Sorafenib Alleviates Inflammatory Signaling of Tumor Microenvironment in Precancerous Lung Injuries.

According to population-based studies, lung cancer is the prominent reason for cancer-related mortality worldwide in males and is also rising in females at an alarming rate. Sorafenib (SOR), which is approved for the treatment of hepatocellular carcinoma and renal cell carcinoma, is a multitargeted protein kinase inhibitor. Additionally, SOR is the subject of interest for preclinical and clinical trials in lung cancer. This study was designed to assess in vivo the possible effects of sorafenib (SOR) in diethylnitrosamine (DEN)-induced lung carcinogenesis and examine its probable mechanisms of action. A total of 30 adult male rats were divided into three groups (1) control, (2) DEN, and (3) DEN + SOR. The chemical induction of lung carcinogenesis was performed by injection of DEN intraperitoneally at 150 mg/kg once a week for two weeks. The DEN-administered rats were co-treated with SOR of 10 mg/kg by oral gavage for 42 alternate days. Serum and lung tissue samples were analyzed to determine SRY-box transcription factor 2 (SOX-2) levels. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß) levels were measured in lung tissue supernatants. Lung sections were analyzed for cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) histopathologically. In addition, cyclooxygenase-2 (COX-2) and c-Jun N-terminal kinase (JNK) were analyzed by immunohistochemistry and immunofluorescence methods, respectively. SOR reduced the level of SOX-2 that maintenance of cancer stemness and tumorigenicity, and TNF-α and IL-1ß levels. Histopathological analysis demonstrated widespread inflammatory cell infiltration, disorganized alveolar structure, hyperemia in the vessels, and thickened alveolar walls in DEN-induced rats. The damage was markedly reduced upon SOR treatment. Further, immunohistochemical and immunofluorescence analysis also revealed increased expression of COX-2 and JNK expression in DEN-intoxicated rats. However, SOR treatment alleviated the expression of these inflammatory markers in DEN-induced lung carcinogenesis. These findings suggested that SOR inhibits DEN-induced lung precancerous lesions through decreased inflammation with concomitant in reduced SOX-2 levels, which enables the maintenance of cancer stem cell properties.

The Role of 18F-FLT PET/CT in Assessing Early Response to Transarterial Radioembolization and Chemoembolization in Patients with Primary and Metastatic Liver Tumors.

Objectives: Metastases and primary malignancies are common in the liver. Local ablative applications such as transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) provide minimally invasive and safe treatment in unresectable liver tumors. Early detection of response to treatment prevents unnecessary toxicity and cost in non-responder patients and provides an earlier use of other options that may be effective. This study aimed to identify the role of 18F-fluorothymidine (FLT) positron emission tomography/computed tomography (PET/CT) in the assessment of early response to TACE and TARE treatments in patients with unresectable primary and metastatic liver tumors. Methods: This single-center study included 63 patients who underwent 18F-FLT PET/CT for response evaluation after TACE and TARE. After excluding 20 patients whose data were missing 43 TARE-receiving patients were analyzed. The compatibility of change in semi-quantitative values obtained from the 18F-FLT PET/CT images with the treatment responses detected in 18F-fluorodeoxyglucose PET/CT, CT, and MR images and survival was evaluated. Results: There was no correlation between early metabolic, morphological response, and 18F-FLT uptake pattern, and change in standardized uptake values (SUV) which were ΔSUVmax, ΔSUVmean, ΔSUVpeak., ΔSUVmean, Δ SUVpeak values. There was no significant correlation between 18F-FLT uptake pattern, ΔSUVmax, ΔSUVmean, ΔSUVpeak, and overall survival, progression-free survival (PFS) for the target lobe PFS for the whole-body. The survival distributions for the patients with >30% change in Δ SUVmax and ΔSUVpeak values were statistically significantly longer than the patients with <30% change (p<0.009 and p<0.024, respectively). Conclusion: There was significant longer PFS for target liver lobe in patients with more than 30% decrease in 18F-FLT SUVmax and SUVpeak of the liver lesion in primary and metastatic unresectable liver tumors undergoing TARE.

Beneficial interaction of pycnogenol with indomethacin in rats.

Cyclooxygenase 2 (COX-2) is responsible for the therapeutic effects of indomethacin, while inhibition of the COX-1 enzyme and oxidative stress are responsible for its gastro-toxic effects. It has been reported that pycnogenol increases the expression of COX-1, suppresses the expression rate of COX-2 and oxidative stress. Our aim in this study is to investigate the antiinflammatory activities of indomethacin, pycnogenol, and their combination (PI) in rats and to examine their effects on stomach tissue. In the study, anti-inflammatory activity was investigated in carrageenan-induced inflammatory paw edema in albino Wistar male rats. Effects on stomach tissue were performed by applying the previous method. PI, indomethacin and pycnogenol were the best suppressors of carrageenan inflammation and oxidative stress in paw tissue, respectively. While the groups with the lowest COX-1 activity in paw tissue were IC, PIC and PC, respectively, PIC, IC and PC were the ones that best inhibited the increase in COX-2 activity. Pycnogenol inhibited the increase of malondialdehyde, the decrease of total glutathione and COX-1 in the stomach, and significantly suppressed the formation of indomethacin ulcers. Our experimental results showed that pycnogenol reduced the toxic effect of indomethacin on the stomach and increased anti-inflammatory activity. This beneficial interaction of pycnogenol and indomethacin suggests that PI will provide superior success in the treatment of inflammatory diseases.

Effect of chronic lung diseases on mortality of prevariant COVID-19 pneumonia patients.

Background: The aim of the study is to assess the effect of chronic lung disease on mortality in patients hospitalized with the diagnosis of prevariant COVID-19 Pneumonia compared to patients without chronic lung disease. Research design and methods: A cohort of 1,549 patients admitted to the pandemic clinic with a COVID-19 Pneumonia diagnosis was analyzed. Group 1 and Group 2 were compared in terms of the treatment they received, admission to intensive care, mortality and follow-up parameters. Results: The patient group with COVID-19 and lung disease consisted of 231 participants (14.91%) (Group 1). The patient group with COVID-19 but without lung disease had 1,318 participants (85.19%). Group 1 cases were found to receive more oxygen therapy and mechanical ventilation than Group 2 cases (p ≤ 0.001), Following univariate and multiple logistic regression analyses, it was determined that patients with chronic lung disease had a 25.76% higher mortality risk [OR: 25.763, 95% CI (Lower-Upper) (2.445-271.465), p = 0.007]. Conclusion: It was found that chronic lung disease contributed significantly to mortality in this study. Among chronic lung diseases, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and interstitial lung diseases (ILDs) were shown to be more effective than other chronic lung diseases in patients with prevariant COVID-19 population.

Role of PD-1/PD-L1-mediated tumour immune escape mechanism and microsatellite instability in the BCG failure of high-grade urothelial carcinomas.

BACKGROUND: Intravesical BCG treatment fails inexplicably in 30%-45% of patients for high-grade nonmuscle-invasive bladder cancer (NMIBC). We aimed to investigate the role of PD-1/PD-L1 interaction on BCG failure of high-grade NMIBC and to identify biomarkers for predicting BCG responsive cases. METHODS: Thirty BCG responsive and 29 nonresponsive NMIBCs were included in the study. Expressions of PDL1(SP-263), MSH2, MSH6, PMS2, and MLH1 were evaluated on pre- and post-BCG transurethral resection (TUR-B) specimens by immunohistochemistry. PD-L1(SP-263) expression was categorised as negative/low, high. DNA mismatch repair protein (MMR) expressions were classified as "reduced" if ≤30% of nuclei stained, "preserved" if >30% of nuclei stained. Microsatellite instability (MSI) testing was performed by PCR using five mononucleotide markers. RESULTS: Reduced DNA MMR protein expression was found to be significantly higher in the pretreatment biopsies of BCG-responsive group than the BCG nonresponsive tumour group (p = 0.022). PD-L1 expression did not show any significant difference between the pre- and posttreatment TUR-B specimens of the BCG nonresponsive tumour group or between the pretreatment TUR-B specimens of BCG nonresponsive and the BCG responsive groups (p = 0.508, p = 0.708, respectively). DISCUSSION: Immune escape of tumour cells by PD-1/PD-L1 interaction does not seem to have any role in BCG failure of NMIBCs. Reduced MMR expression may help to determine cases that will respond well to BCG therapy. A better antitumour activity of BCG in NMIBCs with reduced MMR expression may be related to the ongoing accumulation of cancer neoantigens in correlation with increased tumour mutation load as a result of DNA repair defects.

The Risk of Presarcopenia Is Increased Among Female Patients With Primary Sjögren's Syndrome.

OBJECTIVES: Sarcopenia is a progressive and generalized loss of muscle mass and function. The aim of this study was to evaluate the frequency of sarcopenia among patients with primary Sjögren's syndrome (SS) and the factors related with sarcopenia. METHODS: Forty-four female patients with primary SS and 44 female control subjects were included in this cross-sectional study between February and August 2019. Sarcopenia was evaluated by the handgrip test, Skeletal Muscle Mass Index, and gait speed test. RESULTS: Eleven patients (25.0%) had presarcopenia in the SS group and 2 (4.5%) in the control group (p = 0.007). Compared with control subjects, SS patients had lower results of hand grip and gait speed tests (p = 0.005 and p < 0.001, respectively). According to the Mini Nutritional Assessment Short Form, patients with presarcopenia had higher risk of malnutrition compared with patients without sarcopenia (p = 0.043). Patients with presarcopenia had higher scores in the European League Against Rheumatism Sjögren's Syndrome Patient-Reported Index pain domain and patient visual analog scale for global disease activity compared with patients without sarcopenia (p = 0.044 and p = 0.036, respectively). In multivariate regression analysis, European League Against Rheumatism Sjögren's Syndrome Patient-Reported Index pain was associated with hand grip strength (p = 0.016, R2 = 0.13) and Mini Nutritional Assessment Short Form was associated with Skeletal Muscle Mass Index (p = 0.005). CONCLUSIONS: Risk of sarcopenia is increased in patients with SS. Pain and malnutrition may contribute to presarcopenia. Evaluating pain and patient's global disease activity may help physicians to determine patients with increased risk of sarcopenia. Controlling disease activity and pain and preventing malnutrition may reduce the risk of development of sarcopenia.

Effects of pulmonary rehabilitation on diaphragm thickness and contractility in patients with chronic obstructive pulmonary disease.

BACKGROUND: Studies are showing that pulmonary rehabilitation (PR) increases diaphragmatic excursion by decreasing hyperinflation in patients with chronic obstructive pulmonary disease (COPD). However, there is a lack of knowledge about its effects on the diaphragm thickness (dt) and contractility. This study aims to evaluate the dt and contractility before and after PR in patients with COPD. METHODS: All subjects participated in an out-patient PR of 6 weeks and 3 sessions per week prospectively. Dyspnea severity, the disease-specific quality of life (St. Georges Respiratory Questionnaire-SGRQ), pulmonary function tests (PFT), exercise capacity, the dt at the end of the expiration and at maximal inspiration (B-mode ultrasound) were evaluated at baseline and after PR. RESULTS: A total of 34 patients with a mean age and FEV1 61.05 ± 8.22 years and 57.9 ± 20.4% predicted respectively showed improvements in exercise capacity and some items of PFT and SGRQ. Diaphragmatic thickness at the end of the expiration also significantly improved regardless of the disease severity and was positively correlated with functional performance. The 6-weeks of PR didn't result in a significant difference in diaphragm contractility.

Comparison of the effects of open- and closed-skill exercise on cognition and peripheral proteins: A cross-sectional study.

Previous research indicates that different exercise modes might create different effects on cognition and peripheral protein signals. This study aimed to compare the effects of long-term participation in an open and closed-skill exercise on cognitive functions and Brain-derived neurotrophic factor and Cathepsin B levels. 18 fencers, 18 swimmers, 18 sedentary controls between 18-25 years old participated in the study. Participants performed visuospatial working memory, verbal fluency and selective attention tasks. Blood samples were tested for Brain-derived neurotrophic factor and Cathepsin B using ELISA. The results showed that fencers performed superiorly on some part of visuospatial working memory, verbal fluency, and selective attention tasks than swimmers and sedentary controls. Athlete groups showed higher scores on some subtests of visuospatial working memory and selective attention tasks than sedentary controls. The basal serum Brain-derived neurotrophic factor level was not significant between the groups, but Cathepsin B was higher in fencers than swimmers and sedentary controls. The peripheric protein signal response to acute exercise was significantly higher in athletes, particularly in the open-skill group for Cathepsin B. Our research provided noteworthy results that more cognitively challenging exercise may provide more benefits for some aspects of cognition. Since our findings suggest that open-skill exercise improves specific types of executive-control functioning, this exercise mode might be included in training programs to support cognition and prevent cognitive impairment.

Efficacy and safety of papaverine as an in vitro motility enhancer on human spermatozoa.

PURPOSE: The aim of this study was to examine the ability and safety of papaverine supplementation for in vitro sperm motility enhancement. In addition, sperm motility enhancement of papaverine was compared to pentoxifylline and theophylline. The post-thaw spermatozoa were used as an asthenozoospermia model. METHODS: Post thaw sperm suspensions were divided into two groups: papaverine (100 µmol/L) and control, and each was investigated in two subgroups of 30- and 60-min exposure times. Detailed motility parameters were detected using a computerized sperm motility analyzer. Acrosomal status, viability, apoptosis, and DNA fragmentation were evaluated by flow cytometry. Furthermore, the motility-enhancing capacity of papaverine, pentoxifylline, and theophylline was compared. RESULTS: Cryopreservation impaired sperm parameters dramatically but no significant changes occurred in acrosomal status and apoptosis. Supplementation of papaverine enhanced motility parameters consistently at all exposure intervals, significantly. However, viability was lower at the 60th minute compared to the 30th minute (p=0.019). Papaverine did not alter any acrosomal or apoptotic markers at any time points. All of the compounds compared in this study increased the motility parameters, where theophylline supplementation provided significantly better improvement in total motility compared to papaverine and pentoxifylline. CONCLUSION: Our results suggest that in vitro papaverine treatment for 30 min adequately improves motility of post-thaw sperm, without leading to acrosome reaction, DNA damage, and viability loss. Theophylline's potency on increasing the ratio of total motile spermatozoa was found significantly superior than the two tested compounds. Prospective clinical studies with embryo production, pregnancy, and live birth data should be undertaken.

PFA is superior to glyoxal in preserving oocyte, embryo, and stem cell proteins evidenced by super-resolution microscopical surveys of epitopes.

PURPOSE: Chemical fixation is a critical step to retaining cellular targets as naturally as possible. Recent developments in microscopy allow sophisticated detection and measuring techniques with which spatio-temporal molecular alterations are conceivable. In this study, we compare two members of aldehyde fixatives [i.e., glyoxal (Gly) and paraformaldehyde (PFA)] to determine whether Gly, a less toxic dialdehyde fixative that is considered to retain immunoreactivity could provide a successful and consistent cell fixation in favor of PFA in various cell preparations and types. METHODS: We document the fixation competence of Gly and PFA side-by-side (with or without Triton X-100 permeabilization) in live- and fixed-cell preparations in mouse oocytes, embryos, and human somatic cells (human umbilical cord-derived mesenchymal stromal cells) using protein quantification by Western blot assay and super-resolution microscopy. RESULTS: Although Gly seemed to act faster than PFA, catastrophic consequences were found not acceptable, especially in oocytes and embryos. Due to cell lysate and immunocytochemistry surveys, it was obvious that PFA is superior to Gly in retaining cellular proteins in situ with little/no background staining. In many samples, PFA revealed more reliable and consistent results regarding the protein quantity and cellular localization corresponding to previously defined patterns in the literature. CONCLUSION: Although the use of Gly is beneficial as indicated by previous reports, we concluded that it does not meet the requirement for proper fixation, at least for the tested cell types and proteins. However, PFA alone with no addition of TX displayed a significant cytoplasmic loss by generating membrane blebs during fixation.

Diagnostic Performance of Multiparametric MR Imaging at 3.0 Tesla in Discriminating Prostate Cancer from Prostatitis: A Histopathologic Correlation.

OBJECTIVE: To investigate the diagnostic performance of multiparametric magnetic resonance imaging (mpMRI) in differentiating prostate cancer (PCa) from prostatitis foci. MATERIALS AND METHODS: This retrospective analysis included 81 biopsy-proven lesions (44 prostatitis and 37 PCa). Normalized T2-signal intensity (nT2SI) and SI on diffusion-weighted imaging (b=1000 and 2000 mm2/s), apparent diffusion coefficient (ADC) values, peak SI, SI at the end of the dynamic curves, mean peak time, mean enhancement percentage, and washout percentage obtained from dynamic contrast-enhanced imaging (DCEI) were measured. RESULTS: nT2SI (3.8 vs. 3.2, p=0.003) and ADC values (0.685×10-3 mm2/s vs. 0.874×10-3 mm2/s, p<0.001) were significantly higher in the prostatitis group than in the PCa group. The washout percentage was the only DCEI parameter that was significantly different between the two groups (12% vs. 4%, respectively, p=0.003). The ADC values alone showed higher sensitivity (80.5%) and specificity (75%) than all of the single criteria and most of the combined criteria. The combination of nT2SI, ADC values, and washout percentage (at least two positive criteria were sufficient for a diagnosis of PCa) yielded the highest sensitivity (77.7%) and specificity (85.7%) among all combinations. CONCLUSION: PCa and prostatitis can be discriminated using mpMRI with high sensitivity and specificity.