bluuebunny/crossref_metadata_2025_split huggingface dataset:
High dietary acid load is associated with risk of breast cancer: findings from the Sister Study
Authors: Park Yong‐Moon , Steck Susan , Fung Teresa , Merchant Anwar , Sandler Dale 
Published: November 2023

BackgroundRecently, diet‐induced acid–base imbalance was shown to be associated with metabolic disorders such as insulin resistance and type 2 diabetes. It also has been suggested that diet‐induced acidosis might promote carcinogenesis or tumor progression through influencing molecular activity such as insulin growth factor. However, there is little or no epidemiologic evidence to support a role of diet induced acidosis in cancer risk.MethodsWe used data from 49,731 Sister Study participants who completed a validated 146‐item food frequency questionnaire at enrollment in 2003–2009. Women aged 35 to 74 years in the U.S. and Puerto Rico were eligible if they had a sister who had been diagnosed with breast cancer. The potential renal acid load (PRAL) considering body surface area was used to estimate diet‐induced acid load, based on daily intake of protein, phosphorus, potassium, calcium, and magnesium calculated from the food frequency questionnaire. Cox proportional hazards models were used to estimate multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer risk by PRAL quartiles, after adjusting for potential confounders including known risk factors for breast cancer.ResultsWe identified 2,155 breast cancers at least 1 year after enrollment during follow‐up (mean, 7.6 years). The highest PRAL quartile, reflecting greater acid‐forming potential, was associated with increased risk of overall and invasive breast cancer, compared with the first quartile (HR: 1.21 [95% CI, 1.06–1.39], Ptrend = 0.21; 1.18 [95% CI, 1.00–1.38], respectively). When stratified by time‐varying menopausal status, this association persisted only in postmenopausal breast cancer (HRhighest vs. lowest quartile: 1.29 [95% CI, 1.11–1.50], Ptrend = 0.02; 1.22 [95% CI, 1.03–1.45], respectively). The association tended to be more pronounced in estrogen receptor (ER) negative, progesterone receptor (PR) negative invasive breast cancer (HRhighest vs. lowest quartile: 1.68 [95% CI, 1.06–2.67], Ptrend = 0.08), compared with ER+PR+ invasive breast cancer (HRhighest vs. lowest quartile: 1.14 [95% CI, 0.93–1.40], Ptrend = 0.91), although there was no statistically significant interaction effect. These associations tended to be weaker, but consistent, using the net endogenous acid production (NEAP) score, an alternative index of diet‐induced acid load based on protein and potassium intake. No differential association was observed for normal or overweight/obese body mass index.ConclusionOur findings suggest that diet‐induced acidosis may be a risk factor for breast cancer, especially in postmenopausal breast cancer. Our results need to be confirmed in other populations and further research is warranted to understand the underlying mechanisms.Support or Funding InformationThis research was supported by the Intramural Research Program of the NIH, the National Institute of Environmental Health Sciences (Z01‐ES044005).
Predictors of Carotenoid Concentrations in Human Serum: Role of the Intestinal Microbiome
Authors: Djuric Zora , Bassis Christine , Ren Jianwei , Chan Rena , Kato Ikuko , Ruffin Mack T. , Sen Ananda , Turgeon D. Kim 
Published: November 2023

Carotenoids from fruits and vegetables are suggested to reduce the risks of several cancers. Inter‐individual variability in serum carotenoid concentrations is large, and is only modestly explained by dietary intakes. There is evidence that the colonic microbiota can maximize the bio‐accessibility of carotenoids by digestion of plant cell walls. Here we evaluated if differences in the relative abundance of bacterial taxa in the colon could contribute to the inter‐individual variability in serum concentrations of carotenoids. We utilized data and samples from a dietary intervention study that enrolled healthy individuals at increased risk of colon cancer. Colon mucosal biopsies were obtained without prior preparation of the bowels, and 93% of the biopsies were successfully amplified for the V4 region of the 16s rRNA gene. The relative abundance of bacterial phyla in the colonic mucosa of 89 individuals was: 6.7% Proteobacteria, 60% Firmicutes, 27% Bacteroidetes, 1.9% Actinobacteria and 2.8%Verrucomicrobia. At baseline, higher serum concentrations and higher dietary intakes of carotenoids were both associated with a lower abundance of Firmicutes taxa, unlike the direct association of higher body mass index (BMI) with increased abundance of Firmicutes. Higher serum carotenoids also were positively associated with measures of bacterial diversity in contrast to the negative association of diversity with BMI. Surprisingly, there was little change in bacterial taxa post‐intervention with either a Mediterranean diet or a Healthy Eating diet. Subsequent analyses evaluated the contributions of the microbiome, diet and demographic factors to the inter‐individual variation in serum carotenoid concentrations at baseline. Correlations of individual serum carotenoids with bacterial Operational Taxonomic Units indicated that oxygenated carotenoids, namely xanthophylls, segregated from other carotenoids. In linear regression models with serum xanthophyll concentrations as the outcome, bacterial taxa accounted for an additional 11% of the variance after controlling for BMI, smoking, and dietary xanthophyll intakes, and all these factors together accounted for 35% of the inter‐individual variability in serum xanthophylls. For serum beta‐carotene, bacterial taxa contributed an additional 4% of the variance after controlling for BMI, smoking, and dietary intakes. Regression models for alpha‐carotene and lycopene were not improved by including bacterial abundance. These results are consistent with a significant role for colonic microbiota in accessibility of specific carotenoids from fruits and vegetables in humans, and especially for xanthophylls which are high in fruits and green, leafy vegetables.Support or Funding InformationWe acknowledge support from NIH grants RO1 CA120381, T32 CA009676, P30 CA046592, P60 DK20572, P30 DK089503, UL1RR024986, and the Rose and Lawrence C. Page, Sr. Family Charitable Foundation.
Effect of Mixed‐Carotenoid Supplementation and Physical Activity on Irisin and Adiponectin: A 6‐Month Double Blind Placebo‐Controlled Pilot Study in Children with Obesity
Authors: Canas Jose A. , Lochrie Amanda , McGowan Amy Galena , Schettino Christopher , Hossain Jobayer , Balagopal Babu 
Published: November 2023

BodyShort term supplementation with mixed‐carotenoids (MCA) and physical activity reduces the accrual of abdominal subcutaneous white adipose tissue (scWAT) in children with obesity. Presumptive mechanisms may involve the induction of thermogenic beigeing and myo‐adipocytokines such as irisin, high‐molecular weight adiponectin (HMW‐ADI) and leptin.Method and DesignOf the 20 obese children recruited (Age = 126 ± 5 months), 17 completed a randomized double blind placebo controlled study involving one hour of physical activity for 10‐days of intense life‐style intervention followed by 6 months of usual lifestyle. Patients were randomized to MCA (Jarrow Formulas CaroteneAll®)5000 IU of beta‐carotene (BC) and alpha carotene; 20 mg of lutein; 4 mg of zeaxanthin, 20 mg of lycopene; 1000 mcg of astaxanthin; and 20 mg of gamma tocopherol vs. placebo at entry and were sampled at baseline, three weeks and 6 months. BC measured by HPLC, leptin measured by RIA and HMW‐adiponectin and irisin were measured by ELISA. The percent change in visceral (vWAT) and scWAT was determined by quantitative cross‐sectional multi‐slice MRI (1.5‐T; GE Medical Systems) at baseline and 6 months.ResultsBC was inversely related to BMI Z‐score, vWAT and scWAT (p<0.05 for all). Supplementation resulted in 95 ± 66% increase in BC at 6 months as compared to 3 ± 19% decrease in the placebo group (p=0.001). Pair‐wise comparisons for treatment effects based on estimated marginal mean ± SEM showed there was a 4.1±1.7 ng/mL (p=0.033) increase in irisin at three weeks and a 4.8±1.8 ng/ml (p=0.018) increase in HMW‐adiponectin at six month between supplement and placebo groups after Bonferroni adjustments for age, gender and baseline BMI z‐score. There was a 4% decrease in mean scWAT by MRI in the supplement group (p=0.016) after six months.ConclusionMCA significantly increased irisin after 10 days of physical activity and HMW‐adiponectin after 6 months of supplementation as compared to placebo. These changes may contribute to the decrease in scWAT accrual at 6 months mediated by the induction of thermogenic beigeing signals. Further studies are warranted.Support or Funding InformationThe Players Center for Child Health at Wolfson Children's Hospital
Salmonella typhimurium‐derived Virulence Protein Overcomes Multidrug Resistance in Tumors
Authors: Mercado‐Lubo Regino , Hang Gang , McCormick Beth A. 
Published: November 2023

We have recently developed a novel therapeutic platform for the treatment of cancers that over‐express the multidrug resistance transporter P‐glycoprotein (P‐gp), a major impediment for the success of conventional chemotherapy. This technology is based on our discovery that a Salmonella typhimurium‐derived virulence protein, SipA, not only functionally down‐regulates P‐gp, but also potentiates the cytotoxic effect of chemotherapeutics such as doxorubicin and vinblastine in vitro by significantly increasing the intracellular accumulation of the drugs. To safely deliver SipA in our in vivo models of cancer, we engineered a carboxyl modified 15nm gold nanoparticle (AUNP) packed with a SipA corona to create a SipA‐AuNP biomimetic. We found that SipA‐AuNPs, when used in combination with doxorubicin, promote tumor regression in a subcutaneous model of murine colon cancer, as well as a patient‐derived xenograft mouse model of breast cancer. We are currently working to identify the specific SipA domain responsible for the down‐regulation of P‐gp. Thus far, SipA has been truncated into two fragments: a SipAb C‐terminal fragment426–684 (259 AA), which binds actin, and a SipAa fragment2–425 (424 AA), known for its ability to induce pro‐inflammatory responses. When used in in vitro models of colon cancer, the SipAa fragment exhibits a conserved ability to down‐regulate P‐pg (70% reduction compared to the negative control), whereas the SipAb fragment fails to reduce P‐gp. Concomitantly, we are evaluating the ability of SipA to increase the efficacy of other known P‐gp substrates, such as etoposide, daunorubicin and paclitaxel, since this effect is specific to drugs efluxed by P‐gp. Using a cell proliferation assay, in which human colon carcinoma cells are cultured in media containing etoposide with or without purified‐SipA, we have found that those with SipA exhibit a profound reduction in the IC50 (50.20±0.30 to 8.05±1.15 μM). Given that we observe improved cytotoxicity of drugs effluxed by P‐gp, we are now implementing novel patient‐derived xenograft mouse models of cancers that use P‐gp substrates (i.e. doxorubicin and etoposide) as the first line of treatment, such as of B‐cell lymphomas and ovarian cancer. We believe that SipA could present a significant advancement as an adjuvant therapy when compared to previous P‐gp reversal agents. Furthermore, SipA can potentially facilitate repurposing old cancer drugs and help reduce the amount the chemotherapeutics needed for effective treatment, thereby reducing the side effects associated with chemotherapy.Support or Funding InformationNational Institutes of Health Grants DK56754 and DK33506 awarded to Beth A. McCormickThe Worcester Foundation, and by a UMCCTS Pilot Project Program award (CTSA Grant # UL1TR000161) awarded to Beth A. McCormick Massachusetts Medical School start‐up fund and National Institutes of Health grant R01MH103133
Role of PMNs in inhibition of DNA repair and induction of genomic instability
Authors: Butin‐Israeli Veronika , Mehl Lindsey , Mascarenhas Lorraine Lorraine , Sumagin Ronen 
Published: November 2023

PMNs play key roles in host defense and tissue homeostasis, however, en‐masse tissue infiltration by PMNs often leads to aberrant inflammation and tissue injury, and is a hallmark of inflammatory bowel diseases (IBD). High numbers of mucosa infiltrating PMNs have been correlated with the severity of IBD, whereas IBD patients were found to be at significantly higher risk of developing colorectal cancer (CRC). While the link between inflammation and cancer is well established, little is known about PMN contribution to carcinogenesis. The accumulation of DNA damage is one of the leading causes of carcinogenesis. Activated PMNs can induce DNA damage via generation of reactive oxygen species (ROS). However, in the current work we describe a novel mechanism whereby the release of membrane‐derived microparticles (MPs) by tissue infiltrating/activated PMNs resultes in potent, ROS‐independent accumulation of double stranded DNA breaks (DSBs). PMN‐MP treatment of intestinal epithelial cells (IECs) induced persistent activation of DNA damage responses, including post‐translational modification of protein 53BP1, activation of DNA‐dependent protein kinase (DNA‐PKcs) and phosphorylation of histone H2AX, indicating increased generation of DSBs. Moreover, PMN‐MP treatment (96 hours) resulted in cell cycle arrest in S‐phase, deficient elongation of replication fork and persistent accumulation of γH2AX/53BP1 nuclear foci, suggesting inhibition of Homologous Recombination (HR)‐dependent DSB repair. Importantly, pre‐treatment of PMN‐MPs with RNAse significantly attenuated PMN‐MP‐mediated inhibition of DSB repair suggesting a role for micro‐RNAs (miRNAs) in this process. Indeed, a screen for potential miRNAs candidates with a known role in the regulation of DNA damage/repair responses revealed a significant upregulation of miR‐155 in PMNs following activation with IFNγ or TNFα, and its release in PMN‐MPs. MiR‐155 has been previously suggested to target a key regulator of HR, RAD51, which was found to be downregulated following PMN‐MP treatment. Importantly, an addition of miR‐155 antagonists reversed the loss of RAD51, partially recovered HR and decreased accumulation of DSBs induced by PMN‐MPs. Finally, in an in vitro model simulating PMN induced inflammation (continued co‐culture of IECs with PMN‐MPs over 12 population doublings) we detected an increase in aneuploidy and a high frequency of chromosomal aberrations indicating induction of genomic instability. Thus, our studies show for the first time that PMNs, via secretion of miRNA‐rich MPs, promotes genomic instability through the inhibition of HR, which may lead to mutagenesis and inactivation of tumor suppressor genes, and cellular transformation.Support or Funding InformationThis work was supported by grants from the National Institutes of Health (NIH) DK101675 as well as American Cancer Society IRG‐9303718
Altered Expression of Neuropeptide Receptors in the Bleomycin (Bleo)‐Induced Mouse Model of Scleroderma (SSc)
Authors: Parra James , Ibrahim Mohamed , McKinnon Elizabeth , Levinson Howard , Sunday Mary E 
Published: November 2023

Study ObjectiveBackgroundSSc is a chronic collagen‐vascular disease that initially presents with dermal fibrosis, later progressing to multiple organ fibrosis. There is no treatment to arrest SSc. Recently, a mouse model of SSc was reported, in which Bleo is injected intradermally (ID) for 21–28 days. Two groups showed that reactive oxygen species (ROS) cause this dermal fibrosis. We previously observed that ROS trigger GRP‐mediated pulmonary fibrosis induced by hyperoxia or radiation. We first verified that ROS trigger this dermal fibrosis, and now test the hypothesis that gastrin‐releasing peptide (GRP) from cutaneous nerves has a role in this process by acting on myofibroblasts [alpha‐smooth muscle actin, SMA+] and pericytes [SMA+ and neural/glial antigen 2, NG2+]. We tested expression of the two GRP receptors, GRPR and neuromedin B receptor (NMBR), by using immunohistochemistry.Methods10‐wk old C3H/HeJ females were injected ID on the flank with Bleo (100‐μg) 5d/wk for 3‐wks. Some Bleo‐injected mice also received antioxidant N‐acetylcysteine (NAC) IP, or GRP blocking mAb‐2A11. After 21d, sections of skin lesions were immunostained for SMA, NG2, GRPR, or NMBR. Relative extent of immunostaining in dermis and epidermis was scored on a scale from 0–3, comparing prevalence of (+) cells (0, 1=detected in few cells, 2=many cells (+), & 3=most cells positive. ImageJ analysis (immunopositive area as a percentage of tissue volume) was used to confirm scoring results.ResultsPericytes & myofibroblasts were significantly increased in areas of dermal thickening, with NG2 and SMA immunostaining linearly correlated (R2 = .87. P<0.05). Dermal SMA & NG2 were reduced by NAC (~80% decrease, P<0.001) or mAb2A11 (~50% decrease, P<0.01), similar to measurements of dermal thickness. Epidermal GRPR was decreased by over 50% in Bleo+2A11 mice compared to Bleo alone (P < 0.005). There was no other difference in GRPR between study groups. NMBR expression was generally unchanged between the groups.ConclusionIn the Bleo mouse model of SSc, increased pericytes and myofibroblasts occur in dermal fibrosis. Although either GRPR &/or NMBR could contribute to Bleo‐induced dermal fibrosis their expression in dermis is unchanged between groups. Sustained epidermal expression of both receptors would be consistent with potential GRP signaling in epidermis as a mechanism leading to epidermal hyperplasia and dermal fibrosis, possibly via epithelial‐mesenchymal transformation.Support or Funding InformationThis work was supported by a P30 NIH Pilot Grant Award to M. Sunday by the Duke Skin Disease Research Center [Dr. Russell Hall, Program Director].
Assessing Gliogenesis in a Murine Multifactorial Brain Injury Model System
Authors: Domowicz Miriam S. , Wadlington Natasha L. , Henry Judith G. , Diaz Kasandra , Munoz Miranda J. , Schwartz Nancy B. 
Published: November 2023

Brain injury in humans caused by trauma, intrauterine infections, hypoxia and/or ischemia, pre‐maturity or low birth weight, during the perinatal period which coincides with glial cell (astrocyte and oligodendrocyte) maturation in the brain, often has devastating neurological consequences such as epilepsy, cerebral palsy, and behavioral and cognitive problems. Due to the variety of risk factors associated with these neurodevelopmental disorders, we are using a multifactorial injury model to examine the effects on differentiation and maturation of the two glial subtypes. The model consists of penetrating perinatal traumatic brain injury, with or without intraperitoneal injection of lipopolysaccharide (LPS) as a model of remote pathogen exposure. Postnatal‐day‐6 (P6) mouse pups underwent sham, LPS‐alone, stab‐alone, or stab‐plus‐LPS treatments. At different ages after injury, the pups were harvested and gene‐expression changes for astrocyte, neuron, oligodendrocyte, and precursor‐cell markers were assessed using mRNA in situ hybridization (ISH) and qPCR. In general, the injured (ipsilateral) side exhibited enlarged ventricles, occasional disruption of the cortex structure and sporadic cysts; whereas the uninjured (contralateral) side remained unaffected overall, comparable to sham‐treated animals. Astrocyte‐precursor and mature‐astrocyte marker mRNA levels increased in the stab‐alone and stab‐plus‐LPS treated animals. Microglial/macrophage markers CD208 and CD68 levels, increased in the ipsilateral sides of stab and stab‐plus LPS animals by P10, but the differences resolved by P15. Decreased mRNA expression of mature oligodendrocyte markers, proteolipid protein 1 (PLP) and myelin basic protein (MBP) and the neuronal marker Class III beta‐tubulin (TUBB3), was observed only on the ipsilateral side in stab‐treated pups by ISH. Interestingly, ectopic expression of the neural stem cell marker SRY(sex‐determining region Y)‐box 2 (SOX2), astrocyte precursor SOX9, and the oligodendrocyte precursor marker oligodendrocyte transcription factor (OLIG2) mRNAs were observed in the ipsilateral side following stab injuries with or without LPS treatment at P10. By fluorescent ISH, partial colocalization of SOX2, OLIG2 and SOX9 mRNAs with GFAP‐positive cells was confirmed. These data suggest that shortly following traumatic injury, concomitant with the decrease in mature oligodendrocyte and neuronal marker expression, neural stem cells and glial precursor populations may be attempting to repopulate the injury region.Support or Funding InformationSupported by U.S. Public Health Service Grants HD009402 and GM066522
How the cytosol‐to‐membrane translocation kinetics and signaling of PKCγ are dysregulated in the neurodegenerative spinocerebellar ataxia type14 (SCA14)
Authors: Aslam Naveed , Alvi Farah 
Published: November 2023

The spinocerebellar ataxia type 14 (SCA14) is an autosomal neurodegeneration disease that is clinically characterized by the progressive ataxia of gait accompanied by slurred speech and abnormal eye movements. These symptoms are linked to the loss of Purkinje cells leading to cerebellar neurodegeneration. The onset age of this disease is in the range of 33–43 years. The MRI results clearly show the atrophy of cerebellum and autopsy results indicates the reduction in number of Purkinje cells as well the size and complexity of their dendritic arbor. Observations in Purkinje cells link PKCγ to the SCA14 disease and its gene PRKCG is now widely recognized as a disease‐causing gene. PKCγ. The PKCγ is a brain specific molecule and is highly expressed in cPCs. Observations also show that PKCγ link to SCA14 is established more through gain‐of‐function and in fact both positive and negative regulation of PKCγ expression and activity could result in the changes in number, size and complexity of dendritic arbors in Purkinje cells. Here, we investigate the question that why the membrane residence time of PKCγ is decreased in SCA14 compared to wildtype (WT) cPCs. We explore this question by proposing two signaling models for PKCγ; First model describes the signaling mechanism of how could the activity of WT PKCγ be regulated in cPCs, whereas the second model shows the signaling of mutant PKCγ in SCA14 associated cPCs. Both these models show that in response to extracellular stimuli‐induced depolarization at membrane, both PKCγ and DGKγ translocate to the membrane. Our results also indicate that for same set of parameters the membrane residence time of PKCγ is shorter compared to WT molecule. These results explain that membrane residence time of PKCγ is regulated by DAG and the translocated molecule returns to cytosol as the DAG levels decrease. These results suggest that even though all the kinetic parameters are same in WT & mutant models the residence time of PKCγ is reduced in mutant model due to reduced signaling. This study shows that for the same strength of extracellular signal the membrane life time of mutant PKCγ is decreased due to constitutively active mutant PKCγ molecule in cytosol. This cytosolic molecule in turn, leads to the phosphorylation and activation of DGKγ molecule inside cytosol. Thus, mutant model explains that when both the DAG effector molecules are found in their active states in cytosol their interactions in membrane compartment are reduced thus, reducing the residence time of PKCγ molecule in membrane compartment in mutant model.Support or Funding InformationPrivately Funded