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Sulfadoxine-pyrimethamine (SP) is a key drug recommended by the World Health Organization for the chemoprevention of malaria. However, the strategy is affected by the parasite resistance to SP. This study evaluated Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes, associated with SP resistance, from 508 P. falciparum isolates imported from West African countries to Henan Province, China, during 2012–2022. High mutant prevalence of the genes Pfdhfr (94.7%) and Pfdhps (96.8%) was observed. The mutants Pfdhfr N51I, C59R, S108N, and Pfdhps A437G were at high frequency in all countries analyzed. The overall prevalence of the mutant Pfdhps K540E was low (3.4%), but with a high frequency in Liberia (24.3%). The frequency of mutants Pfdhps I431V, A581G, and A613S was 11.7%, 9.8%, and 16.2%, respectively, all of which had the highest mutant prevalence in Nigeria. The mutant Pfdhps A581G and A613S were identified in the absence of K540E. The partially resistant haplotype (I51R59N108 - G437) was the most common (72.6%), and the fully resistant haplotype (I51R59N108 - G437E540) had a low prevalence of 3.4% and mainly occurred in Liberia. No super resistant haplotype was identified. The mutant Pfdhps I431V and the octuple mutant haplotype I51R59N108 - V431A436G437G581S613 deserve more attention. In areas of high SP resistance, the intervention still reduces low birthweight and maternal anaemia. SP should continue to be used in areas of high SP resistance until more effective alternatives for malaria chemoprevention are found. It is important to continuously monitor the molecular markers associated with SP resistance to better implement intermittent preventive treatment policies in pregnancy (IPTp) and infants (IPTi). [ABSTRACT FROM AUTHOR]

Seasonal Malaria Chemoprevention consisting of monthly administration of amodiaquine/sulfadoxine-pyrimethamine to children aged 3–59 months during the transmission season could promote SP-resistance. Mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes were assessed before and after SMC adoption in Burkina Faso. A total of 769 dried blood spots were selected from studies conducted in Nanoro, Burkina Faso, between 2010 and 2020. Of those, 299 were pre-SMC (2010–2012) and 470 were post-SMC-samples. Pfdhps and Pfdhfr genes were PCR-amplified and sequenced. A systematic review/meta-analysis of published studies conducted in Burkina Faso (2009–2023) was additionally performed. In Nanoro, the prevalence of Pfdhfr triple mutations (CIRNI) rose from 43.6% pre-SMC to 89.4% post-SMC (p < 0.0001). There was no mutation in Pfdhfr 164 and Pfdhps 540; Pfdhps A437G mutation increased from 63.9% (2010–2012) to 84.7% (2020) (p < 0.0001). The VAGKGS haplotype was 2.8% (2020). Pfdhfr/Pfdhps quintuple mutant IRN-436A437G rose from 18.6% (2010–2012) to 58.3% (2020) (p < 0.0001). Meta-analysis results from Burkina Faso showed an increase in mutations at Pfdhfr N51I, C59R, S108N, and Pfdhps A437G after SMC adoption. Post-SMC, the pyrimethamine-resistance marker prevalence increased, while the sulfadoxine-resistance marker prevalence remained stable. Detection of emerging PfdhpsVAGKGS haplotypes in 2020 underscores the importance of continuous SP-resistance monitoring. [ABSTRACT FROM AUTHOR]

Mental health and HIV risk behavior have been studied with ecological momentary assessment (EMA), but this approach has not been combined with tracking of activity space (where people go and what they encounter there) in people with HIV and their social relations, who may be HIV+ or HIV−. Activity space represents a modifiable risk or protective factor for behavior related to health status and quality of life, in both clinical and nonclinical populations. We conducted an observational study with 286 participants (243 HIV+ and 43 HIV−), roughly matched for socioeconomic status and neighborhood of residence via three waves of snowball sampling. Each participant carried a smartphone for up to 4 weeks, making 5 randomly prompted entries and 1 end-of-day entry each day, plus self-initiated event-contingent entries for sexual activity and drug use. Responses to randomly prompted items provided subjective evaluations of the safety of the participant's current social and physical environment (the place they were and the people they were with). GPS-based location tracking—coupled with publicly available statistic indicating neighborhood-level physical disorder and socioeconomic disadvantage—provided an indicator of each participant's exposure to objective psychosocial hazard. We examined possible relationships of these objective and subjective environmental exposures with risky sexual and intravenous drug-use behavior, knowledge and utilization of antiretroviral treatment and prophylaxis, and momentary mental health (mood and stress, which relate to risky behavior and overall well-being). We found that both risky behavior and mental health were more related to participants' subjective evaluations of their activity space than to objective measures of neighborhood-level disorder, suggesting that, even within an objectively hazardous neighborhood, people who find a niche they perceive as socially and physically safe may engage in less risky behavior and have better well-being. Trial registration Clinicaltrials.gov Identifier NCT01571752. [ABSTRACT FROM AUTHOR]

Treatment options for patients with esophageal squamous cell carcinoma (ESCC) often result in poor prognosis and declining health-related quality of life. Screening FDA-approved drugs for cancer chemoprevention is a promising and cost-efficient strategy. Here, we found that dronedarone, an antiarrhythmic drug, could inhibit the proliferation of ESCC cells. Moreover, we conducted phosphorylomics analysis to investigate the mechanism of dronedarone-treated ESCC cells. Through computational docking models and pull-down assays, we demonstrated that dronedarone could directly bind to CDK4 and CDK6 kinases. We also proved that dronedarone effectively inhibited ESCC proliferation by targeting CDK4/CDK6 and blocking the G0/G1 phase through RB1 phosphorylation inhibition by in vitro kinase assays and cell cycle assays. Subsequently, we found that knocking out CDK4 and CDK6 decreased the susceptibility of ESCC cells to dronedarone. Furthermore, dronedarone suppressed the growth of ESCC in patient-derived tumor xenograft models in vivo. Thus, our study demonstrated that dronedarone could be repurposed as a CDK4/6 inhibitor for ESCC chemoprevention. [ABSTRACT FROM AUTHOR]

Rising melanoma rates have spurred interest in preventive strategies. Nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, show potential in reducing cancer risks. NSAIDs act on cyclooxygenase (COX) enzymes, impacting COX-2 associated with inflammation and cancer progression. This paper explores aspirin's role in cutaneous melanoma prevention, elucidating its mechanisms and acknowledging varying literature outcomes. Rather than providing conclusive recommendations, the review emphasizes the influence of individual factors, contributing to the ongoing dialogue on aspirin's complexities in melanoma prevention. A PubMed search using "Aspirin" AND "Cutaneous melanoma" yielded relevant English-language, peer-reviewed studies. Selection criteria focused exclusively on skin cancers, specifically cutaneous melanoma. Exclusions included studies covering various cancers, some non-dermatologic, and those not evaluating aspirin use independently but in conjunction with NSAIDs. The potential chemopreventive effects of aspirin and NSAIDs against melanoma have gained attention due to their association with a reduced risk of various cancers including gastric, colorectal, and breast. By inhibiting COX enzymes and the NF-κB pathway, these agents theoretically slow malignant cell activities, presenting a prospect for cancer prevention. Aspirin exhibits noteworthy effects, depleting growth-stimulating hormones, generating reactive oxygen species harmful to cancerous cells, and inhibiting COX-2 linked to cancer progression. Limited literature suggests survival benefits with aspirin use in stage II and III melanoma, possibly due to slowing disease progression, evident in smaller Breslow depths. Gender-specific responses to aspirin are notable, with some studies reporting a stronger chemopreventive correlation in females. It's crucial to note that geographic disparities, demographic cohorts, and individual-specific factors are confounding variables that may contribute to conflicting findings regarding aspirin's impact on melanoma. The association between aspirin use and melanoma risk is complex, with conflicting findings across diverse populations. Although it appears that more studies suggest a protective role for aspirin rather than not, evidence lacks consistency. Factors such as gender, geography, race, sun exposure, and health conditions play a role in shaping these varied outcomes, necessitating large-scale, prospective studies research and standardized parameters for more conclusive insights that may help guide tailored clinical strategies for melanoma prevention. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review aims to provide a comprehensive overview of the current advances in managing and preventing progression of oral potentially malignant disorders (OPMDs), focusing on their histological and clinicopathological features, and management. Recent Findings: Recent studies, including a multicenter cross-sectional study, have identified oral leukoplakia as the most prevalent form of OPMD, comprising over half of the cases examined. Advances in histological grading, specifically the World Health Organization's three-tier system (mild, moderate, and severe dysplasia), have significantly enhanced the accuracy of risk assessment for malignant transformation. Additionally, treatments such as surgical interventions, photodynamic therapy, and chemopreventive and molecularly targeted agents are being evaluated for their safety and efficacy as well as, immune checkpoint inhibitors being evaluated as potential preventive strategies to halt the progression of OPMDs. Summary: The management of OPMDs remains challenging due to the lack of standardized screening protocols and varied clinical management approaches. Despite this, recent advancements in diagnostic grading and therapeutic interventions provide a framework for improved treatment outcomes. Continued research into the molecular and cellular mechanisms driving development and progression of OPMDs and innovative treatment trials are essential to optimize strategies that prevent malignant progression and thereby reduce the global health burden of oral cancer. [ABSTRACT FROM AUTHOR]

Sorghum is considered a promising food security crop and remarkable rich source of bioactive components including phenolic acids, flavonoids, and tannins. Sorghum phenolics exhibited numerous protective effects against multiple chronic diseases. However, there is no review of the effects of sorghum phenolics on gastrointestinal (GI) health. Specifically, recent studies have highly suggested that sorghum phenolics can maintain gastrointestinal homeostasis and enhance microbial diversity and richness. Furthermore, sorghum phenolics showed GI anticancer effects in both in vitro and in vivo studies against colorectal and esophageal cancers. Treatment of GI related human cancer cell lines stimulated apoptosis and suppressed proliferation. Sorghum intake and extracts treatments reduced intestinal oxidative stress and inflammatory mediators in human and in vivo studies. In addition, understanding the role and mechanisms underlying gastrointestinal health benefits of sorghum phenolics is crucial to determine treatment strategies of different GI diseases. [ABSTRACT FROM AUTHOR]

Background: Early initiation of venous thromboembolism (VTE) chemoprophylaxis in adults with blunt solid organ injury (BSOI) has been demonstrated to be safe but this is controversial in adolescents. We hypothesized that adolescent patients with BSOI undergoing non-operative management (NOM) and receiving early VTE chemoprophylaxis (eVTEP) (≤ 48 h) have a decreased rate of VTE and similar rate of failure of NOM, compared to similarly matched adolescents receiving delayed VTE chemoprophylaxis (dVTEP) (> 48 h). Methods: The 2017–2019 Trauma Quality Improvement Program database was queried for adolescents (12–17 years of age) with BSOI (liver, kidney, and/or spleen) undergoing NOM. We compared eVTEP versus dVTEP using a 1:1 propensity score model, matching for age, comorbidities, BSOI grade, injury severity score, hypotension on arrival, and need for transfusions. We performed subset analyses in patients with isolated spleen, kidney, and liver injury. Results: From 1022 cases, 417 (40.8%) adolescents received eVTEP. After matching, there was no difference in matched variables (all p > 0.05). Both groups had a similar rate of VTE (dVTEP 0.6% vs. eVTEP 1.7%, p = 0.16), mortality (dVTEP 0.3% vs. eVTEP 0%, p = 0.32), and failure of NOM (eVTEP 6.7% vs. dVTEP 7.3%, p = 0.77). These findings remained true in all subset analyses of isolated solid organ injury (all p > 0.05). Conclusions: The rate of VTE with adolescent BSOI is exceedingly rare. Early VTE chemoprophylaxis in adolescent BSOI does not increase the rate of failing NOM. However, unlike adult trauma patients, adolescent patients with BSOI receiving eVTEP had a similar rate of VTE and death, compared to adolescents receiving dVTEP. [ABSTRACT FROM AUTHOR]

Chemical carcinogen-induced oxidative stress has a key role in cell signaling linked to the development of cancer. Oxidative stress leads to oxidative damage to cellular membranes, proteins, chromosomes and genetic material. It is thought that compounds like hesperidin with high antioxidant and anticancer potential can reduce development of cancer induced by chemical carcinogens via neutralizing their oxidative damages. We investigated protective effect of hesperidin against N-Ethyl-N-Nitrosourea (ENU)-induced neurotoxicity, congenital abnormalities and possible brain cancer after exposure of mice during pregnancy as model of glioma. The mice were divided to four groups; control (normal saline), ENU (40 mg/kg daily for three consecutive days from the 17th to the 19th of pregnancy), hesperidin (pretreated with 25 mg/kg for 30 consecutive days, before mating) + ENU and hesperidin alone. Developmental toxicity parameters (the number of pregnant mice, stillbirths, abortion, live and dead offspring), behavioral tests (novel object recognition, open field and elevated plus maze) were performed. Moreover, the activity of butrylcholinesterase and acetylcholinesterase enzymes, oxidative markers and histopathological abnormalities were detected in brain tissue. Our data showed that conversely, the pretreatment of hesperidin reduces various degrees of developmental toxicity, neurobehavioral dysfunction, neurotoxicity, oxidative stress and histopathological abnormalities induced by ENU as a neurotoxic and carcinogenic agent in the next generation. In conclusion, pre-mating exposure with hesperidin may open new avenues for prevention of primary brain cancer in next generation and could be valuable for enhancing the antioxidant defense and minimizing the developmental and neurotoxicity of DNA alkylating agents. [ABSTRACT FROM AUTHOR]

We describe 'Boldrewood', a new accession of watercress (Nasturtium officinale R. Br.) that was initially found to be of short stature with high antioxidant capacity (Payne et al. 2015). This was of particular commercial interest because it offered the potential to develop a novel watercress product with fork-friendly size and improved health-benefits. In two commercial trials comparing Boldrewood to a control, we confirmed that Boldrewood exhibits a dwarf phenotype with a significantly shorter stem and consistently produced more leaves per stem area alongside comparable crop biomass. The antioxidant and chemopreventive capacity of Boldrewood were comparable to the commercial crop. For the first time, we observed a novel increase in glucosinolate concentrations and cytotoxicity to cancer cells, characterised as decreased IC50 (half-maximal concentration of an inhibitor), associated with increased crop age at harvest. This suggests that a slower-growing and longer to harvest crop provides a significant improvement in health benefits gained in this leafy crop which is already known to be highly nutrient dense and with considerable chemopreventive ability. [ABSTRACT FROM AUTHOR]

Nimbolide, one of the main ingredients constituent of Azadirachta indica (neem) leaf extract, has garnered attention for its potential as an anticancer agent. Its efficacy against various cancers and chemopreventive action has been demonstrated through numerous in vivo and in vitro studies. This updated review aims to comprehensively explore the chemopreventive and anticancer properties of nimbolide, emphasizing its molecular mechanisms of action and potential therapeutic applications in oncology. The review synthesizes evidence from various studies that examine nimbolide's roles in apoptosis induction, anti-proliferation, cell death, metastasis inhibition, angiogenesis suppression, and modulation of carcinogen-metabolizing enzymes. Nimbolide exhibits multifaceted anticancer activities, including the modulation of multiple cell signaling pathways related to inflammation, invasion, survival, growth, metastasis, and angiogenesis. However, its pharmacological development is still in the early stages, mainly due to limited pharmacokinetic and comprehensive long-term toxicological studies. Nimbolide shows promising anticancer and chemopreventive properties, but there is need for systematic preclinical pharmacokinetic and toxicological research. Such studies are essential for establishing safe dosage ranges for first-in-human clinical trials and further advancing nimbolide's development as a therapeutic agent against various cancers. The review highlights the potential of nimbolide in cancer treatment and underscores the importance of rigorous preclinical evaluation to realize its full therapeutic potential. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested that medication with statins improves survival in patients with gastric cancer, but methodological issues have limited the interpretability and prohibited conclusive results. We aimed to provide valid evidence as to whether statin use improves survival of gastric adenocarcinoma. Methods: This nationwide and population-based cohort study included virtually all patients who underwent curatively intended surgery (gastrectomy) for gastric adenocarcinoma in Sweden between 2006 and 2015 with follow-up throughout 2019 for disease-specific mortality and 2020 for all-cause mortality. Data came from medical records and national healthcare registries. The exposure was statin use during the year prior to gastrectomy which was compared to no such use during the same period. The outcomes were 5-year disease-specific mortality (main) and 5-year all-cause mortality (secondary). Multivariable Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI), adjusted for age, sex, education, calendar year, comorbidity, low-dose aspirin use, tumour sublocation, pathological tumour stage, neoadjuvant chemotherapy, annual surgeon volume, and surgical radicality. Results: Among 1515 participating patients, the mean age was 69 years and 58.4% were men. Statin use, identified in 399 (26.3%) patients, was not associated with any statistically significantly decreased 5-year disease-specific mortality (HR 0.99, 95% CI 0.82–1.21) or 5-year all-cause mortality (HR 0.94, 95% CI 0.79–1.12). No risk reductions were found across subgroups of age, sex, aspirin user status, or tumour stage, or in patients with long-term preoperative of postoperative use of statins, all with point estimates close to 1. Conclusions: Perioperative use of statins does not seem to improve the 5-year survival in patients who undergo gastrectomy with curative intent for gastric adenocarcinoma in Sweden. [ABSTRACT FROM AUTHOR]

Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( E o ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3β, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent. [ABSTRACT FROM AUTHOR]

Cancer growth is a molecular mechanism initiated by genetic and epigenetic modifications that are involved in cell proliferation, differentiation, apoptosis, and senescence pathways. Chemoprevention is an important strategy for cancer treatment that leads to blocking, reversing, or impeding the multistep process of tumorigenesis, including the blockage of its vital morphogenetic milestones viz. normal, preneoplasia, neoplasia, and metastasis. Naturally occurring phytochemicals are becoming ever more popular compared to synthetic drugs for many reasons, including safety, bioavailability, efficacy, and easy availability. Allyl isothiocyanate (AITC) is a natural compound present in all plants of the Cruciferae family, such as Brussels sprouts, cauliflower, mustard, cabbage, kale, horseradish, and wasabi. In vitro and in vivo studies carried out over the decades have revealed that AITC inhibits tumorigenesis without any toxicity and undesirable side effects. The bioavailability of AITC is exceedingly high, as it was reported that nearly 90% of orally administered AITC is absorbed. AITC exhibits multiple pharmacological properties among which its anticancer activity is the most significant for cancer treatment. Its anticancer activity is exerted via selective modulation of multiple cell signaling pathways related to oxidative stress, inflammation, cell proliferation, cell cycle arrest, apoptosis, angiogenesis, invasion, and metastasis. This review highlights the current knowledge on molecular targets that are involved in the anticancer effect of AITC associated with (i) inhibition of carcinogenic activation and induction of antioxidants, (ii) suppression of pro-inflammatory and cell proliferative signals, (iii) induction of cell cycle arrest and apoptosis, and (iv) inhibition of angiogenic and invasive signals related to metastasis. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. Objective: To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. Methods: This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. Results: A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0–5.43%] and 0% for all other agents and 0.46% (95% CI 0–1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). Conclusions: The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors. [ABSTRACT FROM AUTHOR]

Amaranth, quinoa, and buckwheat are the representatives of pseudocereals, different parts and by-products of which are used in daily nutrition and food processing industry. However, only scarce information exists on the bioactivity of their oils. Thus, oils obtained from amaranth, buckwheat, and red, yellow, and white quinoa seeds were evaluated in terms of their nutritional (fatty acid profile, squalene), cytotoxic (against normal and neoplastic gastrointestinal, prostate, and skin cells), anti-inflammatory and antiradical (interleukin 6, TNF-alpha, nitric oxide, DPPH, Total phenolics, and superoxide dismutase) potential in the in vitro model. Linoleic (42.9–52.5%) and oleic (22.5–31.1%) acids were the two main unsaturated, while palmitic acid (4.9–18.6%) was the major saturated fatty acid in all evaluated oils. Squalene was identified in all evaluated oils with the highest content in amaranth oil (7.6 g/100 g), and the lowest in buckwheat oil (2.1 g/100 g). The evaluated oils exerted a high direct cytotoxic impact on cancer cells of different origins, but also revealed anti-inflammatory and antiradical potentials. Yellow quinoa oil was the most active, especially toward skin (A375; IC50 6.3 µg/mL), gastrointestinal (HT29 IC50 4.9 µg/mL), and prostate cancer cells (LNCaP IC50 7.6 µg/mL). The observed differences in the activity between the oils from the tested quinoa varieties deserve further studies. High selectivity of the oils was noted, which indicates their safety to normal cells. The obtained results indicate that the oils are good candidates for functional foods with perspective chemopreventive potential. [ABSTRACT FROM AUTHOR]

Purpose of Review: To explore the landmark clinical trials which shaped contemporary chemoprevention practice, discuss trends in chemoprevention uptake, and highlight the obstacles faced along the way. Recent Findings: Poor chemoprevention uptake has been attributed to numerous factors, most notably fear of side effects and lack of physician recommendation. A lower dose of tamoxifen taken for a shorter period has been shown to be an effective alternative and harbors fewer side effects than the standard regimen for chemoprevention. Summary: Despite new regimens with more favorable side effect profiles and shorter treatment courses, chemoprevention uptake remains low. Education and decision-support interventions have not proven successful in addressing low uptake. In addition to ongoing trials aimed at maintaining the benefits of therapy while reducing adverse effects, a culture change among providers is needed to destigmatize these risk-reducing medications, with focus on referring appropriate women to specialized breast health centers. [ABSTRACT FROM AUTHOR]

Purpose: While the effects of tranexamic acid (TXA) use on transfusion rates after acetabular fracture surgery are unclear, previous evidence suggests that holding deep vein thrombosis (DVT) chemoprophylaxis may improve TXA efficacy. This study examines whether holding DVT chemoprophylaxis in patients receiving TXA affects intraoperative and postoperative transfusion rates in acetabular fracture surgery. Methods: We reviewed electronic medical records (EMR) of 305 patients who underwent open reduction and internal fixation of acetabular fractures (AO/OTA 62) and stratified patients per the following perioperative treatment: (1) no intraoperative TXA (noTXA), (2) intraoperative TXA and no preoperative DVT prophylaxis (opTXA/noDVTP), or (3) intraoperative TXA and preoperative DVT prophylaxis (opTXA/opDVTP). The primary outcomes were need for intraoperative or postoperative transfusion. Risk factors for each primary outcome were assessed using multivariable regression. Results: Intraoperative or postoperative transfusion rates did not significantly differ between opTXA/opDVTP and opTXA/noDVTP groups (46.2% vs. 36%, p = 0.463; 15.4% vs. 28%, p = 0.181). Median units transfused did not differ between groups (2 ± 1 vs. 2 ± 1, p = 0.515; 2 ± 1 vs. 2 ± 0, p = 0.099). There was no association between preoperative DVT chemoprophylaxis and TXA with intraoperative or postoperative transfusions. EBL, preoperative hematocrit, and IV fluids were associated with intraoperative transfusions; age and Charlson Comorbidity Index (CCI) were associated with postoperative transfusions. Conclusion: Our findings suggest holding DVT prophylaxis did not alter the effect of TXA on blood loss or need for transfusion. [ABSTRACT FROM AUTHOR]

This review will discuss evidence that aspirin possesses anticancer activity. Long-term observational retrospective studies on nurses and health professionals demonstrated that regular aspirin users had a significantly lower incidence of colorectal cancer (RCT). Prospective studies on patients with a high risk of developing colorectal polyps/cancer confirmed that aspirin use significantly lowered colorectal dysplasia. Numerous observational studies focused on the use of aspirin in a broad range of cancers demonstrating a consistent 20–30% preventive effect on cancer incidence and mortality. Random Controlled Trials provided conflicting results on the benefit of aspirin in preventing CRC. Based on the age, weight/body size of the subjects for reasons still being explored. Studies on rats/mice further demonstrated that treatment of animals with aspirin where colon cancer was induced chemically or genetically (APCMin mice) reduced colonic dysplasia and polyp formation. Aspirin treatment was also effective at reducing the growth of cancer cells transplanted into normal/immunocompromised mice, suggesting that aspirin may be effective in treating different cancers. This possibility is also supported in clinical studies that aspirin use pre- and postcancer diagnosis significantly reduced the metastatic spread of cancer and increased patient survival. Lastly, the importance of the antiplatelet actions of aspirin in the drug's anticancer activity and specifically cancer metastatic spread is discussed and the current controversy related to the conflicting recommendations of the USPSTF over the past five years on the use of aspirin to prevent CRC. [ABSTRACT FROM AUTHOR]

Purpose: Low-molecular-weight-heparin (LMWH) has been shown to be associated with a decreased risk of venous thromboembolism (VTE) and mortality compared to unfractionated heparin (UH) in severe traumatic brain injury (TBI). The aim of this study was to see if this association persists among a subset of patients, namely elderly patients with isolated TBI. Methods: This Trauma Quality Improvement Project (TQIP) database study included patients ≥ 65 years old with severe TBI (Abbreviated injury score [AIS] ≥ 3) that received either LMWH or UH for VTE prophylaxis. Patients with associated severe injuries (extracranial AIS ≥ 3), transferals, deaths < 72-h, hospitalization < 2 days, VTE chemoprophylaxis other than UH or LMWH, or with a history of bleeding diathesis were excluded. The association between VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE) with VTE chemoprophylaxis was analyzed with multivariable analysis, subset analyses of different grades of AIS-head injury, and a 1:1 matched LWMH:UH cohort of patients. Results: Out of 14,926 patients, 11,036 (73.9%) received LMWH. Multivariate analysis showed that patients receiving LMWH had a decreased risk of mortality (OR 0.81, 95% CI 0.67–0.97, p < 0.001) but a similar risk of VTE (OR 0.83, 95% CI 0.63–1.08). Analysis according to head-AIS showed that LMWH was associated with a decreased risk of PE in patients AIS-3 but not in AIS 4 or 5. In a 1:1 matched cohort of LMWH:UH patients, the risk of PE, DVT and VTE were all similar but LMWH continued to be associated with a decreased risk of mortality (OR 0.81, CI 0.67–0.97, p = 0.023). Conclusion: LMWH was associated with a decreased risk of overall mortality and reduced risk of PE compared to UH among geriatric patients with a severe head injury. [ABSTRACT FROM AUTHOR]

Background: Although the serrated-neoplasia pathway reportedly accounts for 15–30% of colorectal cancer (CRC), no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. We searched for effective compounds comprehensively from a large series of compounds by employing Connectivity Map (CMAP) analysis of SSL-specific gene expression profiles coupled with in vitro screening using SSL patient-derived organoids (PDOs), and validated their efficacy using a xenograft mouse model of SSL. Methods: We generated SSL-specific gene signatures based on DNA microarray data, and applied them to CMAP analysis with 1309 FDA-approved compounds to select candidate compounds. We evaluated their inhibitory effects on SSL-PDOs using a cell viability assay. SSL-PDOs were orthotopically transplanted into NOG mice for in vivo evaluation. The signal transduction pathway was evaluated by gene expression profile and protein expression analysis. Results: We identified 221 compounds by employing CMAP analysis of SSL-specific signatures, which should cancel the gene signatures, and narrowed them down to 17 compounds. Cell viability assay using SSL-PDOs identified lansoprazole as having the lowest IC50 value (47 µM) among 17 compounds. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. Administration of lansoprazole to mice inhibited the growth of SSL xenograft whereas the tumor in control mice treated with vehicle alone grew gradually over time. The Ki67 index in xenograft lesions from the lansoprazole group was significantly lower compared with the control group. Cell cycle analysis of SSL-PDOs treated with lansoprazole exhibited a significant increase in G1 phase cell population. Microarray and protein analysis revealed that lansoprazole downregulated Skp2 expression and upregulated p27 expression in SSL-PDOs. Conclusions: Our data strongly suggest that lansoprazole is the most effective chemopreventive agent against SSL, and that lansoprazole induces G1 cell cycle arrest by downregulating Skp2 and upregulating p27 in SSL cells. [ABSTRACT FROM AUTHOR]

Breast cancer stands as a prominent contributor to cancer-related fatalities among women globally, characterized by an unfavorable prognosis, low survival rates, and its conventional treatment approach involving chemotherapy. Doxorubicin (DOXO) represents a potent anti-tumor agent widely employed in combating breast cancer. Regrettably, a substantial proportion of patients eventually develop resistance to DOXO treatment, elevating the risk of relapse and adverse clinical outcomes. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), recognized as essential components of the human diet, have exhibited considerable promise in targeting malignant cells, initiating apoptosis, and impeding tumor proliferation and metastatic dissemination. Combining these nutritional supplements, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with DOXO presents a compelling strategy to augment treatment efficacy. The present study was conducted employing a breast cancer cell line, MCF-7, to assess the synergistic potential of DHA, EPA, and DOXO. Remarkably, the combination treatment yielded a substantial increase in cytotoxicity compared to the administration of DOXO alone. Furthermore, an enhancement in the suppression of metastasis was evident in the combination treatment relative to the exclusive use of DOXO. Cell cycle analysis unveiled that cells subjected to the combination treatment exhibited a more pronounced arrest in the G1 phase, signifying the combination's heightened effectiveness in impeding cell progression into the doubling phase. Collectively, the amalgamation of n-3 polyunsaturated fatty acids (n-3 PUFAs) emerges as a potent strategy for enhancing the therapeutic potential of DOXO, effectively restraining the growth and dissemination of breast cancer cells. [ABSTRACT FROM AUTHOR]

Background: Melittin is a water-soluble cationic peptide derived from bee venom that has been thoroughly studied for the cure of different cancers. However, the unwanted interactions of melittin produce hemolytic and cytotoxic effects that hinder their therapeutic applications. To overcome the shortcomings, numerous research groups have adopted different approaches, including conjugation with tumor-targeting proteins, gene therapy, and encapsulation in nanoparticles, to reduce the non-specific cytotoxic effects and potentiate their anti-cancerous activity. Purpose: This article aims to provide mechanistic insights into the chemopreventive activity of melittin and its nanoversion in combination with standard anti-cancer drugs for the treatment of cancer. Methods: We looked over the pertinent research on melittin's chemopreventive properties in online databases such as PubMed and Scopus. Conclusion: In the present article, the anti-cancerous effects of melittin on different cancers have been discussed very nicely, as have their possible mechanisms of action to act against different tumors. Besides, it interacts with different signal molecules that regulate the diverse pathways of cancerous cells, such as cell cycle arrest, apoptosis, metastasis, angiogenesis, and inflammation. We also discussed the recent progress in the synergistic combination of melittin with standard anti-cancer drugs and a nano-formulated version of melittin for targeted delivery to improve its anticancer potential. [ABSTRACT FROM AUTHOR]

In the combat of treating cancer recent therapeutic approaches are focused towards enzymatic targets as they occupy a pivotal participation in the cascade of oncogenesis and malignancy. There are several enzymes that modulate the epigenetic pathways and chromatin structure related to cancer mutation. Among several epigenetic mechanisms such as methylation, phosphorylation, and sumoylation, acetylation status of histones is crucial and is governed by counteracting enzymes like histone acetyl transferase (HAT) and histone deacetylases (HDAC) which have contradictory effects on the histone acetylation. HDAC inhibition induces chromatin relaxation which forms euchromatin and thereby initiates the expression of certain transcription factors attributed with apoptosis, which are mostly correlated with the expression of the p21 gene and acetylation of H3 and H4 histones. Most of the synthetic and natural HDAC inhibitors elicit antineoplastic effect through activation of various apoptotic pathways and promoting cell cycle arrest at various phases. Due to their promising chemo preventive action and low cytotoxicity against normal host cells, bioactive substances like flavonoids, alkaloids, and polyphenolic compounds from plants have recently gained importance. Even though all bioactive compounds mentioned have an HDAC inhibitory action, some of them have a direct effect and others enhance the effects of the standard well known HDAC inhibitors. In this review, the action of plant derived compounds against histone deacetylases in a variety of in vitro cancer cell lines and in vivo animal models are articulated. [ABSTRACT FROM AUTHOR]

Prostate cancer (PC) has historically been the most diagnosed cancer in men. Though treatment for prostate cancer is often effective, it is also often very taxing on the body and commonly has negative quality of life implications. One such example is androgen suppression therapy (AST), which has severe side effects that can be mitigated through physical activity. Natural agents and protocols are increasingly studied for their merit against cancer and for their potential to treat cancer in ways that preserve the quality of life. Many agents and lifestyle choices have been shown to have success against prostate cancer. There is promising evidence that simple treatments such as green tea, pomegranate, and a regular exercise routine can be effective against prostate cancer. These treatments have the potential to enhance current treatment protocols. In this review, we will discuss the viability of many natural agents as treatments for prostate cancer and its complications. [ABSTRACT FROM AUTHOR]

One of the well-studied older molecules, quercetin, is found in large quantities in many fruits and vegetables. Natural anti-oxidant quercetin has demonstrated numerous pharmacological properties in preclinical and clinical research, including anti-inflammatory and anti-cancer effects. Due to its ability to control cell signaling pathways, including NF-κB, p53, activated protein-1 (AP-1), STAT3, and epidermal growth response-1 (Egr-1), which is essential in the initiation and proliferation of cancer, it has gained a lot of fame as an anticancer molecule. Recent research suggests that using nanoformulations can help quercetin to overcome its hydrophobicity while also enhancing its stability and cellular bioavailability both in vitro and in vivo. The main aim of this review is to focus on the comprehensive insights of several nanoformulations, including liposomes, nano gels, micelles, solid lipid nanoparticles (SLN), polymer nanoparticles, gold nanoparticles, and cyclodextrin complexes, to transport quercetin for application in cancer. [ABSTRACT FROM AUTHOR]

Genistein, a commonly occurring isoflavone, has recently gained popularity owing to its ever-expanding spectrum of pharmacological benefits. In addition to health benefits such as improved bone health and reduced postmenopausal complications owing to its phytoestrogen properties, it has been widely evaluated for its anti-cancer potential. Several studies have established the potential for its usage in the management of breast, lung, and prostate cancers, and its usage has significantly evolved from early applications in traditional systems of medicine. This review offers an insight into its current status of usage, the chemistry, and pharmacokinetics of the molecule, an exploration of its apoptotic mechanisms in cancer management, and opportunities for synergism to improve therapeutic outcomes. In addition to this, the authors have presented an overview of recent clinical trials, to offer an understanding of contemporary studies and explore prospects for a greater number of focused trials, moving forward. Advancements in the application of nanotechnology as a strategy to improve safety and efficacy have also been highlighted, with a brief discussion of results from safety and toxicology studies. [ABSTRACT FROM AUTHOR]

There is concern that preprint articles will lead to an increase in the amount of scientifically invalid work available. The objectives of this study were to determine the proportion of prevention preprints published within 12 months, the consistency of the effect estimates and conclusions between preprint and published articles, and the reasons for the nonpublication of preprints. Of the 329 prevention preprints that met our eligibility criteria, almost half (48.9%) were published in a peer-reviewed journal within 12 months of being posted. While 16.8% published preprints showed some change in the magnitude of the primary outcome effect estimate, 4.4% were classified as having a major change. The style or wording of the conclusion changed in 42.2%, the content in 3.1%. Preprints on chemoprevention, with a cross-sectional design, and with public and noncommercial funding had the highest probabilities of publication. The main reasons for the nonpublication of preprints were journal rejection or lack of time. The reliability of preprint articles for evidence-based decision-making is questionable. Less than half of the preprint articles on prevention research are published in a peer-reviewed journal within 12 months, and significant changes in effect sizes and/or conclusions are still possible during the peer-review process. [ABSTRACT FROM AUTHOR]

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research. [ABSTRACT FROM AUTHOR]

Purpose: Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. Methods: We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. Results: There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8 years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40–1.03; P = 0.07). Conclusion: Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary. [ABSTRACT FROM AUTHOR]

Background: Breast Cancer incidence in the UK is estimated to rise to 71,000 per year by 2035. Preventative strategies could significantly reduce this. Preventative therapy reduces women's risk of oestrogen receptor positive breast cancer, but uptake remains low. Having established a preventative therapy clinic as part of a wider breast cancer prevention project, we explored qualitative data to inform future preventative efforts. Method: Women aged 30 to 60 who had benign diagnoses at a symptomatic breast clinic or were under mammographic surveillance in the moderate risk family history clinic were invited to participate in the study. Those who expressed an interest and completed an initial questionnaire had their breast cancer risk calculated using the IBIS risk calculator. Those at increased risk were invited to a consultation about preventative therapy. Results: 182 women were identified as increased risk (≥ 17% lifetime or ≥ 3% 10-year risk NICE guidelines: Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer, 20131) of whom 91 women (50%) would not have been identified by family history criteria alone. 96% attended a risk/prevention consultation and all eligible women accepted screening mammography but only 14 (8%) women requested a preventative therapy prescription during the duration of the study. Reluctance to take medication and inconvenient time of life were common reasons for declining preventative therapy. Despite this, the majority were grateful for breast cancer risk and prevention information. Conclusions: Women at increased risk of breast cancer accept additional screening but are reluctant to take preventative therapy. This suggests that stratified screening methods using risk calculations would have high uptake. Raising awareness of preventative therapy is important and the breast cancer community has yet to find the optimum timing and formula for discussing it and must accept women's informed preferences above artificial targets. Registration numbers: The PIONEER study was granted Health Research Authority (HRA) ethical approval by the Westminster Ethics Committee. IRAS project ID 265619, ClinicalTrials.gov Identifier: NCT04574063. Recruitment began in September 2020 and was completed in October 2021. [ABSTRACT FROM AUTHOR]

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Purpose of Review: The number of deaths due to hepatocellular carcinoma (HCC) continues to rise. Chemoprevention may be a useful strategy to prevent HCC. Recent Findings: We summarize recent clinical and translational studies on the chemoprevention of HCC from the aspects of etiology-specific and generic chemoprevention in the context of contemporary HCC etiologies. Summary: Use of safe and effective HCC chemopreventive agents may reduce the burden of HCC, but more data are required before these can be recommended in routine clinical practice. [ABSTRACT FROM AUTHOR]

Purpose of Review: In which patients is it oncologically safe to offer active surveillance instead of surgery for DCIS or a benign breast lesion with upgrade potential (BWUP)? Recent Findings: Most contemporary studies are retrospective or registry studies for BWUP and frequently demonstrate lower than historically reported upgrade rates for all entities, consistent with improved imaging and biopsy techniques. Determining which patients should undergo surgical excision involves shared decision-making between the patient and surgeon, with input from breast imaging and pathology. Three international trials offering active monitoring (AM) for low-risk DCIS have been activated, although results are still pending. Summary: Opportunities for de-escalation of surgical intervention for BWUP breast lesions exist, and decisions for when to omit surgery should be made as a multidisciplinary team. The oncologic safety of omitting surgery for DCIS has yet to be determined, but AM trials are actively enrolling. [ABSTRACT FROM AUTHOR]

Background: Breast cancer risk models guide screening and chemoprevention decisions, but the extent and effect of variability among models, particularly at the individual level, is uncertain. Objective: To quantify the accuracy and disagreement between commonly used risk models in categorizing individual women as average vs. high risk for developing invasive breast cancer. Design: Comparison of three risk prediction models: Breast Cancer Risk Assessment Tool (BCRAT), Breast Cancer Surveillance Consortium (BCSC) model, and International Breast Intervention Study (IBIS) model. Subjects: Women 40 to 74 years of age presenting for screening mammography at a multisite health system between 2011 and 2015, with 5-year follow-up for cancer outcome. Main Measures: Comparison of model discrimination and calibration at the population level and inter-model agreement for 5-year breast cancer risk at the individual level using two cutoffs (≥ 1.67% and ≥ 3.0%). Key Results: A total of 31,115 women were included. When using the ≥ 1.67% threshold, more than 21% of women were classified as high risk for developing breast cancer in the next 5 years by one model, but average risk by another model. When using the ≥ 3.0% threshold, more than 5% of women had disagreements in risk severity between models. Almost half of the women (46.6%) were classified as high risk by at least one of the three models (e.g., if all three models were applied) for the threshold of ≥ 1.67%, and 11.1% were classified as high risk for ≥ 3.0%. All three models had similar accuracy at the population level. Conclusions: Breast cancer risk estimates for individual women vary substantially, depending on which risk assessment model is used. The choice of cutoff used to define high risk can lead to adverse effects for screening, preventive care, and quality of life for misidentified individuals. Clinicians need to be aware of the high false-positive and false-negative rates and variation between models when talking with patients. [ABSTRACT FROM AUTHOR]

Background: Seasonal administration of antimalaria drug, sulphadoxine/pyrimethamine plus amodiaquine to children 3–59 months is a malaria preventive intervention used for the reduction of childhood malaria morbidity and mortality in area with highly seasonal malaria transmission like sub-Saharan Africa. This intervention has been deployed in Nigeria and other sub-Saharan African countries for years and may continue for more years to come either alone or combination with other novel interventions. Despite the importance of pharmacovigilance, there is currently a dearth of pharmacovigilance data in most African countries, especially in public health interventions like seasonal malaria chemoprevention campaigns. The availability of quality safety data is likely to improve the acceptability of this preventive intervention. Results: The study identified vomiting as the most reported adverse drug reaction. Other reported reactions include weakness, fever, abdominal pain, convulsion, redness of the eyes, swollen hand/face, rash, itching, cough, headache, and excessive salivation. Using Naranjo scale, 69.2% of the reported reactions can be classified as possible; while 29.5% can be classified as probable, only 1.3% is classified as definite. 92.3% of reported adverse drug reactions were from children 12–59 months and 7.7% were from those 3–11 months. The proportion of ADRs classified according to the affected organ/system is as follows: central nervous system (10.26%), gastrointestinal (60.26%), ocular (10.26%), musculoskeletal (7.69%), and dermatological (11.53%). The study also suggests better tolerability to the seasonal malaria chemoprevention medicines with more implementation experience, as states with more implementation experiences reported fewer suspected adverse drug reactions. Conclusions: The findings from this study provide additional information on possible adverse drug reactions during seasonal malaria chemoprevention campaigns. This additional information should be communicated to caregivers during the seasonal malaria chemoprevention campaigns as a way of building trust and improving acceptability of the intervention. Also, strengthening of the national pharmacovigilance system is vital to ensure improved timeliness, quality, and quantity of pharmacovigilance reporting on SMC intervention in Africa, as results from the study show low levels of pharmacovigilance reporting across the states. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease are at an increased risk of venous thromboembolism (VTE). The factor Xa inhibitor rivaroxaban has been shown to provide similar efficacy and a lower risk of bleeding compared with vitamin K antagonists for the treatment and prevention of VTE. Rivaroxaban has been studied in patients with varying degrees of renal impairment, and this review summarizes current knowledge supporting its use in patients with severe renal impairment (creatinine clearance [CrCl] of 15 to < 30 mL/min) for the prevention, treatment, or prophylaxis of VTE. Clinical pharmacology studies have demonstrated an increase in rivaroxaban systemic exposure, factor Xa inhibition, and prothrombin time with decreasing renal function. These changes reach a plateau with comparable increases in exposure among individuals with moderate or severe renal impairment and end-stage renal disease. The clinical development program for the treatment and prevention of VTE as well as prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery excluded patients with CrCl < 30 mL/min; however, a limited number of patients with severe renal impairment were enrolled. Efficacy outcomes in these patients with severe renal impairment were not meaningfully different from those of patients with higher levels of renal function. There was also no increase in the incidence of major bleeding with rivaroxaban in patients with CrCl < 30 mL/min. Taken together, these pharmacological and clinical data suggest that in patients with severe renal impairment, the approved dosages of rivaroxaban can be used in the treatment and prevention of VTE and for prophylaxis of DVT after hip or knee replacement surgery. [ABSTRACT FROM AUTHOR]

Background & Aims: Physical activity offers promise to protect against multiple non-hepatic primary cancers. We performed a systematic review to quantify the association between physical activity and hepatocellular carcinoma (HCC) risk. Methods: We searched the Cochrane Library, Embase, Medline and trial registries through December 2020 for studies that measured physical activity levels in adults at risk for HCC. The primary outcome was HCC. Subgroup analysis was performed limiting to vigorous physical activity. Proportions and random-effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. Results: Seven studies met inclusion criteria, comprising 777,662 subjects (median age 55 years; 55% female). Greater amounts of physical activity were associated with less HCC (OR 0.65, 95% CI 0.45–0.95, p = 0.03) compared to lower amounts. Vigorous physical activity was associated with even less HCC (OR 0.62, 95% CI 0.49–0.79, p < 0.01). Conclusions: This meta-analysis demonstrates that greater amounts of physical activity are associated with lower odds of HCC. These results support the use of regular physical activity as an effective way to prevent HCC and provide helpful data to support a for future exercise-based interventional study to better define the optimal exercise prescription for patients at risk for primary liver cancer. [ABSTRACT FROM AUTHOR]

Introduction: Oral squamous cell carcinoma (OSCC), is associated with high morbidity and mortality. Preemptive interventions have been postulated to provide superior therapeutic options, but their implementation has been restricted by the availability of broadly applicable local delivery systems. Methods: We address this challenge by engineering a delivery vehicle, Janus nanoparticles (JNP), that combine the dual mucoadhesive properties of a first cationic chitosan compartment with a second hydrophobic poly(lactide-co-glycolide) release compartment. JNP are designed to avoid rapid mucus clearance while ensuring stable loading and controlled release of the IL-6 receptor antagonist, tocilizumab (TCZ). Results: The JNP featured defined and monodispersed sizes with an average diameter of 327 nm and a PDI of 0.245, high circularities above 0.90 and supported controlled release of TCZ and effective internalization by oral keratinocytes. TCZ released from JNP retained its biological activity and effectively reduced both, soluble and membrane-bound IL-6Rα (71% and 50%). In full-thickness oral mucosal explants, 76% of the JNP breached the stratum corneum and in 41% were observed in the basal cell layer indicating excellent mucopenetrating properties. When tested in an aggressive OSCC xenograft model, TCZ-loaded JNP showed high levels of xenograft inhibition and outperformed all control groups with respect to inhibition of tumor cell proliferation, reduction in tumor size and reduced expression of the proto-oncogene ERG. Conclusion: By combining critically required, yet orthogonal properties within the same nanoparticle design, the JNP in this study, demonstrate promise as precision delivery platforms for intraoral field-coverage chemoprevention, a vastly under-researched area of high clinical importance. [ABSTRACT FROM AUTHOR]

In nature, varieties of underutilized fruit-bearing plants are available and have remained underexploited for various reasons. However, the different parts of the plant, mainly the fruit, contributed considerably towards the sustainability of food as abundant sources of imperative phytochemical compounds and possess the potential for revenue generation and the conservation of ecological stability. Ethnobotanical information regarding underutilized plants was acquired from a literature exploration of diverse databases for instance Scopus, Google Scholar, and PubMed up to 2020 from research publications. This review article offers an inclusive summary of about 14 underutilized plants, which are supported through experimental evidence, either in vitro or else in vivo. Bioactive compounds such as the secondary plant metabolites phytochemicals and nutrients available in these underutilized plant parts, such as fruits, leaves, and bark, explain their potential applications in different kinds of industries including mainly those of food and pharmaceutical products. In this sense, the phytonutrient significance, biological activities, or possible mechanistic health-related aspects of these compounds are addressed in this review. Based on the accessible indication on the species' safety and pharmacology, we highlighted diverse ways wherein the therapeutic potential effects against different diseases of underutilized plant parts could be appropriately harnessed for probable incorporation into the country's healthcare structure. This study concluded that cited underutilized plants are an immense source of phytochemicals providing diverse antioxidant and other biological activities, viz: anti-inflammatory, antimicrobial, antioxidant, antidiabetic, chemopreventive, and antiallergic, and hence, they can be exploited as alternative sources of therapeutic bioactive compounds for various pharmaceutical applications. [ABSTRACT FROM AUTHOR]

Purpose: Abnormal acetylation modification is a common epigenetic change in tumorigenesis and is closely related to the progression of colorectal cancer (CRC). Our previous studies have suggested that black raspberry (BRB) anthocyanins have a significant chemopreventive effect against CRC. This study investigated whether protein acetylation plays an important role in BRB anthocyanins-mediated regulation of CRC progression. Methods: We used the AOM-induced CRC mouse model and the CRC cell lines SW480 and Caco-2 to explore the potential role of acetylation of histone H4 and NF-κB signaling pathway-related proteins (non-histone proteins) in the antitumor process mediated by BRB anthocyanins. The expression of related proteins was detected by western blot. ROS level was detected by immunofluorescence. Results: BRB anthocyanins affected the acetylation level by down-regulating the expression of Sirtuin1 (SIRT1) and up-regulating the expression of MOF and EP300. The acetylation level of lysine sites on histone H4 (H4K5, H4K12 and H4K16) was increased. Furthermore, following BRB anthocyanins treatment, the expression of ac-p65 was significantly up-regulated and the NF-κB signal pathway was activated, which in turn up-regulated Bax expression and inhibited Bcl-2, cyclin-D1, c-myc and NLRP3 expression to promote CRC cell cycle arrest, apoptosis and relieve inflammation. Conclusion: The findings suggested that protein acetylation could play a critical role in BRB anthocyanins-regulated CRC development. [ABSTRACT FROM AUTHOR]

Background: Many migraine patients do not respond adequately to conventional preventive treatments and are therefore described as treatment/medically resistant or difficult to treat cases. Calcitonin gene-related peptide monoclonal antibodies are a relatively novel molecular treatment for episodic and chronic migraine that have been shown to be effective in short duration clinical trials in approximately 40–50% of all chronic migraine patients. Patient Related Outcome Measures (PROM) or Quality of Life (QoL) questionnaires are used to help measure response to treatment in migraine. Although some open label extension studies have become available for erenumab, there is a lack of real-world data pertaining to quality of life in the medium to long-term for chronic and treatment resistant migraine patients. Methods: A total of 177 treatment resistant CM patients were started on erenumab (70 mg or 140 mg subcutaneous injection every 4 weeks) in our three specialist Headache Clinics. Of these, 174 had their first injection between December 2018 and October 2019. All patients were evaluated with the following PROM: the Headache Impact Test− 6, Migraine Associated Disability Assessment test and Migraine-Specific QoL Questionnaire, before starting treatment with erenumab and at intervals of 3–12 months after starting treatment. The decision to continue treatment was based on subjective clinical improvement of at least 30% (as reported by the patient), supported with diaries and QoL questionnaires. We present here the QoL measurements for this group of 177 patients. Prior preventive migraine treatments included conventional oral prophylactic medications (such as topiramate, candesartan, propranolol, or amitriptyline), at least two cycles of PREEMPT protocol onabotulinumtoxin A or (in a small number of cases) neuromodulation with single pulse Transcranial Magnetic Stimulation. Results: Of the 177 patients who started treatment with erenumab, 68/177 (38.4%) stopped during the first year, either due to lack of efficacy (no significant benefit or only minimal improvement) and/or possible side effects. 109/177 (61.6%) patients reported clinically significant improvement after 6–12 months and wished to stay on treatment. Twelve of these 109 patients subsequently stopped treatment in the period between 1 year and up to June 2021 (mainly due to a worsening of their migraine). Therefore, a total of 97/177 patients (54.8%) remained on treatment as of June 2021 (duration of treatment 17–30 months, median of 25 months). Conclusion: Approximately 55% of treatment resistant or difficult to treat CM patients who trialled erenumab in our clinics reported a subjective benefit and were still on treatment after 17–30 months. [ABSTRACT FROM AUTHOR]

The Upper AeroDigestive Tract (UADT) cancers are most common, invasive and have high morbidity. The two leading risk factors, smoking and alcohol, are well known but there is a long list of other risk factors which are not that well talked about. The aim of this study was to ascertain the dietary factors which could be important in their prevention.The PubMed and Google Scholar databases were searched for relevant studies from January 2001 to November 2021. Refined grains were found directly related to the risk of UADT cancer while the whole grain cereals were found protective. Significant inverse associations were observed for the highest compared to the lowest tertile of whole grains and yellow/orange vegetables. Stricter adherence to the Mediterranean diet was seen associated with a substantial and significant decrease in UADT cancer risk. A significant inverse association was also found between yoghurt intake and UADT cancer risk. Consumption of three or more cups of coffee per day was found to have a significant inverse association with UADT cancer. Carcinogenicity of cannabis consumption was observed for regular cannabis smokers (> 1 per day for years). The current study concludes that the protective dietary factors have substantial activity in the prevention of UADT cancer. Nevertheless, basic research is required in investigating the role of these dietary factors and valid biomarkers will be important for chemoprevention studies. The basic research on risk factors on the basis of current knowledge would ultimately lead to the better prevention of UADT cancer. [ABSTRACT FROM AUTHOR]

DNA damage is one of the primary mechanisms underlying cancer and other chronic degenerative diseases. Early evaluation of this damage in the affected cells and tissues is crucial for understanding pathogenesis and implementing effective prevention strategies. However, isolating target cells from affected organs, such as the lungs, can be challenging. Therefore, an alternative approach is to evaluate genotoxic damage in surrogate cells. Pulmonary alveolar macrophages are ideally suited for this purpose because they are in close contact with the target cells of the bronchial and alveolar epithelium, share the exact mechanisms and levels of exposure, and are easily recoverable in large numbers. This review comprehensively lists all studies using alveolar macrophages as surrogate cells to show genotoxic lung damage in humans or laboratory animals. These investigations provide fundamental information on the mechanisms of DNA damage in the lung and allow for better assessment and management of risk following exposure to inhalable genotoxic agents. Furthermore, they may be a valuable tool in cancer chemoprevention, helping the right choice of agents for clinical trials. [ABSTRACT FROM AUTHOR]

Background and Aims: Recent studies have suggested that right- and left-sided colorectal cancers (CRCs) are molecularly distinct. In this study, we examined the association between the risk of right- and left-sided CRC and drug use to estimate their chemopreventive effects Methods: This multicenter retrospective cohort study was conducted using the data of hospitalized patients between 2014 and 2019 from nine hospital databases. The primary outcomes were right- and left-sided CRC. We evaluated the association of CRCs with drug use and clinical factors. Odds ratios adjusted for age, sex, Charlson Comorbidity Index scores, and smoking status were calculated. We also compared the transcriptional profiling in precancerous lesions, including sessile serrated lesions (SSLs) Results: A total of 307,938 patients, including 2745 with right-sided CRC and 4819 with left-sided CRC, were analyzed. The use of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, cyclooxygenase-2 inhibitors, and steroids was associated with a lower risk of both right- and left-sided CRCs. In contrast, statins, other lipid-lowering agents, and metformin were associated with a lower risk of left-sided CRC. Transcriptomic analysis showed that SSL, which predominantly develops in the right colon, was associated with a lower expression of lipid metabolism-related genes. Conclusions: Targeting lipid metabolism may be useful for chemoprevention of left-sided CRCs, while development of right-sided CRCs may be independent of this pathway. [ABSTRACT FROM AUTHOR]

Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004 and 2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow-up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs 6.5% (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p = 0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts. [ABSTRACT FROM AUTHOR]

Vaccine development for Plasmodium vivax, an important human relapsing malaria, is lagging behind. In the case of the most deadly human malaria P. falciparum, unprecedented high levels of protection have been obtained by immunization with live sporozoites under accompanying chemoprophylaxis, which prevents the onset of blood-stage malaria. Such an approach has not been fully evaluated for relapsing malaria. Here, in the P. cynomolgi-rhesus macaque model for relapsing malaria, we employ the parasites' natural relapsing phenotype to self-boost the immune response against liver-stage parasites, following a single-shot high-dose live sporozoite vaccination. This approach resulted in sterile protection against homologous sporozoite challenge in three out of four animals in the group that was also exposed for several days to blood stages during primary infection and relapses. One out of four animals in the group that received continuous chemoprophylaxis to abort blood-stage exposure was also protected from sporozoite challenge. Although obtained in a small number of animals as part of a Proof-of-Concept study, these results suggest that limited blood-stage parasite exposure may augment protection in this model. We anticipate our data are a starting point for further research into correlates of protection and extrapolation of the single-shot approach to develop efficacious malaria vaccines against relapsing human malaria. [ABSTRACT FROM AUTHOR]

Purpose: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). Methods: This nested case–control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008–2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0–30,000, (3)30,001–136,000, (4)136,001–293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1–500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. Results: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55–0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42–0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46–0.82,p < 0.01) compared to the 0 mg/day group. Conclusions: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect. [ABSTRACT FROM AUTHOR]

Prospective short-term studies on effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) point towards a decrease in the number and size of polyps. Effectiveness and safety in the prevention of progression in familial polyposis with NSAIDs in long-term use, which is the prerequisite for therapeutic evaluation in prospective studies, is unknown. The total absolute observation period of 54 patients under sulindac was 399 patient years with a mean of 7.4 (2–19) years per patient. 36 patients (66.7%) showed a fast decrease of polyp burden, 8 (14.8%) were slow responders, and 9 (16.7%) had stable disease; one patient had a slow progression. Upper gastrointestinal (GI) polyp burden remained stable in 47% patients, increased in 31%, and improved in 22%. Advanced adenomas were found in 8 patients only within the first 5 years of chemoprevention, no patient developed desmoid disease, anamnestically evaluated on every follow-up. There were no life-threatening side-effects. Dosage and delivery pattern were essential for effectiveness. This study provides evidence that chemoprevention with sulindac is effective and safe and can, either alone or in combination with other drugs, become a long-term management option in cases of adenomatous polyposis. These results justify further long-term prospective chemoprevention studies to elaborate treatment protocols and guidelines. [ABSTRACT FROM AUTHOR]