Perioperative Rates of Incidental Prostate Cancer after Aquablation and Holmium Laser Enucleation of the Prostate.

INTRODUCTION: Aquablation and holmium laser enucleation of the prostate (HoLEP) have evolved as established therapeutic options for men with benign prostatic obstruction (BPO). We sought to compare the rates of incidental prostate cancer (iPCa) after aquablation and HoLEP. METHODS: At our center, between January 2020 and November 2022, 317 men underwent aquablation, and 979 men underwent HoLEP for BPO. Histopathological assessment of resected tissue was conducted in all cases. If iPCa was detected, the Gleason score and percentage of affected tissue were assessed. Differences in important predictive factors for prostate cancer between study groups were accounted for by additional matched pairs analysis (with matching on age ± 1 year; PSA ± 0.5 ng/mL; and prostate volume ± 5 mL). RESULTS: Histopathology revealed iPCas in 60 patients (4.6%): 59 (6.03%) after HoLEP and 1 (0.3%) after aquablation (p = 0.001). Of 60 of incidental cancers, 11 had a Gleason score ≥7 (aquablation: 1/1 [100%]; HoLEP: 10/59 [16.9%]). The aquablation and HoLEP study groups differed in patient age, preoperative PSA, and prostate volume. Therefore, matched pairs analysis (aquablation: 132 patients; HoLEP: 132 patients) was conducted to improve comparability. Also after the matching procedure, significantly fewer iPCas were diagnosed after aquablation than HoLEP (aquablation: 0 [0%]; HoLEP: 6 [4.5%]; p = 0.015). CONCLUSION: Significantly fewer iPCas were identified after aquablation than HoLEP procedures. Histopathologic assessment of tissue after aquablation is feasible and may lead to the diagnosis of clinically significant iPCa. Therefore, histopathologic examination of the aquablation resective tissue should not be omitted.

Case report: SARS-CoV-2 specific T-cells are associated with myocarditis after COVID-19 vaccination with mRNA-1273.

Vaccination of SARS-CoV-2 with BNT162b2 or mRNA-1273 both have a low incidence of induction of myocarditis. Here we report on utilizing adaptive immune receptor repertoire sequencing (AIRR-Seq) as a way to assess the specificity of tissue infiltrating immune cells.

Immunohistochemical evidence of striated muscle cells within midfacial superficial musculoaponeurotic system.

INTRODUCTION: The superficial musculoaponeurotic system (SMAS) is a controversial functional fibro-adipose layer that connects the mimic muscles to the skin and is involved in a variety of facial mimic expressions. The presence of muscle fibers within SMAS fibrous septa is hypothetical. The present study analyzed SMAS fibrous septa composition for the existence of striated muscle cells. METHODS: Histological serial sections of the sample borders (n=107) of 19 in sano-resected and diagnosed cutaneous tumors of the midfacial region were investigated. Immunohistochemical (actin and myosin) and hematoxylin and eosin staining were performed to detect striated muscle cells in SMAS fibrous septa. RESULTS: A fibro-neuro-musculo-vascular functional unit within SMAS fibrous septa was demonstrated. SMAS striated muscle cells were morphologically independent from preparotideal and periorbital mimic muscles. Intraseptal blood vessels draining the superficial and deep SMAS vascular system were described. CONCLUSIONS: Striated muscle cells were demonstrated within SMAS fibrous septa. Nerve cells and vascular tissue together with the SMAS fibro-muscular meshwork demonstrated an autonomous operating functional unit that hypothetical modulated individual mimic expression contributing to the diversity of mimic expression. The SMAS develops with mimic muscle contractions as a synergetic effect during facial crease and fold formation processes.

Characterization of the Olfactory Receptor OR10H1 in Human Urinary Bladder Cancer.

Olfactory receptors (ORs) are a large group of G-protein coupled receptors predominantly found in the olfactory epithelium. Many ORs are, however, ectopically expressed in other tissues and involved in several diseases including cancer. In this study, we describe that one OR, OR10H1, is predominantly expressed in the human urinary bladder with a notably higher expression at mRNA and protein level in bladder cancer tissues. Interestingly, also significantly higher amounts of OR10H1 transcripts were detectable in the urine of bladder cancer patients than in the urine of control persons. We identified the sandalwood-related compound Sandranol as a specific agonist of OR10H1. This deorphanization allowed the functional characterization of OR10H1 in BFTC905 bladder cancer cells. The effect of receptor activation was morphologically apparent in cell rounding, accompanied by changes in the cytoskeleton detected by ß-actin, T-cadherin and ß-Catenin staining. In addition, Sandranol treatment significantly diminished cell viability, cell proliferation and migration and induced a limited degree of apoptosis. Cell cycle analysis revealed an increased G1 fraction. In a concentration-dependent manner, Sandranol application elevated cAMP levels, which was reduced by inhibition of adenylyl cyclase, and elicited intracellular Ca2+ concentration increase. Furthermore, activation of OR10H1 enhanced secretion of ATP and serotonin. Our results suggest OR10H1 as a potential biomarker and therapeutic target for bladder cancer.

Cholesteryl Ester Storage Disease: Fatal Outcome without Causal Therapy in a Female Patient with the Preventable Sequelae of Progressive Liver Disease after Many Years of Mild Symptoms.

BACKGROUND Cholesteryl ester storage disease (CESD), also known as lysosomal acid lipase deficiency (LAL-D), is a rare autosomal-recessive inheritable lysosomal storage disease. Since 2015, a causal treatment with sebelipase alfa, which replaces the missing LAL enzyme, has been approved. We report a fatal course of LAL-D in a female patient. CASE REPORT In 1979, CESD was first diagnosed in a 13-year-old female with marked hepatomegaly. At that time, no specific treatment for CESD was available and the spontaneous course of the disease had to be awaited. In 2013, a laparoscopic cholecystectomy for symptomatic gallstones was performed. The patient's CESD had caused a Child-Pugh A/B and Lab-MELD 14 cirrhosis with esophageal varices (grade III), a solitary fundal varix, as well as hepatosplenomegaly with thrombocytopenia. In 2016, the patient was admitted with compensated cirrhosis and splenomegaly for a ligature of esophageal varices which was complicated by vomiting of blood followed by severe coagulopathy and hemorrhagic shock. The dried blood test showed reduced acid lipase (0.03 nmol/spot*3 hours; reference range 0.2-2) and beta-galactosidase (0.08 nmol/spot*21 hours; reference range 0.5-3.2). Then 15 days after the esophageal varices bleed, the patient died due to multiorgan failure as a sequelae of advanced liver disease. CONCLUSIONS LAL-D should be included in the differential diagnosis of lipid metabolism disorder, hepatomegaly, and non-alcoholic fatty liver disease with fibrosis or cirrhosis. Causal treatment with sebelipase alfa should be introduced even in patients who have LAL-D and many years of clinically mild symptoms of this disease to prevent the serious sequelae of cirrhosis or cardiovascular complications.

Olfactory Receptors as Biomarkers in Human Breast Carcinoma Tissues.

Olfactory receptors (ORs) are known to be expressed in a variety of human tissues and act on different physiological processes, such as cell migration, proliferation, or secretion and have been found to function as biomarkers for carcinoma tissues of prostate, lung, and small intestine. In this study, we analyzed the OR expression profiles of several different carcinoma tissues, with a focus on breast cancer. The expression of OR2B6 was detectable in breast carcinoma tissues; here, transcripts of OR2B6 were detected in 73% of all breast carcinoma cell lines and in over 80% of all of the breast carcinoma tissues analyzed. Interestingly, there was no expression of OR2B6 observed in healthy tissues. Immunohistochemical staining of OR2B6 in breast carcinoma tissues revealed a distinct staining pattern of carcinoma cells. Furthermore, we detected a fusion transcript containing part of the coding exon of OR2B6 as a part of a splice variant of the histone HIST1H2BO transcript. In addition, in cancer tissues and cell lines derived from lung, pancreas, and brain, OR expression patterns were compared to that of corresponding healthy tissues. The number of ORs detected in lung carcinoma tissues was significantly reduced in comparison to the surrounding healthy tissues. In pancreatic carcinoma tissues, OR4C6 was considerably more highly expressed in comparison to the respective healthy tissues. We detected OR2B6 as a potential biomarker for breast carcinoma tissues.

Interaction with the GDF8/11 pathway reveals treatment options for adenocarcinoma of the breast.

Breast adenocarcinoma continues to be the most frequently diagnosed tumor entity. Despite established therapy options, mortality for breast cancer remains to be as high as 40,000 patients in the US annually. Thus, a need to develop a patient-oriented, targeted therapy exists. In this study, we investigated the interaction of breast adenocarcinoma with the ubiquitously present protein Follistatin and subsequently the GDF8/11 pathway. We analyzed primary histological samples from adenocarcinoma patients for expression of Follistatin and GDF8/11. Furthermore, expression levels of Follistatin and GDF8/11 in MCF7 were compared with MCF10a cells. From the resulting data, GDF8 and Follistatin were used as chemotherapeutic agents in MCF7 cells and their migratory, proliferative behavior and viability were measured. From the experiments, we were able to detect a significantly increased expression of Follistatin and GDF8/11 in the low malignant breast adenocarcinoma (G1) as compared to benign breast fibroadenoma. Interestingly, a decrease was demonstrated in higher grade malignancies. These findings were accompanied by the clinical observation that increased expression of Follistatin and GDF8 is associated with a higher overall survival rate of breasts cancer patients. Substitution of GDF8 and Follistatin reduces the viability of the MCF7 cells and disrupts the migrative and proliferative potential. In summary, MCF7 cells show high chemosensitivity to Follistatin and especially GDF8 and both proteins might serve as targets to improve systemic treatment in breast cancer. In contrast to most established chemotherapy regimens Follistatin and GDF8 show no cytotoxicity to other organs.

Helional-induced activation of human olfactory receptor 2J3 promotes apoptosis and inhibits proliferation in a non-small-cell lung cancer cell line.

Studies within the last decade have localized the functional expression of olfactory receptors (ORs) to cells outside of the olfactory epithelium. In human hepatocarcinoma and prostate cancer cells, the activation of ORs by odors modulates elementary physiological processes and leads to an inhibitory effect on proliferation. Cells of the respiratory tract are in direct contact with the surrounding air, in which a myriad of volatile molecules, especially odors, are present. Non-small-cell lung cancer (NSCLC) has a high prevalence, a high mortality rate and is difficult to treat. NSCLC cells are nearly resistant to common chemotherapeutic approaches, and surgical resection provides the only possible chance of a cure for most patients. New approaches for the treatment of NSCLC are the focus of many current studies. Thus, it is of interest to characterize the functional expression of ORs in cancer cells of the lung and to investigate the impact of ORs on pathophysiological processes. In the present study, we demonstrate that the expression of OR2J3 and cytosolic Ca2+ increase via the activation of the agonist helional in the NSCLC cell line A549. We further investigated the underlying pathway. Helional triggers phoshoinositol-3 kinase (PI3K), signaling the release of intracellular Ca2+ and phosphorylation of ERK. We observed that OR2J3 activation induces apoptosis and inhibits cell proliferation and migration in long-term stimulus experiments with helional. Our study provides the first evidence of the functional expression of an OR in NSCLC cells and its putative therapeutic impact.

Olfactory signaling components and olfactory receptors are expressed in tubule cells of the human kidney.

Cells of the renal tubule system are in direct contact with compounds dissolved in the urine, such as short chain fatty acids (SCFA). Murine OR78, a member of the olfactory receptor (OR) family, is involved in SCFA-related regulation of renal blood pressure in mice. It is still unclear whether OR signaling has an impact on human renal physiology. In our study, we showed that OR51E1 and OR11H7, both of which can be activated by the SCFA isovaleric acid, are expressed in the HK-2 human proximal tubule cell line. We observed a transient increase in intracellular Ca2+ when isovaleric acid and 4-methylvaleric acid were added to HK-2 cells. The isovaleric acid-induced response was dependent on extracellular Ca2+ and adenylyl cyclase (AC) activation. Furthermore, we demonstrated that the canonical olfactory signaling components Gαolf and ACIII are co-localized with OR51E1. The number of cells responding to isovaleric acid correlated with the presence of primary cilia on HK-2 cells. OR51E1 protein expression was confirmed in the tubule system of human kidney tissue. Our study is the first to show the expression of ORs and olfactory signaling components in human kidney cells. Additionally, we discuss ORs as potential modulators of the renal physiology.

Olfactory Receptors Modulate Physiological Processes in Human Airway Smooth Muscle Cells.

Pathophysiological mechanisms in human airway smooth muscle cells (HASMCs) significantly contribute to the progression of chronic inflammatory airway diseases with limited therapeutic options, such as severe asthma and COPD. These abnormalities include the contractility and hyperproduction of inflammatory proteins. To develop therapeutic strategies, key pathological mechanisms, and putative clinical targets need to be identified. In the present study, we demonstrated that the human olfactory receptors (ORs) OR1D2 and OR2AG1 are expressed at the RNA and protein levels in HASMCs. Using fluorometric calcium imaging, specific agonists for OR2AG1 and OR1D2 were identified to trigger transient Ca(2+) increases in HASMCs via a cAMP-dependent signal transduction cascade. Furthermore, the activation of OR2AG1 via amyl butyrate inhibited the histamine-induced contraction of HASMCs, whereas the stimulation of OR1D2 with bourgeonal led to an increase in cell contractility. In addition, OR1D2 activation induced the secretion of IL-8 and GM-CSF. Both effects were inhibited by the specific OR1D2 antagonist undecanal. We herein provide the first evidence to show that ORs are functionally expressed in HASMCs and regulate pathophysiological processes. Therefore, ORs might be new therapeutic targets for these diseases, and blocking ORs could be an auspicious strategy for the treatment of early-stage chronic inflammatory lung diseases.

The activation of OR51E1 causes growth suppression of human prostate cancer cells.

The development of prostate cancer (PCa) is regulated by the androgen-dependent activity of the androgen receptor (AR). Androgen-deprivation therapy (ADT) is therefore the gold standard treatment to suppress malignant progression of PCa. Nevertheless, due to the development of castration resistance, recurrence of disease after initial response to ADT is a major obstacle to successful treatment. As G-protein coupled receptors play a fundamental role in PCa physiology, they might represent promising alternative or combinatorial targets for advanced diseases. Here, we verified gene expression of the olfactory receptors (ORs) OR51E1 [prostate-specific G-protein coupled receptor 2 (PSGR2)] and OR51E2 (PSGR) in human PCa tissue by RNA-Seq analysis and RT-PCR and elucidated the subcellular localization of both receptor proteins in human prostate tissue. The OR51E1 agonist nonanoic acid (NA) leads to the phosphorylation of various protein kinases and growth suppression of the PCa cell line LNCaP. Furthermore, treatment with NA causes reduction of androgen-mediated AR target gene expression. Interestingly, NA induces cellular senescence, which coincides with reduced E2F1 mRNA levels. In contrast, treatment with the structurally related compound 1-nonanol or the OR2AG1 agonist amyl butyrate, neither of which activates OR51E1, did not lead to reduced cell growth or an induction of cellular senescence. However, decanoic acid, another OR51E1 agonist, also induces cellular senescence. Thus, our results suggest the involvement of OR51E1 in growth processes of PCa cells and its impact on AR-mediated signaling. These findings provide novel evidences to support the functional importance of ORs in PCa pathogenesis.

Submesothelial deposition of carbon nanoparticles after toner exposition: case report.

Inhalation of carbon nanoparticles (CNP) from toner dust has been shown to have impact on the respiratory health of persons exposed. Office printers are known emitters of CNP. We report about a female open office worker who developed weight loss and diarrhoea. Laparoscopy done for suspected endometriosis surprisingly revealed black spots within the peritoneum. Submesothelial aggregates of CNP with a diameter of 31-67 nm were found by scanning and transmission electron microscopy in these tissue specimens. Colon biopsies showed inflammatory bowel disease with typically signs of Crohn disease, but no dust deposits. Transport of CNP via lymphatic and blood vessels after inhalation in the lungs has to be assumed. In this case respiratory symptoms were not reported, therefore no lung function tests were done. We have shown that workers with toner dust exposure from laser printers can develop submesothelial deposition of CNP in the peritoneum. Impact of toner dust exposure on the respiratory health of office workers, as suspected in other studies, has to be evaluated further.

Pancreatic carcinosarcoma. Case report of multimodal therapy and review of the literature.

CONTEXT: Carcinosarcoma (malignant mixed tumor) is a rare variant of a pancreatic neoplasm having a dismal prognosis; very few clinical data and treatment options have been published. Unlike adenocarcinoma of the pancreas, there is nothing specific in the literature for this variant regarding postoperative treatment with chemotherapeutic agents. CASE REPORT: We report the case of a 61-year-old woman presenting with anemia. Examination revealed a mass in the pancreatic head and she underwent a partial pancreaticoduodenectomy. Histopathological examination revealed a pancreatic neoplasm with both adenomatous as well as sarcomatous characteristics. Postoperatively, the patient was treated with gemcitabine and was in a good health for 9 months. Three follow-up CT scans were done, showing complete remission. Eleven months postoperatively, the patient died from a recurrence. CONCLUSION: Carcinosarcoma of the pancreas is a very rare disease having a dismal prognosis. In addition to reviewing the literature on this entity, we present the first published case where gemcitabine was administered as a treatment modality in combination with surgery.

Ultrasound elastography for the age determination of venous thrombi. Evaluation in an animal model of venous thrombosis.

The exact age determination of venous thrombi is important if thrombolytic therapy or surgical thrombectomy is considered. Clinical symptoms as well as duplex-ultrasound and phlebography are unreliable in this respect and do not allow an exact age estimation. Ultrasound elastography can provide information about the elastic properties of thrombi. Since thrombus elasticity decreases with age due to the organisation process, it should be possible to use elastography to stage the degree of organisation and thereby determine the age of venous thrombi. Experimental venous thrombi aging 1, 3, 6, 9, 12 and 15 days were created in a porcine model by laparoscopic ligation of the infrarenal Vena cava in combination with transfemoral infusion of thrombin. The thrombosed iliac veins were explanted and embedded in gelatine, after that they underwent examination by ultrasound elastography. In addition, histological evaluation of the thrombi was performed. Elastography demonstrated a decline in thrombus elasticity between days 6 and 12 with the 12-day-old thrombi being about 3 times harder then the 6-day-old thrombi. This correlated with the histological findings, which demonstrated a marked increase in fibroblast and collagen production in the clots during this time, with the 12- and 15-day thrombi showing signs of advanced organisation. In conclusion, in an experimental setting, ultrasound elastography was helpful in determining the exact age of venous thrombi. The differences in elasticity were most pronounced between days 6 and 12, which is also the most relevant time frame when considering invasive therapies in human venous thrombosis.

Ultrasonic multifeature tissue characterization for prostate diagnostics.

A new system for prostate diagnostics based on multifeature tissue characterization is proposed. Radiofrequency (RF) ultrasonic echo data are acquired during the standard transrectal ultrasound (US) imaging examination. Nine spectral, texture, first order and morphologic parameters are calculated and fed into two adaptive neuro-fuzzy inference systems (FIS) working in parallel. The outputs of the FISs are fed into a postprocessing procedure evaluating contextual information before being combined to form a malignancy map in which areas of high cancer probability are marked in red. The malignancy map is presented to the physician during the examination to improve the early detection of prostate cancer. The system has been evaluated on 100 patients undergoing radical prostatectomy. The ROC curve area using leave-one-out cross-validation over patients is A(Z) = 0.86 when distinguishing between hyperechoic and hypoechoic tumors and normal tissue and A(Z) = 0.84 when distinguishing between isoechoic tumors and healthy tissue, respectively. Tumors that are not visible in the conventional B-mode image can be located. Diagnosis of the prostate carcinoma using multifeature tissue characterization in combination with US imaging allows the detection of tumors at an early stage. Also, biopsy guidance and therapy planning can be improved.