Berberine encapsulated phenylboronic acid-conjugated pullulan nanoparticles: Synthesis, characterization and anticancer activity validated in A431 skin cancer cells and 3D spheroids.

Polysaccharide-based drug delivery systems are in high demand due to their biocompatibility, non-toxicity, and low-cost. In this study, sialic acid receptor targeted 4-carboxy phenylboronic acid modified pullulan-stearic acid conjugate (4-cPBA-PUL-SA) was synthesized and characterized for the delivery of Berberine (BBR). BBR-loaded 4-cPBA-PUL-SA nanoparticles (BPPNPs) were monodispersed (PDI: 0.238 ±â€¯0.07), with an average hydrodynamic particle size of 180.6 nm and 73.6 % encapsulation efficiency. BPPNPs showed controlled BBR release and excellent colloidal stability, indicating their potential for drug delivery application. The cytotoxicity results indicated that BPPNPs exhibited dose and time-dependent cytotoxicity against human epidermoid carcinoma cells (A431) as well as 3D spheroids. Targeted BPPNPs demonstrated significantly higher anticancer activity compared to BBR and non-targeted BPNPs. The IC50 values for BPPNPs (2.29 µg/ml) were significantly lower than BPNPs (4.13 µg/ml) and BBR (19.61 µg/ml), indicating its potential for skin cancer treatment. Furthermore, CSLM images of A431 cells and 3D spheroids demonstrated that BPPNPs have higher cellular uptake and induced apoptosis compared to free BBR and BPNPs. In conclusion, BPPNPs demonstrate promising potential as an effective drug delivery system for skin cancer therapy.

Evodiamine and its nano-based approaches for enhanced cancer therapy: recent advances and challenges.

Evodiamine is a bioactive alkaloid extracted from the Evodia rutaecarpa plant. It has various pharmacological effects including anti-cancer, anti-bacterial, anti-obesity, anti-neurodegenerative, anti-depressant, and cardiac protective properties. Evodiamine demonstrates potent anti-cancer activity by inhibiting the proliferation of cancer cells in vitro and in vivo. Despite the health-promoting properties of evodiamine, its clinical use is hindered by low water solubility, poor bioavailability, and toxicity. Thus, there is a need to develop alternative drug delivery systems for evodiamine to enhance its solubility, permeability, and stability, as well as to facilitate targeted, prolonged, and controlled drug release. Nanocarriers can increase the therapeutic potential of evodiamine in cancer therapy while reducing adverse side effects. To date, numerous attempts have been made through the development of smart nanocarriers to overcome the drawbacks of evodiamine. This review focuses on the pharmacological applications, anti-cancer mechanisms, and limitations of evodiamine. Various nanocarriers, including lipid-based nanoparticles, polymeric nanoparticles, cyclodextrins, and so forth, have been discussed extensively for evodiamine delivery. Nano-drug delivery systems could increase the solubility, bioavailability, stability, and therapeutic efficacy of evodiamine. This review aims to present a comprehensive and critical evaluation of several nano-formulations of evodiamine for cancer therapy. © 2024 Society of Chemical Industry.

Alzheimer's disease-related biomarkers and cancer-related cognitive decline: the thinking and living with cancer study.

PURPOSE: We evaluated whether plasma Alzheimer's Disease (AD)-related biomarkers were associated with cancer-related cognitive decline (CRCD) among older breast cancer survivors. METHODS: We included survivors 60-90 years with primary stage 0-III breast cancers (n = 236) and frequency-matched non-cancer controls (n = 154) who passed a cognitive screen and had banked plasma specimens. Participants were assessed at baseline (pre-systemic therapy) and annually for up to 60-months. Cognition was measured using tests of attention, processing speed and executive function (APE) and learning and memory (LM); perceived cognition was measured by the FACT-Cog PCI. Baseline plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), beta-amyloid 42/40 (Aß42/40) and phosphorylated tau (p-tau181) were assayed using single molecule arrays. Mixed models tested associations between cognition and baseline AD-biomarkers, time, group (survivor vs control) and their two- and three-way interactions, controlling for age, race, WRAT4 Word Reading score, comorbidity and BMI; two-sided 0.05 p-values were considered statistically significant. RESULTS: There were no group differences in baseline AD-related biomarkers except survivors had higher baseline NfL levels than controls (p = .013). Survivors had lower adjusted longitudinal APE than controls starting from baseline and continuing over time (p = <0.002). However, baseline AD-related biomarker levels were not independently associated with adjusted cognition over time, except controls had lower APE scores with higher GFAP levels (p = .008). CONCLUSION: The results do not support a relationship between baseline AD-related biomarkers and CRCD. Further investigation is warranted to confirm the findings, test effects of longitudinal changes in AD-related biomarkers and examine other mechanisms and factors affecting cognition pre-systemic therapy.

Cognitive effects of long-term androgen deprivation therapy in older men with prostate cancer.

OBJECTIVE: Androgen deprivation therapy (ADT) is a common treatment for prostate cancer (PCa), with increasing numbers of men on ADT for longer. Limited evidence suggests ADT impacts cognition. This study addressed gaps in the literature by focusing on older men with PCa and assessing ADT usage longer than 1 year. METHODS: This study of 133 men ≥65 years of age with PCa included two groups: (1) men on ADT for 1-3 years (ADT-exposed), and (2) a comparison group of men with PCa not on ADT (ADT-unexposed). Group comparisons on individual neuropsychological test scores are reported, as well as effect sizes (Cohen's d). RESULTS: Half (n = 67) of the sample was ADT-exposed and half (n = 66) were unexposed. The average age was 72 years, most were White, and over 50% had at least secondary education. There were no statistically significant differences between groups by age, race, or education. Unadjusted analyses showed the ADT-exposed group, compared with the ADT-unexposed group, performed significantly lower in domains of verbal learning (d = 0.45-0.52, p = 0.01 to <0.01), verbal recall (d = 0.33-0.54, p = 0.06 to <0.01), and possible effects in visuospatial construction (d = 0.33, p = 0.08 to 0.06). When controlling for age and education, similar patterns emerged. The ADT exposed-group performed significantly lower in domains of verbal learning (d = 0.45-0.52, p = 0.06 to 0.03) and verbal recall (d = 0.33-0.54, p = 0.11 to 0.03), and possible effects in visuospatial construction d = 0.33, p = 0.18 to 0.13. CONCLUSIONS: This study suggests long-term ADT exposure impacts verbal learning, verbal recall, and possibly visuospatial abilities in older men (≥65) with PCa. The potential cognitive effects of ADT should be discussed with older patients considering long-term use of ADT.

Effect of chemotherapy on hippocampal volume and shape in older long-term breast cancer survivors.

Purpose: The objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5-15 years prior. Methods: This study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C-), and healthy controls (HC). The participants were recruited 5-15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests. Results: At TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = -0.585, p = 0.007). Conclusion: The observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment.

Prediction of cognitive decline in older breast cancer survivors: the Thinking and Living with Cancer study.

PURPOSE: Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment. METHODS: We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function. RESULTS: Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score. CONCLUSIONS: Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings.

Folate conjugated albumin as a targeted nanocarrier for the delivery of fisetin: in silico and in vitro biological studies.

Fisetin (FST), a natural flavonoid compound derived from various fruits and vegetables, including apple, strawberry, and onion, demonstrates potential for a wide range of pharmaceutical applications, including potential anticancer properties. However, challenges such as low bioavailability, poor aqueous solubility, and limited permeability restrict the use of FST in the pharmaceutical sector. Nowadays, targeted nanomedicines have garnered attention to overcome limitations associated with phytochemicals, including FST. In the present study, we have designed and successfully prepared folate-targeted FST nanoparticles (FFNPs). Characterization through DLS and FE-SEM revealed the successful preparation of monodisperse (PDI: 0.117), nanoscale-sized (150 nm), and spherical nanoparticles. Physicochemical characterization including FTIR, XRD, DSC, and TGA analysis, confirmed the encapsulation of the FST within the Folic acid (FA) - conjugated nanoparticles (CNPs) and revealed its amorphous nature. Molecular docking analysis revealed the strong binding affinity and specific amino acid interactions involved in the BSA-FST-FA complex, suggesting the potential synergistic effect of FST and FA in enhancing the therapeutic activity of the FFANPs. Cytotoxic assessments by the MTT assay, migration assay, AO-EtBr staining assay, colony formation assay, and cellular uptake study demonstrated enhanced anticancer efficacy, apoptosis induction, and enhanced uptake of FFNPs compared to pure FST. These findings propose prepared FFNPs as a promising targeted drug delivery nanocarrier for effective FST delivery in cancer therapy.

Synthesis, characterization, and application of honey stabilized inulin nanoparticles as colon targeting drug delivery carrier.

Inulin (INU) is a versatile natural polysaccharide primarily derived from chicory roots. INU possesses the unique quality of evading digestion or fermentation in the early stages of the human digestive tract, instead reaching the lower colon directly. Exploiting on this distinctive attribute, INU finds application in the creation of targeted carrier systems for delivering drugs tailored to colon-related diseases. This study presents a novel method for synthesizing highly stable and non-aggregatory inulin nanoparticles (INU NPs) by ionotropic gelation method, using calcium chloride as crosslinker and natural honey as a stabilizing agent. Different formulation and process parameters were optimized for the synthesis of monodispersed INU NPs. These INU NPs efficiently encapsulated a hydrophilic drug irinotecan hydrochloride trihydrate (IHT) and drug loaded formulation (IINPs) demonstrated excellent colloidal and storage stabilities. Notably, these IINPs exhibited pH-dependent drug release, suggesting potential for colon-specific drug delivery. Anticancer activity of the NPs was found significantly higher in comparison to IHT through cytotoxicity and apoptosis studies against human colorectal carcinoma cells. Overall, this study revealed that the INU NPs synthesized by ionotropic gelation will be an efficient nanocarrier system for colon-targeted drug delivery due to their exceptional biocompatibility and stability in stomach and upper intestinal conditions.

Untargeted metabolomics-based identification of bioactive compounds from Mangifera indica L. seed extracts in drug discovery through molecular docking and assessment of their anticancer potential.

BACKGROUND: Mangifera indica L. (mango), a medicinal plant rich in biologically active compounds, has potential to be used in disease-preventing and health-promoting products. The present investigation reveals and uncovers bioactive metabolites with remarkable therapeutic efficiency from mango (family: Anacardiaceae) seeds. RESULTS: Biological activity was determined by antimicrobial, antioxidant and anticancer assays, and metabolite profiling was performed on gas chromatography coupled to quadrupole time-of-flight mass spectrometry (GC-QTOF-MS) and liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) platforms. Validation of active metabolites was carried out by in silico molecular docking (Molinspiration Cheminformatics Server and PASS). Extracted and identified metabolites were screened; 54 compounds associated with various groups were selected for the in silico interaction study. CONCLUSIONS: Molecular docking revealed lead molecules with a potential binding energy score, efficacy and stable modulation with a selected protein domain. Investigation, directed by in vitro and in silico analysis, confirms mango seeds as an excellent source of potential metabolites as a therapeutic agent. © 2024 Society of Chemical Industry.

Enhancing apoptosis-mediated anticancer activity of evodiamine through protein-based nanoparticles in breast cancer cells.

In the cutting-edge era of developing precision therapeutics, nanoparticles have emerged as a potent drug delivery system. Altering the size of poorly water-soluble drugs to nanoscale could confer change in their physical properties, including enhanced water solubility and bioavailability. Evodiamine (EVO), a natural indolequinone alkaloid extract from Evodia rutaecarpa, has shown several important pharmacological applications, anti-cancer being one of them. Protein-based nano-drug delivery systems have gained the interest of researchers due to their better biocompatibility, biodegradability, non-immunogenicity and non-toxicity. In the present study, EVO encapsulated BSA nanoparticles (ENPs) were synthesized and characterized, which were nanoscale-sized (~ 150 nm), monodispersed, spherical shaped, and showed high entrapment efficiency (~ 86%) and controlled drug release. The in-vitro anti-cancer activity of ENPs on human breast cancer cells was dose- and time-dependent. The apoptotic molecular mechanism investigated using FACS, qRT-PCR, and western blotting analysis, revealed increased expression of p53 and Bax and decreased expression of Bcl-2. Biological studies demonstrated comparatively more efficient and targeted delivery of ENPs than pure EVO. The comprehensive physiochemical characterization and in-vitro validation collectively pinpoint ENPs as a promising avenue for harnessing the therapeutic potential of the natural anti-cancer compound EVO. The findings indicate improved cytotoxicity, positioning ENPs as a propitious strategy for advancing breast cancer treatment.

Development of thiolated xanthan gum-stearylamine conjugate based mucoadhesive system for the delivery of biochanin-A to melanoma cells.

Recently, instead of creating new active compounds, scientists have been working to increase the bioavailability and residence time of existing drugs by modifying the characteristics of the delivery systems. In the present study, a novel mucoadhesive bioconjugate (SN-XG-SH) was synthesized by functionalizing a polysaccharide xanthan gum (XG) with cysteamine hydrochloride (CYS) and a lipid stearylamine (SN). FTIR, CHNS and 1H NMR studies confirmed the successful synthesis of SN-XG-SH. Mucoadhesion of the thiolated XG was enhanced and evaluated by different methods. Disulfide bond formation between thiolated XG and skin mucus enhances mucoadhesive behavior. The mucoadhesive bioconjugate was used to prepare nanoparticles for the delivery of hydrophobic biochanin-A (Bio-A) for the treatment of melanoma. The thiolated xanthan gum nanoparticles also demonstrated high drug entrapment efficiency, sustained drug release, and high storage stability. The drug loaded nanoparticles (Bio-A@TXNPs) significantly improved the cytotoxicity of Bio-A against human epidermoid cancer cells (A431 cells) by inducing apoptosis and changing mitochondrial membrane potential. In conclusion, thiolation of XG improves its mucoadhesive properties and prolongs the release of Bio-A. Thus, thiolated XG conjugate has a high potential for use as a bioadhesive agent in controlled and localised delivery of drugs in different skin diseases including melanoma.

Brain white matter microstructural changes in chemotherapy-treated older long-term breast cancer survivors.

PURPOSE: To assess white matter microstructural changes in older long-term breast cancer survivors 5-15 years post-chemotherapy treatment. METHODS: Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C-) and age- and sex-matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract-based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter. RESULTS: There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p < 0.05 family-wise error (FWE) correction. However, there were no significant group differences between the groups at TP1. Additionally, at TP1, a positive correlation (R = 0.58, p = 0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group. CONCLUSIONS: Brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who had chemotherapy treatment years ago.

Depressive symptom trajectories in older breast cancer survivors: the Thinking and Living with Cancer Study.

PURPOSE: To identify trajectories of depressive symptoms in older breast cancer survivors and demographic, psychosocial, physical health, and cancer-related predictors of these trajectories. METHODS: Recently diagnosed nonmetastatic breast cancer survivors (n = 272), ages 60-98 years, were evaluated for depressive symptoms (Center for Epidemiological Studies Depression Scale, CES-D; scores ≥16 suggestive of clinically significant depressive symptoms). CES-D scores were analyzed in growth-mixture models to determine depression trajectories from baseline (post-surgery, pre-systemic therapy) through 3-year annual follow-up. Multivariable, multinomial logistic regression was used to identify baseline predictors of depression trajectories. RESULTS: Survivors had three distinct trajectories: stable (84.6%), emerging depressive symptoms (10.3%), and recovery from high depressive symptoms at baseline that improved slowly over time (5.1%). Compared to stable survivors, those in the emerging (OR = 1.16; 95% CI = 1.08-1.23) or recovery (OR = 1.26; 95% CI = 1.15-1.38) groups reported greater baseline anxiety. Greater baseline deficit accumulation (frailty composite measure) was associated with emerging depressive symptoms (OR = 3.71; 95% CI = 1.90-7.26). Less social support at baseline (OR = 0.38; 95% CI = 0.15-0.99), but greater improvement in emotional (F = 4.13; p = 0.0006) and tangible (F = 2.86; p = 0.01) social support over time, was associated with recovery from depressive symptoms. CONCLUSIONS: Fifteen percent of older breast cancer survivors experienced emerging or recovery depressive symptom trajectories. Baseline anxiety, deficit accumulation, and lower social support were associated with worse outcomes. IMPLICATIONS FOR CANCER SURVIVORS: Our results emphasize the importance of depression screening throughout the course of cancer care to facilitate early intervention. Factors associated with depressive symptoms, including lower levels of social support proximal to diagnosis, could serve as intervention levers.

Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.

Epigenetic aging in older breast cancer survivors and noncancer controls: preliminary findings from the Thinking and Living with Cancer Study.

BACKGROUND: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. METHODS: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. RESULTS: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. CONCLUSION: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.

Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls.

Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10-8), and rs78786199 (chromosome 2, p = 1.925 × 10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.

Cognitive Aging in Older Breast Cancer Survivors.

BACKGROUND: Cancer and cancer treatments may affect aging processes, altering the trajectory of cognitive aging, but the extant studies are limited in their intervals of assessment (two-five years). We studied the cognitive performance of a cohort of survivors and controls aged from 60 to 89 years utilizing cross-sectional cognitive performance data as an indicator of potential aging trajectories and contrasted these trends with longitudinal data collected over two years. METHODS: Female breast cancer survivors who had been diagnosed and treated at age 60 or older and were 5- to 15-year survivors (N = 328) and non-cancer controls (N = 158) were assessed at enrollment and at 8, 16, and 24 months with standard neuropsychological tests and comprehensive geriatric assessment. RESULTS: A cross-sectional baseline analysis found the expected inverse association of age with cognition in both groups, with survivors performing lower overall than controls in learning and memory (LM). Younger survivors, i.e., those under 75 years of age, exhibited lower performance in both LM and attention, and processing speed and executive function (APE), compared to controls, with no differences being observed between older survivors and controls, which tracked with deficit accumulation trends. CONCLUSION: Cognitive differences between the survivors and controls for the LM and APE domains were prominent in younger survivors, as was deficit accumulation, suggesting a mediating effect on cognition. Deficit accumulation may represent a modifiable risk factor in cancer survivorship that may be targeted for prevention and intervention.

Folate Functionalized and Evodiamine-Loaded Pluronic Nanomicelles for Augmented Cervical Cancer Cell Killing.

Evodiamine (Evo) is a natural, biologically active plant alkaloid with wide range of pharmacological activities. In the present study Evo-loaded folate-conjugated Pluronic F108 nano-micelles (ENM) is synthesized to enhance the therapeutic efficacy of Evo against cervical cancer. ENM are synthesized, physicochemically characterized and in vitro anticancer activity is performed. The study demonstrates that ENM have nanoscale size (50.33 ± 3.09 nm), monodispersity of 0.122 ± 0.072, with high drug encapsulation efficiency (71.30 ± 3.76%) and controlled drug release at the tumor microenvironment. ENM showed dose-dependent and time-dependent cytotoxicity against HeLa human cervical cancer cells. The results of in vitro anticancer studies demonstrated that ENM have significant anticancer effects and greatly induce apoptosis as compared to pure Evo. The cellular uptake study suggests that increased anticancer activity of ENM is due to the improved intracellular delivery of Evo through overexpressed folate receptors. Overall, the designed ENM can be a potential targeted delivery system for hydrophobic anticancer bioactive compound like Evo.

Altered gyrification in chemotherapy-treated older long-term breast cancer survivors.

Purpose: The purpose of this prospective longitudinal study was to evaluate the changes in brain surface gyrification in older long-term breast cancer survivors 5 to 15 years after chemotherapy treatment. Methods: Older breast cancer survivors aged ≥ 65 years treated with chemotherapy (C+) or without chemotherapy (C-) 5-15 years prior and age & sex-matched healthy controls (HC) were recruited (time point 1 (TP1)) and followed up for 2 years (time point 2 (TP2)). Study assessments for both time points included neuropsychological (NP) testing with the NIH Toolbox cognition battery and cortical gyrification analysis based on brain MRI. Results: The study cohort with data for both TP1 and TP2 consisted of the following: 10 participants for the C+ group, 12 participants for the C- group, and 13 participants for the HC group. The C+ group had increased gyrification in 6 local gyrus regions including the right fusiform, paracentral, precuneus, superior, middle temporal gyri and left pars opercularis gyrus, and it had decreased gyrification in 2 local gyrus regions from TP1 to TP2 (p < 0.05, Bonferroni corrected). The C- and HC groups showed decreased gyrification only (p < 0.05, Bonferroni corrected). In C+ group, changes in right paracentral gyrification and crystalized composite scores were negatively correlated (R = -0.76, p = 0.01). Conclusions: Altered gyrification could be the neural correlate of cognitive changes in older chemotherapy-treated long-term breast cancer survivors.