Reducing pain by improving brain and muscle activity with motor cortical neuromodulation in women with interstitial cystitis/bladder pain syndrome: a study protocol for a randomized controlled trial.

INTRODUCTION: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition creating a wide range of urologic and pain symptoms. There is currently limited evidence to understand the mechanisms of IC/BPS. There have been recent studies suggesting that altered function in brain motor areas, particularly the supplementary motor cortex (SMA), relates to altered bladder sensorimotor control and may play an important role in IC/BPS. This study aims to provide evidence that non-invasive stimulation targeting the motor cortex may help reduce IC/BPS pain, as well as better understand the neural mechanism by which this stimulation targets neuromuscular dysfunction. This study is a two-group quadruple-blinded randomized controlled trial (RCT) of active vs. sham repetitive transmagnetic stimulation (rTMS). In addition, our study will also include functional magnetic resonance imaging (fMRI), pelvic floor electromyography (EMG), pelvic exam, and outcome measures and questionnaires to further study outcomes. ETHICS AND DISSEMINATION: All aspects of the study were approved by the Institutional Review Board of the University of Southern California (protocol HS-20-01021). All participants provided informed consent by the research coordinator/assistants. The results will be submitted for publication in peer-reviewed journals and disseminated at scientific conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT04734847. Registered on February 1, 2021.

Coping With Interstitial Cystitis/Bladder Pain Syndrome.

AIMS: Compensatory coping, or maladaptive alterations in behavior with the intention of preventing or managing symptoms, is increasingly being explored as a key factor in how people respond to bladder conditions. Preliminary investigations have identified relations between coping behaviors and psychological distress in urologic conditions, including interstitial cystitis/bladder pain syndrome (IC/BPS). However, previous explorations of coping have not accounted for heterogeneity in coping behaviors or addressed the likelihood that some coping behaviors may be more adaptive than others. This study sought to examine how two specific types of coping behaviors, primary control coping and disengaged coping, are related to distress and symptoms in IC/BPS, and to explore the potential role of pain phenotype in this relationship. MATERIALS AND METHODS: A secondary data analysis was conducted with a large community data set (N = 677 women with IC/BPS) and employed descriptive and inferential statistics to characterize coping patterns and explore novel predictors of distress. RESULTS: Results indicated that almost all participants engaged in at least one compensatory coping behavior within the last week. Both types of coping behaviors correlated with psychological symptoms, and when controlling for relevant clinical variables (i.e., age and severity of urinary symptoms), disengaged coping behaviors were significantly associated with psychological distress. Further, the addition of pain phenotype to multiple regression models resulted in a more effective predictive model when considering the relation between coping behaviors and depression. CONCLUSIONS: By investigating more deeply the relationship between coping and distress, understanding of potential risk factors and mechanisms is increased, offering valuable insights for intervention strategies for IC/BPS patients.

The role of circular RNA targeting IGF2BPs in cancer-a potential target for cancer therapy.

Circular RNAs (circRNAs) are an interesting class of conserved single-stranded RNA molecules derived from exon or intron sequences produced by the reverse splicing of precursor mRNA. CircRNAs play important roles as microRNA sponges, gene splicing and transcriptional regulators, RNA-binding protein sponges, and protein/peptide translation factors. Abnormal functions of circRNAs and RBPs in tumor progression have been widely reported. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) are a highly conserved family of RBPs identified in humans that function as post-transcriptional fine-tuners of target transcripts. Emerging evidence suggests that IGF2BPs regulate the processing and metabolism of RNA, including its stability, translation, and localization, and participate in a variety of cellular functions and pathophysiology. In this review, we have summarized the roles and molecular mechanisms of circRNAs and IGF2BPs in cancer development and progression. In addition, we briefly introduce the role of other RNAs and IGF2BPs in cancer, discuss the current clinical applications and challenges faced by circRNAs and IGF2BPs, and propose future directions for this promising research field.

Exposure to bisphenol compounds accelerates the conjugative transfer of antibiotic resistance plasmid.

Antimicrobial resistance poses the most formidable challenge to public health, with plasmid-mediated horizontal gene transfer playing a pivotal role in its global spread. Bisphenol compounds (BPs), a group of environmental contaminants with endocrine-disrupting properties, are extensively used in various plastic products and can be transmitted to food. However, the impact of BPs on the plasmid-mediated horizontal transfer of antibiotic resistance genes (ARGs) has not yet been elucidated. Herein, we demonstrate that BPs could promote the conjugative transfer frequency of RP4-7 and clinically multidrug-resistant plasmids. Furthermore, the promoting effect of BPs on the plasmid transfer was also confirmed in a murine model. Microbial diversity analysis of transconjugants indicated an increase in α diversity in the BPAF-treated group, along with the declined richness of some beneficial bacteria and elevated richness of Faecalibaculum rodentium, which might serve as an intermediate repository for resistance plasmids. The underlying mechanisms driving the enhanced conjugative transfer upon BPAF treatment include exacerbated oxidative stress, disrupted membrane homeostasis, augmented energy metabolism, and the increased expression of conjugation-related genes. Collectively, our findings highlight the potential risk associated with the exacerbated dissemination of AMR both in vitro and in vivo caused by BPs exposure.

Bisphenol F and Bisphenol S in a Complex Biomembrane: Comparison with Bisphenol A.

Bisphenols are a group of endocrine-disrupting chemicals used worldwide for the production of plastics and resins. Bisphenol A (BPA), the main bisphenol, exhibits many unwanted effects. BPA has, currently, been replaced with bisphenol F (BPF) and bisphenol S (BPS) in many applications in the hope that these molecules have a lesser effect on metabolism than BPA. Since bisphenols tend to partition into the lipid phase, their place of choice would be the cellular membrane. In this paper, I carried out molecular dynamics simulations to compare the localization and interactions of BPA, BPF, and BPS in a complex membrane. This study suggests that bisphenols tend to be placed at the membrane interface, they have no preferred orientation inside the membrane, they can be in the monomer or aggregated state, and they affect the biophysical properties of the membrane lipids. The properties of bisphenols can be attributed, at least in part, to their membranotropic effects and to the modulation of the biophysical membrane properties. The data support that both BPF and BPS, behaving in the same way in the membrane as BPA and with the same capacity to accumulate in the biological membrane, are not safe alternatives to BPA.

[Determination of ten bisphenols and five parabens in urine by solid supported liquid-liquid extraction and liquid chromatography-tandem mass spectrometry].

Bisphenols (BPs) and parabens (PBs) are of great concern for environmental pollution and human health because of their endocrine-disrupting effects and potential health hazards. Urinary biomonitoring of BPs and PBs can provide basic data for human internal exposure evaluation, which is a prerequisite for accurately assessing their health risks. In this study, we developed a new pretreatment procedure based on solid supported liquid-liquid extraction (SLE) for the simultaneous separation of ten BPs and five PBs in human urine, followed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis. In the instrumental analysis, the HPLC conditions and MS/MS parameters were comprehensively optimized. Accurate qualitative and quantitative determination of ten BPs and five PBs was achieved by introducing a ternary gradient elution system of water, methanol, and acetonitrile for LC separation. During sample pretreatment, the extraction solvent and elution volume were optimized. Specifically, urine samples were held at room temperature and centrifuged at 3000 r/min for 10 min. The supernatant (2 mL) was then transferred to a glass tube, and the pH was adjusted to 5.0 using HCl (0.5 mL; 0.1 mol/L) and NaAc-HAc buffer (1.5 mL). Thereafter, ß-glucuronidase-arylsulfatase (20 µL) and surrogate standard solutions (10 ng;13C12-BPS,13C12-BPAF,13C6-MeP, and 13C6-BuP) were added, and the mixture was incubated in a shaker bath in the dark at 37 ℃ for 16 h. After incubation, the hydrolyzed sample (4 mL) was loaded onto an SLE cartridge and equilibrated for a minimum of 5 min to ensure the solution was completely absorbed by the packing material. Subsequently, the target chemicals were eluted with a mixed ethyl acetate/n-hexane solution (3∶7, v/v; 15 mL). Separation of the targets was performed on a ZORBAX SB-C18 reversed-phase column (250 mm×4.6 mm, 5 µm) using an acetonitrile-methanol-water system as the mobile phase. The method was verified by spiking mixed urine samples at three levels (1, 5, and 50 µg/L), with the recoveries ranging from 84.3% to 119.8%. Except for bisphenols (BPS), whose matrix effect was calculated as -21.8%, the matrix effects of other analytes were lower than 20%, indicating low matrix interference. The linear ranges of the analytes varied from 0.1-500 µg/L to 1-500 µg/L, with correlation coefficients higher than 0.995. The method limits of quantification for target chemicals ranged from 0.03 to 0.30 µg/L, and the relative standard deviations of intra- and inter-day experiments were 1.4%-8.4% and 5.7%-14.6%, respectively, suggesting high stability and reproducibility. The method was successfully applied to the determination of ten BPs and five PBs in 10 urine samples from a general population. The concentrations of target chemicals in the human urine samples varied. Methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and bisphenol A (BPA) were detected in all samples, with median mass concentrations of 1.10, 0.60, 0.21, and 0.55 µg/L, respectively. The detection rates of the other chemicals were less than 50%, which may be related to the production and use of specific chemicals, their bioavailability, and biological metabolism in humans.

Occurrence and health risks of multiple emerging bisphenol S analogues in pregnant women from South China.

Recently, there has been increasing concern regarding the emergence of bisphenol S analogues (BPSs) due to their potential toxicity. However, their exposure levels and associated health risks in susceptible populations remain unknown. In our study, we analyzed bisphenol A (BPA), along with 11 common BPA analogues (BPAs), and nine emerging BPSs in urine samples collected from 381 pregnant women in South China. All nine BPSs were first detected in pregnant women's urine. In addition to BPA, two BPAs, three BPSs including Diphenylsulfone (DPS), Bis(phenylsulfonyl)phenol (DBSP) and Bis(3-allyl-4-hydroxyphenyl)sulfone (TGSA), were identified as the predominant bisphenols, with detection frequencies ranging from 53-100 %. BPA still exhibited the highest median concentration at 0.624 ng/mL, followed by DPS (0.169 ng/mL), BPS (0.063 ng/mL) and DBSP (0.023 ng/mL). Importantly, mothers with higher levels of BPA, DBSP, DPS, and TGSA in their urine are statistically more likely to give birth to premature infants with shorter lengths at birth or smaller head circumference (p < 0.05). Although the median exposure to 21 bisphenols did not exceed the tolerable daily intake (TDI) of BPA, it did surpass the recently proposed BPA TDI (0.2 ng/kg bw/day) by a factor ranging from 1.1-99 times. This study signifies the first report unveiling the prevalence of multiple bisphenols, particularly emerging BPSs, in the urine of pregnant women in South China.

Advice to the US FDA to Allow US Pharmacopeia to Create Biological Product Specifications (BPS) to Remove Side-by-Side Analytical Comparisons of Biosimilars with Reference Products.

Pharmacopeia monographs are not intended to establish biosimilarity. However, the US Food and Drug Administration (FDA) has stopped the US Pharmacopeia (USP) from creating monographs for biological drugs due to the need for side-by-side comparisons with the reference products. The USP can create Biological Product Specifications (BPS), not to be labeled as monographs, based on the analytical testing of reference products and validated test methods that will remove the need for side-by-side analytical testing of biosimilars with reference products. Scientific arguments confirm that this plan is logical and capable of creating global quality standards for biosimilars to allow their interchangeability with other biosimilars. While the regulatory agencies have waived many high-cost biosimilar tests, analytical assessment is the most sensitive test; reducing its cost will further enhance the entry of biosimilars with no clinically meaningful difference.

Investigation of bisphenol S (BPS) in packaged fish, meat, cheese, and price labels on their corresponding packages.

As an alternative to bisphenol A (BPA), bisphenol S (BPS) has been used as an ink developer in thermal paper products including price labels on food packaging which have been suggested as the sources of BPS found at high levels in packaged fish samples. BPS in the printed price labels glued onto the outside of plastic film could migrate indirectly from the printed surface through the paper, adhesive and film into the food. In order to investigate if price labels could also be the sources of BPS detected in the meat samples in our previous studies, meat and other food samples packaged under different conditions were collected, and BPS in these samples together with the price labels on the corresponding packaging were extracted with solvent followed by solid phase extraction and stable isotope dilution LC-MS/MS analysis. BPS was detected at very high levels (161.7-222.4 µg/cm2) in all the five sticker type of price labels, indicating BPS being the dominant if not the sole ink developer. BPS was also detected in all the 26 continuous roll type of price labels but at very low levels (0.017-18 ng/cm2), indicating that the dominant ink developer is likely one of the other alternatives, rather than BPS. Despite BPS being detected in all price labels on packaging of fish, meat, and cheese samples, BPS was not detected or detected in only a few fish, meat, and cheese samples at levels considerably lower than the current EU specific migration limit (SML) of 50 ng/g food for BPS authorised under Regulation (EU) 10/2011.

tRF-27 competitively Binds to G3BPs and Activates MTORC1 to Enhance HER2 Positive Breast Cancer Trastuzumab Tolerance.

About 20% of breast cancer patients are positive for HER2. The efficacy of current treatments is limited by primary and secondary resistance to trastuzumab. tRNA-derived fragments (tRFs) have shown crucial regulatory roles in various cancers. This study aimed to evaluate the role of tRF-27 in regulating the resistance of HER2-positive breast cancer against trastuzumab. tRF-27 was highly expressed in trastuzumab-resistant cells, and its expression level could predict the resistance to trastuzumab. High expression of tRF-27 promoted the growth and proliferation of trastuzumab-exposed cells. RNA-pulldown assay and mass spectrometry were performed to identify Ras GTPase-activating protein-binding proteins 1 and 2 (G3BPs) (two proteins targeted by tRF-27); RNA-immunoprecipitation (RIP) to confirm their bindings; co-immunoprecipitation (co-IP) and RNA-pulldown assay to determine the binding domains between G3BPs and tRF-27.tRF-27 bound to the nuclear transport factor 2 like domain(NTF2 domain) of G3BPs through a specific sequence. tRF-27 relied on G3BPs and NTF2 domain to increase trastuzumab tolerance. tRF-27 competed with lysosomal associated membrane protein 1(LAMP1) for NTF2 domain, thereby inhibiting lysosomal localization of G3BPs and tuberous sclerosis complex (TSC). Overexpression of tRF-27 inhibited phosphorylation of TSCs and promoted the activation of mechanistic target of rapamycin complex 1(MTORC1) to enhance cell proliferation and entice the resistance of HER2-positive breast cancer against trastuzumab.