A 3'-pre-tRNA-derived small RNA tRF-1-Ser regulated by 25(OH)D promotes proliferation and stemness by inhibiting the function of MBNL1 in breast cancer.

BACKGROUND: We explored the potential novel anticancer mechanisms of 25-hydroxyvitamin D (25(OH)D), a vitamin D metabolite with antitumour effects in breast cancer. It is stable in serum and is used to assess vitamin D levels in clinical practice. Transfer RNA-derived small RNAs are small noncoding RNAs that generate various distinct biological functions, but more research is needed on their role in breast cancer. METHODS: Small RNA microarrays were used to explore the novel regulatory mechanism of 25(OH)D. High-throughput RNA-sequencing technology was used to detect transcriptome changes after 25(OH)D treatment and tRF-1-Ser knockdown. RNA pull-down and high-performance liquid chromatography-mass spectrometry/mass spectrometry were used to explore the proteins bound to tRF-1-Ser. In vitro and in vivo functional experiments were conducted to assess the influence of 25(OH)D and tRF-1-Ser on breast cancer. Semi-quantitative PCR was performed to detect alternative splicing events. Western blot assay and qPCR were used to assess protein and mRNA expression. RESULTS: The expression of tRF-1-Ser is negatively regulated by 25(OH)D. In our breast cancer (BRCA) clinical samples, we found that the expression of tRF-1-Ser was higher in cancer tissues than in paired normal tissues, and was significantly associated with tumour invasion. Moreover, tRF-1-Ser inhibits the function of MBNL1 by hindering its nuclear translocation. Functional experiments and transcriptome data revealed that the downregulation of tRF-1-Ser plays a vital role in the anticancer effect of 25(OH)D. CONCLUSIONS: In brief, our research revealed a novel anticancer mechanism of 25(OH)D, unveiled the vital function of tRF-1-Ser in BRCA progression, and suggested that tRF-1-Ser could emerge as a new therapeutic target for BRCA.

Findings Favor Haptics Feedback in Virtual Simulation Surgical Education: An Updated Systematic and Scoping Review.

BACKGROUND: Virtual simulations (VSs) enhance clinical competencies and skills. However, a previous systematic review of 9 RCT studies highlighted a paucity of literature on the effects of haptic feedback in surgical VSs. An updated systematic and scoping review was conducted to encompass more studies and a broader range of study methodologies. METHODS: A systematic literature search was conducted on July 31, 2023, in MEDLINE, Embase, and Cochrane. English language studies comparing haptic vs non-haptic conditions and using VSs were included. Studies were evaluated and reported using PRISMA-ScR guidelines. RESULTS: Out of 2782 initial studies, 51 were included in the review. Most studies used RCT (21) or crossover (23) methodologies with medical residents, students, and attending physicians. Most used post-intervention metrics, while some used pre- and post-intervention metrics. Overall, 34 performance results from studies favored haptics, 3 favored non-haptics, and the rest showed mixed or equal results. CONCLUSION: This updated review highlights the diverse application of haptic technology in surgical VSs. Haptics generally enhances performance, complements traditional teaching methods, and offers personalized learning with adequate simulator validation. However, a sparsity of orienting to the simulator, pre-/post-study designs, and small sample sizes poses concerns with the validity of the results. We underscore the urgent need for standardized protocols, large-scale studies, and nuanced understanding of haptic feedback integration. We also accentuate the significance of simulator validation, personalized learning potential, and the need for researcher, educator, and manufacturer collaboration. This review is a guidepost for navigating the complexities and advancements in haptic-enhanced surgical VSs.

The phosphodiesterase DibA interacts with the c-di-GMP receptor LapD and specifically regulates biofilm in Pseudomonas putida.

The ubiquitous bacterial second messenger c-di-GMP is synthesized by diguanylate cyclase and degraded by c-di-GMP-specific phosphodiesterase. The genome of Pseudomonas putida contains dozens of genes encoding diguanylate cyclase/phosphodiesterase, but the phenotypical-genotypical correlation and functional mechanism of these genes are largely unknown. Herein, we characterize the function and mechanism of a P. putida phosphodiesterase named DibA. DibA consists of a PAS domain, a GGDEF domain, and an EAL domain. The EAL domain is active and confers DibA phosphodiesterase activity. The GGDEF domain is inactive, but it promotes the phosphodiesterase activity of the EAL domain via binding GTP. Regarding phenotypic regulation, DibA modulates the cell surface adhesin LapA level in a c-di-GMP receptor LapD-dependent manner, thereby inhibiting biofilm formation. Moreover, DibA interacts and colocalizes with LapD in the cell membrane, and the interaction between DibA and LapD promotes the PDE activity of DibA. Besides, except for interacting with DibA and LapD itself, LapD is found to interact with 11 different potential diguanylate cyclases/phosphodiesterases in P. putida, including the conserved phosphodiesterase BifA. Overall, our findings demonstrate the functional mechanism by which DibA regulates biofilm formation and expand the understanding of the LapD-mediated c-di-GMP signaling network in P. putida.

Sensory nerve regulates progenitor cells via FGF-SHH axis in tooth root morphogenesis.

Nerves play important roles in organ development and tissue homeostasis. Stem/progenitor cells differentiate into different cell lineages responsible for building the craniofacial organs. The mechanism by which nerves regulate stem/progenitor cell behavior in organ morphogenesis has not yet been comprehensively explored. Here, we use tooth root development in mouse as a model to investigate how sensory nerves regulate organogenesis. We show that sensory nerve fibers are enriched in the dental papilla at the initiation of tooth root development. Through single cell RNA-sequencing analysis of the trigeminal ganglion and developing molar, we reveal several signaling pathways that connect the sensory nerve with the developing molar, of which FGF signaling appears to be one of the important regulators. Fgfr2 is expressed in the progenitor cells during tooth root development. Loss of FGF signaling leads to shortened roots with compromised proliferation and differentiation of progenitor cells. Furthermore, Hh signaling is impaired in Gli1-CreER;Fgfr2fl/fl mice. Modulation of Hh signaling rescues the tooth root defects in these mice. Collectively, our findings elucidate the nerve-progenitor crosstalk and reveal the molecular mechanism of the FGF-SHH signaling cascade during tooth root morphogenesis.

Oral Bacteria: Friends and Foes?

The oral cavity is an ideal niche for microbial prosperity due to its stable temperature, suitable pH, and continuous nutrient supply [...].

Efficacy comparisons of solvent-based paclitaxel, liposomal paclitaxel, nanoparticle albumin-bound paclitaxel, and docetaxel after neoadjuvant systemic treatment in breast cancer.

PURPOSE: There are four kinds of taxanes: solvent-based paclitaxel (Sb-P), liposomal paclitaxel (Lps-P), nanoparticle albumin-bound paclitaxel (Nab-P), and docetaxel. This study aims to retrospectively evaluate the efficacy of different taxanes on neoadjuvant systemic treatment (NST) in breast cancer. METHODS: Patients who were diagnosed with breast cancer and had received integral NST from August 2013 to April 2022 were enrolled. The efficacy was divided into total pathological complete response (total-pCR), breast pathological complete response (breast-pCR), and axillary pathological complete response (axillary-pCR) for in-depth analysis and discussion. RESULTS: The choice of taxane was an independent risk factor for total-pCR and breast-pCR rates. The highest total-pCR and breast-pCR rates were found in the Nab-P group. The difference was not significant among all the taxanes in the axillary-pCR rate. CONCLUSION: Nab-P significantly improved the total-pCR and breast-pCR rates. It should be the first choice among taxanes in NST for breast cancer.

Long-term follow-up after discharge witnesses a slow decline of insulin autoantibodies in patients with insulin autoimmune syndrome complicated with Grave's disease: a report of two cases.

BACKGROUND: Insulin autoimmune syndrome (IAS) is a rare cause of hypoglycemia characterized by high levels of blood insulin autoantibodies. It has been documented that drugs containing sulfhydryl groups may result in IAS. In this study, we present two cases of IAS induced by methimazole, along with their corresponding treatments and a long-term follow-up after hospitalization. CASE PRESENTATION: We report two patients with Grave's disease (GD), carrying the HLA-DRB1 04:06 genotype, who experienced hypoglycemic episodes after taking methimazole. Inpatient treatments helped return their blood glucose levels to normal. Although no recurrences of hypoglycemia were present in the two cases studied, insulin autoantibodies remained positive for the previous follow-up sessions, which turned negative only three years after discharge. CONCLUSIONS: GD patients who carry the HLA-DRB1 04:06 genotype are prone to IAS if they take drugs containing sulfhydryl groups. It may take time for the elimination of insulin autoantibodies after the recovery from the hypoglycemic episode in IAS patients.

Stem Cells from the Apical Papilla (SCAPs): Past, Present, Prospects, and Challenges.

Dental diseases occurring on young permanent teeth usually lead to the premature arrest of tooth root development. Sustained tooth root elongation is necessary to achieve the goal of long-term preservation of affected teeth. To this end, stem cell-based regenerative endodontic treatment has been regarded as one of the most promising strategies for treating young permanent teeth with pulp and periapical infections. Endogenous stem cells residing in the apical papilla, named stem cells from the apical papilla (SCAPs), have been intensively investigated due to their critical roles in pulp regeneration and root redevelopment. The present review summarizes advances in the field of SCAPs studies and discusses the challenges that need to be further addressed.

Roles of Streptococcus mutans-Candida albicans interaction in early childhood caries: a literature review.

As one of the most common oral diseases in kids, early childhood caries affects the health of children throughout the world. Clinical investigations show the copresence of Candida albicans and Streptococcus mutans in ECC lesions, and mechanistic studies reveal co-existence of C. albicans and S. mutans affects both of their cariogenicity. Clearly a comprehensive understanding of the interkingdom interaction between these two microorganisms has important implications for ECC treatment and prevention. To this end, this review summarizes advances in our understanding of the virulence of both C. albicans and S. mutans. More importantly, the synergistic and antagonistic interactions between these two microbes are discussed.

Nanoparticle albumin-bound paclitaxel-based neoadjuvant regimen: A promising treatment option for HER2-low-positive breast cancer.

This study aimed to compare the efficacy of neoadjuvant systemic therapy (NST) with solvent-based paclitaxel (Sb-P), liposomal paclitaxel (Lps-P), nanoparticle albumin-bound paclitaxel (Nab-P), and docetaxel in human epidermal growth factor receptor 2 (HER2)-low-positive and HER2-zero breast cancers. A total of 430 patients receiving 2-weekly dose-dense epirubicin and cyclophosphamide (EC) followed by 2-weekly paclitaxel (Sb-P, Lps-P, or Nab-P), or 3-weekly EC followed by 3-weekly docetaxel for NST were enrolled in the study. In HER2-low-positive patients, the pathological complete response (pCR) rate in Nab-P group was significantly higher than that in the other three paclitaxel groups (2.8 % in Sb-P group, 4.7 % in Lps-P group, 23.2 % in Nab-P group and 3.2 % in docetaxel group, p < 0.001). In HER2-zero patients, the pCR rate did not differ significantly among the four paclitaxel groups (p = 0.278). The NST regimen containing Nab-P could be considered a promising treatment option in HER2-low-positive breast cancer.

Volume change rate before and after neoadjuvant systemic therapy of breast cancer is an efficacious evaluation index to predict pathological complete response.

Neoadjuvant systemic therapy (NST) is widely applied in breast cancer treatment, but individuals respond differently to the same NST regimen. It is unclear which patients should adjust their NST regimen and what such an adjustment should be, especially for patients with radiologically partial response (PR). This study aimed to identify a quantitative efficacy evaluation index to evaluate the therapeutic effect of NST. 164 patients were enrolled in this study received four cycles of epirubicin and cyclophosphamide (EC), followed by four cycles of taxanes with trastuzumab [T(H)], if needed. Of patients with a volume change rate of EC treatment (δV1) below 0.80, more than half benefited from subsequent T(H) treatment compared with EC treatment. Importantly, for δV1 of 0.80 and higher, patients' subsequent T(H) treatment was not as efficient as previous EC treatment and they have a lower pathological complete response (pCR) rate. Across all patients, nanoparticle albumin-bound paclitaxel had a numerically higher pCR rate over other taxanes in patients with triple-negative breast cancer. This study showed that the volume change rate is better than the diameter change rate in monitoring the therapeutic effect of NST. Furthermore, δV1 is a good quantitative efficacy evaluation index to distinguish patients resistant to EC treatment and predict the pCR rate and guide the adjustment of individualized NST regimens.

Dehydrogenase MnGutB1 catalyzes 1-deoxynojirimycin biosynthesis in mulberry.

As the prevalence of diabetes continues to increase, the number of individuals living with diabetes complications will reach an unprecedented magnitude. Continuous use of some synthetic agents to reduce blood glucose levels causes severe side effects, and thus, the demand for nontoxic, affordable drugs persists. Naturally occurring compounds, such as iminosugars derived from the mulberry (Morus spp.), have been shown to reduce blood glucose levels. In mulberry, 1-deoxynojirimycin (DNJ) is the predominant iminosugar. However, the mechanism underlying DNJ biosynthesis is not completely understood. Here, we showed that DNJ in mulberry is derived from sugar and catalyzed through 2-amino-2-deoxy-D-mannitol (ADM) dehydrogenase MnGutB1. Combining both targeted and nontargeted metabolite profiling methods, DNJ and its precursors ADM and nojirimycin (NJ) were quantified in mulberry samples from different tissues. Purified His-tagged MnGutB1 oxidized the hexose derivative ADM to form the 6-oxo compound DNJ. The mutant MnGutB1 D283N lost this remarkable capability. Furthermore, in contrast to virus-induced gene silencing of MnGutB1 in mulberry leaves that disrupted the biosynthesis of DNJ, overexpression of MnGutB1 in hairy roots and light-induced upregulation of MnGutB1 enhanced DNJ accumulation. Our results demonstrated that hexose derivative ADM, rather than lysine derivatives, is the precursor in DNJ biosynthesis, and it is catalyzed by MnGutB1 to form the 6-oxo compound. These results represent a breakthrough in producing DNJ and its analogs for medical use by metabolic engineering or synthetic biology.

Prognostic analysis of three forms of Ki-67 in patients with breast cancer with non-pathological complete response before and after neoadjuvant systemic treatment.

BACKGROUND: Patients who do not achieve a pathological complete response (pCR) after neoadjuvant systemic treatment (NST) have a significantly worse prognosis. A reliable predictor of prognosis is required to further subdivide non-pCR patients. To date, the prognostic role in terms of disease-free survival (DFS) between the terminal index of Ki-67 after surgery (Ki-67T ) and the combination of the baseline Ki-67 at biopsy before NST (Ki-67B ) and the percentage change in Ki-67 before and after NST (Ki-67C ) has not been compared. AIM: This study aimed to explore the most useful form or combination of Ki-67 that can provide prognostic information to non-pCR patients. PATIENTS AND METHODS: We retrospectively reviewed 499 patients who were diagnosed with inoperable breast cancer between August 2013 and December 2020 and received NST with anthracycline plus taxane. RESULTS: Among all the patients, 335 did not achieve pCR (with a follow-up period of ≥1 year). The median follow-up duration was 36 months. The optimal cutoff value of Ki-67C to predict a DFS was 30%. A significantly worse DFS was observed in patients with a low Ki-67C (p < 0.001). In addition, the exploratory subgroup analysis showed relatively good internal consistency. Ki-67C and Ki-67T were considered as independent risk factors for DFS (both p < 0.001). The forecasting model combining Ki-67B and Ki-67C showed a significantly higher area under the curve at years 3 and 5 than Ki-67T (p = 0.029 and p = 0.022, respectively). CONCLUSIONS: Ki-67C and Ki-67T were good independent predictors of DFS, whereas Ki-67B was a slightly inferior predictor. The combination of Ki-67B and Ki-67C is superior to Ki-67T for predicting DFS, especially at longer follow-ups. Regarding clinical application, this combination could be used as a novel indicator for predicting DFS to more clearly identify high-risk patients.

Sensory nerve niche regulates mesenchymal stem cell homeostasis via FGF/mTOR/autophagy axis.

Mesenchymal stem cells (MSCs) reside in microenvironments, referred to as niches, which provide structural support and molecular signals. Sensory nerves are niche components in the homeostasis of tissues such as skin, bone marrow and hematopoietic system. However, how the sensory nerve affects the behavior of MSCs remains largely unknown. Here we show that the sensory nerve is vital for mesenchymal tissue homeostasis and maintenance of MSCs in the continuously growing adult mouse incisor. Loss of sensory innervation leads to mesenchymal disorder and a decrease in MSCs. Mechanistically, FGF1 from the sensory nerve directly acts on MSCs by binding to FGFR1 and activates the mTOR/autophagy axis to sustain MSCs. Modulation of mTOR/autophagy restores the MSCs and rescues the mesenchymal tissue disorder of Fgfr1 mutant mice. Collectively, our study provides insights into the role of sensory nerves in the regulation of MSC homeostasis and the mechanism governing it.

Comparison of clinicopathological characteristics and response to neoadjuvant systemic therapy in patients with HER2-low-positive and HER2-zero breast cancer.

Previous studies have observed that human epidermal growth factor receptor 2 (HER2)-low-positive patients and HER2-zero patients have different prognoses. This study was conducted to investigate whether there are differences in clinicopathological characteristics and the response to neoadjuvant systemic therapy (NST) defined as systemic treatment prior to surgery between HER2-low-positive patients and HER2-zero patients. We retrospectively analyzed the data of patients with HER2-negative breast cancer who received NST at the First Affiliated Hospital of Nanjing Medical University from 2014 to 2021. There were 238 patients with HER2-low-positive status and 198 patients with HER2-zero status. The proportion of hormone receptor (HR)-positive patients in the HER2-low-positive group was significantly higher than that in the HER2-zero group (82.8% vs 52.0%, p < 0.001). The HER2-low-positive group had more patients with low Ki67 expression (23.9% vs 16.2%, p = 0.045), higher mastectomy rate (94.5% vs 88.9%, p = 0.031), and larger pathological tumor size (21.6 vs 17.8 mm, p = 0.028) than the HER2-zero group. However, no significant differences were found in pathologic complete response (pCR) rates between the two groups. We draw a conclusion that patients with HER2-low status and HER2-zero status were not found to have different pCR rates after NST, irrespective of HR status. However, differences were observed in some clinicopathological characteristics between the two groups.

A prospective, randomized clinical trial of emergency treatment of chemotherapy-induced neutropenia and febrile neutropenia by pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF).

AIMS: As one of the mainstays of breast cancer therapy, chemotherapy inevitably induces neutropenia. In this study, we explored the role of PEG-rhG-CSF (pegylated recombinant human granulocyte colony-stimulating factor) in the emergency treatment of chemotherapy-induced grades 3-4 neutropenia. METHODS: A total of 100 patients with breast cancer were randomized (1:1) into the study. Fifty patients randomized to the experimental group were treated with PEG-rhG-CSF after grades 3-4 neutropenia following the first cycle of chemotherapy, while 50 patients randomized to the control group received a daily injection of rhG-CSF (recombinant human granulocyte colony-stimulating factor). The primary endpoint was the recovery time of grades 3-4 neutropenia. RESULTS: Compared with patients in the control group, the mean ± SD recovery time of grades 3-4 neutropenia and febrile neutropenia (FN) was significantly shorter for patients in the experimental group (grades 3-4, P = .000; grade 4, P = .000; FN, P = .038). There is no significant difference in the incidence of FN for the two groups. In the experimental group, the duration of grades 3-4 neutropenia in patients aged <60 years and ≥60 years was 2.15 and 3.20 days, respectively (P = .037). Adverse events (AEs) of any grade were reported in 37 (75.5%) and 28 (59.6%) patients from the two groups, respectively. No grade ≥3 AEs were reported. CONCLUSION: This study supported that the PEG-rhG-CSF was more effective and convenient than rhG-CSF for treating grades 3-4 neutropenia and FN in patients with breast cancer and had manageable toxicity.

A novel nomogram containing efficacy indicators to predict axillary pathologic complete response after neoadjuvant systemic therapy in breast cancer.

Background: Neoadjuvant systemic therapy (NST) could make some clinically node-positive (cN+) breast cancer patients achieve axillary pathologic complete response (pCR). This study aimed to identify the patients who are likely to achieve axillary pCR and help surgeons make surgical decisions on the axilla. Methods: The cN+ breast cancer patients who received NST from 2015 to 2021 at The First Affiliated Hospital of Nanjing Medical University were enrolled. Univariate and multivariate logistic regression analyses were performed, and a nomogram was constructed based on the results of multivariate logistic regression analysis to predict the probability of axillary pCR and validated. Results: The axillary pCR was achieved in 208 (38.7%) patients. Patients who had a higher radiological response rate of breast tumor (P = 0.039), smaller longest diameter of positive node after NST (P = 0.028), ER-negative status (P = 0.006), HER2-positive status (P = 0.048) and breast pCR (P < 0.001) were more likely to achieve axillary pCR. The nomogram had an area under the receiver operating characteristic curve (AUC) of 0.795 (95% CI: 0.747-0.843), and the calibration curve showed good agreement. Conclusion: A nomogram was constructed to predict the axillary pCR of cN+ patients receiving NST based on baseline and efficacy indicators to assist surgeons in making surgical decisions on the axilla.

Culture Supernatant of Enterococcus faecalis Promotes the Hyphal Morphogenesis and Biofilm Formation of Candida albicans.

(1) Background: Enterococcus faecalis and Candida albicans are often isolated from infected root canals. The interaction between these two species is not clear enough. Therefore, the objective of this study was to investigate the effect of E. faecalis on the biofilm formation, hyphal morphogenesis and virulence gene expression of C. albicans. (2) Methods: We used the culture supernatant of E. faecalis (CSE) to treat the biofilms of C. albicans. Then, crystal violet staining and colony-forming unit (CFU) counting were performed to evaluate biofilm biomass. Scanning electron microscopy (SEM) and confocal laser scanning microscope (CLSM) were applied to observe fungal morphology. Subsequently, exopolymeric substances (EPS) production, cellular surface hydrophobicity (CSH) and adhesion force of biofilms were investigated by CLSM, water-hydrocarbon two-phase assay and atomic force microscopy (AFM), respectively. Finally, the expression of C. albicans virulence genes (ALS1, ALS3, HWP1 and EFG1) were measured by RT-qPCR assay. (3) Results: The exposure of CSE promoted the biofilm formation and hyphal morphogenesis of C. albicans, increased the EPS production, CSH and adhesion force of C. albicans biofilms, and increased the expression level of EFG1. (4) Conclusions: Our data indicated that CSE promoted the hyphal morphogenesis and biofilm formation of C. albicans.

Nomogram for predicting overall survival in patients with triple-negative apocrine breast cancer: Surveillance, epidemiology, and end results-based analysis.

PURPOSE: Triple-negative apocrine carcinoma (TNAC) is a sort of triple-negative breast cancer (TNBC) that is rare and prognosis of these patients is unclear. The present study constructed an effective nomogram to assist in predicting TNAC patients overall survival (OS). METHODS: A total of 373 TNAC patients from the surveillance, epidemiology, and end results (SEER) got extracted from 2010 to 2016 and were divided into training (n = 261) and external validation (n = 112) groups (split ratio, 7:3) randomly. A Cox regression model was utilized to creating a nomogram according to the risk factors affecting prognosis. The predictive capability of the nomogram was estimated with receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). RESULTS: Multivariate Cox regression analysis revealed age, surgery, chemotherapy, stage, and first malignant primary as independent predictors of OS. A prediction model was constructed and virtualized using the nomogram. The time-dependent area under the curve (AUC) showed satisfactory discrimination of the nomogram. Good consistency was shown on the calibration curves in OS between actual observations and the nomogram prediction. What's more, DCA showed that the nomogram had incredible clinical utility. Through separating the patients into groups of low and high risk group that connects with the risk system that shows a huge difference between the low-risk and high risk OS (P < 0.001). CONCLUSION: To predict the OS in TNAC patients, the nomogram utilizing the risk stratification system that is corresponding. These tools may help to evaluate patient prognosis and guide treatment decisions.