Efficacy of salvage surgery versus re-irradiation for isolated regional lymph node recurrence in patients with nasopharyngeal carcinoma.

BACKGROUND: To compare the clinical characteristics and prognoses of patients with isolated regional lymph node recurrent nasopharyngeal carcinoma (irrNPC) who underwent surgery or re-irradiation treatment. METHODS: We retrospectively reviewed 124 irrNPC patients who underwent initial radiotherapy between January 2010 and December 2020. The staging of regional lymph node recurrence was as follows: 75.8% for rN1, 14.5% for rN2, and 9.7% for rN3. Fifty-five patients underwent regional lymph node surgery (Surgery group), and sixty-nine patients received salvage radiotherapy with or without chemotherapy (Re-irradiation group). The survival rate was compared using Kaplan‒Meier analysis and evaluated by the log-rank test. Cox proportional hazard models were used to analyze prognostic factors. RESULTS: The median follow-up time was 70 months, the 5-year overall survival (OS) was 74%, and the median survival time was 60.8 months. There were no significant differences in 5-year OS (75.6% vs. 72.4%, P = 0.973), regional recurrence-free survival (RRFS, 62.7% vs. 71.1%, P = 0.330) or distant metastasis-free survival (DMFS, 4.2% vs.78.7%, P = 0.677) between the Surgery group and Re-irradiation group. Multivariate analysis revealed age at recurrence, radiologic extra-nodal extension (rENE) status, and recurrent lymph node (rN) classification as independent prognostic factors for OS. The rENE status was an independent prognostic factor for DMFS. Subgroup analysis of the Surgery group revealed that the rN3 classification was an adverse prognostic factor for OS. Age at recurrence ≥ 50 years, GTV-N dose, and induction chemotherapy were found to be independent prognostic factors for OS, RRFS, and DMFS, respectively, in the Re-irradiation group. CONCLUSIONS: For NPC patients with isolated regional lymph node recurrence after initial radiotherapy, those who underwent surgery had survival prognosis similar to those who underwent re-radiotherapy with or without chemotherapy. A prospective study is needed to validate these findings.

Development and Validation of a Prediction Model for 30-Day Mortality and Functional Outcome in Patients with Primary Brainstem Hemorrhage.

INTRODUCTION: Primary brainstem hemorrhage (PBSH) is the most fatal subtype of intracerebral hemorrhage and is associated with poor prognosis. We aimed to develop a prediction model for predicting 30-day mortality and functional outcome in patients with PBSH. METHODS: We reviewed records of 642 consecutive patients with first-time PBSH from three hospitals between 2016 and 2021. Multivariate logistic regression was used to establish a nomogram in a training cohort. Cutoff points of the variables were determined by receiver operating characteristic curve analysis, and certain points were assigned to these predictors to produce the PBSH score. The nomogram and PBSH score were compared with other scoring systems for PBSH. RESULTS: Five independent predictors, comprised of temperature, pupillary light reflex, platelet-to-lymphocyte ratio, Glasgow Coma Scale (GCS) score on admission, and hematoma volume, were incorporated to construct the nomogram. The PBSH score consisted of 4 independent factors with individual points assigned as follows: temperature, ≥38°C (=1 point), <38°C (=0 points); pupillary light reflex, absence (=1 point), presence (=0 points); GCS score 3-4 (=2 points), 5-11 (=1 point), and 12-15 (=0 points); PBSH volume >10 mL (=2 points), 5-10 mL (=1 point), and <5 mL (=0 points). Results showed that the nomogram was discriminative in predicting both 30-day mortality (area under the ROC curve [AUC] of 0.924 in the training cohort, and 0.931 in the validation cohort) and 30-day functional outcome (AUC of 0.887). The PBSH score was discriminative in predicting both 30-day mortality (AUC of 0.923 in the training cohort and 0.923 in the validation cohort) and 30-day functional outcome (AUC of 0.887). The prediction performances of the nomogram and the PBSH score were superior to the intracranial hemorrhage (ICH) score, primary pontine hemorrhage (PPH) score, and new PPH score. CONCLUSIONS: We developed and validated two prediction models for 30-day mortality and functional outcome in patients with PBSH. The nomogram and PBSH score could predict 30-day mortality and functional outcome in PBSH patients.

Thiocyanate promoted difunctionalization and cyclization of unsaturated C-C bonds to construct 1-sulfur-2-nitrogen-functionalized alkenes and 2-thiocyanate indolines.

An unprecedented one-pot route to achieve highly regioselective 1-sulfur-functionalized 2-nitrogen-functionalized alkenes and 2-thiocyanate indolines from unsymmetrical ynamides (readily and generally available amides) using the commercially available inexpensive iodobenzene diacetate (PIDA) as the oxidant and potassium thiocyanate (KSCN) as the thiocyanate (SCN) source has been developed. The interconversion of thiocyanate (SCN) and isothiocyanate (NCS) groups simultaneously forms C-N and C-S bonds in this metal-free approach, while introducing important functional groups into homemade alkynes. A radical-chain mechanism, involving competing kinetically controlled chain transfer at the S atom and sterically-controlled chain transfer at the N atom of the thiocyanogen molecule in this mild approach, is proposed.

LncRNA ADAMTS9-AS2 regulates periodontal ligament cell migration under mechanical compression via ADAMTS9/fibronectin.

BACKGROUND: Periodontal ligament cells (PDLCs) are key mechanosensory cells involved in extracellular matrix (ECM) remodeling during orthodontic tooth movement (OTM). Mechanical force changes the ECM components, such as collagens and matrix metalloproteinases. However, the associations between the changes in ECM molecules and cellular dynamics during OTM remain largely uncharacterized. OBJECTIVES: To investigate the influence of mechanical force on the morphology and migration of PDLCs and explore the interaction between ECM remodeling and cellular dynamics, including the detailed mechanisms involved. METHODS: Human PDLCs (hPDLCs) were subjected to a static mechanical compression to mimic the compression state of OTM in vitro. A mouse OTM model was used to mimic the OTM procedure in vivo. The migration of hPDLCs was compared by wound healing and transwell migration assays. Moreover, expression levels of ADAM metallopeptidase with thrombospondin type 1 motif 9 (ADAMTS9) and fibronectin (FN) in hPDLCs were determined via western blotting, immunofluorescence staining, and enzyme-linked immunosorbent assays. Expression levels of ADAMTS9 and FN in mice were assessed via immunohistochemical staining. Additionally, the relative expression of long non-coding RNA (lncRNA) ADAMTS9-antisense RNA 2 (ADAMTS9-AS2) was assessed via quantitative real-time polymerase chain reaction. ADAMTS9-AS2 knockdown was performed to confirm its function in hPDLCs. RESULTS: Mechanical compression induced changes in the morphology of hPDLCs. It also promoted migration and simultaneous upregulation of FN and downregulation of ADAMTS9, a fibronectinase. The mouse OTM model showed the same expression patterns of the two proteins on the compression side of the periodontium of the moved teeth. RNA sequencing revealed that lncRNA ADAMTS9-AS2 expression was significantly upregulated in hPDLCs under mechanical compression. After knocking down ADAMTS9-AS2, hPDLCs migration was significantly inhibited. ADAMTS9 expression was increased as FN expression decreased compared to that in the control group. Moreover, knockdown of ADAMTS9-AS2 reduced the effect of mechanical compression on hPDLCs migration and reversed the expression change of ADAMTS9 and FN. RNA immunoprecipitation revealed direct binding between ADAMTS9-AS2 and ADAMTS9 protein. CONCLUSION: Our study suggests that mechanical compression induces the expression of ADAMTS9-AS2, which directly binds to ADAMTS9 and inhibits its function, leading to the promotion of downstream FN expression and ECM remodeling to facilitate hPDLCs migration and maintain the stability of the periodontium.

Phenethyl isothiocyanate and irinotecan synergistically induce cell apoptosis in colon cancer HCT 116 cells in vitro.

Irinotecan (IRI), an anticancer drug to treat colon cancer patients, causes cytotoxic effects on normal cells. Phenethyl isothiocyanate (PEITC), rich in common cruciferous plants, has anticancer activities (induction of cell apoptosis) in many human cancer cells, including colon cancer cells. However, the anticancer effects of IRI combined with PEITC on human colon cancer cells in vitro were unavailable. Herein, the aim of this study is to focus on the apoptotic effects of the combination of IRI and PEITC on human colon cancer HCT 116 cells in vitro. Propidium iodide (PI) exclusion and Annexin V/PI staining assays showed that IRI combined with PEITC decreased viable cell number and induced higher cell apoptosis than that of IRI or PEITC only in HCT 116 cells. Moreover, combined treatment induced higher levels of reactive oxygen species (ROS) and Ca2+ than that of IRI or PEITC only. Cells pre-treated with N-acetyl-l-cysteine (scavenger of ROS) and then treated with IRI, PEITC, or IRI combined with PEITC showed increased viable cell numbers than that of IRI or PEITC only. IRI combined with PEITC increased higher caspase-3, -8, and -9 activities than that of IRI or PEITC only by flow cytometer assay. IRI combined with PEITC induced higher levels of ER stress-, mitochondria-, and caspase-associated proteins than that of IRI or PEITC treatment only in HCT 116 cells. Based on these observations, PEITC potentiates IRI anticancer activity by promoting cell apoptosis in the human colon HCT 116 cells. Thus, PEITC may be a potential enhancer for IRI in humans as an anticolon cancer drug in the future.

PW06 suppresses cancer cell metastasis in human pancreatic carcinoma MIA PaCa-2 cells via the inhibitions of p-Akt/mTOR/NF-κB and MMP2/MMP9 signaling pathways in vitro.

PW06 [(E)-3-(9-ethyl-9H-carbazol-3-yl)-1-(2,5-dimethoxyphenyl) prop-2-en-1-one], a kind of the carbazole derivative containing chalcone moiety, induced cell apoptosis in human pancreatic carcinoma in vitro. There is no investigation to show that PW06 inhibits cancer cell metastasis in human pancreatic carcinoma in vitro. Herein, PW06 (0.1-0.8 µM) significantly exists in the antimetastatic activities of human pancreatic carcinoma MIA PaCa-2 cells in vitro. Wound healing assay shows PW06 at 0.2 µM suppressed cell mobility by 7.45 and 16.55% at 6 and 24 hours of treatments. PW06 at 0.1 and 0.2 µM reduced cell mobility by 14.72 and 21.8% for 48 hours of treatment. Transwell chamber assay indicated PW06 (0.1-0.2 µM) suppressed the cell migration (decreased 26.67-35.42%) and invasion (decreased 48.51-68.66%). Atomic force microscopy assay shows PW06 (0.2 µM) significantly changed the shape of cell morphology. The gelatin zymography assay indicates PW06 decreased MMP2's and MMP9's activities at 48 hours of treatment. Western blotting assay further confirms PW06 reduced levels of MMP2 and MMP9 and increased protein expressions of EGFR, SOS1, and Ras. PW06 also increased the p-JNK, p-ERK, and p-p38. PW06 increased the expression of PI3K, PTEN, Akt, GSK3α/ß, and E-cadherin. Nevertheless, results also show PW06 decreased p-Akt, mTOR, NF-κB, p-GSK3ß, ß-catenin, Snail, N-cadherin, and vimentin in MIA PaCa-2 cells. The confocal laser microscopy examination shows PW06 increased E-cadherin but decreased vimentin in MIA PaCa-2 cells. Together, our findings strongly suggest that PW06 inhibited the p-Akt/mTOR/NF-κB/MMPs pathways, increased E-cadherin, and decreased N-cadherin/vimentin, suppressing the migration and invasion in MIA PaCa-2 cells in vitro.

Autophagy mediates cementoblast mineralization under compression through periostin/ß-catenin axis.

Repair of orthodontic external root resorption and periodontal tissue dysfunction induced by mechanical force remains a clinical challenge. Cementoblasts are vital in cementum mineralization, a process important for restoring damaged cementum. Despite autophagy plays a role in mineralization under various environmental stimuli, the underlying mechanism of autophagy in mediating cementoblast mineralization remains unclear. Here we verified that murine cementoblasts exhibit compromised mineralization under compressive force. Autophagy was indispensable for cementoblast mineralization, and autophagic activation markedly reversed cementoblast mineralization and prevented cementum damage in mice during tooth movement. Subsequently, messenger RNA sequencing analyses identified periostin (Postn) as a mediator of autophagy and mineralization in cementoblasts. Cementoblast mineralization was significantly inhibited following the knockdown of Postn. Furthermore, Postn silencing suppressed Wnt signaling by modulating the stability of ß-catenin. Together our results highlight the role of autophagy in cementoblast mineralization via Postn/ß-catenin signaling under compressive force and may provide a new strategy for the remineralization of cementum and regeneration of periodontal tissue.

Compressive force-induced LincRNA-p21 inhibits mineralization of cementoblasts by impeding autophagy.

The mineralization capability of cementoblasts is the foundation for repairing orthodontic treatment-induced root resorption. It is essential to investigate the regulatory mechanism of mineralization in cementoblasts under mechanical compression to improve orthodontic therapy. Autophagy has a protective role in maintaining cell homeostasis under environmental stress and was reported to be involved in the mineralization process. Long noncoding RNAs are important regulators of biological processes, but their functions in compressed cementoblasts during orthodontic tooth movement remain unclear. In this study, we showed that compressive force downregulated the expression of mineralization-related markers. LincRNA-p21 was strongly enhanced by compressive force. Overexpression of lincRNA-p21 downregulated the expression of mineralization-related markers, while knockdown of lincRNA-p21 reversed the compressive force-induced decrease in mineralization. Furthermore, we found that autophagy was impeded in compressed cementoblasts. Then, overexpression of lincRNA-p21 decreased autophagic activity, while knockdown of lincRNA-p21 reversed the autophagic process decreased by mechanical compression. However, the autophagy inhibitor 3-methyladenine abolished the lincRNA-p21 knockdown-promoted mineralization, and the autophagy activator rapamycin rescued the mineralization inhibited by lincRNA-p21 overexpression. Mechanistically, the direct binding between lincRNA-p21 and FoxO3 blocked the expression of autophagy-related genes. In a mouse orthodontic tooth movement model, knockdown of lincRNA-p21 rescued the impeded autophagic process in cementoblasts, enhanced cementogenesis, and alleviated orthodontic force-induced root resorption. Overall, compressive force-induced lincRNA-p21 inhibits the mineralization capability of cementoblasts by impeding the autophagic process.

Knockdown of circHIPK3 promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells through activating the autophagy flux.

Many circular RNAs (circRNAs) involved in the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs) have recently been discovered. The role of circHIPK3 in osteogenesis has yet to be determined. Cell transfection was conducted using small-interfering RNAs (siRNAs). Expression of osteogenic markers were detected by quantitative reverse transcription-polymerase chain reaction, western blotting analysis, and immunofluorescence staining. Ectopic bone formation models in nude mice were used to examined the bone formation ability in vivo. The autophagy flux was examined via western blotting analysis, immunofluorescence staining and transmission electron microscopy analysis. RNA immunoprecipitation (RIP) analysis was carried out to analyze the binding between human antigen R (HUR) and circHIPK3 or autophagy-related 16-like 1 (ATG16L1). Actinomycin D was used to determine the mRNA stability. Our results demonstrated that silencing circHIPK3 promoted the osteogenesis of hBMSCs while silencing the linear mHIPK3 did not affect osteogenic differentiation, both in vivo and in vitro. Moreover, we found that knockdown of circHIPK3 activated autophagy flux. Activation of autophagy enhanced the osteogenesis of hBMSCs and inhibition of autophagy reduced the osteogenesis through using autophagy regulators chloroquine and rapamycin. We also discovered that circHIPK3 and ATG16L1 both bound to HUR. Knockdown of circHIPK3 released the binding sites of HUR to ATG16L1, which stabilized the mRNA expression of ATG16L1, resulting in the upregulation of ATG16L1 and autophagy activation. CircHIPK3 functions as an osteogenesis and autophagy regulator and has the potential for clinical application in the future.

Compressive force regulates orthodontic tooth movement via activating the NLRP3 inflammasome.

Mechanical stress regulates various cellular functions like cell inflammation, immune responses, proliferation, and differentiation to maintain tissue homeostasis. However, the impact of mechanical signals on macrophages and the underlying mechanisms by which mechanical force regulates bone remodeling during orthodontic tooth movement remain unclear. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome has been reported to promote osteoclastic differentiation to regulate alveolar bone resorption. But the relationship between the compressive force and NLRP3 inflammasome in macrophages remains unknown. In this study, immunohistochemical staining results showed elevated expression of NLRP3 and interleukin-1ß, as well as an increased number of macrophages expressing NLRP3, on the compression side of the periodontal tissues, after force application for 7 days. Furthermore, the number of tartrate-resistant acid phosphatase-positive osteoclasts, and the mRNA and protein expression levels of osteoclast-related genes in the periodontal tissue decreased in the Nlrp3-/- mice compared to the WT mice group after orthodontic movement. In vitro mechanical force activates the NLRP3 inflammasome and inhibits autophagy. Intraperitoneal injection of the autophagy inhibitor 3-methyladenine in Nlrp3-/- mice promoted orthodontic tooth movement. This result indicates that the absence of NLRP3 inflammasome activation can be partially compensated for by autophagy inhibitors. Mechanistically, force-induced activation of the NLRP3 inflammasome in macrophages via the cGAS/P2X7R axis. In conclusion, compressive force regulates orthodontic tooth movement via activating the NLRP3 inflammasome.

Multiparametric MRI-based VI-RADS: can it predict 1- to 5-year recurrence of bladder cancer?

OBJECTIVES: To evaluate whether Vesical Imaging-Reporting And Data System (VI-RADS) scores based on multiparametric MRI (mp-MRI) can predict bladder cancer (BCa) recurrence. METHODS: In this retrospective study, 284 patients with pathologically confirmed bladder neoplasms from November 2011 to October 2020 were included. Two radiologists blindly and independently scored mp-MRI scans according to VI-RADS. Scoring inconsistency was resolved in consensus. The latest follow-up was completed in December 2022. Pearson's correlation analyses, independent-sample t-tests, and receiver operating characteristic analyses were performed to assess the efficacy of VI-RADS score for the 1- to 5-year recurrence prognostication. RESULTS: Based on the latest follow-up, 37 (of 284, 13.0%), 69 (of 284, 24.3%), 70 (of 234, 29.9%), 72 (of 190, 37.9%), and 63 (of 135, 46.7%) patients had cancer recurrence at 1- to 5-year follow-up, respectively. VI-RADS scores showed significantly intergroup differences between recurrent and nonrecurrent cases during 1- to 4-year surveillance (p < 0.05). The recurrence-free survival was significantly higher in patients with VI-RADS scores of 1 or 2, compared to those with scores of 3, 4, or 5 (p < 0.05). Areas under the receiver operating characteristic curves for 1- to 5-year recurrence prediction were 0.744, 0.686, 0.656, 0.595, and 0.536, respectively. VI-RADS score of 3 or more was the threshold for 1-year recurrence assessment, and VI-RADS more than 3 was the cutoff for 2-year recurrence prediction. CONCLUSION: VI-RADS score has potential in preoperative prognostication of BCa recurrence, but its predictive power decreases over time. CLINICAL RELEVANCE STATEMENT: VI-RADS has potential in bladder cancer recurrence assessment, but its prognostic value decreases over time. Patients with VI-RADS ≥ 3 may be more likely to recur in 1 or 2 years postoperatively, thus should be performed with intensive surveillances. KEY POINTS: • VI-RADS scores had significant differences in 1- to 4-year recurrent and nonrecurrent patient groups. • Patients with VI-RADS scores of ≤ 2 showed more favorable recurrence-free survival outcomes. • The prognostic value of VI-RADS score decreased over time for bladder cancer recurrence prediction.

Theoretical study on the solvation mechanism of camptothecin in ionic liquids.

To reduce the environmental pollution caused by organic solvents and improve the extraction efficiency, a range of imidazolium-based ionic liquid (IL) combinations of [Omim]+ paired with [Br]-, [BF4]-, [Cl]-, [ClO4]-, [HsO4]-, [NO3]-, [NTf2]-, [OAc]-, [PF6]-, and [TsO]- are explored for the extraction of camptothecin (CPT) using molecular dynamics (MD) simulation and density functional theory (DFT) calculations. It is found that the ILs containing [Br]-, [OAc]-, and [TsO]- anions are the most promising solvents for CPT solvation because they exhibit stronger interaction energy and the lowest self-diffusion coefficient of CPT among all ILs. The microscopic mechanism at the molecular level is revealed based on DFT calculations and MD simulations, and the results demonstrate that the IL (i.e., [Omim][TsO]) containing anions with strong hydrogen bond (HB) acceptability and aromatic ring structure corresponds to both the strongest van der Waals interaction and strongest HB interaction of CPT-anions. Therefore, it is recommended that anions with aromatic ring structures or strong HB acceptability are promising anion candidates, while anions containing electron withdrawing groups and bulky substituents should be avoided. This work provides intermolecular insight into designing and selecting effective ILs for natural insoluble active pharmaceutical ingredient dissolution and extraction in further research.

The long non-coding RNA, miRNA and mRNA landscapes of cementoblasts during cementogenesis.

OBJECTIVE: Stimulation of cementogenesis is essential to cementum regeneration and root restoration. Long non-coding RNAs (lncRNAs) participate in the regulatory networks of periodontal regeneration processes. We identified and analysed differentially expressed lncRNAs, miRNAs and mRNAs associated with cementogenic differentiation of cementoblasts. MATERIALS AND METHODS: OCCM-30 immortalized mouse cementoblast cells were induced in cementogenic medium for 7 and 14 days. Total RNA was extracted and subjected to RNA sequencing to screen for differentially expressed lncRNAs, miRNAs and mRNAs. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to determine the expression levels of RNAs. Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to clarify the potential functions of differentially expressed genes in biological processes and pathways. lncRNA-miRNA-mRNA networks were constructed based on correlation and algorithmic analyses. RESULTS: In all, 461 lncRNAs, 89 miRNAs and 2157 mRNAs showed differential expression in OCCM-30 cells after cementoblast differentiation. At day 7, upregulation of 248 lncRNAs, 30 miRNAs and 905 mRNAs was observed, along with downregulation of 127 lncRNAs, 34 miRNAs and 960 mRNAs. At day 14, 197 lncRNAs, 13 miRNAs and 847 mRNAs were upregulated, while 74 lncRNAs, 12 miRNAs and 760 mRNAs were downregulated. The results of qRT-PCR showed that four candidate lncRNAs, H19, Gdap10, Foxo6os and Ipw, were significantly upregulated after 7 and 14 days of cementogenic induction. The lncRNA-miRNA-mRNA network illustrated a possible competitive endogenous RNA regulatory mechanism. GO analysis showed that consistently differentially expressed mRNAs were involved in blood vessel morphogenesis, cell-substrate adhesion, cell adhesion, ossification and extracellular matrix organization. KEGG analysis indicated that extracellular matrix-receptor interaction, focal adhesion, and the PI3K-Akt, Rap1, mitogen-activated protein kinase, and Ras signalling pathways varied significantly during cementogenesis. CONCLUSION: The expressions of lncRNA, miRNA and mRNA were significantly altered in cementoblasts after cementogenesis. This study highlighted the effect of lncRNAs in the process of cementogenesis and revealed their potential for the discovery of novel biomarkers and therapeutic targets for cementum regeneration.

Carboxymethyl starch as a solid dispersion carrier to enhance the dissolution and bioavailability of piperine and 18ß-glycyrrhetinic acid.

OBJECTIVE: To investigate the applicability of carboxymethyl starch (CMS) as a carrier to prepare solid dispersions (SDs) of piperine (PIP) and 18ß-glycyrrhetinic acid (ß-GA) (PIP-CMS and ß-GA-CMS SDs) and to explore the influence of drug properties on carrier selection. SIGNIFICANCE: The low oral bioavailability of natural therapeutic molecules, including PIP and ß-GA, severely restricts their pharmaceutical applications. Moreover, CMS, a natural polymer, is rarely reported as a carrier for SDs. METHODS: PIP-CMS and ß-GA-CMS SDs were prepared using the solvent evaporation method. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared (FT-IR) spectroscopy, and scanning electron microscopy (SEM) were used for formulation characterization. Additionally, drug release characteristics were investigated. RESULTS: In vitro dissolution studies showed that the dissolutions of PIP-CMS and ß-GA-CMS SDs were 1.90-2.04 and 1.97-2.22 times higher than pure PIP and ß-GA, respectively, at a drug:polymer ratio of 1:6. DSC, XRPD, FT-IR, and SEM analyses confirmed the formation of SDs in their amorphous states. Significant improvements in Cmax and AUC0-24 h of PIP-CMS and ß-GA-CMS SDs (17.51 ± 8.15 µg/mL and 210.28 ± 117.13 µg·h/mL, respectively) and (32.17 ± 9.45 µg/mL and 165.36 ± 38.75 µg·h/mL, respectively) were observed in the pharmacokinetic study. Compared with weakly acidic ß-GA, loading weakly basic PIP seemed to have a profound effect on stability through intermolecular forces. CONCLUSIONS: Our findings showed CMS could be a promising carrier for SDs, and loading weakly basic drug may be more suitable, especially in binary SDs system.

p-Synephrine Indicates Internal Maturity of Citrus grandis (L.) Osbeck cv. Mato Peiyu-Reclaiming Functional Constituents from Nonedible Parts.

The processing of Citrus grandis Osbeck cv. Mato Peiyu (CGMP) fruits generates a considerable amount of waste, mainly the flavedo, albedo, and segment membrane; the generated waste yields severe environmental and economic challenges. In this study, we tried to reclaim some functional chemicals from the waste. Our data indicated that the essential oil content in the flavedo was 0.76-1.34%, with the major component being monoterpenes (93.75% in August, declining to 85.56% in November, including mainly limonene (87.08% to 81.12%) and others such as ß-myrcene). p-Synephrine (mg/100 g dry weight) declined accordingly (flavedo, 10.40 to 2.00; albedo, 1.80 to 0.25; segment membrane, 0.3 in August, 0.2 in September, and none since October). Polyphenols (in µg/g) included gallic acid (70.32-110.25, 99.27-252.89, and 105.78-187.36, respectively); protocatechuic acid (65.32-204.94, 26.35-72.35, and 214.98-302.65, respectively), p-coumaric acid (30.63-169.13, 4.32-17.00, and 6.68-34.32, respectively), ferulic acid (12.36-39.36, 1.21-10.25, and 17.07-39.63, respectively), and chlorogenic acid (59.19-199.36, 33.08-108.57, and 65.32-150.14, respectively). Flavonoids (in µg/g) included naringin (flavedo, 89.32-283.19), quercetin (181.05-248.51), nobiletin (259.75-563.7), hesperidin, and diosmin. The phytosterol content (mg/100 g) was 12.50-44.00 in the flavedo. The total dietary fiber in the segment membrane was 57 g/100 g. The antioxidant activity against the DPPH• and ABTS+• free radicals was moderately high. In conclusion, the waste of CGMP fruits is worth reclaiming for essential oil, p-synephrine, polyphenolics, and dietary fiber. Notably, p-synephrine content (flavedo: <8 mg/100 g dry weight, albedo: <2.0, or segment membrane: <0.4 mg) can serve as a marker of the internal maturation of CGMP fruits.

Sodium hyaluronates applied in the face affects the diversity of skin microbiota in healthy people.

OBJECTIVE: A healthy and stable microbiome has many beneficial effects on the host, while an unbalanced or disordered microbiome can lead to various skin diseases. Hyaluronic acid is widely used in the cosmetics and pharmaceutical industries; however, specific reports on its effect on the skin microflora of healthy people have not been published. This study aimed to determine the effect of sodium hyaluronate on the facial microflora of healthy individuals. METHODS: Face of 20 healthy female volunteers between 18 and 24 years was smeared with sodium hyaluronate solution once per day. Cotton swabs were used to retrieve samples on days 0, 14, and 28, and high-throughput sequencing of 16 S rRNA was used to determine the changes in bacterial community composition. RESULTS: Facial application of HA can reduce the abundance of pathogenic bacteria, such as Cutibacterium and S. aureus, and increase the colonization of beneficial bacteria. CONCLUSION: This is the first intuitive report to demonstrate the effect of hyaluronic acid on facial microflora in healthy people. Accordingly, sodium hyaluronate was found to have a positive effect on facial skin health.

Maxillary molar distalization with a 2-week clear aligner protocol in patients with Class II malocclusion: A retrospective study.

INTRODUCTION: This study aimed to investigate the efficacy of molar distalization with or without anterior teeth retraction. METHODS: Forty-three patients who received maxillary molar distalization with clear aligners were retrospectively enrolled and further divided into 2 groups: a retraction group (with maxillary incisor retraction ≥2 mm in ClinCheck) and a nonretraction group (without anteroposterior movement or with the labial movement of the maxillary incisor in ClinCheck). Pretreatment and posttreatment models were collected and laser-scanned to obtain the virtual models. Three-dimensional digital assessments of molar movement, anterior retraction and arch width were analyzed in the reverse engineering software Rapidform 2006. To calculate the efficacy of tooth movement, the achieved tooth movement assessed on the virtual model was compared with the predicted tooth movement in ClinCheck. RESULTS: The achieved efficacy rates of molar distalization for the maxillary first and second molars were 36.48% and 41.94%, respectively. There was a significant difference in molar distalization efficacy between the retraction group (31.50% at the first molar and 35.63% at the second molar) and the nonretraction group (48.14% at the first molar and 52.51% at the second molar). In the retraction group, the efficacy of incisor retraction was 56.10%. The efficacy of dental arch expansion was more than 100% at the first molar levels in the retraction group and at the second premolar and first molar levels in the nonretraction group. CONCLUSIONS: There is a discrepancy between the outcome and the predicted maxillary molar distalization with clear aligners. The efficacy of molar distalization with clear aligners was significantly affected by anterior teeth retraction, and the arch width significantly increased at the premolar and molar levels.

Maxillary cortical bone remodeling characteristics in extraction patients: A cone-beam computed tomography study.

INTRODUCTION: This study aimed to evaluate labial and palatal cortical bone remodeling (BR) characteristics and related aspects of maxillary incisors after retraction, as these aspects are still controversial among orthodontists. METHODS: Cortical BR and incisor movement of 44 patients (aged 26.18 ± 4.71 years) who underwent maxillary first premolar extraction and incisor retraction were analyzed using superimposed cone-beam computed tomography images. Labial BR/tooth movement (BT) ratios at the crestal, midroot (S2), and apical (S3) levels were compared using the Friedman test and pairwise comparisons. Multivariate linear regressions were used to explore the relationships between the labial BT ratio and several factors, including age, ANB angle, mandibular plane angle, and incisor movement patterns. According to the type of palatal cortical BR observed, the patients were divided into 3 groups: type I (no BR without root penetration of the original palatal border [RPB]), type II (BR with RPB), and type III (no BR with RPB). Student's t test was used to compare the type II and III groups. RESULTS: The mean labial BT ratios at all levels were <1.00 (0.68-0.89). This value at the S3 level was significantly smaller than that at the crestal and S2 levels (P <0.01). Multivariate linear regression indicated that the tooth movement pattern negatively correlates with the BT ratio at S2 and S3 levels (P <0.01). Type I was noted in 40.9% of the patients, and similar proportions exhibited type II (29.5%, 25.0%) or type III remodeling (29.5%, 34.1%). The retraction distance of the incisors in type III patients was significantly larger than in type II patients (P <0.05). CONCLUSIONS: The amount of cortical BR secondary to maxillary incisor retraction is less than the tooth movement. Bodily retraction may lead to lower labial BT ratios at the S3 and S2 levels. Roots penetrating the original border of the cortical plate are necessary for palatal cortical BR initiation.

Multiparametric MRI Evaluation of VI-RADS for Bladder Tumors Located at the Ureteral Orifice.

Background The Vesical Imaging Reporting and Data System (VI-RADS) based on multiparametric MRI scans standardizes preoperative bladder cancer staging. However, limitations have been reported for VI-RADS, particularly for ureteral orifice tumors. Purpose To investigate the diagnostic performance and interobserver agreement of VI-RADS in evaluating muscle invasion for bladder tumors located at the ureteral orifice. Materials and Methods In this retrospective study, patients with histopathologically confirmed bladder cancer occurring at the ureteral orifice from January 2012 to November 2021 were analyzed. Two blinded radiologists independently scored multiparametric MRI scans according to VI-RADS. Interobserver agreement of the VI-RADS scores was evaluated with weighted κ analysis. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance of the VI-RADS scores in the prediction of muscle invasion. Results A total of 78 patients (mean age, 67 years ± 7 [SD]; age range, 46-90 years; 67 men) were included in the final analysis: 25 with non-muscle-invasive bladder cancer and 53 with muscle-invasive bladder cancer (MIBCa). At consensus reading, one (1%) case was scored as VI-RADS 1, 27 cases (35%) were scored as VI-RADS 2, six (8%) were scored as VI-RADS 3, 10 (13%) were scored as VI-RADS 4, and 34 (44%) were scored as VI-RADS 5. On comparison of the VI-RADS score with histopathologic findings, it was confirmed that the presence of muscle invasion was 0% (zero of one) for VI-RADS 1, 15% (four of 27) for VI-RADS 2, 83% (five of six) for VI-RADS 3, 100% (10 of 10) for VI-RADS 4, and 100% (34 of 34) for VI-RADS 5. The area under the receiver operating characteristic curve of VI-RADS in the detection of MIBCa was 0.96 (95% CI: 0.92, 1.00). Conclusion The Vesical Imaging Reporting and Data System could be used to accurately predict muscle invasion for bladder tumors occurring at the ureteral orifice. © RSNA, 2022 Online supplemental material is available for this article.

Amide Proton Transfer-weighted MRI in Predicting Histologic Grade of Bladder Cancer.

Background Bladder cancer is classified into high and low grades with different clinical treatments and prognoses. Thus, accurate preoperative evaluation of the histologic grade through imaging techniques is essential. Purpose To investigate the potential of amide proton transfer-weighted (APTw) MRI in evaluating the grade of bladder cancer and to evaluate whether APTw MRI can add value to diffusion-weighted imaging (DWI) at MRI. Materials and Methods In this single-center prospective study, participants with pathologic analysis-confirmed bladder cancer with no previous treatment, lesions larger than 10 mm, and adequate MRI quality were enrolled from July 2020 to September 2021 in a university teaching hospital. All participants underwent preoperative multiparametric MRI, including APTw MRI and DWI. The mean APTw and apparent diffusion coefficient (ADC) values of the primary tumor were measured independently by two radiologists. Receiver operating characteristic curves were generated to evaluate the diagnostic performance of these quantitative parameters. Results In total, 83 participants (mean age, 64 years ± 13 [SD]; 72 men) were evaluated: 51 with high-grade and 32 with low-grade bladder cancer. High-grade bladder cancer showed higher APTw values (6% [IQR, 4%-12%] vs 2% [IQR, 1%-3%]; P < .001) and lower ADC values (0.92 × 10-3 mm2/sec ± 0.17 vs 1.21 × 10-3 mm2/sec ± 0.25; P < .001) than low-grade bladder cancer. The area under the receiver operating characteristic curve (AUC) of APTw and ADC for differentiating low- and high-grade bladder cancer was similar (0.84 for both; P = .94). Moreover, the combination of the two techniques improved the diagnostic performance (AUC, 0.93; all P = .01). Conclusion The combination of amide proton transfer-weighted and diffusion-weighted MRI has the potential to improve the histologic characterization of bladder cancer by differentiating low- from high-grade cancers. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Milot in this issue. An earlier incorrect version appeared online. This article was corrected on July 7, 2022.