBL, BCL2 DH-HGBL and all but one BCL6 DH-HGBL cases had expired or were lost to follow-up. Progression-free survival (PFS) was longer for the non-DH/TH-HGBL group compared with the DH/TH-HGBL group. While the patients with BCL2 DH-HGBL were lost to follow-up by day 800, their remaining TH-HGBL and BCL6 DH-HGBL peers exhibited very poor PFS, regardless of age strata. More so, patients with BCL6 rearrangement were 5.5-fold more likely associated with extranodal involvement compared with their BCL2-rearranged peers. Moreover, ~60.0% of the BCL6-rearranged DH-HGBL cases were non-GCB, suggesting that including screening for BCL6 rearrangement in patients with the non-GCB phenotype may aid medical decision-making and therapeutic strategy. Contrary to contemporary data from western countries, 2 in every 3 patients with DH/TH-HGBL in Taiwan harbor BCL6 rearrangement. Consistent with present findings, we recommend mandatory screening for BCL6 rearrangement in patients with aggressive HGBL in Taiwan.

Associations of soluble metals and lung and liver toxicity in mice induced by fine particulate matter originating from a petrochemical complex.

Adverse health effects have been observed in nearby residents due to exposure to petrochemical-derived chemicals. The objective of this study was to examine associations of soluble metals with lung and liver toxicity in fine particulate matter (PM2.5) in the vicinity of a petrochemical complex. PM2.5 was collected in the vicinity of a petrochemical complex of Mailiao Township (Yunlin County, Taiwan) to investigate lung and liver toxicity in BALB/c mice. The PM2.5 concentration was 30.2 ± 11.2 µg/m3, and the PM2.5 was clustered in major local emissions (19.1 µg/m3) and minor local emissions (14.1 µg/m3) using a k-means clustering model. The PM2.5 (50 and 150 µg/kg) and PM2.5-equivalent soluble nickel (Ni), vanadium (V), and lead (Pb) concentrations were intratracheally instilled into BALB/c mice. PM2.5 and V significantly decreased the tidal volume after exposure (p < 0.05). The peak expiratory flow (PEF) and peak inspiratory flow (PIF)/PEF ratio were significantly altered by 150 µg/kg V (p < 0.05). V and Pb significantly increased total protein and lactate dehydrogenase (LDH) levels in bronchoalveolar lavage fluid (BALF) (p < 0.05). Interleukin (IL)-6 in BALF significantly increased after exposure to Pb (p < 0.05) accompanied by lung inflammatory infiltration. PM2.5 and Pb significantly increased levels of 8-isoprostane (p < 0.05). The level of caspase-3 activity significantly increased after exposure to Pb (p < 0.05). LDH in the liver was significantly increased by PM2.5 (p < 0.05). 8-Isoprostane in the liver was significantly increased by PM2.5 and Pb (p < 0.05). IL-6 in the liver was significantly increased by PM2.5, Ni, V, and Pb after exposure (p < 0.05), accompanied by liver inflammatory infiltration. Our results demonstrated that V in PM2.5 was associated with an increase in 8-isoprostane for all emissions and major local petrochemical emissions. In conclusion, V contributes to in vivo liver toxicity induced by PM2.5 in the vicinity of a petrochemical complex.

Successful Treatment for BK Virus Nephropathy by Leflunomide in a Kidney Transplant Patient: A Case Report.

INTRODUCTION: The immunosuppressant agents in kidney transplantation (KT) may lead to various complications such as opportunistic infections and malignancies. BK virus associated nephropathy is a significant complication following KT, and it can result in graft failure. BK virus causes tubulointerstitial nephritis, ureter stenosis, and even graft failure in KT recipients with impaired immune system. We described a 63-year-old woman, who was a hepatitis C carrier and on dialysis for 22 years before KT, who received cadaveric-donor KT 2 years previously. She reported decreasing urine output and general weakness. The serum creatinine level was slightly increased from 2.94 to 4.38 mg/dL. METHODS: Immunosuppressant medications including prednisolone, everolimus, cyclosporin, and mycophenolate sodium were continued as maintenance therapy post KT. Kidney biopsy was performed due to deterioration of graft function. RESULTS: The kidney biopsy showed consistent results with early-stage polyomavirus nephropathy, characterized by focal viral cytopathic changes with positive immunohistochemical signals and mesangial proliferative glomerulonephritis, immune-complex-mediated (Fig 1 and Fig 2). Negative C4d staining at peritubular capillary was reported. The dosage of mycophenolate sodium was tapered from 720 to 360 mg daily and that of everolimus increased from 0.5 to 1.0 mg daily due to BK viral infection with BK nephropathy. The serum creatinine level was 2.75 mg/dL after treatment. CONCLUSION: Early detection of BK nephropathy and decreasing immunosuppressant agents are the mainstay of treatment. Substituting leflunomide for mycophenolate sodium and increasing dosage of everolimus has been proposed to solve BK nephropathy. We presented that the use of leflunomide in such situation is in a timely manner.

Investigation into the pulmonary inflammopathology of exposure to nickel oxide nanoparticles in mice.

We investigated the effects of nickel oxide nanoparticles (NiONPs) on the pulmonary inflammopathology. NiONPs were intratracheally installed into mice, and lung injury and inflammation were evaluated between 1 and 28 days. NiONPs caused significant increases in LDH, total protein, and IL-6 and a decrease in IL-10 in the BALF and increases in 8-OHdG and caspase-3 in lung tissues at 24 h. Airway inflammation was present in a dose-dependent manner from the upper to lower airways at 24 h of exposure as analyzed by SPECT. Lung parenchyma inflammation and small airway inflammation were observed by CT after NiONP exposure. 8-OHdG in lung tissues had increased with formation of fibrosis at 28 days. Focal adhesion was the most important pathways identified at 24 h as determined by protemics, whereas glutathione metabolism was the most important identified at 28 days. Our results demonstrated the pulmonary inflammopathology caused by NiONPs based on image-to-biochemical approaches.

Effects of physical characteristics of carbon black on metabolic regulation in mice.

Potential adverse effects of human exposure to carbon black (CB) have been reported, but limited knowledge regarding CB-regulated metabolism is currently available. To evaluate how physical parameters of CB influence metabolism, we investigated CB and diesel exhaust particles (DEPs) and attempted to relate various physical parameters, including the hydrodynamic diameter, zeta potential, and particle number concentrations, to lung energy metabolism in female BALB/c mice. A body weight increase was arrested by 3 months of exposure to CB of smaller-size fractions, which was negatively correlated with pyruvate in plasma. There were no significant differences in cytotoxic lactate dehydrogenase (LDH) or total protein in bronchoalveolar lavage fluid (BALF) after 3 months of CB exposure. However, we observed alterations in acetyl CoA and the NADP/NADPH ratio in lung tissues with CB exposure. Additionally, the NADP/NADPH ratio was associated with the zeta potential of CB. Mild peribronchiovascular and interstitial inflammation and multinucleated giant cells (macrophages) with a transparent and rhomboid appearance and containing foreign bodies were observed in lung sections. We suggest that physical characteristics of CB, such as the zeta potential, may disrupt metabolism after pulmonary exposure. These results, therefore, provide the first evidence of a link between pulmonary exposure to CB and metabolism.

Pulmonary pathobiology induced by zinc oxide nanoparticles in mice: A 24-hour and 28-day follow-up study.

Inhaled zinc oxide nanoparticles (ZnONPs) have high deposition rates in the alveolar region of the lungs; however, the adverse health effects of ZnONPs on the respiratory system are unclear. Herein, pathobiological responses of the respiratory system of mice that received intratracheal administration of ZnONPs were investigated by a combination of molecular and imaging (SPECT and CT) approaches. Also, normal BEAS-2B and adenocarcinoma A549 cells were used to confirm the results in mice. First, female BALB/c mice were administrated a series of doses of 20-nm ZnONPs and were compared to the phosphate-buffered saline control for 24-h and 28-day follow-up observations. Field emission-scanning electron microscopy and an energy-dispersive X-ray microanalysis were first used to characterize ZnONPs. After 24h, instilled ZnONPs had caused significant increases in lactic dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), caspase-3, and the p63 tumor marker in lung tissues (p<0.05). Airway inflammation was present in a dose-dependent manner from the upper to the lower airway as analyzed by SPECT. After 28days, p63 had significantly increased due to ZnONP exposure in lung tissues (p<0.05). Pulmonary inflammatory infiltration mainly occurred in the left and right subsegments of the secondary bronchial bifurcation as observed by CT. A significant increase in p63 and decrease in TTF1 levels were observed in BEAS-2B cells by ZnONP (p<0.05), but not in A549 cells. Our results demonstrated that regional lung inflammation occurred with ZnONP exposure. We also showed that p63 was consistently overexpressed due to ZnONP exposure in vivo and in vitro. This work provides unique findings on the p63 response and the pathobiology in response to ZnONPs, which could be important to the study of pulmonary toxicity and repair.

Targeting of Topoisomerase I for Prognoses and Therapeutics of Camptothecin-Resistant Ovarian Cancer.

DNA topoisomerase I (TOP1) levels of several human neoplasms are higher than those of normal tissues. TOP1 inhibitors are widely used in treating conventional therapy-resistant ovarian cancers. However, patients may develop resistance to TOP1 inhibitors, hampering chemotherapy success. In this study, we examined the mechanisms associated with the development of camptothecin (CPT) resistance in ovarian cancers and identified evodiamine (EVO), a natural product with TOP1 inhibiting activity that overcomes the resistance. The correlations among TOP1 levels, cancer staging, and overall survival (OS) were analyzed. The effect of EVO on CPT-resistant ovarian cancer was evaluated in vitro and in vivo. TOP1 was associated with poor prognosis in ovarian cancers (p = 0.024). EVO induced apoptosis that was detected using flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The tumor size decreased significantly in the EVO treatment group compared with the control group (p < 0.01) in a xenograft mouse model. Effects of drugs targeting TOP1 for prognosis and therapy in CPT-resistant ovarian cancer are anticipated. EVO with TOP1 can be developed as an antiproliferative agent for overcoming CPT resistance in ovarian cancers.

Effects of non-protein-type amino acids of fine particulate matter on E-cadherin and inflammatory responses in mice.

Exposure to particulate matter less than 2.5 µm (PM2.5) in size is an urgent issue for the protection of human health. Chemicals with PM2.5 collected during a period of intensive haze episodes in Beijing (BJ), Xian (XA) and Hong Kong (HK) were characterised for organic carbon (OC), elemental carbon (EC), total carbon (TC) and free amino acids. BALB/c mice underwent aspiration exposure of 50 or 150 µg of PM2.5/mouse (BJ, XA and HK) on days 1 and 7 and were euthanised on day 14. The effects of these exposures on E-cadherin and inflammatory responses in the mouse lungs were analysed. The PM2.5 chemicals consisted of significant amounts of OC: 36.6 ± 17.2 µg/m(3) for BJ, 38.8 ± 3.8 µg/m(3) for XA and 7.2 ± 1.4 µg/m(3) for HK. A total of 23 free amino compounds for the PM2.5 samples were analysed: 4075 ± 1578 pmol/m(3) for BJ, 4718 ± 2190 pmol/m(3) for XA and 1145 ± 213 pmol/m(3) for HK. Exposure to PM2.5 resulted in the suppression of E-cadherin levels in the lung tissues and increased IFN-γ, IL-2, IL-4, IL-6 and IL-10 in the bronchoalveolar lavage fluid. The alterations in E-cadherin, IFN-γ, IL-6 and IL-10 were associated with OC, TC and some amino acids, particularly non-protein-type amino acids. These data emphasised the deleterious health effects of PM2.5.

Angiomyomatous hamartoma in an inguinal lymph node with proliferating pericytes/smooth muscle cells, plexiform vessel tangles, and ectopic calcification.

Angiomyomatous hamartoma (AMH) is a rare benign lesion, which occurs almost exclusively in the inguinal lymph nodes. We herein report a case of a female elder who presented with a long-standing inguinal mass. Microscopically, the mass showed a zonal distribution, characterized by thick-walled muscular vessels, fibrosis, and calcification in the hilum and proliferating spindle cells around thin-walled vessels and plexiform vessel tangles at the periphery. The spindle cells show positive immunoreactivity of smooth muscle actin and CD34 with a heterogeneous expression of desmin and CD44. Although the pathogenesis of AMH remains uncertain, the histological features and immunohistochemical findings of this case imply a disordered or exuberant angiogenic process.

Cardiopulmonary toxicity of pulmonary exposure to occupationally relevant zinc oxide nanoparticles.

Exposure to zinc oxide (ZnO) metal fumes is linked to adverse human health effects; however, the hazards of ZnO nanoparticles (ZnONPs) remain unclear. To determine pulmonary exposure to occupationally relevant ZnONPs cause cardiopulmonary injury, Sprague-Dawley rats were exposed to ZnONPs via intratracheal (IT) instillation and inhalation. The relationship between intrapulmonary zinc levels and pulmonary oxidative-inflammatory responses 72 h after ZnONP instillation was determined in bronchoalveolar lavage fluid (BALF). Instilled ZnONPs altered zinc balance and increased the levels of total cells, neutrophils, lactate dehydrogenase (LDH) and total protein in BALF and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in blood after 72 h. The ZnONPs accumulated predominantly in the lungs over 24 h, and trivial amounts of zinc were determined in the heart, liver, kidneys and blood. Furthermore, the inflammatory-oxidative responses induced by occupationally relevant levels of 1.1 and 4.9 mg/m(3) of ZnONP inhalation for 2 weeks were determined in BALF and blood at 1, 7 and 30 days post-exposure. Histopathological examinations of the rat lungs and hearts were performed. Inhalation of ZnONP caused an inflammatory cytological profile. The total cell, neutrophil, LDH and total protein levels were acutely increased in the BALF, and there was an inflammatory pathology in the lungs. There were subchronic levels of white blood cells, granulocytes and 8-OHdG in the blood. Cardiac inflammation and the development of fibrosis were detected 7 days after exposure. Degeneration and necrosis of the myocardium were detected 30 days after exposure. The results demonstrate that ZnONPs cause cardiopulmonary impairments. These findings highlight the occupational health effects for ZnONP-exposed workers.

Allergenicity and toxicology of inhaled silver nanoparticles in allergen-provocation mice models.

Silver nanoparticles (AgNP) have been associated with the exacerbation of airway hyperresponsiveness. However, the allergenicity and toxicology of AgNP in healthy and allergic individuals are unclear. We investigated the pathophysiological responses to AgNP inhalation in a murine model of asthma. Continuous and stable levels of 33 nm AgNP were maintained at 3.3 mg/m(3) during the experimental period. AgNP exposure concomitant with ovalbumin challenge increased the enhanced pause (Penh) in the control and allergic groups. AgNP evoked neutrophil, lymphocyte and eosinophil infiltration into the airways and elevated the levels of allergic markers (immunoglobulin E [IgE] and leukotriene E4 [LTE4]), the type 2 T helper (Th2) cytokine interleukin-13 (IL-13), and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG]) in healthy and allergic mice. Bronchocentric interstitial inflammation was observed after AgNP inhalation. After inhalation, the AgNP accumulated predominantly in the lungs, and trivial amounts of AgNP were excreted in the urine and feces. Furthermore, the AgNP induced inflammatory responses in the peritoneum. The inhalation of AgNP may present safety concerns in healthy and susceptible individuals.

Multicentric paraspinal neuroglial heterotopia with Müllerian and renal agenesis: a variant of Mayer-Rokitansky-Küster-Hauser syndrome?

Neuroglial heterotopia is a rare congenital anomaly that mostly involves the head and neck region. We report a female fetus with multicentric paraspinal neuroglial heterotopia in the retropharyngeal and retroperitoneal spaces, right renal agenesis, left renal hypoplasia, and Müllerian agenesis. Additional findings included bilateral preaxial polydactyly of the hands, megacystis, rectovesical fistula, and imperforate anus. The karyotype was 46, XX. This fetus had the features of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome with paraspinal neuroglial heterotopia. This is the first report of the co-occurrence of these two malformations which could share a common pathogenetic mechanism. We suggest this to be a variant MRKH syndrome. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3246922721015286.

Jejunal and multiple mesenteric calcifying fibrous pseudotumor induced jejunojejunal intussusception.

We describe here a patient with an unusual presentation--mesenteric calcifying fibrous pseudotumor in association with jejunojejunal intussusception. This 25-year-old woman came to our emergency department with severe abdominal distension and intermittent epigastric cramping pain. She was found to have rebound tenderness and an ill-defined mass palpable in her lower abdomen. Abdominal computed tomography revealed an inhomogeneous soft tissue mass with target sign and intussusception of small intestine was suspected. Emergency laparotomy showed jejunojejunal intussusception involving ~30cm of jejunum with multiple tumors on the mesentery surface extending over the whole bowel mesenteric and peritoneal surfaces. One of the mesenteric tumors formed the leading point of the intussusception. Segmental resection of jejunum with primary anastomosis was done. Some larger tumors were resected but most of the other tumors were left in place because they were small and numerous and total resection was impossible. Pathology confirmed that the lesions were benign mesenteric calcifying fibrous pseudotumors. In such patients, surgery might be curative. If a large segment of the bowel is affected by calcifying fibrous pseudotumor, smaller pseudotumors might be left in place because these tend to be asymptomatic. But they might become the leading points of recurrent intussusception.

Adventitial cystic disease.

Adventitial cystic disease (ACD) is an unusual cystic tumor of blood vessels characterized by the accumulation of mucinous substance in the adventitia of the non-axial blood vessels adjacent to joints. Patients with ACD often suffer from intermittent claudication and/or limb pain, mostly involving the popliteal artery. We report a 30-year-old male who presented with intermittent claudication in his left leg. Angiography showed an obstructive lesion in the left popliteal artery. The lesion was treated successfully by surgical excision followed by graft vessel replacement. ACD involving the popliteal artery was diagnosed by pathologic findings of multiple cysts of the adventitia with external compression and focal narrowing of the vascular lumen. The cysts contained acid mucin and were partially lined by multiple rows of cytologically bland, synovium-like cells with positive immunoreactivity to vimentin and CD68 but negative immunoreactivity to cytokeratin. The histopathologic findings in this case suggest that it was caused by the developmental rests of mucin-secreting mesenchymal cells derived from the knee joint.

Gastrointestinal stromal tumor of the prostate: a case report and literature review.

We report a case of gastrointestinal stromal tumor (GIST) of the prostate in a 75-year-old man with dysuria and urinary retention. Digital rectal examination revealed a markedly enlarged prostate. The serum level of prostate-specific antigen was 0.2 ng/dL. Imaging studies showed an expanded prostate, measuring 6.7 x 5.6 x 5.5 cm, with heterogeneity in contrast enhancement. No metastatic disease was found. The pathologic diagnosis of prostatic GIST was made based on characteristic morphological features, immunoprofiles, and molecular analysis. The possibility of secondary involvement by a rectal GIST was excluded by radiological and intraoperative findings. To our knowledge, this is the second case of a primary GIST of the prostate reported in the literature.