Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification.

Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.

Endoscopic polidocanol foam sclerobanding for the treatment of grade II-III internal hemorrhoids: A prospective, multi-center, randomized study.

BACKGROUND: Endoscopic rubber band ligation (ERBL) is a nonsurgical technique for the treatment of symptomatic internal hemorrhoids but is limited by recurrence and post-procedural pain. AIM: To evaluate satisfaction, long-term recurrence, and post-procedural pain in managing internal hemorrhoids using a combination of polidocanol foam sclerotherapy and ERBL. METHODS: This was a prospective, multicenter, randomized study. A total of 195 consecutive patients diagnosed with grade II-III internal hemorrhoids were enrolled from four tertiary hospitals and randomly divided into a cap-assisted endoscopic polidocanol foam sclerobanding (EFSB) or an ERBL group. All patients were followed-up for 12 months. Symptom-based severity and post-procedural pain were assessed using a hemorrhoid severity score (HSS) and a visual analog scale (VAS). Continuous variables were reported as medians and interquartile range. RESULTS: One hundred and ninety-five patients were enrolled, with 98 in the EFSB group. HSS was lower in the EFSB group than in the ERBL group at 8 weeks [4.0 (3.0-5.0) vs 5.0 (4.0-6.0), P = 0.003] and 12-month [2.0 (1.0-3.0) vs 3.0 (2.0-3.0), P < 0.001] of follow-up. The prolapse recurrence rate was lower in the EFSB group at 12 months (11.2% vs 21.6%, P = 0.038). Multiple linear regression analysis demonstrated that EFSB treatment [B = -0.915, 95% confidence interval (CI): -1.301 to -0.530, P = 0.001] and rubber band number (B = 0.843, 95%CI: 0.595-1.092, P < 0.001) were negatively and independently associated with the VAS score 24 hours post-procedure. The median VAS was lower in the EFSB group than in the ERBL [2.0 (1.0-3.0) vs 3.0 (2.0-4.0), P < 0.001]. CONCLUSION: Cap-assisted EFSB provided long-term satisfaction and effective relief from the recurrence of prolapse and pain 24 hours post-procedure.

Application of Polymer Materials in Targeting Glioma.

Glioma is a serious life-threatening disease, and traditional treatments have little effect. In recent decades, polymer materials have been developed for the treatment of glioma as a new research area. The ability to target reactive polymeric carriers is important for treating glioma. Polymer materials have good designability and expansibility. They respond to different stimuli, leading to a change in the macroscopic properties of materials. Sensitive polymer carriers respond to biological stimuli (pH, oxidative stress, enzyme, temperature, ions and nucleic acids) and the tumour microenvironment. They can be used as intelligent polymer carriers to transport chemotherapy and imaging drugs for glioma treatment. The ability of these polymer carriers to control the release of molecules at tumour-specific sites has aroused great interest. This review summarizes current research on sensitive polymer-carriers for glioma treatment over the past decade, focusing on their clinical application prospects. Finally, future applications of polymer carriers in nanomedicine are reviewed.

Mapping the mechanical gradient of human dentin-enamel-junction at different intratooth locations.

OBJECTIVES: The local structures and mechanical properties within tooth dentin-enamel-junction (DEJ) regions have been focused for numerous studies. The reported results, however, remain inconsistent particularly on the functional width and gradient architecture of the DEJ. The current study aims at systematically determining the mechanical gradient of the DEJ at different intratooth locations such that a clearer understanding on the tooth properties and the potential correlations with the tooth function could be obtained. METHODS: We re-examined how mechanical properties such as elastic modulus and hardness transitioned from those of dentin to those of enamel using combined static and dynamic nanoindentation mapping techniques. A new mapping method and associated image processing procedures were developed to improve the measurement accuracy and resolution. RESULTS: A thin, sigmoidally-transitioned interphase layer of the DEJ was identified with an accurate functional width of 2-3µm. The DEJ width and gradient architecture were found intratooth location-dependent, with the DEJ at the occlusal sites being wider and transitioning smoother than that at the cervical sites. Such different widths and architectures of the interphase layer at sites subjected to different types and magnitudes of loadings during mastication could promote more efficient stress transferring between enamel and dentin without compromising the overall stiffness of the tooth. SIGNIFICANCE: The presented study not only adds our understanding in the local mechanical properties within tooth DEJ regions, it could also further advance the development of DEJ-mimetic, functional gradient interphase for strong and ultra-durable jointing between dissimilar materials.

Measurement of mucosal thickness in denture-bearing area of edentulous mandible.

BACKGROUND: The thickness of the alveolar mucosa influences the probability of the occurrence of denture-induced irritations. Thick denture-supporting tissues offer relief from mucosal tenderness and ulcers; however, the uniformity of the thickness across the entire mandibular alveolar mucosa cannot be accurately determined in edentulous patients. This study aimed to assess the mucosal thickness of the denture-bearing area in the edentulous mandible. METHODS: Twenty-seven edentulous patients underwent cone-beam computed tomography scanning, wherein the patients wore a record base to retract soft tissues away from the alveolar mucosa. The measured regions were the central incisor (IC), lateral incisor (IL), canine (Ca), first premolar (P1), second premolar (P2), first molar (M1), and second molar (M2) regions. The thickness was measured in the alveolar ridge crest (T), buccal (B1-B4), and lingual (L1-L4) alveolar ridge mucosa. The average thickness of the mucosa at buccal sides (B) and lingual sides (L) were also assessed. RESULTS: The differences in the mucosal thickness between the left and right sides were not significant. In the Ca-M2 regions, T was the thickest, and L3 was the thinnest of all the measured points in the same regions. L was significantly less than B in posterior regions (P < 0.01). On the other hand, M2 at L4 was thinnest of all the measured regions from Ca to M2 (P < 0.01), and was thicker than IC, IL, P1, and P2 at B2. CONCLUSIONS: Since the mucosal thickness of denture-bearing area in the edentulous mandible is not uniform; the tissue surface of the denture base or custom tray should be selectively relieved, which may reduce the risk of denture-induced irritations.

Effect of occlusal splints for the management of patients with myofascial pain: a randomized, controlled, double-blind study.

BACKGROUND: Occlusal splints have been the preferred modalities in the management of myofascial temporomandibular disorders (TMDs), but now controversy exists in reporting whether they are successful for TMDs treatments. The aim of this study was to give objective evidence to the assessment of treatment effect of occlusal splints for myofascial TMDs patients by clinical assessments and surface electromyography (sEMG) measurements of masseter muscles (MM). METHODS: Thirty-six patients (12 males and 24 females) aged 16 - 57 (38 ± 11) years participated in the study. All participants diagnosed with myofascial TMD were randomized into two groups (18 of each). Patients in the first group (A) were treated with occlusal splints for 1 month, while patients in the second group (B) were treated with placebo (non-occluding palatal) splints. Clinical assessments were performed at the beginning of the study and 1 month after treatment. sEMG measurements for MM were performed at mandibular postural position (MPP) and maximum intercuspal contacted position (ICP) 1 month after the treatment. The root mean square (RMS) and the median frequency (MF) as linear indices of sEMG data were used to demonstrate muscle activity and muscle fatigue. Data were analyzed by ANOVA and post hoc SNK test. The differences were considered significant at P < 0.05. RESULTS: It was found that 89% of group A either completely recovered (39%) or clinically improved (50%), while only 22% of group B had a spontaneous improvement. sEMG analysis showed that at MPP, the mean of RMS value of MM in group A was lower than that of group B, which shows statistical differences (P < 0.01). At ICP, the RMS value of MM in group A was higher than that of group B, which shows statistical differences (P < 0.01). At MPP, MF value of MM in group A was higher than that of group B (P < 0.05). At ICP, MF value of MM was lower than that of group B (P < 0.01). CONCLUSIONS: Occlusal splint could eliminate or improve the signs and symptoms of TMD patients with myofascial pain. sEMG analysis indicates that the wearing of occlusal splints may reduce the degree of fatigue of the masticatory muscles. The splint therapy outcome has a correlation with the electromyographic changes in the masticatory muscles.

[Effect of unilateral mastication on the remodeling of the glenoid fossae in Wistar rats].

OBJECTIVE: To investigate the effect of unilateral mastication on glenoid fossae by means of animal experiment. METHODS: An animal model of unilateral mastication was established by extracting right mandibular molars of Wistar rats. The rats were sacrificed in different period to examine the location changes of glenoid fossae through sagittal and horizontal plane. RESULTS: The anterior points of glenoid fossae in non-masticatory side of experimental groups were more anterior than those in masticatory sides. The anterior points of the glenoid fossae of non-masticatory sides in experimental groups were more anterior than those of the same sides in the control groups after inducing unilateral mastication for two and four months. After inducing unilateral mastication for two and four months, the anterior and the posterior points of the glenoid fossae of non-masticatory sides in experimental groups became closer to the midline by comparison with masticatory sides as well as the same sides in control groups. Locations of glenoid fossae in masticatory sides showed no changes in comparison with the same side of the control groups. CONCLUSION: The forward and inward remodeling of the glenoid fossae can be observed after unilateral mastication was induce to the non-masticatory sides of experimental rats. It is concluded that unilateral mastication might be one of the etiologic factor of temporomandibular joint disorders.