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Abstract Background Currently, there is a lack of biomarkers to identify breast cancer (BC) patients who would benefit from CDK4/6 inhibitors. This study combined machine learning (ML) algorithms based on transcriptomic data with both in vivo and in vitro experiments to identify therapeutic efficacy-related biomarkers of the CDK4/6 inhibitor ribociclib from the perspective of long non-coding RNA (lncRNA). Methods We used the Genomics of Drug Sensitivity in Cancer database along with the “oncoPredict” algorithm to calculate the half maximal inhibitory concentration (IC50) values for ribociclib based on transcriptome data. ML algorithms were utilized to select key lncRNAs related to ribociclib and to establish a model which could be used for selection of potential beneficiaries of ribociclib. Cellular experiments were conducted to validate the ML analysis and explore the potential biological mechanisms by which RERE-AS1 influences ribociclib efficacy and malignant phenotype of BC cells. Correlation analysis with clinical pathological factors, RT-qPCR experiments on tissue specimens, and pan-cancer analysis were carried out to explore the expression pattern, and the prognostic and diagnostic potential of RERE-AS1 in cancers. Results We have identified 11 key ribociclib-related lncRNAs and constructed an artificial neural network model (ANNM) based on lncRNA. Cellular experiments demonstrated that overexpression of RERE-AS1 promoted the anti-tumor activity of ribociclib in BC cells. Furthermore, RERE-AS1 is crucial in suppressing the malignant traits of BC cells through the reduction of MEK and ERK phosphorylation levels. Patients with smaller primary tumors and lower pathological stage exhibited higher levels of RERE-AS1 expression. Lastly, a pan-cancer analysis revealed that RERE-AS1 exhibits distinctly abnormal expression patterns, prognostic significance, and clinical diagnostic value in BC, compared to other cancers. Conclusions The ANNM established through ML algorithms can serve as predictive indicators for the efficacy of ribociclib in BC patients. LncRNA RERE-AS1, a newly discovered biomarker, holds significant promise for diagnosis, treatment, and enhancing the therapeutic response to ribociclib in BC. Graphical Abstract

Abstract Background Triangular fibrocartilage complex (TFCC) injury is a frequent soft tissue injury that has been observed to accompany distal radius fractures (DRFs) with concomitant changes in radiologic parameters. The aim of this study was to investigate the relevance of distal radial radiologic parameters associated with DRF and traumatic TFCC injury. Methods A total of 172 patients with distal radius fractures who underwent X-ray, CT, and MRI before undergoing volar locking plate or external splint fixation between October 2021 and December 2022 were included in this study. An analysis of various radiologic parameters and the classification of fracture type and TFCC injuries by CT and MRI was performed. All patients were divided into the TFCC uninjured group and the injured group. The incidence and relevant radiologic parameters were compared. Results This study included 76 males and 96 females with a mean age of 56.1 years. Among all patients, 33 (19.2%), 40 (23.2%), and 99 (57.6%) had DRF with A, B, and C fractures, respectively, according to the AO/OTA classification. In patients with fractures, the TFCC was found to be injured in 54.1% (93/172) of patients (type 1A in 21, 1B in 46, 1C in 39, and 1D in 35) but uninjured in 45.9% (79/172). There were significant differences between the TFCC injured and uninjured groups regarding the radius length (p = 0.044) and DRUJ distance (p = 0.040) of radiologic parameters that changed with DRF, although there were no differences between the two groups regarding gender, age, injured side, intra- and extra-articular, radius inclination and palmer tilt angle, or sagittal translation. Within the TFCC injured group, the radius length and DRUJ distance were 4.83 mm and 2.95 mm less or wider than 7.19 mm and 1.83 mm of the uninjured group. Moreover, shorter radius length was related to type lB TFCC injury (p = 0.041). Both radius length (AUC = 0.658) and DRUJ distance (AUC = 0.582) had no convincing predictive value for TFCC injury in DRF. Conclusion 1B TFCC injury is most common in patients with DRF and concomitant TFCC injury. Both radius length and DRUJ distance have a significant statistical correlation with TFCC injury, and patients with TFCC injury tend to have a shortened radius and wider DRUJ distance, although they have no predictive value for TFCC injury in DRF. In addition, a shorter radius length was related to type lB TFCC injury.

Abstract Background The group care is a well-established maternal care model that has been widely used in many developed countries, but in China, it is confined to prenatal care services. In addition, affected by traditional birth culture, Chinese women tend to focus more on their fetuses and newborns but lack attention to their own intrapartum and postpartum care. The aim of this study was to construct and implement a prenatal, intrapartum, and the postpartum continuous group care model that combines online and offline service in Hainan Province, China, and to evaluate the effect on maternal women and newborns. Methods This study was a randomized controlled trial involving 144 pregnant women in a first-class tertiary general hospital in Hainan Province, China. Women were divided into an intervention group and a control group using the random number table, with 72 women in each group. The control group received routine maternal care services, and the intervention group received the continuous group care based on the routine maternal care services. Count data such as rate of cesarean section and incidence rate of fetal macrosomia were analyzed with the chi-square test or Fisher’s exact test, and the General Self-efficacy Scale scores were analyzed by repeated measures ANOVA. P 0.05). Conclusion The continuous group care with online and offline service can effectively control the gestational weight gain, reduce the rate of cesarean section, macrosomia, and postpartum depression. It can improve the self-efficacy of women and the rate of exclusive breastfeeding effectively. Trial registration Chinese Clinical Trial Regestry (ChiCTR2200065765, 04/11/2022, Retrospectively registered).

Abstract Background Previous studies have reported inconsistent effects of premolar extraction on the oropharynx and hyoid bones. Currently, no strong evidence is available regarding the effect of extraction on upper airway size. Hence, the aim of this study was to analyse the effects of first premolar extraction on the oropharynx and hyoid bone positions in female adult patients, and further explored differences in oropharynx and hyoid bone changes among skeletal patterns. Methods The study population included 40 female adult patients who did not undergo extraction and 120 female adult patients who underwent extraction of four premolars; the including patients had four distinct sagittal and vertical skeletal patterns. Cone-beam computed tomography was performed before (T0) and after (T1) orthodontic treatment. Eight oropharynx variables and five hyoid bone variables were measured using Dolphin 3D Imaging software. Paired and independent t-tests were used to analyse measurements between timepoints and groups, respectively. Results The oropharynx volume increased significantly in the extraction group; changes did not differ significantly between extraction and non-extraction groups. Oropharynx variables did not differ significantly at T0 among the four skeletal pattern groups. After orthodontic extraction treatment, the oropharynx volume increased significantly in the class I-norm and class I-hyper subgroups, but not in the class II-norm and class II-hyper subgroups. Significant increases were observed in the oropharynx volume and most constricted axial area from T0 to T1 in the moderate retraction group, but not in the maximum retraction group. Extraction patients exhibited significant posterior movement of the hyoid, particularly among maximum retraction patients. Conclusions In female adult patients, first premolar extraction tends to increase the oropharynx size and cause posterior movement of the hyoid bone, particularly in skeletal class I patients. For skeletal class II and hyperdivergent patients with a narrow oropharynx, first premolar extraction does not negatively influence oropharynx size or hyoid bone position. The differences of oropharyngeal changes between moderate retraction patients and maximum retraction patients were not significant.

Abstract Background Pulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule β (RELM-β) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-β has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear. Methods We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs. Results Overexpression of RELM-β caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-β partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-β gene overexpression or silencing, respectively. Recombinant RELM-β protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-β on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor. Conclusions Our findings suggest that RELM-β acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-β are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Abstract Transplantation of mesenchymal stem cells (MSCs) has been considered an effective therapeutic treatment for a variety of diseases including bone fracture. However, there are associated complications along with MSCs transplantation. There is evidence to show that exosomes (Exos) derived from MSCs exert a similar paracrine function. In addition, repair capabilities of MSCs decline with age. Hence, this study aims to confirm whether the Exos protective function on osteogenic differentiation and fracture healing from aged MSCs was attenuated. This information was used in order to investigate the underlying mechanism. MSCs were successfully isolated and identified from young and aged rats, and Exos were then obtained. Aged-Exos exhibited significantly attenuated effects on MSCs osteogenic differentiation in vitro and facture healing in vivo. Using miRNA array analysis, it was shown that miR-128-3p was markedly upregulated in Aged-Exos. In vitro experiments confirmed that Smad5 is a direct downstream target of miR-128-3p, and was inhibited by overexpressed miR-128-3p. A series gain- and loss- function experiment indicated that miR-128-3P serves a suppressor role in the process of fracture healing. Furthermore, effects caused by miR-128-3P mimic/inhibitor were reversed by the application of Smad5/siSmad5. Taken together, these results suggest that the therapeutic effects of MSCs-derived Exos may vary according to differential expression of miRNAs. Exosomal miR-128-3P antagomir may act as a promising therapeutic strategy for bone fracture healing, especially for the elderly.

Abstract Background Spinal cord injury (SCI) can lead to severe motor and sensory dysfunction with high disability and mortality. In recent years, mesenchymal stem cell (MSC)-secreted nano-sized exosomes have shown great potential for promoting functional behavioral recovery following SCI. However, MSCs are usually exposed to normoxia in vitro, which differs greatly from the hypoxic micro-environment in vivo. Thus, the main purpose of this study was to determine whether exosomes derived from MSCs under hypoxia (HExos) exhibit greater effects on functional behavioral recovery than those under normoxia (Exos) following SCI in mice and to seek the underlying mechanism. Methods Electron microscope, nanoparticle tracking analysis (NTA), and western blot were applied to characterize differences between Exos and HExos group. A SCI model in vivo and a series of in vitro experiments were performed to compare the therapeutic effects between the two groups. Next, a miRNA microarray analysis was performed and a series of rescue experiments were conducted to verify the role of hypoxic exosomal miRNA in SCI. Western blot, luciferase activity, and RNA-ChIP were used to investigate the underlying mechanisms. Results Our results indicate that HExos promote functional behavioral recovery by shifting microglial polarization from M1 to M2 phenotype in vivo and in vitro. A miRNA array showed miR-216a-5p to be the most enriched in HExos and potentially involved in HExos-mediated microglial polarization. TLR4 was identified as the target downstream gene of miR-216a-5p and the miR-216a-5p/TLR4 axis was confirmed by a series of gain- and loss-of-function experiments. Finally, we found that TLR4/NF-κB/PI3K/AKT signaling cascades may be involved in the modulation of microglial polarization by hypoxic exosomal miR-216a-5p. Conclusion Hypoxia preconditioning represents a promising and effective approach to optimize the therapeutic actions of MSC-derived exosomes and a combination of MSC-derived exosomes and miRNAs may present a minimally invasive method for treating SCI.