Isoform selectivity and kinetics of morphine 3- and 6-glucuronidation by human udp-glucuronosyltransferases: evidence for atypical glucuronidation kinetics by UGT2B7.

Morphine elimination involves UDP-glucuronosyltransferase (UGT) catalyzed conjugation with glucuronic acid to form morphine 3- and 6-glucuronides (M3G and M6G, respectively). It has been proposed that UGT2B7 is the major enzyme involved in these reactions, but there is evidence to suggest that other isoforms also catalyze morphine glucuronidation in man. Thus, we have characterized the selectivity and kinetics of M3G and M6G formation by recombinant human UGTs. UGT 1A1, 1A3, 1A6, 1A8, 1A9, 1A10, and 2B7 all catalyzed M3G formation, but only UGT2B7 formed M6G. The kinetics of M3G formation by the UGT1A family isoforms was consistent with a single enzyme Michaelis-Menten model, with apparent Km values ranging from 2.6 to 37.4 mM. In contrast, M3G and M6G formation by UGT2B7 exhibited atypical kinetics. The atypical kinetics may be described by a model with high- and low-affinity Km values (0.42 and 8.3 mM for M3G, and 0.97 and 7.4 mM for M6G) from fitting to a biphasic Michaelis-Menten model. However, a multisite model with an interaction between two identical binding sites in a negative cooperative manner provides a more realistic approach to modeling these data. According to this model, the respective binding affinities (Ks) for M3G and M6G were 1.76 and 1.41 mM, respectively. These data suggest that M6G formation may be used as a selective probe for UGT2B7 activity, and morphine glucuronidation by UGT2B7 appears to involve the simultaneous binding of two substrate molecules, highlighting the need for careful analysis of morphine glucuronidation kinetics in vitro.     

Patterns of cyclin E, retinoblastoma protein, and p21Cip1/WAF1 immunostaining in the oncogenesis of papillary thyroid carcinoma.

PURPOSE: Uncontrolled cell proliferation, a hallmark of cancer, may result from an increased expression of cell cycle up-regulators, and/or from a reduced expression of cell cycle down-regulators. In the present study, we analyzed, by immunohistochemistry, the expression of a panel of three proteins: cyclin E and two cell cycle inhibitors, p21(Cip1/WAF1) and retinoblastoma protein (pRb) product, in different stages of papillary thyroid carcinomas (PTC). EXPERIMENTAL DESIGN: We investigated immunostaining patterns of the proteins in question in 51 resected PTC in pathologic stages, ranging from pT(1a) to pT(4), taking into consideration their relation to clinicohistopathologic factors. RESULTS: We observed a significant, progressive loss of expression of p21(Cip1/WAF1) with advancing tumor grade. The differences reached values of significance between pT(1a) [papillary thyroid microcarcinomas (PMC)] and pT(2) and between PMC and pT(4) stages of PTC. pRb presented a similar immunostaining pattern to that of p21(Cip1/WAF1) and the differences reached values of significance between pT(1a) and pT(2), and between PMC and pT(4) stages of PTC. The results of cyclin E immunostaining corresponded to our recently published result, and a negative correlation was observed between the immunostaining index of cyclin E and pRb. CONCLUSIONS: The results of the present study suggest that cyclin E expression and suppression of pRb and p21(Cip1/WAF1) may be characteristic patterns of immunostaining for PTC with a tendency to early metastasizing. If our results are confirmed in a larger study, the diagnostic panel, constructed of the antibodies against these proteins, may become a valuable tool in predicting the metastatic potential in PTC.     

Dietary-Lifestyle Patterns Associated with Bone Turnover Markers,and Bone Mineral Density in Adult Male Distance Amateur Runners—A Cross-Sectional Study

Background: Excessive mileage can be detrimental to bone mineral density among long-distance runners. The negative effects of mileage could be alleviated by appropriate nutrition. The purpose of this study was to analyse the dietary-lifestyle patterns in relation to bone mineral density and bone turnover markers among amateur marathoners. Methods: A total of 53 amateur male distance runners were divided into two clusters by k-means cluster analysis. Bone mineral density was measured by dual X-ray absorptiometry (DXA). Blood was drawn to analyse bone resorption marker C-terminal telopeptide (cTX) and bone formation marker amino-terminal propeptide of type I collagen (PINP). Food frequency intake and lifestyle information were measured by multicomponent questionnaire KomPAN^®. Yearly average mileage per month was taken from each participant. Results: There were two distinguished clusters: Less-healthy-more-active-low-Z-score (LessHA) (n = 33) and More-healthy-less-active-high-Z-score (MoreHLA) (n = 20). LessHA had a lower frequency intake of pro-healthy food groups, a lower number of meals during a typical day, and a higher mileage training than the group of athletes who followed the MoreHLA. Athletes following the LessHA pattern also had a lower Z-score in the lumbar spine and femoral bone and a lower PINP. Conclusion: The current study suggests that pro-healthy dietary patterns and lower mileage may favour higher bone mineral density in male amateur marathoners.     

Satiety of Edible Insect-Based Food Products as a Component of Body Weight Control

Among the many aspects determining the nutritional potential of insect-based foods, research into the satiating potential of foods is an important starting point in the design of new functional foods, including those based on edible insects. The aim of this study was to assess the satiating value of products with the addition of freeze-dried insect flour. The test material included wheat pancakes in which corresponding proportions of wheat flour were substituted with 10% Mw, 0% Mw, and 30% Mw of flour from freeze-dried Tenebrio molitor, 10% Bw, 20% Bw, and 30% Bw of flour from Alphitobius diaperinus, and 10% Cr, 20% Cr, and 30% Cr of flour from Acheta domesticus. The study included the characterisation of physico-chemical properties and their effect on the satiating potential of the analysed pancakes. A total of 71 healthy volunteers (n = 39 women, n = 32 men) with no food phobias were qualified for the study. Each subject rated the level of hunger and satiety before and after ingestion at 30 min intervals over the subsequent 180 min on two separate graphical scales. The rating was done on an unstructured 100 mm visual analogue scale (VAS). A portion intended for testing had a value of 240 kcal. The highest average satiety values were noted for the pancakes with an addition of 30% Alphitobius diaperinus (Bw) and with the addition of 20% and 30% addition of Acheta domesticus flour (Cr). The Tenebrio molitor-based products were the least satiating. However, the largest addition of 30% of an insect flour for each variant considerably increased the satiating potential as compared to the control sample. Satiety was influenced the most by the protein content in the test wheat pancakes. The results support the idea of a possible usage of insect-based food products in the composition of obesity treatment diets, carbohydrate-limiting diets, and as alternative sources of protein.     

Artificial Anisotropy in Ge2Sb2Te5 Thin Films after Femtosecond Laser Irradiation

Ge₂Sb₂Te₅ (GST225) looks to be a promising material for rewritable memory devices due to its relatively easy processing and high optical and electrophysical contrast for the crystalline and amorphous phases. In the present work, we combined the possibilities of crystallization and anisotropic structures fabrication using femtosecond laser treatment at the 1250 nm wavelength of 200 nm thin amorphous GST225 films on silicon oxide/silicon substrates. A raster treatment mode and photoexcited surface plasmon polariton generation allowed us to produce mutually orthogonal periodic structures, such as scanline tracks (the period is 120 ± 10 μm) and laser-induced gratings (the period is 1100 ± 50 nm), respectively. Alternating crystalline and amorphous phases at the irradiated surfaces were revealed according to Raman spectroscopy and optical microscopy studies for both types of structures. Such periodic modulation leads to artificial optical and electrophysical anisotropy. Reflectance spectra in the near infrared range differ for various polarizations of probing light, and this mainly results from the presence of laser-induced periodic surface structures. On the other hand, the scanline tracks cause strong conductivity anisotropy for dc measurements in the temperature range of 200–400 K. The obtained results are promising for designing new GST225-based memory devices in which anisotropy may promote increasing the information recording density.     

Comparative Analysis of Postoperative Complications of Sentinel Node Identification Using the SentiMag® Method and the Use of a Radiotracer in Patients with Breast Cancer

(1) Background: The purpose of the study was a retrospective, comparative assessment of complications of the surgical sentinel node biopsy (SNB) procedure in breast cancer using the radiotracer method and the SentiMag^® method on groups of patients after 3.5 years of use. (2) Methods: The material was a group of 345 patients with primary surgical breast cancer who underwent the SNB procedure with the use of a radiotracer in combination with wide local excision (WLE), simple amputation (SA) with SNB and an independent SNB procedure in the period from May 2018 to January 2021 in the Department of Oncological Surgery. Of the patients who were monitored in the Hospital Outpatient Clinic, 300 were enrolled. The analyzed group was compared in terms of the occurrence of the same complications with the group of 303 patients also operated on in our center in the period from January 2014 to September 2017, in which SN identification was performed using the SentiMag^® method. (3) Results: The most common complications found were sensation disorders in the arm, which occurred in 16 (14.1%) patients using the radiotracer method, SentiMag^®-11 (9.9%). By comparing the complication rate between the methods with the radiotracer (n = 300) and SentiMag^® (n = 303), no significant differences were found. (4) Conclusions: Sentinel node (SN) identification using the radiotracer method and the SentiMag^® method are comparable diagnostic methods in breast cancer, with a low risk of complications.     

Ribociclib Plus Letrozole in Patients with Hormone Receptor-positive,HER2-negative Advanced Breast Cancer with No Prior Endocrine Therapy: Subgroup Safety Analysis from The Phase 3b CompLEEment-1 Trial

BackgroundThe CDK4/6 inhibitor, ribociclib in combination with endocrine therapy significantly improved progression-free survival in the first line setting in post-menopausal patients with HR+/HER2− advanced breast cancer (ABC) in a pivotal phase 3, placebo-controlled trial (MONALEESA-2) and demonstrated superior overall survival in premenopausal patients with HR+/HER2− ABC (MONALEESA-7). The multinational, phase 3b, CompLEEment-1 trial, which assessed the safety and efficacy of ribociclib plus letrozole in a broader population of patients who have not received prior endocrine therapy for advanced disease, is the largest phase 3 clinical trial to date to evaluate the safety and efficacy of a CDK4/6 inhibitor. We report a subanalysis of data from patients (N = 339) enrolled in the central and south European countries of the SERCE (Southern Europe, RUC, Central Europe) cluster of CompLEEment-1.Patients and methodsMen and women of any menopausal status with HR+/HER2− ABC received once-daily oral ribociclib 600 mg (3-weeks on/1-week-off), plus letrozole 2.5 mg continuously. Men/premenopausal women also received a GnRH-agonist. The primary outcome was the number of patients with adverse events (AEs) over a timeframe of approximately 36 months. Time-to-progression, overall response rate, and clinical benefit rate were also measured.ResultsSafety results in the SERCE subgroup were consistent with those in the pivotal clinical trials of ribociclib in combination with endocrine therapy. Treatment-related AEs leading to dose adjustments/interruption occurred in 63.1% of patients but led to treatment discontinuation in only 10.6%. The most common treatment-related AEs of grade ≥ 3 were neutropenia and transaminase elevations. There were no fatal treatment-related events.ConclusionsThese findings from the SERCE subgroup support the safety and manageable tolerability of ribociclib in a broad range of patients with HR+/HER2− ABC more representative of patients in real-world clinical practice.Key words: CDK4/6 inhibitor, ribociclib, HR+, HER2−, advanced breast cancer, CompLEEment-1 trial     

Evaluation of Food Labelling the Products with Information Regarding the Level of Sugar: A Preliminary Study

The aim of this article is to explore the reasons for seeking selected information on a food label, with particular emphasis on certain information about sugar. In order to meet the aim, in 2020, a survey was conducted among consumers aged 18–45. Predictive models (Logistic Regression) were developed for noticing “light” products and reading food labels. The results of our study indicate that consumers are mainly discouraged from reading label information by a large amount of information, the lack of time, and a general reluctance to be interested in label information. When it comes to the factors that lead people to read label information, the naturalness of the product, its organic origin, and physical activity are important. Moreover, respondents who declared that they noticed products on the market defined as “light” were those who were interested in the naturalness of the product, but also consumers declaring that they have nutritional knowledge. The results of the study indicate the need to intensify information campaigns in order to emphasize how important it is for consumers to read the information on food labels. The amount and complexity of information currently appearing on the food label may unfortunately discourage consumers from reading it, so it is important to continuously improve this form of communication with the consumer.     

Feasibility and clinical utility of real-time tele-echocardiography using personal mobile device-based pocket echocardiograph

IntroductionRecently introduced microUSB ultrasound probe, which can be connected to personal mobile device constitutes a new class of diagnostic pocket size imaging devices (PSID).The aim of this study was to assess the feasibility and clinical utility of real-time tele-echocardiography with the use such device.Material and methodsThe study group comprised 30 patients (18 men and 12 women; mean age: 54 ±14 years; mean body mass index: 27 ±6 kg/m²), admitted to various hospital departments (infectious diseases, internal medicine and cardiology). All patients underwent focused echocardiographic examination performed by an inexperienced operator using PSID and collaborating remotely in real-time with cardiologist by means of tele-consultation. Before commencing the examination, the operators underwent 1 h training in use of the PSID.ResultsIn most of patients PSID imaging provided sufficient diagnostic image quality. The dimensions of left ventricle, left atrium and the aorta obtained during the this examination showed good correlation with standard echocardiography (r = 0.89, r = 0.82, r = 0.92 respectively), but the correlation for TAPSE measurements was less pronounced (r = 0.52). The agreement in detection of pathologies (wall motion abnormalities, morphological and functional valvular abnormalities) between the tele-echocardiography and standard echocardiographic examination was good to very good (κ ranged from 0.648 to 0.823).ConclusionsPocket size imaging devices allows an inexperienced operator to perform a focused echocardiographic examination under a remote supervision of an experienced cardiologist. The introduction of new technology in the form of PSID with tele-echocardiography feature can revolutionize access to this imaging technique.     

Effects of Apnea,Obesity, and Statin Therapy on Proprotein Convertase Subtilisin/Kexin 9 Levels in Patients with Obstructive Sleep Apnea

ObjectivesObstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9).MethodsFull-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined.ResultsPCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m²) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m² when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026–7.912], p = 0.044).ConclusionStatin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9.