The therapeutic potential of circular RNA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is among the most aggressive subtypes of the disease that does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Circular RNAs (circRNAs) are a type of non-coding RNA with a circular shape formed by non-standard splicing or reverse splicing. Numerous circRNAs exhibit abnormal expression in various malignancies, showing their critical role in the emergence and growth of tumors. Recent studies have shown evidence supporting the idea that certain circRNAs regulate the proliferation and metastasis of TNBC. In addition, circRNAs alter metabolism and the immune microenvironment to promote or inhibit the development of TNBC. Notably, circRNAs may affect the efficacy of clinical drug therapy, serve as therapeutic targets, and be used as molecular biomarkers in the future. Herein, we will first summarize the biogenesis and function of circRNAs. Then, we will explain current research on circRNAs related to TNBC and their potential to serve as therapeutic targets or biomarkers for future drug development, providing a new direction and idea for TNBC therapy.

Titration of sedentary behavior with varying physical activity levels reduces mortality in patients with type 2 diabetes.

CONTEXT: Both physical activity (PA) and sedentary behavior (SB) exert important impact on type 2 diabetes, but it remains unclear how maximum impact on improving the mortality and optimized proportion of the two lifestyles combination exists. OBJECTIVE: To explore the impacts of PA/SB combinations on mortality in patients with diabetes. METHODS: Patients with type 2 diabetes patients samplings were collected from the National Health and Nutrition Examination Survey (NHANES) dataset. Their lifestyles were categorized into eight groups based on combinations of the PA and SB levels. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals. RESULTS: During the follow-up period, 1,148 deaths (18.94%) were recorded. High SB (sedentary time ≥6 hours/day) was significantly associated with higher all-cause mortality (HR 1.65). In participants with low SB (<6 hours/day), low PA was associated with lower all-cause mortality (HR 0.43), while further increase of PA level did not show further reduction in either all-cause or cardiovascular mortality. In contrast, in participants with high SB，all levels of PA were associated with lower all-cause mortality (p<0.05), but only moderate PA was associated with lower cardiovascular mortality (HR 0.30). CONCLUSIONS: In patients with type 2 diabetes, different combinations of various levels of PA and SB are associated with different degree of risk for all-cause or cardiovascular mortality.

Is a soft tissue reinforcing mesh necessary in immediate prosthetic breast reconstruction for early breast cancer in patients with low-volume breast? A single-center, retrospective Chinese clinical study.

It is controversial as to whether soft tissue reinforcement mesh should be used for immediate prosthetic breast reconstruction after nipple-sparing mastectomy for low-volume breast early breast cancer (LVBEBC) in Chinese adult women. We collected data on 89 patients with LVBEBC who underwent such a surgery and divided them into two groups: 39 patients in the totally subpectoral prosthesis-only breast reconstruction group (simple group) and 50 patients in the prosthesis-combined titanium-coated polypropylene mesh (TCPM) group (or the so-called "dual plane" or "mesh-assisted partially subpectoral breast reconstruction group") (combined group). The results demonstrated no difference in operative time, intraoperative bleeding, and postoperative complications between the two groups; however, total drainage volume and extubation time were less and shorter, respectively, in the combined group. The median follow-up time was 18.6 months without local recurrence or distant metastasis in both groups. At 24 months after surgery, the excellent and good rates of breast reconstruction were higher in the combined group. However, patients' BMI, breast morphology, and breast volume of 300 mL or more had an effect on the shape of the reconstructed breast; in addition, in patients with higher BMI, conical breast morphology, and breast volume over 300 mL, the shape of the breast was more perfect with the prosthesis combined with TCPM reconstruction.Trial registration: This retrospective study was "retrospectively registered" in the Sixth Affiliated Hospital of South China University of Technology of China on March 15, 2022 (No. 2022018) and in the National Medical Research Registry filing system of China ( https://www.medicalresearch.org.cn ) (No. MR-44-22-003618).

Nanoformulation of Paclitaxel: Exploring the Cyclodextrin / PLGA Nano Delivery Carrier to Slow Down Paclitaxel Release, Enhance Accumulation in Vivo.

Background: Improving the aggregation and penetration in tumor sites increases the anti-tumor efficacy of nanomedicine. In the current study, we designed cyclodextrin modified PLGA nanoparticles loaded with paclitaxel to elevate the accumulation and prolong circulation of chemotherapy drugs in vivo. Methods: The PLGA nanoparticles loaded with paclitaxel (PTX PLGA NPs) and cyclodextrin (CD) modified PLGA nanoparticles loaded with paclitaxel (PTX PLGA/CD NPs) were prepared using the emulsification solvent evaporation method. The nanoparticles were characterized by particle size, zeta potential, encapsulation efficiency, infrared spectroscopy analysis and X-Ray diffraction (XRD). Then, drug release of the nanoparticles was evaluated via reverse dialysis method in vitro. Finally, the in vivo distribution fate and pharmacokinetic characteristics of the nanoparticles were assessed in mice and rats. Results: The average particle size, zeta potential, and encapsulation efficiency of PTX PLGA NPs were (163.57±2.07) nm, - (20.53±2.79) mV and (60.44±6.80)%. The average particle size, zeta potential, and encapsulation efficiency of PTX PLGA/CD NPs were (148.57±1.66) nm, - (11.42±0.84) mV and (85.70±2.06)%. In vitro release studies showed that PTX PLGA/CD NPs were released more slowly compared to PTX PLGA NPs under normal blood pH conditions, while PTX PLGA/CD NPs were released more completely under tumor site pH conditions. The modified PLGA nanocarrier (PLGA/CD NPs) increased drug residence time and accumulation than the plain PLGA nanocarrier (PLGA NPs) in vivo distribution. In addition, the elimination half-life, area under the drug-time curve, and maximum blood concentration of the nanoparticle group were higher than those of Taxol®, especially the PTX PLGA/CD NPs group, which was significantly different from Taxol® and plain nanoparticle groups (p<0.001). Conclusions: The 2-HP-ß-CD modified PLGA nanoparticles prolonged circulation time and accumulation of the chemotherapy drug paclitaxel in vivo.

Genetic polymorphism of clopidogrel metabolism related gene CYP2C19 gene in Chinese from Foshan area of Guangdong Province.

BACKGROUND: The CYP2C19 gene is highly polymorphic, and CYP2C19 is involved in the broad interindividual variability of the clinical efficacy of certain clinical medications, such as clopidogrel. However, data on the CYP2C19 genotype in the Chinese population of the Foshan area of Guangdong Province are scarce. The purpose of this study was to determine CYP2C19 genetic polymorphisms in patients in the Foshan area and to compare the CYP2C19 genotype frequencies in different populations to determine the allele distribution pattern to identify the most appropriate prescription. METHODS: The CYP2C19 gene was detected in 1231 patients on a gene chip platform, and the genotype frequencies of CYP2C19 in Foshan populations from different populations were compared. RESULTS: The frequencies of CYP2C19*1, *2 and *3 in the Foshan population were 63.89%, 30.46% and 5.65%, respectively. For the three metabolic types, the frequency associated with the rapid metabolism type (*1/*1) was 41.51 [95% confidence interval (CI) 40.11 to 42.91%]; that for the intermediate metabolism type (*1/*2, *1/*3) was 44.76% (95% CI 43.34 to 46.18) and that for the slow metabolism type (*2/*2, *2/*3, *3/*3) was 13.73% (95% CI 12.75 to 14.71%). In the Foshan population, the frequencies of the CYP2C19 *2 and *3 alleles were similar to those previously reported for Chinese and other Asian populations. CONCLUSION: Our study is a report on the genetic basis of CYP2C19 polymorphism in the Foshan population. Our results will potentially contribute to the improvement of pharmacotherapy effectiveness by providing personalized medicine for the Foshan population.

Disrupted coupling between salience network segregation and glucose metabolism is associated with cognitive decline in Alzheimer's disease - A simultaneous resting-state FDG-PET/fMRI study.

The aberrant organization and functioning of three core neurocognitive networks (NCNs), i.e., default-mode network (DMN), central executive network (CEN), and salience network (SN), are among the prominent features in Alzheimer's disease (AD). The dysregulation of both intra- and inter-network functional connectivities (FCs) of the three NCNs contributed to AD-related cognitive and behavioral abnormalities. Brain functional network segregation, integrating intra- and inter-network FCs, is essential for maintaining the energetic efficiency of brain metabolism. The association of brain functional network segregation, together with glucose metabolism, with age-related cognitive decline was recently shown. Yet how these joint functional-metabolic biomarkers relate to cognitive decline along with mild cognitive impairment (MCI) and AD remains to be elucidated. In this study, under the framework of the triple-network model, we performed a hybrid FDG-PET/fMRI study to evaluate the concurrent changes of resting-state brain intrinsic FCs and glucose metabolism of the three NCNs across cognitively normal (CN) (N = 24), MCI (N = 21), and AD (N = 21) groups. Lower network segregation and glucose metabolism were observed in all three NCNs in patients with AD. More interestingly, in the SN, the coupled relationship between network segregation and glucose metabolism existed in the CN group (r = 0.523, p = 0.013) and diminished in patients with MCI (r = 0.431, p = 0.065) and AD (r = 0.079, p = 0.748). Finally, the glucose metabolism of the DMN (r = 0.380, p = 0.017) and the network segregation of the SN (r = 0.363, p = 0.023) were significantly correlated with the general cognitive status of the patients. Our findings suggest that the impaired SN segregation and its uncoupled relationship with glucose metabolism contribute to the cognitive decline in AD.

Distinct Functional and Metabolic Alterations of DMN Subsystems in Alzheimer's Disease: A Simultaneous FDG-PET/fMRI Study.

The default mode network (DMN) dysfunction has been widely identified in Alzheimer's disease (AD). Increasing evidence has shown that the functional heterogeneity of DMN has been associated with distinct cognitive functions. The pathophysiological changes of these two DMN subsystems, i.e., anterior DMN (aDMN) and posterior DMN (pDMN), also showed different patterns in the AD patients. Yet the underlying metabolic mechanism remains not clear. In this work, we performed a simultaneous FDG-PET/fMRI study, to investigate the distinct functional and metabolic alterations of DMN subsystems in AD. Significantly decreased functional connectivity strength (FCS) in pDMN but not aDMN was found in AD patients. The retaining connectivity in aDMN might represent a compensatory strategy. Concurrently, significant glucose hypometabolism was shown in pDMN and aDMN of AD patients, respectively. Moreover, the reduction of FCS in pDMN was positively correlated with MMSE score of patients. Our study suggests that resting state functional connectivity and glucose metabolism changed differently in the aDMN and pDMN of AD. Our findings brought new insights in understanding the underlying metabolism changes along with functional alterations in AD.

Simultaneous PET/fMRI Detects Distinctive Alterations in Functional Connectivity and Glucose Metabolism of Precuneus Subregions in Alzheimer's Disease.

As a central hub in the interconnected brain network, the precuneus has been reported showing disrupted functional connectivity and hypometabolism in Alzheimer's disease (AD). However, as a highly heterogeneous cortical structure, little is known whether individual subregion of the precuneus is uniformly or differentially involved in the progression of AD. To this end, using a hybrid PET/fMRI technique, we compared resting-state functional connectivity strength (FCS) and glucose metabolism in dorsal anterior (DA_pcu), dorsal posterior (DP_pcu) and ventral (V_pcu) subregions of the precuneus among 20 AD patients, 23 mild cognitive impairment (MCI) patients, and 27 matched cognitively normal (CN) subjects. The sub-parcellation of precuneus was performed using a K-means clustering algorithm based on its intra-regional functional connectivity. For the whole precuneus, decreased FCS (p = 0.047) and glucose hypometabolism (p = 0.006) were observed in AD patients compared to CN subjects. For the subregions of the precuneus, decreased FCS was found in DP_pcu of AD patients compared to MCI patients (p = 0.011) and in V_pcu for both MCI (p = 0.006) and AD (p = 0.008) patients compared to CN subjects. Reduced glucose metabolism was found in DP_pcu of AD patients compared to CN subjects (p = 0.038) and in V_pcu of AD patients compared to both MCI patients (p = 0.045) and CN subjects (p < 0.001). For both FCS and glucose metabolism, DA_pcu remained relatively unaffected by AD. Moreover, only in V_pcu, disruptions in FCS (r = 0.498, p = 0.042) and hypometabolism (r = 0.566, p = 0.018) were significantly correlated with the cognitive decline of AD patients. Our results demonstrated a distinctively disrupted functional and metabolic pattern from ventral to dorsal precuneus affected by AD, with V_pcu and DA_pcu being the most vulnerable and conservative subregion, respectively. Findings of this study extend our knowledge on the differential roles of precuneus subregions in AD.