Previous Screening Research Articles

Protective Effects of Pelargonidin against DMBA-Induced Mammary Tumorigenesis in BALB/c Mice through Reduced Oxidative Stress and Lipid Anomalies

Among luminal types of breast cancers, ER + breast cancer is the most frequently diagnosed cancer globally. ER + breast cancer is commonly treated with SERM drugs that block ER to prevent ER-mediated cancerous growth. Our previous computational screening found pelargonidin (PG) can inhibit ER-signaling with potent bioactivity and satisfactory toxicological features. The present study explored the anti-tumoral prospect of PG against DMBA-induced ER + murine mammary carcinogenesis. The female BALB/c mice were divided into control (A) and DMBA-exposed groups. Following tumor appearance, the DMBA-exposed group was divided into five groups: tumor control, PG-treated (Groups P25, P50, and P100), and tamoxifen-treated (TAM). The results indicated that PG-treatment dose-dependently reduced the mean tumor volume, reinstated body weight loss, and enhanced the percentage survival of tumor-bearing mice. In addition, we recorded a significant reduction in LPO, total cholesterol, and triglycerides and a surge in the activity of antioxidases and phase II detoxifying enzymes in PG-treated animals. PG also dose-dependently increased the serum level of unbound estradiol, an indicator of competitive ER binding by an ER agonist/antagonist. These data suggest that pelargonidin has potent anticancer potential against the animal model of ER + breast cancer that matches the efficiency of tamoxifen with conceivably fewer side effects.

Impacts of COVID-19 on Appropriate Use of Screening Colonoscopy in a Large Integrated Healthcare Delivery System.

Decreasing low-value colonoscopy is critical to optimizing access for high-need patients, particularly in resource-constrained environments such as those created by the COVID-19 pandemic. We hypothesized that rates of screening colonoscopy overuse would decline during COVID compared to pre-COVID due to enhanced procedural scrutiny and prioritization in the setting of constrained access. To characterize impacts of COVID-19 on screening colonoscopy overuse DESIGN: Retrospective national cohort study using Veterans Health Administration administrative data PARTICIPANTS: Veterans undergoing screening colonoscopy in Q4 2019 (pre-COVID) and Q4 2020 (COVID) at 109 endoscopy facilities MAIN MEASURES: Rates of screening colonoscopy overuse KEY RESULTS: 18,376 screening colonoscopies were performed pre-COVID, 19% (3,641) of which met overuse criteria. While only 9,360 screening colonoscopies were performed in Q4 2020, 25% met overuse criteria. Overall change in median facility-level overuse during COVID compared to pre-COVID was 6% (95%CI 5%-7%), with significant variability across facilities (IQR: 2%-11%). Of colonoscopies meeting overuse criteria, the top reason for overuse in both periods was screening colonoscopy performed <9 years after previous screening procedure (55% pre-COVID, 49% during COVID). The largest shifts in overuse category were in screening procedures performed <9 years after prior screening colonoscopy (-6% decline COVID vs. pre-COVID) and screening procedures performed in patients below average-risk screening age (i.e., age <40 (5% increase COVID compared to pre-COVID), age 40-44 (4% increase COVID vs. pre-COVID)). Within facility performance was stable over time; 83/109 facilities changed their performance by <=1 quartile during COVID compared to pre-COVID. Despite pandemic-related resource constraints and enhanced procedural scrutiny and prioritization in the setting of COVID-related backlogs, screening colonoscopy overuse rates remained roughly stable during COVID compared to pre-COVID, with continued variability across facilities. These data highlight the need for systematic and concerted efforts to address overuse, even in the face of strong external motivating factors.

The correlation between CpG island methylation of hTERT promoter and human age prediction

DNA methylation is an epigenetic modification that occurs during the life cycle of individuals. Its degree is closely associated with the methylation status of CpG sites in its promoter region. Based on the previous screening that the hTERT methylation is both related to tumors and age, we suspected that the age inference based on hTERT methylation would be disturbed by the disease of the tested person. Herein, eight CpG sites in the hTERT promoter region were analyzed by real-time methylation-specific PCR, and we found that CpG2, CpG5, and CpG8 were closely related to the tumor (P < 0.05). The remaining five CpG sites had a large error in predicting age alone. Combining them to establish a model yielded better results, with an average age error of 4.35 years. This study provides a reliable and accurate detection method for the DNA methylation status of multiple CpG sites on the hTERT gene promoter, which can be used for the prediction of forensic age and assistant diagnosis of clinical diseases.

Enzymatic Screening of β-Amyloid Precursor Protein-Based Substrates

We performed an enzymatic screening of synthetic peptides based on β-amyloid precursor protein substrates. The template peptide sequence was a decapeptide derived from our previous screening study, which determined several effective unnatural amino acids. In this study, new libraries containing some unnatural amino acid compounds were prepared in the solid phase and digested with the β-site amyloid precursor protein-cleaving enzyme. The reaction mixture was analyzed using high-performance liquid chromatography combined with mass spectrometry. The peptides that showed a higher cleavage than the template sequence were determined and reported.

Cervical Cancer Screening in Women Aged Older Than 65 Years.

Considerable debate exists among guidelines regarding when cervical cancer screening can be safely stopped. The authors aimed to compare the efficiency of human papillomavirus (HPV) test, cytology, and previous screening history for the diagnosis of cervical intraepithelial neoplasia (CIN) 2+ lesions in women aged older than 65 years. This is a retrospective cohort study. Multiple logistic regressions were used to compare the efficiency of the HPV test, cytology, and previous screening history for the diagnosis of histologically proven CIN 2+ lesions. A total of 5,427 women were included in the study. A total of 2,143 women were tested with HPV and 52 (2.4%) of them were HPV-positive. Abnormal cytology was detected in 359 (6.6%) women. Most of the women (70.4%) had inadequate screening in the previous 10 years. According to regression analysis, an HPV-positive test increases the risk of probability of CIN 2+ 136.111 times [95% CI for odds ratio (OR) = 41.212-449.538] compared with an HPV-negative test ( p < .001). Abnormal cytology increases the probability of CIN 2+ 13.072 times (95% CI for OR = 3.878-44.062) compared with normal cytology ( p < .001). Inadequate or positive previous screening increases the likelihood of CIN 2+ 9.705 times (95% CI for OR = 1.603-58.756) compared with adequate and negative previous screening ( p = .013). Adequate previous screening is a valuable strategy, and abnormal cytology is an important screening test in women aged older than 65 years. However, the HPV test is the most determinant parameter for CIN 2+ risk in elderly women.

P016 To rescreen or not to rescreen, that is the question: an evaluation of practice of rescreening for infections when switching advanced therapies in rheumatology patients

Abstract Background/Aims The 2018 British Society for Rheumatology guidelines mandate pre-treatment screening for infections (including tuberculosis [TB], viral hepatitis and HIV) in patients prior to treatment initiation with advanced therapies. It is increasingly common for patients to switch advanced therapies due to inefficacy or intolerance. There is no established guideline stipulating the frequency of rescreening patients for infections when switching advanced therapies. Rescreening is expensive and can delay the prescribing process. This audit reviewed the current practice at a single tertiary rheumatology centre. Methods A retrospective case note analysis of 100 consecutive patients who underwent biologic switch between April 2021 to March 2022 was included. Data extraction included patient demographics, rheumatic diagnosis, drug exposures, co-morbidities including past infections and rescreening tests were undertaken (including T-SPOT.TB, chest X-ray and serological tests for hepatitis B, C and HIV). Results The median age of this cohort (64 female, 36 male) was 53 (IQR 41 - 60). The most common diagnosis was rheumatoid arthritis (n = 62), followed by psoriatic arthritis (n = 27) and ankylosing spondylitis (n = 7). Seven patients were identified as high-risk individuals: two patients with hepatitis B, one with latent TB, one with previous positive TSPOT.TB and three with underlying lung diseases. 69 patients were partially rescreened for infections and 21 patients had a complete re-screen including chest X-ray, TSPOT.TB, HIV serology, HBsAg, Anti-HbC and Anti HCV. 31 patients did not have any re-screening tests when switching to a different biological drug. The range since the previous pre-advanced therapy screening was between 6 months and 5 years. There was no significant difference in the rate of rescreening investigations between those who switched drugs within the same class, versus those switching drug classes (p = 0.874). No new infections, active or latent, were identified on rescreening. The total cost involved in rescreening this cohort of patients was estimated at £5930. Conclusion Our audit data showed that rescreening for infections at 18 months or less has a low yield for identifying new incident infections. The decision to rescreen patients was primarily driven by the clinician’s judgement. It is pertinent to standardise the practice by establishing an evidence-based guideline based on a robust risk assessment which may then lead to long-term cost-savings. Disclosure A. Masood: None. Y. Xiang: None. S. Rose-Hartwell: None. S. Subesinghe: None.

Impact of prior cryptococcal antigen screening on in-hospital mortality in cryptococcal meningitis or fungaemia among HIV-seropositive individuals in South Africa: a cross-sectional observational study

ObjectivesWe investigated whether patients with cryptococcal meningitis (CM) or fungaemia detected through South Africa's laboratory cryptococcal antigen (CrAg) screening programme had better outcomes than those presenting directly to the hospital. MethodsWe compared 14-day in-hospital case-fatality ratios of HIV-seropositive individuals with CD4 counts below 100 cells/μL and laboratory-confirmed CM/fungaemia from 2017–2021, with or without evidence of a positive blood CrAg test within 14 days prior to diagnosis. We evaluated whether the impact of prior CrAg screening on mortality varied according to the study period (pre–COVID-19: before March 2020 vs. COVID-19: after March 2020). ResultsOverall, 24.5% (830/3390) of patients had a prior positive CrAg test within 14 days of diagnosis. CrAg-screened patients were less likely to have an altered mental status at baseline than non-CrAg-screened patients (38.1% [296/776] vs. 42.6% [1010/2372], p = 0.03), and had a lower crude 14-day case-fatality ratio (24.7% [205/830] vs. 28.3% [724/2560]; OR, 0.83 [95% CI, 0.69–0.99]; p = 0.045). Previous CrAg screening was associated with a greater reduction in the crude 14-day mortality during the COVID-19 period (OR, 0.64 [0.47–0.87]; p = 0.005) compared with before (OR, 0.95 [0.76–1.19]; p = 0.68). After adjustment, previous CrAg screening within 14 days was associated with increased survival only during the COVID-19 period (adjusted OR, 0.70 [0.51–0.96]; p = 0.03). DiscussionPrevious CrAg screening was associated with a survival benefit in patients hospitalized with CM/fungaemia during the COVID-19 period, with fewer patients having an altered mental status at baseline, suggesting that these patients may have been diagnosed with cryptococcosis earlier.

The Barriers to Bowel Cancer Screening Scale: Examining Structural Validity, Measurement Invariance, and Criterion Validity.

The success of national cancer screening programs, such as the National Bowel Cancer Screening Program (NBCSP) in Australia, depends on public participation, which is currently an alarming 43.5% for the NBCSP. Understanding the barriers that impede screening participation requires valid measurement instruments. This study aims to cross-validate such an instrument with a new, large, and varied sample, as well as assess measurement invariance across subsamples at a greatest risk of nonparticipation (ie, testing whether the scale functions in similar ways across groups). A cross-sectional sample of 1158 participants from the target screening population (50-74 years) provided demographic information, responses to the Barriers to Home Bowel Screening (BB-CanS) scale, and information on their previous screening participation. Both the full and the brief versions of the BB-CanS scale showed good model fit for the full sample and for gender and age subsamples. Despite the inter-factor correlations being high, the unidimensional and bi-factor models exhibited poorer fit. Improvement in fit was observed with scale refinement involving the removal of 7 items. All versions of the BB-CanS scale were invariant across gender and age subsamples. Age and gender differences emerged across several barriers and variance in all 4 barriers significantly predicted prior screening participation. The BB-CanS scale is a valid measure of 4 highly correlated barriers to home bowel cancer screening: disgust relating to screening, avoidance of test outcomes, practical difficulty (or challenges), and the need for a sense of greater autonomy. All versions of the instrument measure the equivalent construct across age and gender groups. Observed differences in barriers across at-risk groups provide targets for future intervention.

A Pilot Study of Implementing Diabetic Retinopathy Screening in the Oslo Region, Norway: Baseline Results.

to gain insight into the baseline parameters of a population with diabetes mellitus (DM) included in a pilot diabetic retinopathy (DR) screening program at Oslo University Hospital (OUH), Norway. This was a cross-sectional study of a cohort of adult patients (≥18 years) with type 1 or 2 DM (T1D and T2D). We measured the best-corrected visual acuity (BCVA), blood pressure (BP), heart rate (HR), intraocular pressure (IOP), height and weight. We also collected HbA1c, total serum cholesterol and urine-albumin, -creatinine and -albumin-to-creatinine ratio (ACR), as well as socio-demographic parameters, medications and previous screening history. We obtained color fundus photographs, which were graded by two experienced ophthalmologists according to the International Clinical Disease Severity Scale for DR. The study included 180 eyes of 90 patients: 12 patients (13.3%) had T1D and 78 (86.7%) had T2D. In the T1D group, 5 patients (41.7%) had no DR, and 7 (58.3%) had some degree of DR. In the T2D group, 60 patients (76.9%) had no DR, and 18 (23.1%) had some degree of DR. None of the patients had proliferative DR. Of the 43 patients not newly diagnosed (time of diagnosis > 5 years for T1D and >1 years for T2D), 37.5% of the T1D patients and 5.7% of the T2D patients had previously undergone regular screening. Univariate analyses found for the whole cohort significant associations between DR and age, HbA1c, urine albumin-to-creatinine ratio, body mass index (BMI) and duration of DM. For the T2D group alone, there were significant associations between DR and HbA1c, BMI, urine creatinine, urine albumin-to-creatinine ratio and duration of DM. The analysis also showed three times higher odds for DR in the T1D group than the T2D group. This study underscores the need for implementing a systematic DR screening program in the Oslo region, Norway, to better reach out to patients with DM and improve their screening adherence. Timely and proper treatment can prevent or mitigate vision loss and improve the prognosis. A considerable number of patients were referred from general practitioners for not being followed by an ophthalmologist.Among patients not newly diagnosed with DM, 62.8% had never had an eye exam, and the duration of DM for these patients was up to 18 years (median: 8 years).

Prevalence of Anaplasma phagocytophilum, Borrelia burgdorferi sensu lato, Rickettsia spp. and Babesia spp. in cattle serum and questing ticks from Belgium

BackgroundAnaplasmosis, borreliosis, rickettsiosis and babesiosis are tick-borne diseases of medical, veterinary and economic importance. In Belgium, little is known on the prevalence of these diseases in animals and previous screenings relate only to targeted geographic regions, clinical cases or a limited number of tested samples. We therefore performed the first nationwide seroprevalence study of Anaplasma spp., A. phagocytophilum, Borrelia spp., Rickettsia spp. and Babesia spp. in Belgian cattle. We also screened questing ticks for the aforementioned pathogens. MethodsELISAs and IFATs were performed on a representative sample set of cattle sera stratified proportionally to the number of cattle herds per province. Questing ticks were collected in areas where the highest prevalence for the forenamed pathogens in cattle serum were observed. Ticks were analyzed by quantitative PCR for A. phagocytophilum (n = 783), B. burgdorferi sensu lato (n = 783) and Rickettsia spp. (n = 715) and by PCR for Babesia spp. (n = 358). ResultsThe ELISA screening for antibodies to Anaplasma spp. and Borrelia spp. in cattle sera showed an overall seroprevalence of 15.6% (53/339) and 12.9% (52/402), respectively. The IFAT screening for antibodies against A. phagocytophilum, Rickettsia spp. and Babesia spp. resulted in an overall seroprevalence of 34.2% (116/339), 31.2% (99/317) and 3.4% (14/412), respectively. At the provincial level, the provinces of Liege and Walloon Brabant harboured the highest seroprevalence of Anaplasma spp. (44.4% and 42.7% respectively) and A. phagocytophilum (55.6% and 71.4%). East Flanders and Luxembourg exhibited the highest seroprevalence of Borrelia spp. (32.4%) and Rickettsia spp. (54.8%) respectively. The province of Antwerp showed the highest seroprevalence of Babesia spp. (11%). The screening of field-collected ticks resulted in a prevalence of 13.8% for B. burgdorferi s.l., with B. afzelii and B. garinii being the most common genospecies (65.7% and 17.1%, respectively). Rickettsia spp. was detected in 7.1% of the tested ticks and the only identified species was R. helvetica. A low prevalence was found for A. phagocytophilum (0.5%) and no Babesia positive tick was detected. ConclusionsThe seroprevalence data in cattle indicate hot spots for tick-borne pathogens in specific provinces and highlights the importance of veterinary surveillance in anticipating the emergence of diseases among humans. The detection of all pathogens, with the exception of Babesia spp. in questing ticks, underlines the need of raising awareness among public and professionals on other tick-borne diseases along with lyme borreliosis.

Biosorption of Pollutants in Diyala River by Using Irrigated Vegetables

In the absence of environmental regulation, food stays to be contaminated with heavy metals, which is becoming a big worry for human health. The present research focusses on the environmental and health effects of irrigating a number of crops grown in the soils surrounding the Al-Rustamia old plant using treated wastewater generated by the plant. The physicochemical properties, alkalinity, and electrical conductivity of the samples were evaluated, and vegetable samples were tested for Cd, Pb, Ni, and Zn, levels, and even the transfer factor (TF) from soils to crops and crop and multi-targeted risk, daily intake (DIM) of metals, and health risk index (HRI) was calculated. The findings found that the average contents of Zn, Pb, Ni, and Cd in soil and vegetation were less than the Food and Agriculture Organization’s standards of food safety enhancers. The flooded soil included Zn (56.5), Pb (15.1), Ni (9.30), and Cd (0.850) mg·kg-1. The heavy-metal concentration trend in all samples was Zn, Pb, Ni, and Cd. Daily metal intake in crops species was above acceptable limits for Zinc (0.011 – 0.019 mg·kg-1), Lead (2.010-5 – 5.910-5 mg·kg-1), Ni (2.410-4 – 5.210-4 mg·kg-1) and Cd (1.310-5 – 3.310-5 mgkg-1). The HRI for zinc varied between 0.037 and 0.063, for lead between 5.10-3 and 1.410-2, for nickel from 1.210-2 to 2.610-2, and for cadmium from 1.310-2 to 3.310-2. The HRI for such components was larger than one, suggesting that no possible health issue existed. Crop cultivation using wastewater is a typical solution for water-stressed nations; nevertheless, previous screening and processing of such industrial wastewaters is required to minimise its detrimental effects on the environment.

Overview of organisational methods of primary cervical lesion screening programmes that use human papillomavirus testing.

Many factors need to be considered when planning and managing a screening programme for the early detection of cervical cancer (CC). A non-systematic international review of the organisation of CC screening using high-risk human papillomavirus (HPV-HR) testing, aimed at identifying the organisational methods of these programmes, was conducted with a view to supporting the future of the French system in the context of the transition to HPV-HR testing. In countries where HPV testing has been implemented or planned, the initial reflection process has provided an opportunity to rethink the previous (cytological) screening organisation. Despite considerable differences between countries, a nationally or regionally centralised organisational model appears to be the preferred option in most countries. This model is based on a national/regional structure tasked with all invitations, reminders, follow-up and coordination, centralised laboratories integrating both biology and pathology laboratories, and a unified information system integrated with routine health management tools used by health practitioners and nurses. Besides quality considerations, grouped purchasing makes it possible to implement a public procurement policy that includes price negotiations with suppliers. Discussions around the introduction of HPV testing have resulted in most countries reviewing or creating information systems and quality assurance processes. While the WHO seems to recommend the systematic use of vaginal self-sampling, very few countries have considered this option. More and more countries are planning to implement vaginal self-sampling, but no clear organisational model has emerged from the countries where it has been implemented to date.

Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor.

Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X receptor family, is expressed in sensory neurons and involved in nociception. P2X3R inhibition was shown to reduce chronic and neuropathic pain. In a previous screening of 2000 approved drugs, natural products, and bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found to inhibit P2X3R-mediated currents. Methods: To investigate whether the inhibition of P2X receptors contributes to the analgesic effect of NSAIDs, we characterized the potency and selectivity of various NSAIDs at P2X3R and other P2XR subtypes using two-electrode voltage clamp electrophysiology. Results: We identified diclofenac as a hP2X3R and hP2X2/3R antagonist with micromolar potency (with IC50 values of 138.2 and 76.7µM, respectively). A weaker inhibition of hP2X1R, hP2X4R, and hP2X7R by diclofenac was determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, and hP2X7R (IC50 values of 221µM, 264.1µM, and ∼900µM, respectively), calling into question its use as a non-selective ion channel blocker, when P2XR-mediated currents are under study. Inhibition of hP2X3R or hP2X2/3R by diclofenac could be overcome by prolonged ATP application or increasing concentrations of the agonist α,β-meATP, respectively, indicating competition of diclofenac and the agonists. Molecular dynamics simulation showed that diclofenac largely overlaps with ATP bound to the open state of the hP2X3R. Our results suggest a competitive antagonism through which diclofenac, by interacting with residues of the ATP-binding site, left flipper, and dorsal fin domains, inhibits the gating of P2X3R by conformational fixation of the left flipper and dorsal fin domains. In summary, we demonstrate the inhibition of the human P2X3 receptor by various NSAIDs. Diclofenac proved to be the most effective antagonist with a strong inhibition of hP2X3R and hP2X2/3R and a weaker inhibition of hP2X1R, hP2X4R, and hP2X7R. Discussion: Considering their involvement in nociception, inhibition of hP2X3R and hP2X2/3R by micromolar concentrations of diclofenac, which are rarely reached in the therapeutic range, may play a minor role in analgesia compared to the high-potency cyclooxygenase inhibition but may explain the known side effect of taste disturbances caused by diclofenac.

In vivo anti-hyperuricemia and anti-gouty arthritis effects of the ethanol extract from Amomumvillosum Lour.

The incidence of hyperuricemia and gout has been increasing year by year, and it is showing a younger trend. However, the first-line drugs currently used for hyperuricemia and gouty arthritis have serious side effects that limit their clinical application. Amomum villosum Lour. has been widely used in China for thousands of years as a traditional medical and edible plant, and previous screening showed that the ethanol extract of Amomum villosum Lour. could effectively inhibit the activity of xanthine oxidase. Based on this discovery, this paper had achieved in-depth mechanism research. The results showed that the ethanol extract of Amomum villosum Lour. could treat hyperuricemia by reducing the production of uric acid via inhibition of xanthine oxidase and increasing the excretion of uric acid via regulation of urate transporters. Meanwhile, the extract also showed a certain protective effect on hepatic and renal damage caused by hyperuricemia. With the formation of extensive uric acid, gouty arthritis will be induced by the deposition of monosodium urate in the joint. The extract could also relieve the inflammation by reducing the expression of inflammatory cytokines. In conclusion, the extract deserves focused research and development as a potential medicine, health care product or supplemented food for the prevention and treatment of hyperuricemia and gouty arthritis.

Library Screening and Preliminary Characterization of Synthetic Cannabinoids Against Prostate and Pancreatic Cancer Cell Lines.

Background: Our previous screening efforts with colorectal cancer cell lines suggested potential cannabinoid therapeutic leads for other solid cancers. Objectives: The aim of this study was to identify cannabinoid lead compounds that have cytostatic and cytocidal activities against prostate and pancreatic cancer cell lines and profile cellular responses and molecular pathways of select leads. Materials and Methods: A library of 369 synthetic cannabinoids was screened against 4 prostate and 2 pancreatic cancer cell lines with 48 h of exposure at 10 μM in medium with 10% fetal bovine serum using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) viability assay. Concentration titration of the top 6 hits was carried out to identify their concentration-response patterns and calculate IC50 values. Three select leads were examined for cell cycle, apoptosis, and autophagy responses. The role of cannabinoid receptors (CB1 and CB2) and noncanonical receptors in apoptosis signaling was examined with selective antagonists. Results: Two independent screening experiments in each cell line detected growth inhibitory activities against all six or a majority of cancer cell lines for HU-331 (a known cannabinoid topoisomerase II inhibitor), (±)5-epi-CP55,940, and PTI-2, each previously identified in our colorectal cancer study. 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 were novel hits. Morphologically and biochemically, (±)5-epi-CP55,940 elicited caspase-mediated apoptosis of PC-3-luc2 (a PC-3 subline with luciferase) prostate cancer and Panc-1 pancreatic cancer cell lines, each the most aggressive of the respective organ site. The apoptosis induced by (±)5-epi-CP55,940 was abolished by the CB2 antagonist, SR144528, but not modulated by the CB1 antagonist, rimonabant, and GPR55 antagonist, ML-193, nor TRPV1 antagonist, SB-705498. In contrast, 5-fluoro NPB-22 and FUB-NPB-22 did not cause substantial apoptosis in either cell line, but resulted in cytosolic vacuoles and increased LC3-II formation (suggestive of autophagy) and S and G2/M cell cycle arrests. Combining each fluoro compound with an autophagy inhibitor, hydroxychloroquine, enhanced the apoptosis. Conclusions: 5-Fluoro NPB-22, FUB-NPB-22, and LY2183240 represent new leads against prostate and pancreatic cancer cells in addition to the previously reported compounds, HU-331, (±)5-epi-CP55,940, and PTI-2. Mechanistically, the two fluoro compounds and (±)5-epi-CP55,940 differed regarding their structures, CB receptor involvement, and death/fate responses and signaling. Safety and antitumor efficacy studies in animal models are warranted to guide further R&D.

Active and latent TB screening in recently arrived persons from Afghanistan: feasibility and lessons learned

We describe an active and latent tuberculosis (TB) screening programme undertaken in Manchester, UK in response to the arrival of a cohort of refugees from Afghanistan. In total, 217 adults and 347 children were offered screening, which involved a symptom questionnaire, Mantoux test or interferon gamma release assay, blood-borne virus screening and a chest X-ray in participants over the age of 11. We found a latent TB infection (LTBI) rate of 15% in adults and 1.5% in children, which is lower than global LTBI estimates. One case of active TB was detected. Screening was undertaken in the hotels where participants were temporarily housed, leading to high participant engagement levels. Attendance rates were almost doubled compared with a previous hospital-based screening programme. Hotel-based screening for TB presented several challenges, including transfer of information and results to secondary care. Understanding these challenges and learning from the programme has helped us refine our screening protocol to optimise migrant TB screening in Manchester in the future.

Independent risk factors for high-risk human papillomavirus infection among rural women in Shanxi Province, China: a population-based, case-control study.

Persistent high-risk human papillomavirus (hrHPV) infection is associated with most cervical cancers. This study aims to investigate the prevalence of and independent risk factors for hrHPV infection among women residing in rural areas of Shanxi Province, China. Data from the records of the cervical cancer screening programs for rural women in Shanxi Province were retrospectively collected. Women receiving primary HPV screening between January 2014 and December 2019 were included. The detection rate of hrHPV was calculated, and the independent risk factors for hrHPV infection were analyzed by multivariate logistic regression. Among the women included, the overall infection rate of hrHPV was 14.01% (15,605/111,353), with the top five subtypes being HPV16 (24.79%), HPV52 (14.04%), HPV58 (10.26%), HPV18 (7.25%), and HPV53 (5.00%). The independent risk factors for hrHPV infection were specific geographical regions, testing years, older age, lower education level, inadequate previous screening, bacterial vaginosis, trichomonas vaginitis, and cervical polyps. Rural women over 40years of age, especially those who had never received screening, have a significantly increased risk for hrHPV infection and should be the target population with priority in cervical cancer screening.

Proportion of subsequent clinic visits among persons without regular clinic visits who were screened as having hyperglycemia: A retrospective cohort study.

We aimed to examine the proportion of subsequent clinic visits for persons screened as having hyperglycemia based on glycated hemoglobin (HbA1c) levels at screening and the presence/absence of hyperglycemia at health checkups before 1 year of the screening among those without previous diabetes-related medical care and attending regular clinic visits. This retrospective cohort study used the 2016-2020 data of Japanese health checkups and claims. The study analyzed 8,834 adult beneficiaries aged 20-59 years without regular clinic visits who had never received diabetes-related medical care and whose recent health checkups showed hyperglycemia. The rates of 6-month subsequent clinic visits after health checkups were evaluated according to HbA1c levels and the presence/absence of hyperglycemia at checkups a year before. The overall clinic visit rate was 21.0%. The HbA1c-specific rates were 17.0, 26.7, 25.4 and 28.4% for <7.0, 7.0-7.4, 7.5-7.9 and ≥8.0% (64 mmol/mol), respectively. Persons with hyperglycemia at a previous screening had lower clinic visit rates than those without hyperglycemia, particularly in the HbA1c category of <7.0% (14.4% vs 18.5%; P < 0.001) and 7.0-7.4% (23.6% vs 35.1%; P < 0.001). The overall rate of subsequent clinic visits among those without previous regular clinic visits was <30%, including for participants with HbA1c ≥8.0%. Persons with previously detected hyperglycemia had lower clinic visit rates, despite requiring more health counseling. Our findings might be useful for designing a tailored approach to encourage high-risk individuals to seek diabetes care through clinic visits.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Prevalence of Anaplasma phagocytophilum, Borrelia burgdorferi sensu lato, Rickettsia spp. and Babesia spp. in cattle serum and questing ticks from Belgium.

Anaplasmosis, borreliosis, rickettsiosis and babesiosis are tick-borne diseases of medical, veterinary and economic importance. In Belgium, little is known on the prevalence of these diseases in animals and previous screenings relate only to targeted geographic regions, clinical cases or a limited number of tested samples. We therefore performed the first nationwide seroprevalence study of Anaplasma spp., A. phagocytophilum, Borrelia spp., Rickettsia spp. and Babesia spp. in Belgian cattle. We also screened questing ticks for the aforementioned pathogens. ELISAs and IFATs were performed on a representative sample set of cattle sera stratified proportionally to the number of cattle herds per province. Questing ticks were collected in areas where the highest prevalence for the forenamed pathogens in cattle serum were observed. Ticks were analyzed by quantitative PCR for A. phagocytophilum (n=783), B. burgdorferi sensu lato (n=783) and Rickettsia spp. (n=715) and by PCR for Babesia spp. (n=358). The ELISA screening for antibodies to Anaplasma spp. and Borrelia spp. in cattle sera showed an overall seroprevalence of 15.6% (53/339) and 12.9% (52/402), respectively. The IFAT screening for antibodies against A. phagocytophilum, Rickettsia spp. and Babesia spp. resulted in an overall seroprevalence of 34.2% (116/339), 31.2% (99/317) and 3.4% (14/412), respectively. At the provincial level, the provinces of Liege and Walloon Brabant harboured the highest seroprevalence of Anaplasma spp. (44.4% and 42.7% respectively) and A. phagocytophilum (55.6% and 71.4%). East Flanders and Luxembourg exhibited the highest seroprevalence of Borrelia spp. (32.4%) and Rickettsia spp. (54.8%) respectively. The province of Antwerp showed the highest seroprevalence of Babesia spp. (11%). The screening of field-collected ticks resulted in a prevalence of 13.8% for B. burgdorferi s.l., with B. afzelii and B. garinii being the most common genospecies (65.7% and 17.1%, respectively). Rickettsia spp. was detected in 7.1% of the tested ticks and the only identified species was R. helvetica. A low prevalence was found for A. phagocytophilum (0.5%) and no Babesia positive tick was detected. The seroprevalence data in cattle indicate hot spots for tick-borne pathogens in specific provinces and highlights the importance of veterinary surveillance in anticipating the emergence of diseases among humans. The detection of all pathogens, with the exception of Babesia spp. in questing ticks, underlines the need of raising awareness among public and professionals on other tick-borne diseases along with lyme borreliosis.